Quinolone compound and application thereof

Abstract

Provided herein are compounds of Formula (IA) and other quinolones wherein the variables are as defined in the specification, and their use in the treatment or prevention of diseases or disorders such as autoimmune diseases, allergic diseases, inflammatory diseases and pain. # imgabs0 #

Description

Technical Field

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

[0002] Mast cells (MCs) are myeloid cells present in the connective tissues of our body, widely distributed around blood vessels and nerve endings in various tissues. They are a type of immune cells crucial for triggering inflammatory responses, mainly related to the innate immune response, which is a non-specific branch of the immune system. They are particularly important in allergic reactions but are also involved in many other immune functions. For a long time, mast cells have been considered to be related to the pathogenesis of allergic (hypersensitivity), autoimmune diseases, and inflammatory diseases (especially inflammatory skin diseases, chronic inflammatory diseases). Mast cell-related G-protein-coupled receptors (MRGPRs) are involved in the signal transduction of itching, inflammation, and pain in the body. Among them, the MRGPRX2 target is widely distributed in barrier tissues and is involved in regulating mast cell-related allergic reactions. In the case of MRGPRX2 activation, mast cell degranulation occurs; in the case of inhibiting MRGPRX2, the mast cell degranulation phenomenon is significantly inhibited. The activation of MCs mediated by MRGPRX2 does not depend on the activation of immunoglobulin E (IgE). A variety of basic secretagogues such as SP, vasoactive intestinal peptide, cationic antimicrobial peptides, and the classical activator compound 48 / 80 can act as ligands on MRGPRX2. In recent years, with the in-depth study of MRGPRX2, its function has been found to be increasingly important. MRGPRX2 is mainly involved in non-IgE-mediated mast cell activation-related allergic reactions, inflammatory reactions, neuroinflammation, pain, and itching, etc., and can promote the innate immune response of the skin and intestine to harmful stimuli or pathogen invasion. Such as atopic dermatitis, urticaria, alopecia areata, inflammatory bowel disease, asthma, etc. Therefore, MRGPRX2 antagonists can be used to treat or prevent diseases or disorders such as autoimmune diseases, allergic diseases, inflammatory diseases, itching, and pain. Recently, it has also been found that mast cell degranulation caused by MRGPRX2 activation can promote IgE-mediated allergic reactions. Researchers have 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 caused by mast cell activation.

[0003] Autoimmune diseases are complex diseases, including psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), urticaria, allergic rhinitis, asthma, alopecia areata, etc. The causes of onset are usually diseases triggered by abnormal or excessive reactions of the body's immune system, which usually attack its own tissues or organs, leading to inflammation, damage or dysfunction. The occurrence of this disease may be related to factors such as genetics, environment, and infection. Autoimmune diseases affect approximately one-tenth of the population, and over time, the incidence of various autoimmune diseases worldwide is also increasing. A study published in The Lancet investigated the incidence of autoimmune diseases in more than 22 million people between 2000 and 2019. During the investigation period, 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 pain to patients.

[0004] Psoriasis is an immune-mediated chronic, systemic inflammatory skin disease with a wide prevalence. The typical skin manifestation of psoriasis is silver-white scales covering erythema.

[0005] Atopic dermatitis is a disease caused by immune system disorders. Its symptoms are relatively severe in adolescents and adults, while its prevalence is higher in infants and children. Thickening of the skin at the affected area is a significant manifestation of atopic dermatitis.

[0006] Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and even bloody stools. It is known that the inflammatory response caused by abnormal reactions of the intestinal mucosal immune system plays an important role in the onset of IBD.

[0007] Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease mainly mediated by immunoglobulin E (IgE) after atopic individuals are exposed to allergens. Clinical manifestations include nasal itching, sneezing, runny nose, nasal congestion, etc. The global average prevalence of AR is as high as about 20%, which not only seriously affects the quality of life of patients but is also an independent risk factor for inducing asthma. For the construction of the AR model, 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 IgE during the immune response, which is similar to humans, and its genetic data is more complete.

[0008] Bronchial asthma (referred to as asthma) is a chronic non - specific airway disease. Airway inflammation, airway mucus hypersecretion, airway hyperresponsiveness, and airway remodeling are its characteristic manifestations. With the deterioration of climate and environment, its incidence rate has been increasing year by year and has currently become a risk factor seriously endangering human life and health. Given the limitations of human trials, asthma - related research is mainly carried out through asthma animal models at present. An ideal animal model should reflect the pathophysiological mechanisms of human asthma as much as possible, including allergic inflammation, eosinophilia, and massive mucus secretion in the airway, etc. BALB / c and C57BL / 6 mice, as commonly used experimental animals for asthma models, mainly have the following characteristics: clear genetic background, multiple strains, low price, and are easy to induce characteristic symptoms of asthma.

[0009] Rosacea is a chronic inflammatory skin disease involving the cheeks, nose, chin, and forehead, and its clinical manifestations are recurrent flushing, telangiectasia, persistent facial erythema, and papulopustules.

[0010] Urticaria is a common immune - related skin disease mainly manifested by wheals and itching. Mast cells are the key effector cells in the pathogenesis of urticaria. The clinical symptoms are mainly local edema caused by transient increased vascular permeability of the skin and mucosa, that is, wheals. Wheals can be accompanied by obvious severe itching and scratching.

[0011] Overview of the present disclosure

[0012] This overview is provided to introduce some concepts in a simplified form, which will be further described in the detailed description below. This overview is not intended to identify the 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 for the treatment or prevention of autoimmune diseases, allergic diseases, inflammatory diseases, itching, and pain through an immunomodulatory mechanism, such as psoriasis, atopic dermatitis, inflammatory bowel disease (IBD), chronic urticaria, allergic rhinitis, asthma, alopecia areata, urticaria, allergic urticaria, rosacea, radiation dermatitis, eczema, pseudo - allergic reactions, anaphylactic shock, generalized itching, neurogenic itching, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory system inflammation, postoperative pain, and vitiligo, etc., and have low toxicity and can be taken orally.

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

[0015]

[0016] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein each variable is as defined herein, which is used to antagonize MRGPRX2.

[0017] The present disclosure also provides a compound of formula (IB):

[0018]

[0019] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein each variable is as defined herein.

[0020] The above compounds, the general formula compounds and specific compounds disclosed in the context of the present disclosure, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates and solvates, are referred to herein as "the compounds of the present disclosure".

[0021] The compounds of the present disclosure are antagonists of MRGPRX2 and can be used to treat or prevent MRGPRX2-mediated diseases or disorders, especially diseases or disorders caused by mast cell degranulation, especially can 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, radiodermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo, etc.

[0022] The present disclosure provides the compounds of the present disclosure for use as MRGPRX2 antagonists.

[0023] The present disclosure provides the compounds of the present disclosure for the treatment or prevention of MRGPRX2-mediated diseases or disorders.

[0024] The present disclosure provides the compounds of the present disclosure for the treatment or prevention of diseases or disorders caused by mast cell degranulation.

[0025] The present disclosure provides the compounds of the present disclosure for the treatment or prevention of 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, radiodermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0026] The present disclosure provides the use of the compounds of the present disclosure for the preparation of a medicament for treating or preventing 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, generalized pruritus, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0027] The present disclosure provides a method for treating or preventing an MRGPRX2-mediated disease or disorder, which method comprises administering to an individual in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0028] The present disclosure provides a method for treating or preventing a disease or disorder in an individual, which comprises administering to an individual 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, 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, generalized pruritus, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0029] The present disclosure provides a method for antagonizing MRGPRX2 in vitro, which method comprises using a compound of the present disclosure or a pharmaceutically acceptable salt thereof in an in vitro test for MRGPRX2.

[0030] The present disclosure also provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0031] Additionally, the present disclosure also provides a pharmaceutical combination (combination product) or a kit, which combination product or kit comprises 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 pharmaceutical compositions thereof). They are used for simultaneous, separate or sequential use in the treatment or prevention of an MRGPRX2-mediated disease or disorder.

[0032] Detailed description of the present disclosure

[0033] Embodiments of the present disclosure - Part A

[0034] Embodiment 1. A compound of formula (IA), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, for the treatment or prevention of an MRGPRX2-mediated disease or disorder,

[0035]

[0036] wherein:

[0037] R1 is -C 3-6 cycloalkyl or -C 1-6 straight-chain or branched alkyl;

[0038] R2 is -COOH, -COOC 1-6 straight-chain or branched alkyl, -C(O)NH2, -C(O)-NH-C 1-6 straight-chain or branched alkyl, -C(O)-N(C 1-6 straight-chain or branched alkyl)2 or -C(O)-NH-OH;

[0039] R3 is halogen;

[0040] B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-6 straight-chain or branched alkyl;

[0041] A is C 6-10 aryl or 5-6 membered heteroaryl;

[0042] 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;

[0043] Ra and R d each independently selected from C 1-20 a straight-chain or branched-chain alkyl group, C 2-20 a straight-chain or branched-chain alkenyl group, C 2-20 a straight-chain or branched-chain alkynyl group, C 3-10 a cycloalkyl group having from 3 to 10 carbon atoms and a heterocycloalkyl group having from 4 to 10 carbon atoms, wherein said heterocycloalkyl group contains one or more heteroatoms selected from N, O, and S, and said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 a straight-chain or branched-chain alkyl group, -OC 1-6 a straight-chain or branched-chain alkyl group, -NHC 1-6 a straight-chain or branched-chain alkyl group, and -N(C 1-6 a straight-chain or branched-chain alkyl group)2;

[0044] R b and R c together with the N atom to which they are attached form a heterocycloalkyl group having from 4 to 10 carbon atoms, said heterocycloalkyl group containing one or more heteroatoms selected from N, O, and S, and said heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 a straight-chain or branched-chain alkyl group, -OC 1-6 a straight-chain or branched-chain alkyl group, -NHC 1-6 a straight-chain or branched-chain alkyl group, and -N(C 1-6 a straight-chain or branched-chain alkyl group)2;

[0045] 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

[0046] n is 0, 1, 2, or 3.

[0047] Embodiment 2. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R1 is -C 3-4 a cycloalkyl group or -C 1-3 a straight-chain or branched-chain alkyl group.

[0048] Embodiment 3. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R1 is or -C 1-3 a straight-chain or branched-chain alkyl group.

[0049] Embodiment 4. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R1 is

[0050] Embodiment 5. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R1 is

[0051] Embodiment 6. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R2 is -COOH, -COOC 1-3 a straight-chain or branched-chain alkyl group, -C(O)NH2, -C(O)-NH-C 1-3 a straight-chain or branched-chain alkyl group, -C(O)-N(C 1-3 a straight-chain or branched-chain alkyl group)2 or -C(O)-NH-OH.

[0052] Embodiment 7. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R2 is -COOH, -COOC 1-3 a straight-chain or branched-chain alkyl group or -C(O)NH2.

[0053] Embodiment 8. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R2 is -COOH or -COOC 1-3 a straight-chain or branched-chain alkyl group.

[0054] Embodiment 9. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R2 is -COOH or -COOCH3.

[0055] Embodiment 10. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R2 is -COOCH3 or -COOCH2CH3.

[0056] Embodiment 11. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R2 is -COOH.

[0057] Embodiment 12. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R3 is F.

[0058] Embodiment 13. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 a straight-chain or branched-chain alkyl group.

[0059] Embodiment 14. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein B1 is -CR6 or N, where R6 is H, F, Cl or -OCH3.

[0060] Embodiment 15. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein B1 is -CR6, where R6 is H or -OCH3.

[0061] Embodiment 16. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein B1 is -CR6, where R6 is H.

[0062] Embodiment 17. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein B1 is -CR6, where R6 is -OCH3.

[0063] Embodiment 18. A compound for the said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein B1 is N.

[0064] Embodiment 19. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein A is phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0065] Embodiment 20. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein A is phenyl or pyridyl.

[0066] Embodiment 21. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein A is phenyl.

[0067] Embodiment 22. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein A is pyridyl.

[0068] Embodiment 23. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, 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 -S-R d .

[0069] Embodiment 24. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, 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 -S-R d .

[0070] Embodiment 25. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, 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 -S-R d .

[0071] Embodiment 26. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, 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 -S-R d 。

[0072] Embodiment 27. A compound for use in said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, 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 -S-R d 。

[0073] Embodiment 28. A compound for use in said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, 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 。

[0074] Embodiment 29. A compound for use in said use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, 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 。

[0075] Embodiment 30. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R4 is selected from -S(O)2-NH2, -S(O)2-NHR a and -S(O)2-NR b R c 。

[0076] Embodiment 31. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R4 is -S(O)2-NHR a 。

[0077] Embodiment 32. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R a and R d are each independently selected from C 1-15 straight-chain or branched-chain alkyl, C 2-15 straight-chain or branched-chain alkenyl, C 2-15 straight-chain or branched-chain alkynyl, C 3-10 cycloalkyl having 3 to 10 carbon atoms and 4- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl contains one or more heteroatoms selected from N, O and S, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with 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.

[0078] Embodiment 33. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R a is selected from C 1-15 straight-chain or branched-chain alkyl, C 2-15 straight-chain or branched-chain alkenyl, C 2-15 straight-chain or branched-chain alkynyl, C 3-10cycloalkyl and 4- to 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 linear or branched alkyl, -OC 1-3 linear or branched alkyl and -NHC 1-3 linear or branched alkyl; for example, R a is C 1-15 linear or branched alkyl, and the alkyl is optionally substituted with 1, 2, or 3 halogens.

[0079] Embodiment 34. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R a is selected from C 1-15 linear or branched alkyl, C 3-6 cycloalkyl and 4- to 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 linear or branched alkyl, -OC 1-3 linear or branched alkyl and -NHC 1-3 linear or branched alkyl; for example, R a is C 1-15 linear alkyl, and the alkyl is optionally substituted with 1, 2, or 3 halogens.

[0080] Embodiment 35. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R a is selected from C 1-15 linear or branched alkyl, C 3-6 cycloalkyl and 4- to 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 is C 1-15 linear alkyl, and the alkyl is optionally substituted with 1, 2, or 3 halogens (such as 3 F).

[0081] Embodiment 36. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R a is selected from C 1-12 linear or branched alkyl, C 3-6Acyclic alkyl and 4- to 6-membered heterocyclic alkyl, wherein the heterocyclic alkyl 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 is C 1-12 a straight-chain or branched-chain alkyl, which is optionally substituted with 1, 2, or 3 halogens (e.g., 3 F).

[0082] Embodiment 37. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R a is selected from C 1-9 a straight-chain or branched-chain alkyl, C 5-6 a 3- to 6-membered cyclic alkyl, and a 5- to 6-membered heterocyclic alkyl, wherein the heterocyclic alkyl 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 is C 1-9 a straight-chain or branched-chain alkyl, which is optionally substituted with 1, 2, or 3 halogens (e.g., 3 F).

[0083] Embodiment 38. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R a is selected from C 1-9 a straight-chain or branched-chain alkyl, C 1-9 a straight-chain or branched-chain alkyl-OH, C 1-9 a straight-chain or branched-chain alkyl-NH2, C 1-9 a halogenated straight-chain or branched-chain alkyl (e.g., C 1-9 a chlorinated straight-chain or branched-chain alkyl, C 1-9 a fluorinated straight-chain or branched-chain alkyl, or C 1-8 a straight-chain or branched-chain alkyl-CF3), cyclohexyl, and tetrahydropyranyl; for example, C 1-9 a straight-chain alkyl or C 1-8 a straight-chain alkyl-CF3.

[0084] Embodiment 39. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R a is selected from C 1-9 a straight-chain or branched-chain alkyl, for example, C 1-9 a straight-chain alkyl.

[0085] Embodiment 40. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein Ra Selected from C 1-9 Straight-chain or branched-chain alkyl-OH.

[0086] Embodiment 41. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein R a Selected from C 1-9 Straight-chain or branched-chain alkyl-NH2.

[0087] Embodiment 42. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein R a Selected from C 1-9 Halogenated straight-chain or branched-chain alkyl, such as C 1-9 Chlorinated straight-chain or branched-chain alkyl, C 1-9 Fluorinated straight-chain or branched-chain alkyl or C 1-8 Straight-chain or branched-chain alkyl-CF3, such as C 1-8 Straight-chain alkyl-CF3.

[0088] Embodiment 43. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein R a Selected from cyclohexyl and tetrahydropyranyl.

[0089] Embodiment 44. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein R d Selected from C 1-15 Straight-chain or branched-chain alkyl, C 2-15 Straight-chain or branched-chain alkenyl and C 2-15 Straight-chain or branched-chain alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted by 1, 2 or 3 substituents selected from: halogen, -OH, -NH2, -CN and -NO2.

[0090] Embodiment 45. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein R d Selected from C 1-12 Straight-chain or branched-chain alkyl, C 2-12 Straight-chain or branched-chain alkenyl and C 2-12 Straight-chain or branched-chain alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted by 1, 2 or 3 substituents selected from: halogen, -OH and -CN.

[0091] Embodiment 46. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R d is 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 by 1, 2 or 3 substituents selected from the following: halogen, -OH, and -CN.

[0092] Embodiment 47. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R d is 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 group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, and -CN.

[0093] Embodiment 48. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R d is selected from C 1-3 a straight-chain or branched-chain alkyl group, C 2-3 a straight-chain or branched-chain alkenyl group, and C 2-3 a straight-chain or branched-chain alkynyl group, wherein the alkyl group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, and -CN.

[0094] Embodiment 49. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R d is selected from C 1-3 a straight-chain or branched-chain alkyl group (such as n-propyl), C 2-3 a straight-chain or branched-chain alkenyl group (such as allyl), and C 2-3 a straight-chain or branched-chain alkynyl group (such as propargyl), wherein the alkyl group is optionally substituted by 1 -OH group (such as -C 1-3 a straight-chain alkyl-OH, such as hydroxyethyl).

[0095] Embodiment 50. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein R b and R cTogether with the N atom to which they are attached, form a 4- to 10-membered heterocycloalkyl group containing one or more heteroatoms selected from N, O and S, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 a straight-chain or branched alkyl group, -OC 1-6 a straight-chain or branched alkyl group, -NHC 1-6 a straight-chain or branched alkyl group and -N(C 1-6 a straight-chain or branched alkyl group)2.

[0096] Embodiment 51. A compound for use in the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R b and R c Together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -SC 1-3 a straight-chain or branched alkyl group, -OC 1-3 a straight-chain or branched alkyl group and -NHC 1-3 a straight-chain or branched alkyl group.

[0097] Embodiment 52. A compound for use in the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein 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, 2 or 3 heteroatoms selected from N, O and S, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -SC 1-3 a straight-chain or branched alkyl group, -OC 1-3 a straight-chain or branched alkyl group and -NHC 1-3 a straight-chain or branched alkyl group.

[0098] Embodiment 53. A compound for use in the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein 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, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2 and -CN.

[0099] Embodiment 54. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein 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, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 halogens.

[0100] Embodiment 55. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein 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 or O, and the heterocycloalkyl group is optionally substituted by 2 F atoms; for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl or 3,3-difluoroazetidinyl.

[0101] Embodiment 56. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein 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 heteroatom selected from N, and the heterocycloalkyl group is optionally substituted by 2 F atoms; for example, azetidinyl, pyrrolidinyl, piperidinyl, difluoroazetidinyl or 3,3-difluoroazetidinyl.

[0102] Embodiment 57. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, 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, 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 and -NH-C(O)-C 1-6 a halogenated straight-chain or branched-chain alkyl group.

[0103] Embodiment 58. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6Straight-chain or branched-chain alkyl, C 1-6 Straight-chain or branched-chain alkyl, C 1-6 Straight-chain or branched-chain alkoxy, -C(O)-NH2, -C(O)-NH-C 1-6 Straight-chain or branched-chain alkyl and -NH-C(O)-C 1-6 Halogenated straight-chain or branched-chain alkyl.

[0104] Embodiment 59. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the said use according to any one of the foregoing embodiments, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 Straight-chain or branched-chain alkyl, C 1-6 Straight-chain or branched-chain alkyl and C 1-6 Straight-chain or branched-chain alkoxy.

[0105] Embodiment 60. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the said use according to any one of the foregoing embodiments, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-3 Straight-chain or branched-chain alkyl, C 1-3 Straight-chain alkyl and C 1-3 Straight-chain or branched-chain alkoxy.

[0106] Embodiment 61. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the said use according to any one of the foregoing embodiments, wherein R5 is selected from halogen (e.g. F), -CN, -NH2 and C 1-3 Straight-chain alkoxy (e.g. methoxy).

[0107] Embodiment 62. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the said use according to any one of the foregoing embodiments, wherein n is 0, 1 or 2.

[0108] Embodiment 63. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the said use according to any one of the foregoing embodiments, wherein n is 0.

[0109] Embodiment 64. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the said use according to any one of the foregoing embodiments, wherein n is 1.

[0110] Embodiment 65. A compound for the use according to any one of the foregoing embodiments, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein n is 1 or 2.

[0111] Embodiment 66. A compound for the use according to Embodiment 1, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein:

[0112] A is phenyl or pyridyl;

[0113] R4 is -S(O)2-NHR a or -S(O)2-NR b R c ;

[0114] R a is selected from C 1-9 linear alkyl, cyclohexyl and tetrahydropyran, the alkyl being optionally substituted by 1, 2 or 3 groups selected from halogen, -OH, -NH2 and -SCH3 (for example the alkyl is optionally substituted by 1 group selected from halogen, -OH, -NH2 and -SCH3, or optionally substituted by 3 halogens), such as -CF3 or C 1-8 linear alkyl -CF3;

[0115] 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 or O, the heterocycloalkyl group being optionally substituted by 2 F atoms (for example azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl, 3,3-difluoroazetidinyl);

[0116] R5 is selected from halogen, -CN, -NH2, C 1-3 linear alkyl, C 1-3 linear alkoxy, -C(O)-NH2 and -NH-C(O)-C 1-3 halogenated linear or branched alkyl; and

[0117] n is 0 or 1.

[0118] Embodiment 67. A compound for the use according to Embodiment 1, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein:

[0119] A is phenyl or pyridyl;

[0120] R4 is -S(O)-NH-R a or -S-NH-R a ;

[0121] R a is C 1-9 a straight-chain alkyl group, optionally substituted with 1, 2 or 3 halogens (e.g., -CF3 or C 1-8 straight-chain alkyl -CF3); and

[0122] n is 0.

[0123] Embodiment 68. A compound for said use according to Embodiment 1, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein:

[0124] A is phenyl or pyridyl;

[0125] R4 is -S(O)-R a , R a is C 1-6 a halogenated straight-chain or branched-chain alkyl group (e.g., R4 is -S(O)-C 1-6 chlorinated straight-chain or branched-chain alkyl); and

[0126] n is 0.

[0127] Embodiment 69. A compound for said use according to Embodiment 1, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein:

[0128] A is phenyl or pyridyl;

[0129] R4 is -NH-S(O)2-R a ;

[0130] R a is a straight-chain or branched-chain C 1-6 straight-chain or branched-chain alkyl; and

[0131] n is 0.

[0132] Embodiment 70. A compound for said use according to Embodiment 1, its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates, wherein:

[0133] A is phenyl or pyridyl;

[0134] R4 is -C(O)-NH-R a or -NH-C(O)-R a ;

[0135] R a is a straight-chain or branched-chain C 1-6A straight-chain or branched-chain alkyl group, said alkyl group being optionally substituted by 1, 2 or 3 groups selected from halogen and -OH (for example, said alkyl group 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 straight-chain alkyl -CF3);

[0136] 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 halogenated straight-chain or branched-chain alkyl; and

[0137] n is 0 or 1.

[0138] Embodiment 71. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the foregoing Embodiments 1, wherein:

[0139] R1 is For example

[0140] R2 is -COOH or -COOC 1-3 straight-chain or branched-chain alkyl; for example, -COOH or -COOCH3;

[0141] R3 is F;

[0142] B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 straight-chain or branched-chain alkyl, such as H, F or -O-CH3;

[0143] A phenyl or pyridyl;

[0144] 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 ;

[0145] R a is selected from C 1-12 straight-chain or branched-chain alkyl, C 3-6Acyclic C3-C7 alkyl and 4-6 membered heterocyclic alkyl, wherein said heterocyclic alkyl contains 1 or 2 heteroatoms selected from N, O and S, and said alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen and -OH;

[0146] R b and R c together with the N atom to which they are attached form a 4-6 membered heterocyclic alkyl, said heterocyclic alkyl contains 1 or 2 heteroatoms selected from N, O and S, and said heterocyclic alkyl is optionally substituted with 1, 2 or 3 halogens; and

[0147] n is 0.

[0148] Embodiment 72. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R4 is -S(O)2-NH2.

[0149] Embodiment 73. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R4 is -S(O)2-NHR a .

[0150] Embodiment 74. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R4 is -S(O)2-NR b R c .

[0151] Embodiment 75. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R a is selected from C 1-10 linear or branched alkyl, C 3-6 acyclic C3-C7 alkyl and 4-6 membered heterocyclic alkyl, wherein said heterocyclic alkyl contains 1 or 2 heteroatoms selected from N or O, and said alkyl is optionally substituted with 1, 2 or 3 substituents selected from the following: halogen and -OH;

[0152] Embodiment 76. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for use in the use according to any one of the foregoing embodiments, wherein R a is a linear or branched C 1-9 alkyl optionally substituted with 1, 2 or 3 hydroxyls or halogens (e.g., linear or branched alkyl-CF3), or tetrahydropyranyl. 1-8 (such as linear or branched alkyl-CF3), or tetrahydropyranyl.

[0153] Embodiment 77. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein 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 and O, and the heterocycloalkyl group 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.

[0154] Embodiment 78. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein the compound is selected from Example Compounds 1-173.

[0155] Embodiment 79. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein the disease or disorder is a disease or disorder caused by mast cell degranulation.

[0156] Embodiment 80. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein the disease or disorder is selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0157] Embodiment 81. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, 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, neurogenic pruritus, nodular prurigo, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0158] Embodiment 82. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for the use according to any one of the foregoing embodiments, wherein the disease or disorder is selected from rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and asthma.

[0159] Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding embodiments 1-78 in the manufacture of a medicament for the treatment or prevention of an MRGPRX2-mediated disease or disorder.

[0160] Embodiment 84. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding embodiments 1-78 in the manufacture of a medicament for the treatment or prevention of a disease or disorder caused by mast cell degranulation.

[0161] Embodiment 85. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding embodiments 1-78 in the manufacture of a medicament for the treatment or prevention of autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0162] Embodiment 86. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding embodiments 1-78 in the manufacture of a medicament 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, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0163] Embodiment 87. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding embodiments 1-78 in the manufacture of a medicament for the treatment or prevention of rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0164] Embodiment 88. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the preceding embodiments 1-78, wherein the disease or disorder is an MRGPRX2-mediated disease or disorder.

[0165] Embodiment 89. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-78, wherein the disease or disorder is a disease or disorder caused by mast cell degranulation.

[0166] Embodiment 90. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-78, wherein the disease or disorder is selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0167] Embodiment 91. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-78, 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, neurogenic pruritus, nodular prurigo, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0168] Embodiment 92. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-78, wherein the disease or disorder is selected from rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and asthma.

[0169] Embodiment 93. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-78 for treating or preventing an MRGPRX2-mediated disease or disorder.

[0170] Embodiment 94. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-78 for treating or preventing a disease or disorder caused by mast cell degranulation.

[0171] Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing embodiments 1-78 for the treatment or prevention of autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0172] Embodiment 96. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing embodiments 1-78 for the treatment or prevention of 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, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0173] Embodiment 97. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing embodiments 1-78 for the treatment or prevention of rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and asthma.

[0174] Embodiment 98. A pharmaceutical composition for the treatment or prevention of an MRGPRX2-mediated disease or disorder, which comprises a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing embodiments 1-78.

[0175] Embodiment 99. A pharmaceutical composition for the treatment or prevention of a disease or disorder caused by mast cell degranulation, which comprises a compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing embodiments 1-78.

[0176] Embodiment 100. 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 foregoing embodiments 1-78 for in vitro testing of MRGPRX2.

[0177] Embodiments of the present disclosure - Part B

[0178] Embodiment 1. A compound of formula (IB), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof,

[0179]

[0180] Wherein:

[0181] R1 is -C 3-6 cycloalkyl or -C 1-6 a straight-chain or branched-chain alkyl;

[0182] R2 is -COOH or -COOC 1-6 a straight-chain or branched-chain alkyl;

[0183] R3 is a halogen;

[0184] B1 is -CR6 or N, where R6 is H, a halogen or -O-C 1-6 a straight-chain or branched-chain alkyl; and

[0185] A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 a straight-chain or branched-chain alkyl, -S(O)2-NH-C 1-6 a straight-chain or branched-chain alkyl-CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c -S(O)-NH-C 1-6 a straight-chain or branched-chain alkyl-CF3, -S-NH-C 1-6 a straight-chain or branched-chain alkyl-CF3, -NH-S(O)2-C 1-6 a straight-chain or branched-chain alkyl, -C(O)-NH2, -C(O)-NH-C 2-6 a straight-chain or branched-chain alkyl, -C(O)-NR b R c -NH-C(O)-CF3, -NH-C(O)-CH2Cl, -NH-C 1-6 a straight-chain or branched-chain alkyl, -NH-C 1-6 a straight-chain or branched-chain alkenyl and -NH-C 1-6 a straight-chain or branched-chain alkynyl; wherein, R b and R c together with the N atom to which they are attached form azetidinyl or difluoroazetidinyl;

[0186] 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 a straight-chain or branched-chain alkyl, -S(O)2-NH-C 8-12 a straight-chain or branched-chain alkyl, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c -S(O)-NH-C 1-6Straight-chain or branched alkyl, -S-NH-C 1-6 Straight-chain or branched alkyl-CF3, -NH-S(O)2-C 2-6 Straight-chain 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 -S-C 1-6 Hydroxy straight-chain or branched alkyl; wherein, R b and R c together with the N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0187] Embodiment 2. A compound according to any one of the foregoing 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 alkyl.

[0188] Embodiment 3. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is or -C 1-3 Straight-chain or branched alkyl.

[0189] Embodiment 4. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is

[0190] Embodiment 5. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R1 is

[0191] Embodiment 6. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOH or -COOC 1-3 Straight-chain or branched alkyl.

[0192] Embodiment 7. A compound according to any one of the foregoing embodiments 1-7, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOH or -COOCH3.

[0193] Embodiment 8. A compound according to any one of the foregoing Embodiments 1-7, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOCH3 or -COOCH2CH3.

[0194] Embodiment 9. A compound according to any one of the foregoing Embodiments 1-7, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOH.

[0195] Embodiment 10. A compound according to any one of the foregoing Embodiments 1-7, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R2 is -COOCH3.

[0196] Embodiment 11. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein R3 is F.

[0197] Embodiment 12. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 a straight-chain or branched alkyl.

[0198] Embodiment 13. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is -CR6 or N, where R6 is H, F, Cl or -OCH3.

[0199] Embodiment 14. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is -CR6, where R6 is H or -OCH3.

[0200] Embodiment 15. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is -CR6, where R6 is H.

[0201] Embodiment 16. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is -CR6, where R6 is -OCH3.

[0202] Embodiment 17. A compound according to any one of the foregoing embodiments, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein B1 is N.

[0203] Embodiment 18. A compound according to any one of the foregoing 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 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, -NH-C(O)-CF3, -NH-C(O)-CH2Cl, -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.

[0204] Embodiment 19. A compound according to any one of the foregoing 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 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 、-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, -NH-C(O)-CF3, -NH-C 1-6 a straight-chain or branched alkyl group and -NH-C 1-6 a straight-chain or branched alkenyl group; wherein R b and R c together with the N atom to which they are attached form azetidinyl or difluoroazetidinyl.

[0205] Embodiment 20. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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.

[0206] Embodiment 21. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing Embodiments 1-18, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 a straight-chain or branched-chain alkyl group, -S(O)2-NH-C 1-6 a straight-chain or branched-chain alkyl group-CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c -, -C(O)-NH2, -C(O)-NH-C 2-6 a straight-chain or branched-chain alkyl group, -NH-C(O)-CF3 and -NH-C 1-6 a straight-chain or branched-chain alkenyl group; wherein R b and R c together with the N atom to which they are attached form difluoroazetidinyl.

[0207] Embodiment 22. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing Embodiments 1-18, wherein A is phenyl; and R4 is selected from -S(O)2-NH-C 8-12 a straight-chain alkyl group, -S(O)2-NH-C 1-6 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 1-6 a straight-chain alkenyl group; wherein Rb and R c together with the N atom to which they are attached form a difluoroazetidinyl group;

[0208] Embodiment 23. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments 1-18, 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-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 group.

[0209] Embodiment 24. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments 1-18, 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 N atom to which they are attached form a difluoroazetidinyl group.

[0210] Embodiment 25. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, wherein A is pyridyl; and R4 is -S(O)2-NH-C 8-12 a straight-chain or branched-chain alkyl group, or -S(O)2-NH-C 1-6 a straight-chain or branched-chain alkyl group-CF3.

[0211] Embodiment 26. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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 a straight-chain or branched-chain alkyl group, -S(O)2-NH-C8-12 a straight-chain or branched alkyl group, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-NH-S(O)2-C 2-6 a straight-chain or branched alkyl group, -C(O)-NH-C 3-6 a branched alkyl group, -NH-C(O)-CF2, -NH-C(O)-CH2CF3, -NH-C 1-6 a straight-chain or branched alkyl group and -S-C 1-6 a hydroxy straight-chain or branched 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.

[0212] Embodiment 27. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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 a straight-chain or branched alkyl group, -S(O)2-NH-C 8-12 a straight-chain or branched alkyl group, -S(O)2-NH-cyclohexyl, -S(O)2-NH-tetrahydropyranyl, -S(O)2-NR b R c 、-NH-S(O)2-C 2-6 a straight-chain or branched alkyl group, -C(O)-NH-C 3-6 a branched alkyl group, -NH-C(O)-CF2, -NH-C(O)-CH2CF3 and -S-C 1-6 a hydroxy straight-chain or branched 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.

[0213] Embodiment 28. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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 a straight-chain alkyl group, -S(O)2-NH-C 8-10Linear 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 Linear alkyl, -C(O)-NH-C 3-6 Branched alkyl, -NH-C(O)-CF2, -NH-C(O)-CH2CF3 and -S-C 2-4 Hydroxy linear alkyl; wherein, R b And R c Together with the N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0214] Embodiment 29. A compound according to any one of the foregoing embodiments 1-26, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, wherein A is pyridyl; and R4 is selected from -S(O)2-NH2, -S(O)2-NH-C 4-6 Linear or branched alkyl, -S(O)2-NH-C 8-12 Linear 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 N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0215] Embodiment 30. A compound according to any one of the foregoing embodiments 1-26, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, 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; wherein, R b And R c Together with the N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0216] Embodiment 31. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing Embodiments 1-26, wherein A is pyridinyl; 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 N atom to which they are attached form azetidinyl, difluoroazetidinyl, pyrrolidinyl or piperidinyl.

[0217] Embodiment 32. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, wherein,

[0218] R1 is For example

[0219] R2 is -COOH or -COOC 1-3 a straight-chain or branched alkyl; for example -COOH or -COOCH3;

[0220] R3 is F;

[0221] B1 is -CR6 or N, where R6 is H, halogen or -O-C 1-3 a straight-chain or branched alkyl, such as H, F, Cl or -O-CH3; and

[0222] A is phenyl; and R4 is selected from -S(O)2-NH-C 8-10 a straight-chain alkyl, -S(O)2-NH-C 2-4 a straight-chain alkyl-CF3, -S(O)2-NR b R c 、-C(O)-NH-C 2-6 a straight-chain or branched alkyl, -NH-C(O)-CF3 and -NH-C 2-4 a straight-chain alkenyl; wherein, R b and R c together with the N atom to which they are attached form difluoroazetidinyl;

[0223] Alternatively, A is pyridinyl; 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 Rc Together with the N atom to which they are attached, form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0224] Embodiment 33. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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.

[0225] Embodiment 34. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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.

[0226] Embodiment 35. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of the foregoing embodiments, 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.

[0227] Embodiment 36. A compound selected from:

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0249] Embodiment 37. A pharmaceutical composition comprising the 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.

[0250] Embodiment 38. The compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used as a medicine.

[0251] Embodiment 39. The compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used for treating or preventing diseases or disorders mediated by MRGPRX2.

[0252] Embodiment 40. The compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used for treating or preventing diseases or disorders caused by mast cell degranulation.

[0253] Embodiment 41. The compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used for treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0254] Embodiment 42. The compound according to any one of Embodiments 1-36 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used for treating or preventing 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. The compound according to any one of Embodiments 1-36, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, which is used for treating or preventing rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0255] Embodiment 43. Use of the 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 an MRGPRX2-mediated disease or disorder.

[0256] Embodiment 44. Use of the 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.

[0257] Embodiment 45. Use of the 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, pruritus and pain, such as inflammatory skin diseases.

[0258] 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 the treatment or prevention of 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, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

[0259] Embodiment 47. Use of a compound as defined in any one of embodiments 1-36, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof in the preparation of a medicament for the treatment or prevention of rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0260] Embodiment 48. 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 according to 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.

[0261] Embodiment 49. 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 according to 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.

[0262] Embodiment 50. 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 according to 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.

[0263] Embodiment 51. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of Embodiments 1-36, 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, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0264] Embodiment 52. A method for treating or preventing a disease or disorder in an individual, the method comprising administering to the individual in need thereof an effective amount of the compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof as defined in any one of the foregoing Embodiments 1-36, wherein the disease or disorder is selected from rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and asthma.

[0265] Embodiment 53. Use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of Embodiments 1-36 for treating or preventing an MRGPRX2-mediated disease or disorder.

[0266] Embodiment 54. Use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of Embodiments 1-36 for treating or preventing a disease or disorder caused by mast cell degranulation.

[0267] Embodiment 55. Use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of Embodiments 1-36 for treating or preventing autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, such as inflammatory skin diseases.

[0268] Embodiment 56. Use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof according to any one of Embodiments 1-36 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, neurogenic pruritus, prurigo nodularis, neurogenic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain, and vitiligo.

[0269] Use of the compound as defined in any one of Embodiments 1-36, its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate for the treatment or prevention of rosacea, psoriasis, urticaria, atopic dermatitis, inflammatory bowel disease, allergic rhinitis and asthma.

[0270] Embodiment 58. A method for antagonizing MRGPRX2 in vitro, the method comprising using an effective amount of the compound as described in any one of Embodiments 1-36 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate for in vitro testing of MRGPRX2.

[0271] Embodiment 59. A pharmaceutical composition for the treatment or prevention of MRGPRX2-mediated diseases or disorders, which comprises the compound as described in any one of Embodiments 1-36 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate.

[0272] Embodiment 60. A pharmaceutical composition for the treatment or prevention of diseases or disorders caused by mast cell degranulation, which comprises the compound as described in any one of Embodiments 1-36 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate.

[0273] Embodiment 61. A drug combination, which comprises the compound as described in any one of Embodiments 1-36 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate, and one or more other therapeutic agents.

[0274] Embodiments of the present disclosure - Part C

[0275] The present invention specifically provides the use of a class of compounds represented by formula (I) and their pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of a drug for an MRGPRX2 antagonist.

[0276]

[0277] Wherein:

[0278] B1 is selected from -CR4 or an N atom; wherein R4 is selected from a hydrogen atom, a C1-C3 alkyl group, a halogen, a C1-C3 alkoxy group or a nitro group;

[0279] 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 heterocycle optionally substituted or unsubstituted by a short-chain alkyl group;

[0280] B2 is selected from -NH, an oxygen atom, -CH=CH-, or is empty; when B2 is empty, is wherein, is a connection point;

[0281] R2 is selected from a hydrogen atom, -C(=O)OR5 or -C(=O)NHR5'; wherein R5 is selected from a hydrogen atom, a C1-C4 alkyl group; R5' is selected from a hydrogen atom or a hydroxyl group;

[0282] 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 forms an isothiazolinone by bonding with B3;

[0283] R3 is selected from a halogen, a nitro group or a hydrogen atom;

[0284] Ring A is selected from unsubstituted or substituted aryl groups, and the substitution includes mono-substitution, di-substitution, tri-substitution, or tetra-substitution, and the substituents are independently selected from: halogen, hydroxyl, nitro, cyano, C1-C3 alkyl groups, C1-C3 alkoxy groups, C1-C3 alkyl groups substituted with 1-3 halogen atoms, C1-C3 alkyl groups substituted with a hydroxyl group, C1-C3 alkyl groups substituted with a phenolic hydroxyl group, C1-C3 alkyl groups substituted with an amino group, C1-C3 alkyl groups substituted with an aniline group, unsubstituted or substituted amino groups, aminosulfonyl groups, aminosulfinyl groups, aminocarbonyl groups, sulfenyl groups, or alkyl iminosulfoxide groups.

[0285] In one embodiment of the present invention, the aryl group is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, triazinyl,

[0286] In one embodiment of the present invention:

[0287] The unsubstituted or substituted amino group -NR a R a ’, and the substitution is divided into mono-substitution and di-substitution, wherein the substituents R a 、R a ’ are independently selected from H, C1-C9 alkyl groups, C1-C9 alkyl groups substituted with 1-3 halogen atoms, C3-C25 straight-chain or branched-chain alkyl groups containing 1-10 unsaturated bonds, C3-C6 cycloalkyl groups, C1-C9 alkyl groups substituted with a hydroxyl group, C1-C9 acyl groups, C2-C9 acyl groups substituted with 1-3 halogen atoms, C2-C9 acyl groups substituted with a hydroxyl group, C2-C5 alkoxycarbonyl groups, C1-C25 alkylsulfonyl groups;

[0288] The unsubstituted or substituted aminosulfonyl group -SO2-NR b R b’, the substitution is divided into single substitution and double substitution, and the substituents R b 、R b ’ are each independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 alkyl substituted by an amino group, C1-C9 alkyl substituted by C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring 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;

[0289] Unsubstituted or substituted aminosulfinyl -SO-NR c R c ’, the substitution is divided into single substitution and double substitution, and the substituents R c 、R c ’ are each independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 alkyl substituted by an amino group, C3-C25 linear 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;

[0290] Unsubstituted or substituted aminocarbonyl -CO-NR d R d ’, the substitution is divided into single substitution and double substitution, and the substituents R d 、R d ’ are each independently selected from H, C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 alkyl substituted by an amino group, C3-C25 linear 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;

[0291] Unsubstituted or substituted sulfenyl -S-R e ,and the substituent R e is selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxyl-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0292] Unsubstituted or substituted alkyliminosulfoxide -S(=O)(=NRf )-R f ’ (i.e., ), the substituent R f is selected from H, C1-C9 linear or branched alkyl, C3-C25 linear 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; R f ’ is selected from C1-3 alkyl.

[0293] In one embodiment of the present invention, the above R a , R a ’ can be simultaneously H, or not simultaneously H, or not simultaneously non-H.

[0294] In one embodiment of the present invention, the above R b , R b ’ are not simultaneously H, or not simultaneously H, or not simultaneously non-H.

[0295] In one embodiment of the present invention, the above R c , R c ’ are not simultaneously H, or not simultaneously H, or not simultaneously non-H.

[0296] In one embodiment of the present invention, the above R d , R d ’ are not simultaneously H, or not simultaneously H, or not simultaneously non-H.

[0297] In one embodiment of the present invention, is selected from the groups of the following formula:

[0298] (1) phenyl substituted with zero to four substituents, and the substituents are selected from:

[0299] (a) C1-C3 alkyl;

[0300] (b) C1-C3 alkoxy;

[0301] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0302] (d) C1-C3 alkyl substituted by a hydroxyl group;

[0303] (e) C1-C3 alkyl substituted by a phenolic hydroxyl group;

[0304] (f) C1-C3 alkyl substituted by an amino group;

[0305] (g) C1-C3 alkyl substituted by an anilino group;

[0306] (h) halogen;

[0307] (i) hydroxy group;

[0308] (j) nitro group;

[0309] (k) cyano group;

[0310] (l) unsubstituted or substituted amino group, the substitution is divided into mono-substitution and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by hydroxy group, C1-C9 acyl group, C2-C9 acyl group substituted by 1-3 halogens, C2-C9 acyl group substituted by hydroxy group, C2-C5 alkoxycarbonyl group, C1-C25 alkylsulfonyl group;

[0311] (m) unsubstituted or substituted aminosulfonyl group, the substitution is divided into mono-substitution 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 group, C1-C9 alkyl substituted by amino group, C1-C9 alkyl substituted by C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl group, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring group containing 1-3 heteroatoms, C2-C25 alkenyl group, C2-C9 alkynyl group, C1-C5 acyl group, C2-C5 acyl group substituted by 1-3 halogens or C2-C5 alkoxycarbonyl group;

[0312] (n) unsubstituted or substituted aminosulfinyl group, the substitution is divided into mono-substitution 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 group, C1-C9 alkyl substituted by amino group, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl group, C2-C9 alkynyl group, C1-C5 acyl group, C2-C5 acyl group substituted by 1-3 halogens or C2-C5 alkoxycarbonyl group;

[0313] (o) unsubstituted or substituted aminocarbonyl group, the substitution is divided into mono-substitution 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 group, C1-C9 alkyl substituted by amino group, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl group, C2-C9 alkynyl group, C1-C5 acyl group, C2-C5 acyl group substituted by 1-3 halogens or C2-C5 alkoxycarbonyl group;

[0314] (p) An unsubstituted or substituted sulfenyl group, wherein the substituent is selected from a C1-C9 straight-chain or branched-chain alkyl group, a C3-C6 cycloalkyl group, a halogenated C1-C9 alkyl group, a hydroxy-substituted C1-C9 alkyl group, a C1-C5 acyl group, or a halogenated C2-C5 acyl group;

[0315] (q) An unsubstituted or substituted alkylimidosulfinyl group -S(=O)(=NR f )-R f ’ (i.e., ), and the substitution is divided into mono-substitution and di-substitution, wherein the substituent is selected from a C1-C9 straight-chain or branched-chain alkyl group, a C3-C25 straight-chain or branched-chain alkyl group having 1-10 unsaturated bonds, a C3-C6 cycloalkyl group, a halogenated C1-C9 alkyl group, a C1-C5 acyl group, a C2-C5 acyl group substituted with 1-3 halogen atoms, or a C2-C5 alkoxycarbonyl group; R f ’ is selected from a C1-3 alkyl group;

[0316] (2) A 2-pyridyl group with zero to three substitutions, and the substituent is selected from:

[0317] (a) A C1-C3 alkyl group;

[0318] (b) A C1-C3 alkoxy group;

[0319] (c) A C1-C3 alkyl group substituted with 1-3 halogen atoms;

[0320] (d) A C1-C3 alkyl group substituted with a hydroxy group;

[0321] (e) A C1-C3 alkyl group substituted with a phenol hydroxy group;

[0322] (f) A C1-C3 alkyl group substituted with an amino group;

[0323] (g) A C1-C3 alkyl group substituted with an aniline group;

[0324] (h) A halogen;

[0325] (i) A hydroxy group;

[0326] (j) A nitro group;

[0327] (k) A cyano group;

[0328] (l) An unsubstituted or substituted amino group, and the substitution is divided into mono-substitution and di-substitution, wherein the substituent is independently selected from a C1-C9 alkyl group, a C1-C9 alkyl group substituted with 1-3 halogen atoms, a C3-C25 straight-chain or branched-chain alkyl group having 1-10 unsaturated bonds, a C3-C6 cycloalkyl group, a C1-C9 alkyl group substituted with a hydroxy group, a C1-C9 acyl group, a C2-C9 acyl group substituted with 1-3 halogen atoms, a C2-C9 acyl group substituted with a hydroxy group, a C2-C5 alkoxycarbonyl group, or a C1-C25 alkylsulfonyl group;

[0329] (m) unsubstituted or substituted aminosulfonyl, the substitution is divided into mono-substitution 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 hydroxyl, C1-C9 alkyl substituted by amino, C1-C9 alkyl substituted by C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring 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;

[0330] (n) unsubstituted or substituted aminosulfinyl, the substitution is divided into mono-substitution 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 hydroxyl, C1-C9 alkyl substituted by amino, C3-C25 linear 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;

[0331] (o) unsubstituted or substituted aminocarbonyl, the substitution is divided into mono-substitution 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 hydroxyl, C1-C9 alkyl substituted by amino, C3-C25 linear 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;

[0332] (p) unsubstituted or substituted sulfinyl, the substituents are selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxyl-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0333] (q) unsubstituted or substituted alkylimidosulfinyl -S(=O)(=NR f )-R f ’ (i.e. ), the substitution is divided into mono-substitution and di-substitution, and the substituents are selected from C1-C9 linear or branched alkyl, C3-C25 linear 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; Rf ' is selected from C1-3 alkyl;

[0334] (3) 3-pyridyl which is unsubstituted or substituted by one to three substituents selected from:

[0335] (a) C1-C3 alkyl;

[0336] (b) C1-C3 alkoxy;

[0337] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0338] (d) C1-C3 alkyl substituted by a hydroxyl group;

[0339] (e) C1-C3 alkyl substituted by a phenolic hydroxyl group;

[0340] (f) C1-C3 alkyl substituted by an amino group;

[0341] (g) C1-C3 alkyl substituted by an anilino group;

[0342] (h) halogen;

[0343] (i) hydroxyl;

[0344] (j) nitro;

[0345] (k) cyano;

[0346] (l) unsubstituted or substituted amino group, the substitution is divided into mono-substitution and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 acyl, C2-C9 acyl substituted by 1-3 halogens, C2-C9 acyl substituted by a hydroxyl group, C2-C5 alkoxycarbonyl, C1-C25 alkylsulfonyl;

[0347] (m) unsubstituted or substituted aminosulfonyl group, the substitution is divided into mono-substitution 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 a hydroxyl group, C1-C9 alkyl substituted by an amino group, C1-C9 alkyl substituted by C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring 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;

[0348] (n) An unsubstituted or substituted aminosulfinyl group, the substitution being divided into mono-substitution and di-substitution, and the substituents being independently selected from C1-C9 alkyl, C1-C9 alkyl substituted with 1-3 halogens, C1-C9 alkyl substituted with a hydroxyl group, C1-C9 alkyl substituted with an amino group, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0349] (o) An unsubstituted or substituted aminocarbonyl group, the substitution being divided into mono-substitution and di-substitution, and the substituents being independently selected from C1-C9 alkyl, C1-C9 alkyl substituted with 1-3 halogens, C1-C9 alkyl substituted with a hydroxyl group, C1-C9 alkyl substituted with an amino group, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens, or C2-C5 alkoxycarbonyl;

[0350] (p) An unsubstituted or substituted sulfinyl group, and the substituents are selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C9 alkyl substituted with a hydroxyl group, C1-C5 acyl, or halogenated C2-C5 acyl;

[0351] (q) An unsubstituted or substituted alkylimidosulfinyl -S(=O)(=NR f )-R f ’ (i.e., ), the substitution being divided into mono-substitution and di-substitution, and the substituents being selected from C1-C9 linear or branched alkyl, C3-C25 linear or branched 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 ’ is selected from C1-3 alkyl;

[0352] (4) A 4-pyridyl group with zero to three substitutions, and the substituents are selected from:

[0353] (a) C1-C3 alkyl;

[0354] (b) C1-C3 alkoxy;

[0355] (c) C1-C3 alkyl substituted with 1-3 halogens;

[0356] (d) C1-C3 alkyl substituted with a hydroxyl group;

[0357] (e) C1-C3 alkyl substituted with a phenolic hydroxyl group;

[0358] (f) C1-C3 alkyl substituted by an amino group;

[0359] (g) C1-C3 alkyl substituted by an anilino group;

[0360] (h) Halogen;

[0361] (i) Hydroxyl;

[0362] (j) Nitro;

[0363] (k) Cyano;

[0364] (l) Unsubstituted or substituted amino group, the substitution is divided into mono-substitution and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 acyl group, C2-C9 acyl group substituted by 1-3 halogens, C2-C9 acyl group substituted by a hydroxyl group, C2-C5 alkoxycarbonyl group, C1-C25 alkylsulfonyl group;

[0365] (m) Unsubstituted or substituted aminosulfonyl group, the substitution is divided into mono-substitution 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 a hydroxyl group, C1-C9 alkyl substituted by an amino group, C1-C9 alkyl substituted by C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl group, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring group containing 1-3 heteroatoms, C2-C25 alkenyl group, C2-C9 alkynyl group, C1-C5 acyl group, C2-C5 acyl group substituted by 1-3 halogens or C2-C5 alkoxycarbonyl group;

[0366] (n) Unsubstituted or substituted aminosulfinyl group, the substitution is divided into mono-substitution 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 a hydroxyl group, C1-C9 alkyl substituted by an amino group, C3-C25 straight-chain or branched-chain alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl group, C2-C9 alkynyl group, C1-C5 acyl group, C2-C5 acyl group substituted by 1-3 halogens or C2-C5 alkoxycarbonyl group;

[0367] (o) Unsubstituted or substituted carbamoyl, the substitution being divided into mono-substitution 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 hydroxyl, C1-C9 alkyl substituted by amino, C3-C25 straight-chain 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;

[0368] (p) Unsubstituted or substituted sulfenyl, the substituents being selected from C1-C9 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, hydroxyl-substituted C1-C9 alkyl, C1-C5 acyl, halogenated C2-C5 acyl;

[0369] (q) Unsubstituted or substituted alkylimidosulfinyl -S(=O)(=NR f )-R f ’ (i.e., ), the substitution being divided into mono-substitution and di-substitution, and the substituents are selected from C1-C9 straight-chain or branched-chain alkyl, C3-C25 straight-chain or branched-chain 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; R f ’ is selected from C1-3 alkyl;

[0370] (5) 2-Pyrimidinyl with zero to two substitutions, and the substituents are selected from:

[0371] (a) C1-C3 alkyl;

[0372] (b) C1-C3 alkoxy;

[0373] (c) C1-C3 alkyl substituted by 1-3 halogens;

[0374] (d) C1-C3 alkyl substituted by hydroxyl;

[0375] (e) C1-C3 alkyl substituted by phenol hydroxyl;

[0376] (f) C1-C3 alkyl substituted by amino;

[0377] (g) C1-C3 alkyl substituted by anilino;

[0378] (h) Halogen;

[0379] (i) Hydroxyl;

[0380] (j) Nitro;

[0381] (k) Cyano;

[0382] (l) An unsubstituted or substituted amino group, the substitution being divided into mono-substitution and di-substitution, wherein the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted with 1-3 halogens, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C1-C9 alkyl substituted with a hydroxyl group, C1-C9 acyl, C2-C9 acyl substituted with 1-3 halogens, C2-C9 acyl substituted with a hydroxyl group, C2-C5 alkoxycarbonyl, C1-C25 alkylsulfonyl;

[0383] (m) An unsubstituted or substituted aminosulfonyl group, the substitution being divided into mono-substitution and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted with 1-3 halogens, C1-C9 alkyl substituted with a hydroxyl group, C1-C9 alkyl substituted with an amino group, C1-C9 alkyl substituted with C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring group containing 1-3 heteroatoms, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens or C2-C5 alkoxycarbonyl substituted;

[0384] (n) An unsubstituted or substituted aminosulfinyl group, the substitution being divided into mono-substitution and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted with 1-3 halogens, C1-C9 alkyl substituted with a hydroxyl group, C1-C9 alkyl substituted with an amino group, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens or C2-C5 alkoxycarbonyl substituted;

[0385] (o) An unsubstituted or substituted aminocarbonyl group, the substitution being divided into mono-substitution and di-substitution, and the substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted with 1-3 halogens, C1-C9 alkyl substituted with a hydroxyl group, C1-C9 alkyl substituted with an amino group, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 acyl substituted with 1-3 halogens or C2-C5 alkoxycarbonyl substituted;

[0386] (p) An unsubstituted or substituted sulfinyl group, and the substituents are selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C9 alkyl substituted with a hydroxyl group, C1-C5 acyl, halogenated C2-C5 acyl;

[0387] (q) unsubstituted or substituted alkyl iminosulfinyl - S(=O)(=NR f ) - R f ’ (i.e., ), the substitution is divided into mono - substitution and di - substitution, and the substituents are selected from C1 - C9 straight - chain or branched - chain alkyl groups, C3 - C25 straight - chain or branched - chain alkyl groups containing 1 - 10 unsaturated bonds, C3 - C6 cycloalkyl groups, halogenated C1 - C9 alkyl groups, C1 - C5 acyl groups, C2 - C5 acyl groups substituted by 1 - 3 halogens, or C2 - C5 alkoxycarbonyl groups; R f ’ is selected from C1 - 3 alkyl groups;

[0388] (6) 5 - pyrimidinyl with zero to two substitutions, and the substituents are selected from:

[0389] (a) C1 - C3 alkyl groups;

[0390] (b) C1 - C3 alkoxy groups;

[0391] (c) C1 - C3 alkyl groups substituted by 1 - 3 halogens;

[0392] (d) C1 - C3 alkyl groups substituted by hydroxyl groups;

[0393] (e) C1 - C3 alkyl groups substituted by phenolic hydroxyl groups;

[0394] (f) C1 - C3 alkyl groups substituted by amino groups;

[0395] (g) C1 - C3 alkyl groups substituted by anilino groups;

[0396] (h) halogens;

[0397] (i) hydroxyl groups;

[0398] (j) nitro groups;

[0399] (k) cyano groups;

[0400] (l) unsubstituted or substituted amino groups, the substitution is divided into mono - substitution and di - substitution, and the substituents are independently selected from C1 - C9 alkyl groups, C1 - C9 alkyl groups substituted by 1 - 3 halogens, C3 - C25 straight - chain or branched - chain alkyl groups containing 1 - 10 unsaturated bonds, C3 - C6 cycloalkyl groups, C1 - C9 alkyl groups substituted by hydroxyl groups, C1 - C9 acyl groups, C2 - C9 acyl groups substituted by 1 - 3 halogens, C2 - C9 acyl groups substituted by hydroxyl groups, C2 - C5 alkoxycarbonyl groups, C1 - C25 alkylsulfonyl groups;

[0401] (m) An unsubstituted or substituted aminosulfonyl group, with the substitution being divided into mono-substitution and di-substitution. The substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 alkyl substituted by an amino group, C1-C9 alkyl substituted by C1-3 alkylthio (C1-3 alkyl-S-), C1-C25 alkylsulfonyl, C3-C25 linear or branched alkyl containing 1-10 unsaturated bonds, C3-C6 cycloalkyl, 3-6 membered ring 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;

[0402] (n) An unsubstituted or substituted aminosulfinyl group, with the substitution being divided into mono-substitution and di-substitution. The substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 alkyl substituted by an amino group, C3-C25 linear 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;

[0403] (o) An unsubstituted or substituted aminocarbonyl group, with the substitution being divided into mono-substitution and di-substitution. The substituents are independently selected from C1-C9 alkyl, C1-C9 alkyl substituted by 1-3 halogens, C1-C9 alkyl substituted by a hydroxyl group, C1-C9 alkyl substituted by an amino group, C3-C25 linear 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;

[0404] (p) An unsubstituted or substituted sulfinyl group, and the substituents are selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, halogenated C1-C9 alkyl, C1-C9 alkyl substituted by a hydroxyl group, C1-C5 acyl, halogenated C2-C5 acyl;

[0405] (q) An unsubstituted or substituted alkylimidosulfinyl group -S(=O)(=NR f )-R f ’ (that is ), with the substitution being divided into mono-substitution and di-substitution. The substituents are selected from C1-C9 linear or branched alkyl, C3-C25 linear 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; R f ’ is selected from C1-3 alkyl;

[0406] (7) Triazinyl;

[0407] (8) A group of the following formula;

[0408]

[0409] wherein, R7 is selected from a hydrogen atom, a hydroxyl group or an amino group;

[0410] wherein, R8 is selected from -(CH2) n -XR9; wherein, n is selected from 0 - 3; X is selected from heteroatoms; R9 is selected from a benzene ring, a fused ring or a fused hetero ring;

[0411] (9) A group of the following formula:

[0412]

[0413] In one embodiment of the present invention, is selected from unsubstituted or substituted phenyl, wherein the substitution is from mono-substitution to tetra-substitution, and the substituents are defined as above, wherein at least one substituent is selected from (a) unsubstituted or substituted amino group, and the substituents are selected from the same range as above; (b) aminosulfonyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above; (c) aminosulfinyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above; (d) aminocarbonyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above; (e) alkyl iminosulfinyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above.

[0414] In one embodiment of the present invention, is selected from unsubstituted or substituted 2-pyridyl, wherein the substitution is from mono-substitution to tri-substitution, and the substituents are defined as above, wherein at least one substituent is selected from (a) unsubstituted or substituted amino group, and the substituents are selected from the same range as above; (b) aminosulfonyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above; (c) aminosulfinyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above; (d) aminocarbonyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above; (e) alkyl iminosulfinyl group, wherein the amino group can be substituted, and the substitution is divided into mono-substitution and bis-substitution, and the substituents are selected from the same range as above.

[0415] In one embodiment of the present invention, Selected from unsubstituted or substituted 3-pyridyl, wherein the substitution is mono-substitution to tri-substitution, and the substituents are defined as the same above, wherein at least one substituent is selected from (a) unsubstituted or substituted amino group, and the substituents are selected from the same range as above; (b) aminosulfonyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above; (c) aminothionyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above; (d) aminocarbonyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above; (e) alkylimidosulfinyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above.

[0416] In one embodiment of the present invention, Selected from unsubstituted or substituted 4-pyridyl, wherein the substitution is mono-substitution to tri-substitution, and the substituents are defined as the same above, wherein at least one substituent is preferably selected from (a) C1-C3 alkyl; (b) C1-C3 alkoxy; (c) unsubstituted or substituted amino group, and the substituents are selected from the same range as above; (d) aminosulfonyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above; (e) aminothionyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above; (f) aminocarbonyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above; (g) alkylimidosulfinyl group, wherein the amino group can be substituted, and the substitution is mono-substitution and di-substitution, and the substituents are selected from the same range as above.

[0417] In one embodiment of the present invention, the amino group may also be selected from

[0418] In one embodiment of the present invention, The C atoms in the alkyl carbon chain in the definition can be substituted by heteroatoms at any position allowed by the normal valence state.

[0419] In one embodiment of the present invention, the unsaturated bond includes carbon-carbon double bond and / or carbon-carbon triple bond.

[0420] In one embodiment of the present invention, the C2-C25 alkenyl refers to a C2-C25 alkenyl containing 1-10 unsaturated double bonds. For example: (H or a C1-C23 alkyl containing 0-9 unsaturated double bonds)-CH=CH-.

[0421] 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-. The unsaturated bonds include carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0422] In one embodiment of the present invention, the C1-C5 acyl group refers to (H or a C1-C4 alkyl group)-C(=O)-. The C1-C9 acyl group refers to (H or a C1-C8 alkyl group)-C(=O)-.

[0423] In one embodiment of the present invention, the 1-3 halogen-substituted C2-C5 acyl group refers to (a 1-3 halogen-substituted C1-C4 alkyl group)-C(=O)-. The 1-3 halogen-substituted C2-C9 acyl group refers to (a 1-3 halogen-substituted C1-C8 alkyl group)-C(=O)-.

[0424] In one embodiment of the present invention, the C2-C5 alkoxycarbonyl group refers to (a C2-C5 alkyl group)-O-C(=O)-.

[0425] 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)-.

[0426] In one embodiment of the present invention, the C1-C25 alkylsulfonyl group refers to (a C1-C25 alkyl group containing 0-10 unsaturated bonds)-SO2-.

[0427] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salts, prodrugs or solvate compounds as immunomodulators in the preparation of drugs for autoimmune diseases.

[0428] The present invention also provides an immunomodulator, which contains the compound represented by the above formula (I) and its pharmaceutically acceptable salts, prodrugs or solvate compounds.

[0429] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for treating or preventing rosacea.

[0430] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for treating or preventing urticaria.

[0431] The present invention also provides the use of the compound represented by the above formula (I) and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for treating or preventing atopic dermatitis.

[0432] The present invention also provides the use of the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of a medicament for treating or preventing psoriasis.

[0433] The present invention also provides the use of the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of a medicament for treating or preventing radiation dermatitis.

[0434] The present invention also provides the use of the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of a medicament for treating or preventing vitiligo.

[0435] The present invention also provides the use of the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of a medicament for treating or preventing alopecia areata.

[0436] The present invention also provides the use of the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of a medicament for treating or preventing inflammatory bowel disease.

[0437] The present invention also provides a pharmaceutical combination, comprising the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds as active ingredients, and a pharmaceutically acceptable carrier.

[0438] The present invention also provides the use of the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds, and the above pharmaceutical composition in the preparation of a medicament related to an MRGPRX2 receptor antagonist.

[0439] The present invention also provides that the medicament related to the MRGPRX2 receptor antagonist is applicable to the treatment of autoimmune diseases.

[0440] The present invention also provides that the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds can be used for treating or preventing MRGPRX2-mediated diseases or disorders.

[0441] In one embodiment of the present invention, the compound represented by the above formula (I), and its pharmaceutically acceptable salts, prodrugs or solvate compounds can treat or prevent MRGPRX2-mediated diseases or disorders through the oral route;

[0442] Alternatively, it can treat or prevent MRGPRX2-mediated diseases or disorders through the topical application route.

[0443] In certain embodiments, the present invention includes the compound of formula (I), wherein B1 and R1 are bonded to form a 6-membered heterocycle optionally substituted with an alkyl group. Examples of such compounds include, but are not limited to, the compounds of formula (II) - formula (III).

[0444]

[0445] Wherein, Z is O or S; R n is selected from C1-C4 alkyl, halogen.

[0446] 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 forms an isothiazolone by bonding with B3. Examples of such compounds include, but are not limited to, compounds of formula (IV)-formula (V).

[0447]

[0448] More specifically, the present disclosure provides the following solutions:

[0449] 1. Use of a compound of formula (I) as shown, and its pharmaceutically acceptable salt, prodrug or solvate in the preparation of a drug for an MRGPRX2 antagonist.

[0450]

[0451] In the formula:

[0452] B1 is selected from -CR4 or an N atom; wherein R4 is selected from a hydrogen atom, C1-C3 alkyl, halogen, C1-C3 alkoxy or nitro;

[0453] R1 is selected from a hydrogen atom, C1-C3 alkyl, C1-C3 alkyl substituted by 1-3 halogens, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by 1-3 halogens, or R1 and B1 bond to form a 6-membered heterocycle optionally substituted or unsubstituted by short-chain alkyl;

[0454] B2 is selected from -NH, an oxygen atom, -CH=CH- or is empty;

[0455] R2 is selected from a hydrogen atom, -C(=O)OR5 or -C(=O)NHR5'; wherein R5 is selected from a hydrogen atom, C1-C4 alkyl; R5' is selected from a hydrogen atom or a hydroxyl group;

[0456] 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 forms an isothiazolone by bonding with B3;

[0457] R3 is selected from halogen, nitro or a hydrogen atom;

[0458] Ring A is selected from unsubstituted or substituted aryl, and the substitution includes mono-substitution, di-substitution, tri-substitution, 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, aminocarbonyl, sulfenyl, or alkyl iminosulfoxide.

[0459] 2. The compound according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds, wherein the aryl is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, triazinyl,

[0460]

[0461] 3. The compound according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds, wherein Ring A is selected from unsubstituted or substituted aryl, and the substitution includes mono-substitution, di-substitution, tri-substitution, or tetra-substitution, and at least one of the substituents is selected from: unsubstituted or substituted amino, aminosulfonyl, aminosulfinyl, aminocarbonyl, sulfenyl, or alkyl iminosulfoxide.

[0462] 4. Use of the compound of formula (I) according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds as an immunomodulator in the preparation of drugs for autoimmune diseases.

[0463] 5. Use of the compound of formula (I) according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of immunomodulators.

[0464] 6. Use of the compound of formula (I) according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for the treatment or prevention of rosacea.

[0465] 7. Use of the compound of formula (I) according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for the treatment or prevention of urticaria.

[0466] 8. Use of the compound of formula (I) according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for the treatment or prevention of atopic dermatitis.

[0467] 9. Use of the compound of formula (I) according to Scheme 1 and its pharmaceutically acceptable salts, prodrugs or solvate compounds in the preparation of drugs for the treatment or prevention of psoriasis.

[0468] 2. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing radiation dermatitis.

[0469] 3. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing vitiligo.

[0470] 4. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing alopecia areata.

[0471] 5. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing inflammatory bowel disease.

[0472] 6. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing diseases related to the MRGPRX2 target.

[0473] 7. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing radiation stomatitis.

[0474] 8. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing inflammatory responses.

[0475] 9. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing Henoch-Schönlein purpura.

[0476] 10. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing irritable bowel syndrome.

[0477] 11. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing allergic rhinitis.

[0478] 12. The use of the compound represented by formula (I) according to Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing asthma.

[0479] 21. Use of the compound represented by formula (I) described in Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing multiple sclerosis.

[0480] 22. Use of the compound represented by formula (I) described in Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing systemic lupus erythematosus.

[0481] 23. Use of the compound represented by formula (I) described in Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing rheumatoid arthritis.

[0482] 24. Use of the compound represented by formula (I) described in Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing autoimmune liver disease.

[0483] 25. Use of the compound represented by formula (I) described in Scheme 1, and its pharmaceutically acceptable salts, prodrugs or solvate compounds, in the preparation of a medicament for treating or preventing autoimmune kidney disease.

[0484] Definitions

[0485] The following words, phrases and symbols used in this disclosure have the meanings described below, unless otherwise specified in the context in which they are used.

[0486] As used herein, the singular forms and "the", "said" are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0487] As used herein, "comprising", "including", "having" and their variants are intended to indicate the presence of the recited features, elements or steps, but they do not exclude the presence or addition of one or more other features, elements, steps. Unless otherwise specified, "comprising", "including" or "having" as used herein encompasses the case consisting of the recited features, elements or steps.

[0488] According to the convention in this technical field, here in the structural formula is used to depict the bond at the connection point of the group moiety or substituent with the core or backbone structure.

[0489] The term "halogen atom" as used herein refers to F atom, Cl atom, Br atom and I atom, preferably F or Cl.

[0490] The term "heteroatom" as used herein refers to N atom, O atom and S atom.

[0491] The term "alkyl" as used herein refers to a straight-chain or branched-chain saturated hydrocarbon group, which is, for example, a group containing 1 to 20 carbon atoms (C1-20 ), a straight-chain or branched-chain saturated hydrocarbon radical having 1 to 15 carbon atoms (C 1-15 ), a straight-chain or branched-chain saturated hydrocarbon radical having 1 to 12 carbon atoms (C 1-12 ), a straight-chain or branched-chain saturated hydrocarbon radical having 1 to 10 carbon atoms (C 1-10 ), a straight-chain or branched-chain saturated hydrocarbon radical having 1 to 9 carbon atoms (C 1-9 ), a straight-chain or branched-chain saturated hydrocarbon radical having 3 to 9 carbon atoms (C 3-9 ), a straight-chain or branched-chain saturated hydrocarbon radical having 1 to 6 carbon atoms (C 1-6 ), or a straight-chain or branched-chain saturated hydrocarbon radical having 1 to 3 carbon atoms (C 1-3 ). The term "C x～y alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon radical 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 radical containing 1 to 12 carbon atoms, and "C 1-6 alkyl" or "C 1-6 straight-chain or branched-chain alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 6 (1, 2, 3, 4, 5, or 6) carbon atoms. Examples of alkyl groups 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.

[0492] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon radical containing one or more carbon-carbon double bonds, such as a straight-chain or branched-chain unsaturated hydrocarbon radical 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 ). One, two, three, or four C═C double bonds may be present in these groups. 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 - 7 carbon atoms, and "C 2-6 alkenyl" or "C 2-6 straight-chain or branched-chain alkenyl" refers to a straight-chain or branched-chain alkenyl containing 2 - 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, hexenyl, etc.

[0493] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon group containing a straight-chain or branched-chain hydrocarbon group having one or more carbon-carbon triple bonds, such as a straight-chain 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 ). One, two, three, or four C═C double bonds may be present in these groups. For example, "C 2-6 alkynyl" or "C 2-6 straight-chain or branched-chain alkynyl" represents a straight-chain or branched-chain alkynyl having 2-6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0494] As used herein, the term "alkoxy" refers to -O-alkyl, where alkyl is as defined above, such as 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-pentyloxy, s-pentyloxy, n-heptyloxy, and n-octyloxy.

[0495] As used herein, the term "haloalkyl" refers to a straight-chain or branched-chain alkyl as defined herein, where one or more hydrogen atoms, such as 1, 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by halogen atoms, the halogen atoms may be the same or different from each other. Examples of haloalkyl 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 is C 1-6 trifluoroalkyl, more preferably -CF3.

[0496] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3-10 ring atoms (3-10 membered), such as 3-9 ring atoms (3-9 membered), 3-7 ring atoms (3-7 membered), 3-6 ring atoms (3-6 membered), or 5-6 ring atoms (5-6 membered), which may have one or more rings, for example, 1 or 2 rings. For example, the cycloalkyl is a monocyclic cycloalkyl, preferably monocyclic C 3-7Cycloalkyl, 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 bicyclic C6-C 10 Cycloalkyl. Bicyclic cycloalkyls include fused rings, bridged rings or spiro rings. Examples of bridged cycloalkyls 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[3.3.1.03,7]nonane (octahydro-2,5-methano-cyclopentadiene or noradamantane) and tricyclo[3.3.1.13,7]decane (adamantane). As used herein, the term "heterocycloalkyl" refers to a saturated ring having 4-10 ring atoms (4-10 membered), such as 4-9 ring atoms (4-9 membered), 4-7 ring atoms (4-7 membered), 4-6 ring atoms (4-6 membered), 5-7 ring atoms (5-7 membered), 5-6 ring atoms (5-6 membered) or 7-9 ring atoms (7-9 membered), one or more, such as 1, 2 or 3, preferably 1 or 2 of the ring atoms being heteroatoms independently selected from N, O and S, the remaining ring atoms being 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 optionally be oxidized to various oxidation states. The point of attachment of the heterocyclic group may be on an N heteroatom or a C atom. Heterocyclic 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 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), optionally substituted by one or more halogens, such as being substituted by 2 F atoms on the same C atom; examples thereof are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, difluoroazetidinyl or 3,3-difluoroazetidinyl. For example, a 5-6 membered heterocycloalkyl 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 O); examples thereof are tetrahydropyranyl (e.g., tetrahydrofuran-4-yl).

[0497] As used herein, the term "aryl" refers to a monocyclic or polycyclic fused aromatic carbocyclic group, such as phenyl or naphthyl.

[0498] As used herein, the term "heteroaryl" refers to an aromatic ring group having 5 - 6 ring atoms (5 - 6 membered), 5 ring atoms (5 membered) or 6 ring atoms (6 membered), wherein one or more, such as 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 heteroatoms are optionally oxidized to various oxidation states. Examples of heteroaryl include, but are not limited to: furyl (including, but not limited to: furan - 2 - yl), imidazolyl (including, but not limited to: 1H - imidazol - 1 - yl), isoxazolyl, isothiazolyl, oxadiazolyl, 1,3 - oxazolyl, pyridyl (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: thiophene - 2 - yl and thiophene - 3 - yl), triazolyl and triazinyl, e.g.,

[0499]

[0500] As used herein, the terms "optionally", "optional" or "optionally" mean that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, "optionally substituted by..." includes "unsubstituted" and "substituted by 1, 2, 3 or more...". Those skilled in the art understand that for any group containing one or more substituents, the group does not include any substitutions or substitution patterns that are spatially impracticable, chemically incorrect, synthetically infeasible and / or inherently unstable.

[0501] 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. Such combinations are permitted only when each combination of substituents and / or each variable results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is robust enough to be isolated from the reaction mixture.

[0502] The compounds of the present disclosure may exist in isotopically labeled or enriched forms, which contain one or more atoms having an atomic weight or mass number different from the atomic weight or mass number of the atom most abundantly found in nature. The isotopes may be radioactive or non - radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to:2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing these and / or other isotopes of these and other atoms are within the scope of the present invention.

[0503] Those skilled in the art will understand that some of the compounds disclosed herein may contain one or more chiral centers or rings and thus there are two or more stereoisomers. Racemic mixtures, individual isomers, and enantiomer-enriched mixtures of these isomers, as well as diastereomers and mixtures enriched in specific diastereomer moieties when there are two chiral centers, are all within the scope of the present disclosure. Those skilled in the art should also understand that the present disclosure includes all individual stereoisomers of the compounds of formula (I) (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), racemates, mixtures thereof, and, if appropriate, their individual tautomeric forms.

[0504] The term "pharmaceutically acceptable salt" as used herein includes, but is not limited to: acid addition salts formed by the compounds disclosed herein with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by the compounds disclosed herein with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates, and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH2) n -COOH (where n is 0 - 4), etc. "Pharmaceutically acceptable salts" also include base addition salts formed by the compounds disclosed herein with acidic groups with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0505] The term "individual" as used herein refers to mammals and non-mammals. Mammals refer to any member of the mammalian class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. In some embodiments, the individual is a human.

[0506] All numerical ranges in this document should be understood to disclose every and all values within the range and every and all subsets of values 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 numerical value within the numerical range, such as each integer within the numerical range. This disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limits of the range.

[0507] The technical and scientific terms not specifically defined herein have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0508] Each of the embodiments described in this disclosure and the features in each of the embodiments should be understood to be combinable with each other in any manner, and each of the resulting combinations is included within the scope of this disclosure, as if the combinations thus obtained were specifically and individually listed herein, unless the context clearly indicates otherwise.

[0509] To the extent permitted by law, the entire contents of all patents, patent applications, and other documents cited or mentioned herein are incorporated herein by reference. The discussion of these references is only intended to summarize the claims therein. No admission is made that any of the said patents, patent applications, or documents, or any part thereof, is relevant material or prior art. The right is specifically reserved to challenge the accuracy and relevance of any assertion that any of the said patents, patent applications, and other documents is relevant material or prior art.

[0510] Administration and Therapy

[0511] The compounds of this disclosure (such as any compound in the examples herein) alone or in combination with one or more additional therapeutic agents can be formulated into pharmaceutical compositions. The pharmaceutical compositions include: (a) the compounds of this disclosure; (b) a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0512] A pharmaceutically acceptable carrier refers to an excipient or auxiliary material that is compatible with the active ingredient in the composition (and in some embodiments, can stabilize the active ingredient) and is harmless to the individual being treated. Suitable pharmaceutically acceptable carriers are disclosed in standard reference books in the art (such as Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy), including one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light blockers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide a good appearance of the drug (i.e., the compounds or their pharmaceutical compositions of the present disclosure) or to facilitate the manufacture of the pharmaceutical product (i.e., the medicament).

[0513] The compounds of the present disclosure can be administered in various known ways, such as orally, topically, parenterally, by inhalation, or by implantation, etc. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intraspinal, intralesional, and intracranial injection or infusion. Oral or topical administration is preferred, such as topical administration to the skin or mucosa, such as external application by smearing.

[0514] The compounds of the present disclosure can be administered in any convenient formulation, such as tablets, capsules, ointments, creams, gels, pastes, emulsions, powders, patches, solutions, dispersions, suspensions, syrups, sprays, suppositories, etc.

[0515] The exact dose of the compounds of the present disclosure that can treat or prevent MRGPRX2-mediated diseases or disorders depends on multiple factors, including the host, the nature and severity of the condition to be treated, and the mode of administration.

[0516] The beneficial technical effects achieved by the present invention at least include:

[0517] (1) Currently commercially available fluoroquinolone drugs, such as ciprofloxacin, are mostly considered to be agonists of MRGPRX2, so that some patients may experience side effects such as itching and rashes after using fluoroquinolone compounds. However, the inventors surprisingly found that the compounds provided by the present disclosure can be used as MRGPRX2 antagonists for the treatment or prevention of autoimmune diseases, allergic diseases, inflammatory diseases, itching, and pain, etc.

[0518] (2) The MRGPRX2 target is mainly concentrated in barrier tissues. By local administration, such as local administration to the skin, more targeted treatment can be achieved for local lesions, and side effects caused by systemic absorption of the drug can also be reduced, improving the treatment experience of patients.

[0519] General Synthesis Method

[0520] In the preparation of the compounds of the present invention, different synthetic routes are applied. The compounds of formula (IA), (IB) and (I) can be synthesized by the following synthetic methods.

[0521] Wherein the variables are as defined in formula (IA), (IB) or (I). For example, for formula (IA), R9 is correspondingly C 1-6 A straight-chain or branched-chain alkyl group or a hydrogen atom, preferably C 1-3 A straight-chain or branched-chain alkyl group, R3 is a halogen; ring A is further substituted by R4 and (R5) n (not shown in the formula), B2 is absent; for, for example, for formula (IB), R9 is correspondingly C 1-6 A straight-chain or branched-chain alkyl group or a hydrogen atom, preferably C 1-3 A straight-chain or branched-chain alkyl group, R3 is a halogen; ring A is further substituted by R4 (not shown in the formula), B2 is absent.

[0522] Reaction Scheme 1:

[0523]

[0524] It is synthesized by reacting Intermediate 1 and Intermediate 2 through a Suzuki reaction in the presence of a base such as K2CO3, Na2CO3, Cs2CO3, etc., in a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocene dichloropalladium(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 under normal pressure in 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.

[0525] Reaction Scheme 1 also corresponds to the case where B2 is empty (i.e., absent) and B3 is CH in the compound of formula (I).

[0526] Reaction Scheme 2:

[0527]

[0528] The compound of general formula (B) can be prepared by hydrolyzing the compound (A). The hydrolysis of the 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.

[0529] Reaction Scheme 2 also corresponds to the case where B2 is empty (i.e., absent) and B3 is CH in the compound of formula (I).

[0530] Reaction Scheme 3:

[0531]

[0532] The compound of general formula (C) can be synthesized from the compound of general formula (B) through a condensation reaction. The compound of formula (B) can react with the relevant amine in the presence of a condensing agent (such as 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.

[0533] Reaction Scheme 3 corresponds to the case where B2 is empty (i.e., absent) and B3 is CH in the compound of formula (I).

[0534] Reaction Scheme 4:

[0535]

[0536] Intermediate 2 can be prepared by reacting compound (D) with bis(pinacolato)diboron compound (E) in the presence of a palladium catalyst and a base in a typical inert solvent. The reaction is carried out under normal pressure in an inert gas environment including nitrogen, argon, etc. The reaction can usually be carried out at a temperature from room temperature to about 150 °C for about 16 to 24 hours.

[0537] Reaction Scheme 5:

[0538]

[0539] Wherein, R7 is a hydrogen atom or a halogen atom.

[0540] The compound of formula (F) is synthesized by reacting Intermediate 3 and Intermediate 1 through Buchwald reaction, Kumada reaction, Negishi reaction or Ullmann reaction in the presence of a base such as K2CO3, Na2CO3, Cs2CO3, LDA, NaH, etc. and in the presence of a copper catalyst such as CuI, Cu(I), or a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocene dichloropalladium(II), palladium(II) chloride and palladium(II) acetate, etc. in a solvent such as DMF, DMSO, THF, toluene, etc. The reaction can be carried out under normal pressure in an inert gas environment including nitrogen, argon, etc. The reaction is usually carried out at a temperature from room temperature to about 80 - 150 °C for about 16 - 24 hours.

[0541] Reaction Scheme 5 corresponds to the case where B2 is empty (i.e., absent) and B3 is CH in the compound of formula (I). Examples

[0542] In this application, when the chemical name and the structural formula are inconsistent, the structural formula shall prevail, unless it can be inferred from the context that the chemical name rather than the structural formula is correct.

[0543] All non-aqueous reactions were carried out using oven-dried glassware under a dry argon atmosphere. The progress of the reaction 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. The mass spectra of the compounds were recorded using an Agilent G7115A liquid chromatography-mass spectrometry instrument. The NMR spectra were recorded at ambient temperature using a Bruker Avance 400 spectrometer. Relative to external tetramethylsilane, 1 the chemical shifts of H were reported in parts per million (δ) and referenced to the signals of the residual protons in the deuterated solvents.

[0544] The experimental materials and reagents used in the following examples were commercially available unless otherwise specified.

[0545] Preparation of intermediate compound 7:

[0546]

[0547] Preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (2)

[0548]

[0549] To a solution of 2,4,5-trifluoro-3-methoxybenzoic acid (1) (30.0 g, 145.5 mmol) in SOCl2 (180 mL) was added, and the mixture was stirred at 85 °C for 3 hours. After cooling to room temperature, the solvent was evaporated and dried under vacuum to obtain a pale yellow oil (32.0 g, 142.5 mmol, yield 97.9%), which was used directly in the next step without further purification.

[0550] Preparation of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propionate (3)

[0551]

[0552] To a solution of potassium 3-ethoxy-3-oxopropionate (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 protection. Then trimethylamine (28.8 g, 284.6 mmol) was added to the mixture, and the mixture was stirred at room temperature for another 30 minutes. 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 crude product as a brown oil (58.0 g).

[0553] Preparation of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4)

[0554]

[0555] To a solution of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propionate (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 the mixture was 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 cyclopropylamine (14.4 g, 252.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then K2CO3 (43.4 g, 314.8 mmol) was added to the mixture, and the mixture was stirred at 100 °C for another 1 hour. After cooling to room temperature, water (500 mL) was added to the mixture and the mixture was stirred for 10 minutes. The suspension was filtered to remove the filtrate, the filtered solid was washed with water (50 mL), and dried in vacuo to obtain the target product as a white solid (21.0 g, 65.0 mmol, 45.6% two-step yield).

[0556] Preparation of ethyl 7-azido-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5)

[0557]

[0558] 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 the mixture was stirred at 70 °C for 36 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, and 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 obtain the crude product as a brown solid (5.6 g).

[0559] Preparation of ethyl 7-amino-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (6):

[0560]

[0561] 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), and the mixture was purged with hydrogen three times and stirred at room temperature under hydrogen (balloon) for 4 h. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 - 20 / 1) to obtain a white solid (3.8 g, 11.86 mmol, 38.3% two-step yield).

[0562] Preparation of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (7):

[0563]

[0564] 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-butanol (1.84 g, 17.84 mmol) and CuBr2 (5.30 g, 23.73 mmol), and the mixture was stirred at 70 °C for 2 h. After the mixture was cooled to room temperature, it was 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 min. The suspension was filtered to remove the filtrate, and the filtered solid was dried in vacuo to obtain the target product as a yellow solid (2.0 g, 5.21 mmol, 43.9%).

[0565] LCMS: 386.1 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 8.77 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H),

[0566] 4.33 (q, J = 7.1 Hz, 2H), 4.14 - 4.10 (m, 1H), 3.94 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.26 - 1.16 (m, 2H), 1.09 - 0.99 (m, 2H).

[0567] Preparation of Intermediate Compound 9:

[0568]

[0569] Preparation of N-(2-Hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (9)

[0570]

[0571] At room temperature, B2Pin2 (1.2 g, 4.28 mmol), KOAc (1.05 g, 10.71 mmol) and Pd(dppf)Cl2 (259.04 mg, 356.97 mmol) were added to a mixture of 4-bromo-N-(2-hydroxyethyl)benzenesulfonamide (8) (1 g, 3.57 mmol) in 1,4-dioxane (10 mL). Subsequently, the mixture was heated to 90 °C and stirred for 16 hours. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column (DCM:MeOH = 20:1) to obtain the title product (582 mg, 312.24 mmol, 58.2%), as a brown solid. LCMS: 327.9 [M+H] + 。

[0572] A series of derivatives can be obtained by replacing similar starting materials through the same preparation route as above.

[0573] Example 1 Ethyl 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0574] The synthetic route is as follows:

[0575]

[0576] At room temperature, 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (7) (100 mg, 260.28 μmol), K3PO4 (165.74 mg, 780.84 μmol) and Pd(dtbpf)Cl2 (16.81 mg, 26.03 μmol) were added to N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (9) (146 mg, 312.24 μmol) in a mixture of 1,4-dioxane (3 mL) and H2O (1 mL). Subsequently, the mixture was heated to 90 °C and stirred for 16 h. Then the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH from 1:0 to 20:1, to give a brown solid product (66 mg, 130.81 μmol, 35.18%).

[0577] LCMS: 505.1[M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H),

[0578] 7.86 - 7.68 (m, 3H), 4.72 (t, J = 5.6 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.05 (dt, J = 6.4, 2.5 Hz, 1H), 3.47 - 3.23 (m, 5H), 2.88 (t, J = 6.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.36 - 1.03 (m, 7H).

[0579] Example 2 1-Cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0580] The synthetic route is shown in the following formula

[0581]

[0582] 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 μmol) in THF (3 mL), H2O (1 mL) and LiOH (12.53 mg, 523.26 μmol) were added. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the pH was adjusted to neutral, and the reaction mixture was diluted with DCM (10 mL) and washed with water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid product (22 mg, 46.17 μmol, 35.30%).

[0583] LCMS: 477.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 8.82 (s, 1H), 7.98 (dd, J = 8.7, 4.7 Hz, 3H), 7.77 (dd, J = 13.3, 6.9 Hz, 3H), 4.72 (t, J = 5.2 Hz, 1H), 4.28 - 4.17 (m, 1H), 3.44 - 3.36 (m, 5H), 2.88 (q, J = 6.0 Hz, 2H), 1.23 - 1.12 (m, 4H).

[0584] Example 3 7-(4-(N-(2-Chloroethyl)aminosulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0585]

[0586] At room temperature, 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 μmol) in THF (3 mL), H2O (1 mL) and SOCl2 (5 mL) were added. After completion of the reaction detected by MS, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (0.1% FA, H2O) to obtain a white solid product (13.70 mg, 36.37 μmol, 78.77%).

[0587] LCMS: 495.1 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 8.82 (s, 1H), 8.16 (d, J = 10.6 Hz, 1H), 7.98 (d, J = 11.1 Hz, 3H), 7.80 (d, J = 7.9 Hz, 2H), 4.21 (q, J = 5.8 Hz, 1H), 3.61 (t, J = 6.1 Hz, 2H), 3.39 (s, 3H), 3.21 - 3.17 (m, 2H), 1.20 - 1.13 (m, 4H).

[0588] Example 4 7-(3-Cyano-4-(2,2,2-trifluoroacetamido)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0589] Preparation of Ethyl 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0590]

[0591] A mixture of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg, 561.57 umol), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (205.62 mg, 842.35 umol), Pd(dtbpf)Cl2 (36.26 mg, 56.16 umol), and K3PO4 (357.6 mg, 1.68 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was stirred under a nitrogen atmosphere at 90 °C for 16 h. After the reaction was cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with DCM:MeOH = 20:1, to give a white solid product (130 mg, 561.57 ummol, 54.93%). LCMS: 422.0 [M+H] + 。

[0592] Preparation of 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0593]

[0594] Ethyl 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (130 mg, 308.47 μmol), LiOH (29.55 mg, 1.23 μmol) in a mixture of THF (3 mL) and H2O (1 mL) was stirred at room temperature for 2 h. 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 obtain a white solid product (22.73 mg, 308.47 μmol, 18.73%). LCMS: 394.1 [M+H] + .

[0595]

[0596] At room temperature, 2,2,2-trifluoroacetic anhydride (28.03 mg, 133.46 μmol) and TEA (13.51 mg, 133.46 μmol) were added to DCM (3 mL) of 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (35 mg, 88.97 μmol). After the mixture was stirred at room temperature for 1 h, it was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (0.1% formic acid in water) to obtain a white solid product (17.35 mg, 88.97 μmol, 39.85%).

[0597] LCMS: 489.8 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 11.94 (s, 1H), 8.82 (s, 1H), 8.21 (s, 1H), 8.06 - 7.91 (m, 2H), 7.81 (d, J = 8.4 Hz, 1H), 4.33 - 4.10 (m, 1H), 3.43 (s, 3H), 1.27 - 1.09 (m, 4H).

[0598] 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

[0599] Referring to the preparation process in Examples 1-4, similar raw materials were replaced to obtain the target product with the following structure:

[0600]

[0601] LCMS: 517.2 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 8.51 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.69–7.62 (m, 2H), 7.52–7.44 (m, 2H), 6.88 (d, J = 11.7 Hz, 1H), 4.25–4.15 (m, 1H), 3.84 (s, 3H), 3.72 (dt, J = 12.1, 7.2 Hz, 2H), 3.57 (dt, J = 12.5, 7.0 Hz, 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).

[0602] Example 6 7-(3-Cyano-4-(N-cyclohexylaminosulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0603] Referring to the preparation procedures in Examples 1 - 4, replacing similar raw materials to obtain the target compound with the following structure:

[0604]

[0605] LCMS: 540.3 [M + H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 14.85 (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 = 12.1 Hz, 1H), 4.13 - 3.80 (m, 4H), 3.36 - 3.15 (m, 1H), 1.75 - 0.88 (m, 14H).

[0606] Example 7 1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-(piperidin-1-ylsulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid

[0607] Referring to the preparation procedures in Examples 1 - 4, replacing similar raw materials to obtain the target compound with the following structure:

[0608]

[0609] LCMS: 501.1 [M + H] + 。 11H NMR (400 MHz, DMSO-d6) δ 14.80 (s, 1H), 8.61 (s, 1H), 8.04 (d, J = 7.8 Hz, 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).

[0610] Example 8 1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid

[0611] Referring to the preparation procedures in Examples 1 - 4, replacing similar raw materials to obtain the target compound with the following structure:

[0612]

[0613] LCMS: 487.1 [M + H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 14.79 (s, 1H), 8.56 (s, 1H), 7.94 (d, J = 7.8 Hz, 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).

[0614] Example 9 7-(4-(azetidin-1-ylsulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0615] Referring to the preparation procedures in Examples 1 - 4, replacing similar raw materials to obtain the target compound with the following structure:

[0616]

[0617] LCMS: 473.1 [M + H] +。1H NMR (400 MHz, DMSO-d6) δ 14.77 (s, 1H), 8.62 (s, 1H), 7.94 (d, J = 7.8 Hz, 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).

[0618] 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

[0619] Referring to the preparation procedures in Examples 1 - 4, similar raw materials were replaced to obtain the target compound with the following structure:

[0620]

[0621] LCMS: 509.1 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 14.75 (s, 1H), 8.61 (s, 1H), 7.91 (d, J = 8.2 Hz, 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).

[0622] According to a similar method, the present invention also synthesized a series of compounds with the structures shown below:

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] Bioactivity test:

[0649] 1. In vitro target binding experiment:

[0650] 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 the relevant proteins to be linked to an energy donor (such as luciferase) and an energy acceptor (such as fluorescent protein). When the relevant drug molecules interact with the protein, the protein structure changes, the distance between the energy donor and the energy acceptor changes, and the chemiluminescence energy induced by the chemical reaction is transferred to the corresponding acceptor, resulting in an increase in the emission of the acceptor and generating a BRET signal. In this work, the DNA-synthesized target human MRGPRX2 and the donor luciferase Nluc ( Promega) (Source: Beijing Tsingke, Lot number: SZ0171228-1), and the receptor fluorescent protein Venus and the related test protein, human β-arrestin1 (ARRB1) (Source: Guangzhou Dahong Biotechnology, Lot number HY22694-4396). And they were inserted into the eukaryotic expression vector plasmid pcDNA3.1(+) (Source: Qiyun Biotechnology, Lot number: QY2310) in the form of a fusion gene through the Linker sequence (GGSG). The cell line selected for the experiment was human embryonic kidney cells HEK-293T, which were routinely cultured in 10-cm cell culture dishes, and the complete cell medium used had the following composition: high-glucose DMEM medium plus 10% (V / V) fetal bovine serum. On the first day of culture, 6 cells were seeded at a density of 2×10 6 cells / 10-cm dish, and passaged every 72 h with the same cell number. One day before transfection, the cells were resuspended and counted, and seeded at a density of 2×10 6 cells / 6-cm dish or 4×10 5 cells / mL, and then seeded into a flat-bottom white 96-well microplate at 100 μL / well, with 3 - 5×10 4 cells per well. First, 10 μL of antagonist compounds diluted with HBSS at different concentrations was added to the wells, and then a specific concentration of agonist compound (EC 80) After reacting for 2 min, add the substrate Furimazine with a final concentration of 10 μM (source: TargetMol, batch number: 362434). After reacting for another 2 min, place the 96-well plate into a PHERAstar FSX microplate reader (source: BMG Labtech) to simultaneously detect the readings at wavelengths of 440 nm and 530 nm. Calculate the Ratio value and the net BRET value based on the fluorescence readings at 440 nm and 530 nm. Ratio = Em530 nm / Em440 nm, net BRET = Ratio co-transfection - Ratio single transfection. Input the calculated net BRET value into Graphpad Prism 9, and fit the curve and IC 50 Calculation.

[0651] R-ZINC-3573 (source: MCE, product number: HY-118069) has been reported to have an agonistic effect on MRGPRX2 and is used as an agonist in this experiment. The IC 50 values are shown in Table 1.

[0652] Table 1

[0653]

[0654]

[0655] Note: 80 μM > IC 50 > 10 μM is +, 10 μM > IC 50 > 1 μM is ++, 1 μM > IC 50 > 0.1 μM is +++.

[0656] 2. In vivo pharmacodynamic experiment:

[0657] 2.1 Rosacea

[0658] Experimental animals: BALB / c mice, Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0659] Model establishment:

[0660] Shave the hair on the back of the mice, mark the modeling area on the back skin, avoiding the positions with rich subcutaneous blood vessels. Use a microsyringe to aspirate the LL-37 (an antimicrobial peptide for rosacea modeling) (source: Qiangyao Biotech, batch number: 20240319) solution, and inject the LL-37 solution intradermally along the skin, slowly pull out the syringe after injection, and the modeling lasts for 5 - 7 days, twice a day.

[0661] Animal grouping and drug administration:

[0662] Medication began on the day of grouping, defined as D1, and was administered continuously for 7 days, once a day. The normal control group and the model control group were only administered the vehicle under the same conditions. The skin lesions at the injection site on the back of the mice in each group were observed, and a score ranging from 0 to 4 was given according to the degree of erythema. Among them, no erythema was recorded as 0 points, faintly visible erythema was recorded as 1 point, presenting a pale erythema with blurred boundaries was recorded as 2 points, showing erythema with clear boundaries was recorded as 3 points, and erythema with a deep color and clear boundaries was recorded as 4 points. The medication regimen for the mouse rosacea model is as follows:

[0663]

[0664]

[0665] The experimental results showed that the model group (administered with the vehicle) presented typical rosacea-like skin lesions with obvious erythema, the blank group (administered with the vehicle) had no abnormal skin symptoms, and the example group significantly improved the erythema symptoms during the experiment, which was statistically significant. The erythema scores of each group are shown in Table 2, and the data are expressed as the mean ± standard error of the mean (SEM).

[0666] Table 2

[0667] Group D1 D2 D3 D4 D5 D6 D7 G1 0 0 0 0 0 0 0 G2 1.6±0.2 3.1±0.3 3.3±0.2 3.0±0.2 2.4±0.2 2.1±0.3 1.7±0.3 G3 1.6±0.2 2.1±0.3* 2.5±0.2* 1.8±0.2** 1.9±0.2* 1.6±0.2 1.5±0.3 G4 1.6±0.3 2.7±0.2 2.7±0.2* 2.4±0.2* 1.7±0.2* 1.6±0.3 1.5±0.3 G5 1.6±0.2 2.2±0.2* 2.2±0.1* 1.7±0.2** 1.7±0.2* 1.3±0.3* 1.2±0.2 G6 1.6±0.3 2.6±0.2 2.6±0.2* 2.3±0.3* 1.8±0.2* 1.5±0.3 1.2±0.3 G7 1.7±0.2 2.2±0.2* 2.5±0.2* 1.8±0.2** 1.7±0.2* 1.3±0.2* 1.2±0.2 G8 1.6±0.3 2.3±0.3* 2.6±0.3* 2.2±0.3* 1.7±0.2* 1.3±0.2* 1.3±0.2

[0668] * Compared with the model control group, P < 0.05; ** compared with the model control group, P < 0.01.

[0669] 2.2 Psoriasis

[0670] Experimental animals: BALB / c mice, Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0671] The severity of psoriasis clinical disease was evaluated using the Psoriasis Activity and Severity Index (PASI) score. The PASI scoring criteria for mice are as follows:

[0672]

[0673] Model establishment:

[0674] The hair on the back of the mice was shaved off, and the application area was marked with a marker pen. Imiquimod cream (source: Sichuan Mingxin Pharmaceutical Co., Ltd., batch number: 24054002) was continuously applied to the back of the mice for multiple days to establish a psoriasis mouse model. Before each application, the residual cream was removed with pure water.

[0675] Animal grouping and medication:

[0676] Medication was started on the day of grouping, defined as D1, and administered continuously for 8 days, once a day. The normal control group and the model control group were only administered the vehicle under the same conditions. The mice were scored according to PASI (Psoriasis area and severity index). The dosing regimens for the mouse psoriasis models are as follows:

[0677] Group Drug Number of Animals Dosing Dose Route of Administration Dosing Period G1 Normal Control Group 6 - Skin Application 8 Days G2 Model Control Group 6 - Skin Application 8 Days G3 Example 10 6 4mg / g Skin Application 8 Days G4 Example 18 6 4mg / g Skin Application 8 Days G5 Example 69 6 4mg / g Skin Application 8 Days G6 Example 90 6 4mg / g Skin Application 8 Days G7 Example 106 6 4mg / g Skin Application 8 Days G8 Example 133 6 4mg / g Skin Application 8 Days

[0678] The experimental results showed that typical psoriatic lesions appeared in the model group: erythema, scales, and skin thickening. There were no abnormal symptoms in the skin of the blank group. The psoriatic lesions in the example group were significantly improved at the end of the experiment, which was statistically significant. The PASI scores of each group are shown in Table 3, and the data are expressed as mean ± standard error of the mean (SEM).

[0679] Table 3

[0680] Group D1 D2 D3 D4 D5 D6 D7 D8 G1 0 0 0 0 0 0 0 0 G2 0 0.6±0.3 1.9±0.3 3.4±0.4 4.3±0.4 5.5±0.4 6.8±0.5 9.1±0.5 G3 0 0.5±0.3 1.7±0.3 2.8±0.3 3.6±0.4 4.3±0.4** 5.3±0.4** 6.6±0.4* G4 0 0.5±0.3 1.6±0.3 3.0±0.4 3.7±0.3 4.6±0.4* 5.5±0.4* 6.7±0.4* G5 0 0.6±0.3 1.7±0.3 3.1±0.3 3.8±0.3 4.6±0.4* 5.5±0.4* 6.6±0.4* G6 0 0.6±0.3 1.9±0.3 3.1±0.3 3.9±0.4 4.7±0.3* 5.7±0.3* 6.6±0.5* G7 0 0.5±0.3 1.8±0.3 2.6±0.3* 3.3±0.3* 4.4±0.4** 5.1±0.3** 6.4±0.5** G8 0 0.6±0.3 1.6±0.3 2.7±0.4 3.4±0.3* 4.6±0.4* 5.6±0.4* 6.7±0.5*

[0681] * P < 0.05 compared with the model control group; ** P < 0.01 compared with the model control group.

[0682] 2.3 Urticaria

[0683] Experimental animals: BALB / c mice, Hangzhou Ziyuan Experimental Animal Technology Co., Ltd.

[0684] Model establishment:

[0685] After randomly grouping the mice, the hair on the back was removed in advance, and the depilated area was about 2 cm × 2 cm. Except for the normal control group, the mice in the other groups were sensitized by injecting anti-dinitrophenyl monoclonal antibody (source: Sigma-Aldrich, batch number: 0000241402) (0.2 ng / mL) into the tail vein, 0.5 mL / mouse. After 24 h, 50 μL of 0.15% dinitrofluorobenzene (source: Shanghai Macklin, batch number: C14969320) was applied to the back of both ears of the mice in each sensitized group for challenge. The normal control group was injected and smeared with normal saline under the same conditions.

[0686] The dosing regimens for the mouse urticaria models are as follows (the normal control group and the model control group were only administered the vehicle under the same conditions) (once a day):

[0687] Group Drug Number of Animals Dosing Dose Route of Administration Dosing Period G1 Normal Control Group 6 - - 6 Days G2 Model Control Group 6 - - 6 Days G3 Example 10 6 4mg / kg Skin Application 6 Days G4 Example 10 6 25mg / kg Oral Administration 6 Days G5 Example 54 6 4mg / kg Skin Application 6 Days G6 Example 54 6 25mg / kg Oral Administration 6 Days G7 Example 69 6 4mg / kg Skin Application 6 Days G8 Example 69 6 25mg / kg Oral Administration 6 Days G9 Example 164 6 4mg / kg Skin Application 6 Days G10 Example 164 6 25mg / kg Oral Administration 6 Days

[0688] The experimental results showed that typical urticaria wheal symptoms appeared in the model group, there were no abnormal skin symptoms in the blank group, and the number of wheals in the example group was significantly improved at the end of the experiment, which was statistically significant. Moreover, the detection results of serum IgE and histamine after the experiment were significantly improved, which was statistically significant. The number of wheals, serum IgE and histamine content in each group are shown in Table 4, and the data are expressed as mean ± standard error of the mean (SEM).

[0689] Mouse IgE ELISA detection kit: purchased from Shanghai Enzyme-linked Biotechnology Co., Ltd., batch number: ml1037602.

[0690] Mouse histamine ELISA detection kit: purchased from Shanghai Enzyme-linked Biotechnology Co., Ltd., batch number: ml1001877.

[0691] Microplate reader, manufacturer BioTeK, model Epoch.

[0692] Table 4

[0693] Group Number of Wheals IgE Content (ug / mL) Histamine Content (ng / mL) G1 1.2±1.7 6.4±0.9 4.2±0.9 G2 15.8±1.5 23.0±2.5 9.7±1.0 G3 <![CDATA[10.6±2.0 * > <![CDATA[12.2±2.0 ** > <![CDATA[6.3±1.0 ** > G4 <![CDATA[8.4±1.0 ** > <![CDATA[11.5±2.0 ** > <![CDATA[5.8±1.0 ** > G5 <![CDATA[10.6±1.5 * > <![CDATA[14.8±1.0 ** > <![CDATA[6.4±1.0 ** > G6 <![CDATA[6.5±1.5 ** > <![CDATA[17.3±1.5 * > <![CDATA[6.9±1.0 ** > G7 <![CDATA[11.4±2.0 * > <![CDATA[15.2±2.0 ** > 7.4±1.0* G8 <![CDATA[10.0±2.0 * > <![CDATA[11.5±2.0 ** > <![CDATA[5.8±1.0 ** > G9 9.7±2.0* <![CDATA[14.9±2.0 ** > <![CDATA[6.5±1.0 ** > G10 <![CDATA[8.8±2.0 ** > <![CDATA[10.5±2.0 ** > <![CDATA[5.6±1.0 ** >

[0694] * Compared with the model control group, P < 0.05; ** Compared with the model control group, P < 0.01.

[0695] 2.4 Atopic dermatitis

[0696] Experimental animals: BALB / c mice, Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0697] Model establishment:

[0698] MC903 (calcipotriol) (source: TargetMol, batch number: 235760) was applied to the right ear of mice once a day for 14 days.

[0699] Animal grouping and administration:

[0700] The animals were randomly divided into 6 groups before induction on day D1. The model control group was only administered the vehicle under the same conditions. Administration was carried out according to the following groups:

[0701] Group Group Description Dosing Dose (mg / kg) Dosing Frequency (times / day) Dosing Method Number of Animals G1 Model Control Group - - - 5 G2 Example 10 50 BID p.o. 5 G3 Example 41 50 BID p.o. 5 G4 Example 54 50 BID p.o. 5 G5 Example 85 50 BID p.o. 5 G6 Example 116 50 BID p.o. 5

[0702] Note: BID, twice a day; p.o., oral administration.

[0703] During the experiment, the thickness of the right ear of mice was measured. The results showed that compared with the model group, the thickness of the right ear of mice in each example group decreased, which was statistically significant. The data are expressed as mean ± standard error of the mean (SEM).

[0704]

[0705] *Compared with the model control group, P<0.05; **compared with the model control group, P<0.01.

[0706] 2.5 Inflammatory bowel disease (IBD)

[0707] Experimental animals: C57BL / 6 mice, Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0708] Model establishment and grouping:

[0709] Using C57BL / 6 mice, prepare an aqueous solution of 3% DSS (dextran sulfate sodium) (source: MPBIO, batch number: YD11024) as the drinking water for mice.

[0710] Group Group Description Dosing Dose Treatment Method Dosing Method Number of Animals G1 Normal Control Group - Drinking Water without DSS - 6 G2 Model Control Group - 3% DSS Drinking Water for 7 Consecutive Days - 6 G3 Example 7 20mg / kg 3% DSS Drinking Water + QD for 7 Consecutive Days p.o. 6 G4 Example 13 20mg / kg 3% DSS Drinking Water + QD for 7 Consecutive Days p.o. 6 G5 Example 19 20mg / kg 3% DSS Drinking Water + QD for 7 Consecutive Days p.o. 6 G6 Example 54 20mg / kg 3% DSS Drinking Water + QD for 7 Consecutive Days p.o. 6 G7 Example 105 20mg / kg 3% DSS Drinking Water + QD for 7 Consecutive Days p.o. 6 G8 Example 164 20mg / kg 3% DSS Drinking Water + QD for 7 Consecutive Days p.o. 6

[0711] Note: QD, once a day; p.o., oral administration; the solvent is the administration solvent of the preparation example.

[0712] During the experiment, weigh the animals regularly every day, observe the animal status (including feces, death situation), and evaluate the drug efficacy through DAI scoring. DAI scoring rules: normal feces 0 points, soft but formed feces 1 point, soft feces 2 points, soft and wet feces 3 points, loose stools 4 points; no occult blood 0 - 1 point, positive occult blood 2 points, visible bloody stools 3 points, severe bloody stools 4 points; no weight loss or weight gain 0 points, 1% - 5% weight loss 1 point, 6% - 10% weight loss 2 points, 11% - 15% weight loss 3 points, more than 15% weight loss 4 points. The sum of the three scores is the total DAI score, and weigh and score every other day. The experimental results show that the administration group showed significant drug efficacy, with statistical significance. The DAI scores are shown in Table 5, and the data are expressed as mean ± standard error of the mean (SEM):

[0713] Table 5

[0714]

[0715] *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.

[0716] 2.6 Allergic rhinitis

[0717] Experimental animals: BALB / c mice, Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0718] Model establishment

[0719] Modeling began on the day of grouping, which was defined as M1. Except for the normal group, each mouse in all modeling groups was intraperitoneally injected with 250ug of OVA (ovalbumin) (source: Shanghai McLean, batch number: C16255388) mixed with 5mg aluminum hydroxide / mL, while the normal control group was given an equal amount of sterile PBS solution. The injection time period was M1, M7, and M14. From M21, the nasal drops were performed once a day for 7 consecutive days. The stimulating solution was 50mg / mL OVA solution, and the volume of each nostril was dropped into 10ul each time. The normal control group did not perform nasal drops.

[0720] Animal grouping and drug administration

[0721] The drug was administered on the day of nasal drop provocation, 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 drug administration scheme of the mouse allergic rhinitis model is as follows:

[0722]

[0723]

[0724] Evaluation indicators

[0725] Rhinitis symptom score

[0726] During the medication period, the number of sneezes in each group was recorded 10 minutes after nasal drop stimulation every day.

[0727] During the experiment, the allergic rhinitis model mice showed typical symptoms: shortness of breath, scratching ears and noses, sneezing, etc. Compared with the model group, the embodiment group can significantly reduce the number of sneezes. The counting results of each group are shown in Table 6, the unit is (number of sneezes / mouse), and the data are expressed as mean ± standard error (SEM).

[0728] Table 6

[0729] Group D1 D2 D3 D4 D5 D6 D7 G1 0 0 0 0 0 0 0 G2 1.7 4.0 13.0 14.7 22.2 27.7 20.0 G3 2.5 3.3 10.2 14.5 11.3 15.8 13.2 G4 2.0 1.4 14.6 7.8 9.1 13.0 10.4 G5 1.5 4.7 15.2 13.5 9.8 14.0 12.0 G6 2.8 3.1 10.2 14.9 10.7 16.1 13.4 G7 2.4 1.3 14.5 7.6 7.2 13.4 14.8 G8 1.5 3.7 15.2 12.5 10.8 13.0 15.2

[0730] Note: The unit is the number of sneezes / sneezes.

[0731] IgE testing

[0732] Blood was collected from the eyeballs before dissection. After the mouse blood was collected, it was centrifuged at 4℃1800r / min for 15min and the upper serum was collected and stored at -80℃ for testing. At the same time, nasal lavage fluid and tracheal tissue were collected. The IgE content of the above three samples was detected by ELISA (source: Shanghai ELISA Biotechnology Co., Ltd., batch number: ml1037602).

[0733] IgE detection (ELISA instrument, manufacturer BioTeK, model 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, lavage fluid and tracheal tissue of each group are shown in Table 7.

[0734] Table 7

[0735]

[0736] *Compared with the model control group, P<0.05; **Compared with the model control group, P<0.01.

[0737] 2.7 Asthma

[0738] Experimental animals: BALB / c mice, Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0739] Model building

[0740] Modeling began on the day of grouping, which was defined as M1. Except for the normal group, each mouse in all modeling groups was intraperitoneally injected with 500ug of OVA (ovalbumin) (source: Shanghai McLean, batch number: C16255388) mixed with 5mg aluminum hydroxide / mL sensitization solution, while the normal control group was given an equal amount of sterile PBS solution. The injection cycle was M1, M7, and M14. From M21, continuous nebulization stimulation was performed for 7 days, and the stimulation solution was 20mg / mL OVA (ovalbumin) solution, and each nebulization stimulation lasted 30 minutes. The normal control group was not nebulized.

[0741] Animal grouping and drug administration

[0742] The drug was administered starting from day M21, 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 drug administration scheme for the mouse asthma model is as follows:

[0743] Group Drug Number of Animals Dosing Dose Route of Administration Dosing Period G1 Normal Control Group 6 - PO 7 Days G2 Model Control Group 6 - PO 7 Days G3 Example 5 6 5mg / kg PO 7 Days G4 Example 37 6 5mg / kg PO 7 Days G 5 Example 117 6 5mg / kg PO 7 Days G 6 Example 144 6 5mg / kg PO 7 Days

[0744] Evaluation indicators

[0745] Bronchoalveolar lavage (BALF) cell differential count

[0746] The lungs were gently lavaged twice with normal saline, and BALF was collected. The recovered BALF was stored at 4°C, and the cell classification count was detected using a fully automatic blood analyzer (source: manufacturer SYSMEX, model XN-1000). During the experiment, the asthma model mice showed typical symptoms: shortness of breath, scratching the ears and nose, etc. Compared with the model group, the embodiment group can significantly reduce the number of inflammatory cells in the alveolar lavage fluid. The results of the cell classification counts of the alveolar lavage fluid in each group are shown in Table 8, and the data are expressed as mean ± standard error (SEM).

[0747] Table 8

[0748]

[0749] *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.

[0750] Serum IgE test

[0751] Before the autopsy, blood was collected from the eyeballs. After the mouse blood was collected, the upper serum was centrifuged at 4°C 1800r / min for 15min and then stored at -80°C for testing. At the same time, alveolar lavage fluid and lung tissue were collected. The above three samples were tested for IgE content using ELISA (source: Shanghai ELISA Biotechnology Co., Ltd., batch number: ml1037602). Compared with the model group, the embodiment group can significantly reduce the IgE content in peripheral blood, alveolar lavage fluid and lung tissue. The results of IgE content in peripheral blood, lavage fluid and lung tissue of each group are shown in Table 9, and the data are expressed as mean ± standard error (SEM).

[0752] Table 9

[0753] Group Peripheral Blood IgE Concentration (ng / mL) Alveolar Lavage Fluid IgE Concentration (ng / mL) Lung Tissue IgE Concentration (ng / mL) G1 10.3±3.0 1.9±0.4 7.1±1.9 G2 22.6±2.0 33.5±1.7 58.3±3.0 G3 15.6±5.8* 12.8±0.9** 39.8±2.4* G4 14.7±4.3* 12.1±1.8** 37.2±3.5** G5 12.1±3.2** 14.8±3.5** 48.9±4.6* G6 11.9±2.3** 6.3±1.7*** 32.8±4.1***

[0754] Notes: *: 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.

[0755] ELISA detector, manufacturer: BioTeK, model: Epoch.

[0756] 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 of execution. Based on this disclosure, those skilled in the art can make obvious improvements to the present invention in combination with the existing prior art, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. Use of a compound of formula (IA), 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, in: R1 is -C 3-6 Cycloalkyl or -C 1-6 Straight or branched chain alkyl; 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 Straight or branched alkyl)2 or -C(O)-NH-OH; R3 is halogen; B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-6 Straight or branched chain alkyl; A is for C 6-10 Aryl or 5-6 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 Each independently selected from C 1-20 Straight or branched alkyl, C 2-20 Straight or branched alkenyl, C 2-20 Straight-chain or branched alkynyl, C 3-10 wherein the heterocycloalkyl contains one or more heteroatoms selected from N, O and S, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 Straight or branched alkyl, -OC 1-6 Straight or branched alkyl, -NHC 1-6 Straight or branched alkyl and -N(C 1-6 Straight chain or branched chain alkyl)2; R b and R c Together with the N 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, and the heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents selected from the following: halogen, -OH, -NH2, -CN, -NO2, -SC 1-6 Straight or branched alkyl, -OC 1-6 Straight or branched alkyl, -NHC 1-6 Straight or branched 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 Straight or branched alkyl, -N(C 1-6 Straight chain or branched chain alkyl)2, C 1-6 Straight 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 n is 0, 1, 2 or 3.

2. The method according to claim 1, wherein: R1 is 3. The use according to any one of the preceding claims, wherein R2 is -COOH, -COOC 1-3 Straight chain or branched chain alkyl or -C(O)NH2.

4. The use according to any one of the preceding claims, wherein R3 is F.

5. The use according to any one of the preceding claims, wherein B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 Straight chain or branched chain alkyl.

6. The use according to any one of the preceding claims, wherein A is phenyl or pyridyl.

7. 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-SR d .

8. 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. The use according to any one of the preceding claims, wherein R a Selected from C 1-15 Straight 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 by 1, 2 or 3 halogens.

10. The use according to any one of the preceding claims, wherein R d Selected from C 1-6 Straight or branched alkyl, C 2-6 Straight or branched alkenyl and C 2-6 Straight or branched chain alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with 1, 2 or 3 substituents selected from halogen, -OH and -CN.

11. 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 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.

12. The use according to any one of the preceding claims, wherein R5 is selected from halogen, -CN, -NH2, -OH, -NH-C 1-6 Straight or branched alkyl, C 1-6 Straight or branched alkyl and C 1-6 Straight-chain or branched-chain alkoxy.

13. The use according to any one of the preceding claims, wherein n is 0 or 1.

14. The use according to any one of the preceding claims 1, wherein: R1 is R2 is -COOH or -COOC 1-3 Straight or branched alkyl; for example -COOH or -COOCH3; R3 is F; B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 Straight or branched alkyl, such as H, F or -O-CH3; A 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 Straight 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, O and S, and the alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen and -OH; 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, O and S, which is optionally substituted with 1, 2 or 3 halogens; and n is 0.

15. The use according to any one of the preceding claims, wherein the compound is selected from:

16. The method according to any one of claims 1 to 15, wherein The disease or disorder is especially a disease or disorder caused by mast cell degranulation, the disease or disorder is preferably selected from autoimmune diseases, allergic diseases, inflammatory diseases, pruritus and pain, 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, radiation dermatitis, eczema, pseudoallergic reaction, anaphylactic shock, generalized pruritus, neuropathic pruritus, nodular prurigo, neuropathic 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 as defined in any one of the preceding claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof for in vitro testing of MRGPRX2.

18. A compound of formula (IB), a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, in: R1 is -C 3-6 Cycloalkyl or -C 1-6 Straight or branched chain alkyl; R2 is -COOH or -COOC 1-6 Straight or branched chain alkyl; R3 is halogen; B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-6 A straight or branched chain alkyl group; and 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 or branched alkyl -CF3, -S(O)2-NH-cyclohexyl, -S(O)2-NR b R c 、-S(O)-NH-C 1-6 Straight or branched alkyl -CF3, -S-NH-C 1-6 Straight 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, -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 A straight chain or branched chain alkynyl group; wherein R b and R c Together with the N atom to which they are attached they form an azetidinyl or difluoroazetidinyl group; 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 1-6 Straight 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 or branched alkyl and -SC 1-6 Hydroxyl linear or branched alkyl; wherein R b and R c Together with the N atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

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

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

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

23. A compound according to any one of the preceding claims, 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 N atom to which they are attached they form an azetidinyl or difluoroazetidinyl group.

24. A compound according to any one of the preceding claims, 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 8-10 Straight 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 straight chain alkyl; Among them, R b and R c Together with the N atom to which they are attached, they form an azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group; for example, A is pyridinyl; 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; where R b and R c Together with the N atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

25. A compound according to any one of the preceding claims, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof, wherein: R1 is For example R2 is -COOH or -COOC 1-3 Straight or branched alkyl; for example -COOH or -COOCH3; R3 is F; B1 is -CR6 or N, wherein R6 is H, halogen or -OC 1-3 Straight or branched alkyl, such as H, F, Cl or -O-CH3; and 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 N atom to which they are attached they form a difluoroazetidinyl group; 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; where R b and R c Together with the N atom to which they are attached they form azetidinyl, difluoroazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

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

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

28. Use of a compound according to any one of claims 18 to 26 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof in the preparation of a medicament for treating or preventing MRGPRX2-mediated diseases or disorders, especially diseases or disorders caused by mast cell degranulation, wherein the diseases or disorders are preferably selected from autoimmune diseases, allergic diseases, inflammatory diseases, itching and pain, and the diseases or disorders are more preferably 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, systemic pruritus, neuropathic pruritus, nodular prurigo, neuropathic inflammation, ulcerative colitis, Crohn's disease, irritable bowel syndrome, respiratory inflammation, postoperative pain and vitiligo.

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

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

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