Mrgprx2 antagonists and uses thereof

Abstract

The present disclosure relates to the use of MrgprX2 antagonists in the treatment of inflammatory conditions, for example, skin inflammatory conditions. The present invention also relates to pharmaceutical compositions comprising a MrgprX2 antagonist and a pharmaceutically acceptable carrier for topical or oral administration.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application Serial No. 62 / 931,186, filed November 5, 2019; U.S. Provisional Application Serial No. 62 / 931,576, filed November 6, 2019; and U.S. Provisional Application Serial No. 63 / 046,481, filed June 30, 2020, the contents of which are hereby incorporated by reference in their entirety. Background Technology

[0003] Atopic dermatitis (AD) is the most common inflammatory skin disease, with an overall prevalence of 6% in adults in the United States and 1-3% globally in adults and 15-20% in children. 17.8 million Americans have AD. The disease typically presents in childhood, with 60% of patients showing skin manifestations by age 1. Clinical presentations include erythematous papules and plaques, exudation, crusting, hypopigmentation, and lichenification. However, the hallmark symptom of AD is intense, chronic itching lasting more than 6 weeks. Despite the high prevalence of chronic itching in AD patients, there is currently no safe and effective first-line treatment. Itching has a significant impact on the quality of life of these patients, including sleep disturbances, which can ultimately lead to poor performance at work or school. Health-related quality of life in children is negatively correlated with disease severity. Sleep is affected by persistent nighttime itching.

[0004] Oral antihistamines provide moderate symptom relief due to their sedative effects without directly altering the itching. Topical calcineurin inhibitors (TCIs) and topical corticosteroids (TCSs) may help reduce itching. However, their side effects (TCS: skin atrophy, hypopigmentation, and telangiectasia; TCI: black box warning regarding skin cancer and malignancy) make them less than ideal for long-term use, especially in young children. Therefore, there is a strong need among patients and their families to find new treatment options for pruritus. Furthermore, relief of chronic pruritus can disrupt the pruritus-scratching cycle, resulting in minor beneficial effects such as improved skin barrier function and potentially leading to improvement in skin lesions and erythema.

[0005] Finding a cure and effective treatment for chronic pruritus in Alzheimer's disease (AD) has been a major challenge. Histamine is not a primary pruritogen in AD; therefore, histamine blockers work in AD patients only through their sedative effects, particularly for nocturnal pruritus. Proteases released from immune and skin cells of AD patients and acting on GPCRs have been investigated as major pruritogenic factors in AD. Cathepsin S has been described in the literature as a highly pro-inflammatory protease that triggers pruritus. Overexpression of cathepsin S leads to an AD phenotype in mice with severe chronic pruritus. Recently, a group reported that cathepsin S induces pruritus via MrgprX2. However, knowledge about key pruritus mediators in AD is limited, although some mediators have been identified and hypothesized to play a role.

[0006] Another pruritogenic neuropeptide is substance P, released by both neuronal and non-neuronal dermal cells, which is a pro-inflammatory and vasoactive neuropeptide that also acts as a pruritogen. Therefore, targeting its homologous receptor NK1 has been considered an ideal therapeutic approach, and aprepitant has been used in studies. However, despite preclinical data in mice, the NK1R antagonist aprepitant has failed to significantly block pruritus in humans.

[0007] MrgprX2 is a promising target because it exhibits mixed ligand-binding properties with various pruritus mediators. Many pruritus mediators known or presumed to be associated with AD pathogenesis appear to bind to MrgprX receptors rather than their homologous receptors.

[0008] The need for effective treatments for Alzheimer's disease (AD) and its symptoms remains unmet. This invention addresses this need, as well as other important objectives. Summary of the Invention

[0009] This article describes topical and oral compositions comprising MrgprX2 antagonists, and methods of using MrgprX2 antagonists to treat inflammatory conditions such as AD.

[0010] Therefore, in a first aspect, this disclosure provides compounds as MrgprX2 antagonists.

[0011] In a second aspect, this disclosure provides topical and oral compositions comprising a MrgprX2 antagonist and a pharmaceutically acceptable excipient.

[0012] In a third aspect, this disclosure provides a method for treating an inflammatory condition, the method comprising administering to a subject in need a topical or oral composition having a therapeutically effective amount of a MrgprX2 antagonist (e.g., a MrgprX2 antagonist according to this disclosure); and a dermatologically or orally acceptable excipient.

[0013] In a fourth aspect, this disclosure provides a method for reducing inflammation in mammalian skin, the method comprising administering an effective amount of a topical or oral composition to a subject in need of the mammalian skin, the topical or oral composition comprising a MrgprX2 antagonist (e.g., a MrgprX2 antagonist according to this disclosure) and a dermatologically or orally acceptable excipient.

[0014] In a fifth aspect, this disclosure provides a method for reducing the incidence or severity of pruritus in a subject in need, the method comprising administering to the subject in need a therapeutically effective amount of a topical or oral composition comprising a MrgprX2 antagonist (e.g., a MrgprX2 antagonist according to this disclosure). Detailed Implementation

[0015] This article provides topical or oral compositions for treating inflammatory conditions, such as skin conditions characterized by inflammation. In particular, the pharmaceutical compositions comprise a compound that acts as an antagonist of the Mas-associated G protein-coupled receptor MrgprX2.

[0016] MrgprX2 antagonist for use in the disclosed compositions and methods

[0017] In several embodiments, this disclosure provides a compound [compound 1], which is a MrgprX2 antagonist having formula I:

[0018]

[0019] in:

[0020] G2 is

[0021]

[0022] q is 0 or 1;

[0023] m is 0 or 1;

[0024] n is 0, 1, or 2;

[0025] k is 0 or 1;

[0026] The premise is that k, q, and m are not all 0;

[0027] The premise is that when m and k are both 1, q is not 0;

[0028] R1 and R2 are independently H and C. 1-6 Alkyl; C 3-6 Cycloalkyl; 5-10 membered heterocycloalkyl groups having 1-3 cyclic heteroatoms, said cyclic heteroatoms being independently selected from N, O, and S; wherein each C 1-6 Alkyl, C3-6 Cycloalkyl and 5-10 membered heterocyclic alkyl groups are optionally surrounded by 1 to 3 R groups. 20 Group substitution;

[0029] The premise is that R1 and R2 are not both H at the same time;

[0030] Each R 20 Independently selected from 1) hydroxyl, 2) cyano, 3) C 1-3 Alkyl, 4)C 1-3 Alkoxy, 5)C 1-3 alkyl haloide, 6) halogen, 7) C 1-3 Alkyl group, 8) C6 groups optionally substituted with 1-3 substituents 3-6 cycloalkyl, wherein the substituent is selected from hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl groups and halogens, and 9) 5-10 membered heterocyclic alkyl groups having 1-3 cyclic heteroatoms optionally substituted with 1-3 substituents, wherein the cyclic heteroatoms are independently selected from N, O, and S, and the substituents are selected from hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and halogens;

[0031] Alternatively, R1 and R2, together with the nitrogen atom to which they are attached, can form a 5- or 6-membered saturated, partially unsaturated, or aromatic heterocycle having 1-3 cyclic heteroatoms, wherein the cyclic heteroatoms are independently selected from N, O, and S, and the heterocycle is optionally substituted by 1, 2, or 3 groups selected from hydroxyl, C, and S groups. 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups, cyano groups, and halogens;

[0032] R3 is H or C. 1-3 alkyl;

[0033] Each R4 and R5 is independently H or C. 1-3 alkyl;

[0034] G1 is C 6-10 Aryl; C 3-7 cycloalkyl; C 1-3 Halogenated alkyl; C 1-3 Alkyl groups and 5-10-membered heteroaryl groups having 1-3 cyclic heteroatoms, wherein the cyclic heteroatoms are independently selected from N, O, and S; wherein the C 6-10 Aryl, C 3-7 cycloalkyl, C 1-3 Each of the haloalkyl and 5-10 heteroaryl groups is optionally represented by one, two, or three independently selected R groups. 30Group substitution;

[0035] Each R 30 Independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl groups, C groups optionally substituted with halogens 1-3 Alkyl and hydroxyl groups;

[0036] Or its stereoisomers, solvates, tautomers or pharmaceutically acceptable salts.

[0037] This disclosure further provides compounds as follows:

[0038] 1.1 Compound 1, wherein G1 is an optionally substituted C 6-10 Aryl;

[0039] 1.2 Compound 1, wherein G1 is a phenyl group that has been optionally substituted;

[0040] 1.3 Compound 1, wherein G1 is a optionally substituted pyridinyl group;

[0041] 1.4 Compound 1, wherein G1 is an optionally substituted C 3-6 cycloalkyl;

[0042] 1.5 Compound 1, wherein G1 is a optionally substituted cyclopropyl or cyclohexyl group;

[0043] 1.6 Compound 1, wherein G1 is a phenyl group optionally having one or two substituents;

[0044] 1.7 Compound 1, wherein G1 is a phenyl group optionally having one or two substituents;

[0045] 1.8 Compound 1, wherein G1 is a phenyl group substituted at the 3-position;

[0046] 1.9 Compound 1, wherein G1 is a phenyl group substituted at the 3- and 5-positions;

[0047] 1.10 Compound 1, wherein G1 is a phenyl group substituted at the 2- and 5-positions;

[0048] 1.11 Compound 1, wherein G1 is a phenyl group substituted at the 2- and 4-positions;

[0049] 1.12 Compound 1, wherein G1 is a phenyl group substituted at the 2- and 3-positions;

[0050] 1.13 Compound 1, wherein G1 is a phenyl group substituted at the 3- and 4-positions;

[0051] 1.14 Any one of the aforementioned compounds, wherein each R 30It is independently selected from mono, di, or trihalomethyl, fluorine, chlorine, methoxy, cyano, and methyl;

[0052] 1.15 Any one of the aforementioned compounds, wherein each R 30 It is independently selected from difluoromethyl, trifluoromethyl, fluorine, chlorine, methoxy, cyano, and methyl;

[0053] 1.16 Any one of the aforementioned compounds, wherein each R 30 Independently selected from fluorine and chlorine;

[0054] 1.17 Any one of the aforementioned compounds, wherein each R 30 It is fluorine;

[0055] 1.18 Compound 1, where G1 is C 1-3 Halogenated alkyl groups;

[0056] 1.19 Compound 1, wherein G1 is a trifluoromethyl group;

[0057] 1.20 Any one of the aforementioned compounds, where n is 1;

[0058] 1.21 Any one of the aforementioned compounds, where n is 2;

[0059] 1.22 Any one of the aforementioned compounds, wherein m, k, and q are each 1;

[0060] 1.23 Any one of the aforementioned compounds, where q and m are each 1, and k is 0;

[0061] 1.24 Any one of the aforementioned compounds, where m is 0; and k and q are each 1;

[0062] 1.25 Any one of the aforementioned compounds, where k is 0; and m and q are each 1;

[0063] 1.26 Any of the aforementioned compounds, wherein R1 and R2 are each independently and optionally controlled by one to three R... 20 C with substituent group 1-3 alkyl;

[0064] 1.27 Any of the aforementioned compounds, wherein R1 and R2 are each independently and optionally controlled by one to three R... 20 C with substituent group 1-3 Alkyl, the R 20 The group is independently selected from hydroxyl, di- or tri-halomethyl, such as difluoromethyl or trifluoromethyl, methoxy, halogen and cyano;

[0065] 1.28 Any one of the aforementioned compounds, wherein R1 is H or C. 1-3Alkyl group, and R2 is a heterocyclic ring selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, wherein each is optionally substituted by 1, 2, or 3 groups selected from hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups, cyano groups, and halogens;

[0066] 1.29 Any of the aforementioned compounds, wherein R1 is H or C. 1-3 Alkyl, and R2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine and tetrahydropyran, wherein each is optionally substituted by 1, 2 or 3 groups selected from hydroxyl, methyl, hydroxymethyl, hydroxyethyl, methoxy, di or trihalomethyl, such as difluoromethyl or trifluoromethyl, cyano and halogen;

[0067] 1.30 Any one of the aforementioned compounds, wherein R1 is H or C. 1-3 Alkyl group, and R2 is selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, tetrahydropyran, and C. 3-6 Cycloalkyl cyclic substitution C 1-3 Alkyl groups, each of which is optionally substituted with one, two or three groups selected from hydroxyl, methyl, hydroxymethyl, hydroxyethyl, methoxy, di or trihalomethyl, such as difluoromethyl or trifluoromethyl, cyano and halogen;

[0068] 1.31 Any of the preceding compounds, wherein R1 and R2, together with the nitrogen atom to which they are attached, form a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, wherein each is optionally substituted by one, two, or three groups selected from hydroxyl, C... 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups, cyano groups, and halogens;

[0069] 1.32 Any one of the preceding compounds, wherein the compound is selected from the compounds in Table 1 herein, or their stereoisomers, solvates, tautomers or pharmaceutically acceptable salts.

[0070] According to this disclosure, a topical or oral composition [Composition 1] is also provided, comprising a MrgprX2 antagonist and a dermatologically or orally acceptable excipient. In some embodiments, the MrgprX2 antagonist is compound I having the above formula I.

[0071] This disclosure further provides the following compositions:

[0072] 1.1 Composition 1, wherein the MrgprX2 antagonist is compound I having the above formula I;

[0073] 1.2 Composition 1, wherein G1 is optionally substituted C 6-10 Aryl;

[0074] 1.3 Composition 1, wherein G1 is a optionally substituted phenyl group;

[0075] 1.4 Composition 1, wherein G1 is a optionally substituted pyridinyl group;

[0076] 1.5 Composition 1, wherein G1 is optionally substituted C 3-6 cycloalkyl;

[0077] 1.6 Composition 1, wherein G1 is optionally substituted cyclopropyl or cyclohexyl;

[0078] 1.7 Composition 1, wherein G1 is a phenyl group having one or two substituents;

[0079] 1.8 Composition 1, wherein G1 is a phenyl group having one or two substituents;

[0080] 1.9 Composition 1, wherein G1 is a 3-substituted phenyl group;

[0081] 1.10 Composition 1, wherein G1 is a phenyl group substituted at the 3- and 5-positions;

[0082] 1.11 Composition 1, wherein G1 is a phenyl group substituted at the 2- and 5-positions;

[0083] 1.12 Composition 1, wherein G1 is a phenyl group substituted at the 2- and 4-positions;

[0084] 1.13 Composition 1, wherein G1 is a phenyl group substituted at the 2- and 3-positions;

[0085] 1.14 Composition 1, wherein G1 is a phenyl group substituted at the 3- and 4-positions;

[0086] 1.15 Any one of the foregoing compositions, wherein each R 30 It is independently selected from mono, di, or trihalomethyl, fluorine, chlorine, methoxy, cyano, and methyl;

[0087] 1.16 Any of the foregoing compositions, wherein each R 30 It is independently selected from difluoromethyl, trifluoromethyl, fluorine, chlorine, methoxy, cyano, and methyl;

[0088] 1.17 Any of the foregoing compositions, wherein each R 30 Independently selected from fluorine and chlorine;

[0089] 1.18 Any of the foregoing compositions, wherein each R 30 It is fluorine;

[0090] 1.19 Composition 1, wherein G1 is C 1-3 Halogenated alkyl groups;

[0091] 1.20 Composition 1, wherein G1 is trifluoromethyl;

[0092] 1.21 Any one of the aforementioned compositions, wherein n is 1;

[0093] 1.22 Any one of the aforementioned compositions, wherein n is 2;

[0094] 1.23 Any one of the aforementioned compositions, wherein m, k, and q are each 1;

[0095] 1.24 Any of the aforementioned compositions, wherein q and m are each 1, and k is 0;

[0096] 1.25 Any one of the aforementioned compositions, wherein m is 0; and k and q are each 1;

[0097] 1.26 Any one of the aforementioned compositions, wherein k is 0; and m and q are each 1;

[0098] 1.27 Any of the foregoing compositions, wherein R1 and R2 are each independently and optionally controlled by 1 to 3 R... 20 C with substituent group 1-3 alkyl;

[0099] 1.28 Any of the foregoing compositions, wherein R1 and R2 are each independently and optionally constituted by 1 to 3 R... 20 C with substituent group 1-3 Alkyl, the R 20 The group is independently selected from hydroxyl, di- or tri-halomethyl, such as difluoromethyl or trifluoromethyl, methoxy, halogen and cyano;

[0100] 1.29 Any of the foregoing compositions, wherein R1 is H or C 1-3 Alkyl group, and R2 is a heterocyclic ring selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, wherein each is optionally substituted by 1, 2, or 3 groups selected from hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups, cyano groups, and halogens;

[0101] 1.30 Any of the foregoing compositions, wherein R1 is H or C 1-3Alkyl, and R2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine and tetrahydropyran, wherein each is optionally substituted by 1, 2 or 3 groups selected from hydroxyl, methyl, hydroxymethyl, hydroxyethyl, methoxy, di or trihalomethyl, such as difluoromethyl or trifluoromethyl, cyano and halogen;

[0102] 1.31 Any of the foregoing compositions, wherein R1 is H or C 1-3 Alkyl group, and R2 is selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, tetrahydropyran, and C. 3-6 Cycloalkyl cyclic substitution C 1-3 Alkyl groups, each of which is optionally substituted with one, two or three groups selected from hydroxyl, methyl, hydroxymethyl, hydroxyethyl, methoxy, di or trihalomethyl, such as difluoromethyl or trifluoromethyl, cyano and halogen;

[0103] 1.32 Any of the foregoing compositions, wherein R1 and R2, together with the nitrogen atom to which they are attached, form a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, wherein each is optionally substituted by one, two, or three groups selected from hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups, cyano groups, and halogens;

[0104] 1.33 Any one of the preceding compounds, wherein the compound is selected from the compounds in Table 1 herein, or their stereoisomers, solvates, tautomers or pharmaceutically acceptable salts.

[0105] 1.34 Any of the foregoing compositions, wherein the composition is an oral dosage form.

[0106] 1.35 Any of the foregoing compositions, wherein the composition is in the form of a cream, gel, spray or ointment.

[0107] 1.36 Any of the foregoing compositions, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.% based on the total weight of the composition.

[0108] 1.37 Any of the foregoing compositions, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.% based on the total weight of the composition.

[0109] 1.38 Any of the foregoing compositions, further comprising a skin absorption enhancer.

[0110] 1.39 Any of the foregoing compositions further comprises a skin absorption enhancer, said skin absorption enhancer comprising one or more of the following: mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., lauryl azone), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexanediol, polyethylene glycol, diethylene glycol), surfactants (also commonly found in dosage forms), and terpenes.

[0111] 1.40 Any of the foregoing compositions, wherein the composition is applied to the patient’s skin once daily.

[0112] 1.41 Any of the foregoing compositions, wherein the composition is applied to the patient’s skin twice daily.

[0113] 1.42 Any of the foregoing compositions, wherein the composition is applied to the patient’s skin three times a day.

[0114] 1.43 Any of the foregoing compositions, wherein the composition is applied to a patient suffering from an inflammatory condition.

[0115] 1.44 The aforementioned composition, wherein the inflammatory condition is a skin condition.

[0116] 1.45 The aforementioned composition, wherein the skin is human skin.

[0117] 1.46 Composition 1.64-1.66, wherein the inflammatory condition activates MrgprX2 or is caused by the activation of MrgprX2.

[0118] 1.47 The aforementioned composition, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudohyperallergic reactions triggered by small molecules, such as allergy-like drug reactions, anaphylactic shock, erythematosus acne, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

[0119] 1.48 Composition 1.63-1.67, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0120] 1.49 Any one of compositions 1.63-1.66, wherein the inflammatory condition is atopic dermatitis.

[0121] 1.50 Any of the foregoing compositions, wherein the subject is a human being.

[0122] 1.51 Any of the foregoing compositions, wherein the mammalian skin is human skin.

[0123] 1.52 Any of the foregoing compositions, wherein the composition is for oral administration.

[0124] As used herein, "topical composition" refers to formulations of the compounds of the present invention and of media generally accepted in the art for delivering bioactive compounds to mammalian skin, such as human skin. Such media include all dermatologically acceptable carriers, diluents, or excipients.

[0125] "Stereoisomers" are compounds formed by identical atoms bonded by identical bonds, but with different, non-interchangeable, three-dimensional structures. This invention considers various stereoisomers and mixtures thereof and includes "enantiomers," which are two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0126] A solvate is a form of compound formed by the complexation of solvent molecules.

[0127] "Tautomers" refer to two molecules that are structural isomers that can easily interconvert.

[0128] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts.

[0129] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, are not undesirable in biological or other respects, and are formed with inorganic and organic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and such organic acids as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2 Hydroxyethanesulfonic acid, formic acid, fumaric acid, galactosic acid, gentian acid, glucoheponic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

[0130] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not undesirable in biological or other respects. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzylamine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0131] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers, which may be defined in absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present invention aims to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers involve chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC).

[0132] "Dermatologically acceptable excipients" include, but are not limited to, any adjuvant, carrier, medium, excipient, flow aid, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, including those approved by the U.S. Food and Drug Administration for use in human or animal dermatological purposes, or those known for use or suitable for use in dermatological compositions.

[0133] "Optional" or "optionally" means that the situation or event described below may or may not occur, and the description includes instances where the event or situation occurs and instances where it does not occur. When a functional group is described as "optionally substituted," and subsequently the substituents on the functional group are also "optionally substituted," etc., such iterations are limited to three times for the purposes of this invention.

[0134] The term "alkyl" is intended to denote a straight-chain or branched carbon radical containing the indicated number of carbon atoms. Some examples contain 1 to 5 carbons. Some examples contain 1 to 4 carbons. Some examples contain 1 to 3 carbons. Some examples contain 1 to 2 carbons. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, etc.

[0135] The term "cycloalkyl" is intended to denote a saturated cyclic radical containing the indicated number of carbon atoms. Some examples contain 3 to 6 carbons. Some examples contain 3 to 5 carbons. Some examples contain 5 to 7 carbons. Some examples contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0136] The term "haloalkyl" is intended to represent a radical comprising an alkyl group having the indicated number of carbon atoms, which is substituted with one or more halogens. For example, C1-C6 haloalkyl groups can be fully substituted, in which case it can be derived from the formula C n L 2n+1 The term "halogenated alkyl group" indicates that L is a halogen and n is 1, 2, 3, 4, 5, or 6. When more than one halogen is present, they may be the same or different and are selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the alkyl group contains 1 to 5 carbons. In some embodiments, the alkyl group contains 1 to 4 carbons. In some embodiments, the alkyl group contains 1 to 3 carbons. In some embodiments, the alkyl group contains 1 or 2 carbons. Examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, etc. When used without a prefix indicating the number of halogen substituents, the "alkyl group" contains 1, 2, or 3 halogen atoms.

[0137] The term "hydroxyalkyl" is intended to represent a free radical comprising an alkyl group having the indicated number of carbon atoms, which is substituted with one or more hydroxyl (i.e., -OH) groups. When used without a prefix indicating the number of hydroxyl substituents, the "hydroxyalkyl" group contains one, two, or three hydroxyl groups.

[0138] The term "halogen" is intended to refer to fluorine, chlorine, bromine, or iodine groups.

[0139] The term "aryl" is intended to denote a ring system containing 6 to 10 carbon atoms, which may contain a single ring or two fused rings, and at least one of the rings is aromatic. Examples include phenyl, indanyl, and naphthyl.

[0140] The term "heteroaryl" is intended to denote a ring system containing 5 to 14 ring atoms, which may contain a single ring, two fused rings, or three fused rings, wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected, for example, from O, S, and N. Some embodiments contain 5 to 6 ring atoms, such as furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc. Some embodiments contain 8 to 14 ring atoms, such as quinazinyl, quinolinyl, isoquinolinyl, cyclolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indoleyl, isoindoleyl, indazoleyl, indazinyl, purineyl, naphridinyl, pteridinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridyl, benzothiophenyl, benzofuranyl, isobenzofuran, 2,3-di Hydrobenzofuranyl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-isoquinolinyl, 1,4,6,7-tetrahydro-imidazo[1,5-c]pyridyl, 7,8-dihydro-5H-[1,6]naphthyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxacyclopentenyl, pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, etc.

[0141] The term "cyano" refers to the -CN group.

[0142] The term "alkoxy" refers to a group of the formula -O-alkyl having the indicated number of carbon atoms.

[0143] As used herein, the term "heterocyclic alkyl" is intended to denote a non-aromatic 3-6-membered heterocycle optionally fused to a 3-6 membered saturated, partially unsaturated, or aromatic aryl or heteroaryl ring. Examples of non-aromatic 3-6-membered heterocycles include oxetane, acridine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyran, morpholine, piperazine, hexahydropyrimidine, hexahydropyridazine, etc. Heterocyclic alkyl groups may contain one or more oxo (i.e., -C=O-) groups within the ring, and the thiocyclic heteroatom may be present as a thiodione. Examples of such heterocyclic alkyl rings include sulfolane, tetrahydro-2H-thiaran-1,1,-dione, thiomorpholine 1,1-dioxide, 2-pyrrolidone, piperidin-2-one, piperazine-2-one, morpholino-3-one, etc. Examples of heterocyclic alkyl groups having fused rings include dihydroindole, such as 1,3-dihydroindole.

[0144] The term "spiroalkyl" is intended to denote a structure of two or more rings, wherein two rings share a common atom, and wherein at least one ring is a cycloalkyl ring containing the indicated number of carbon atoms. Examples include spirocyclopropane and spirocyclobutane.

[0145] Methods using the compounds of the present invention

[0146] The compounds of the present invention can be used to treat inflammatory conditions such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudohypersensory reactions triggered by small molecules, such as allergic drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, and adverse drug reactions. Therefore, the administration or use of preferred MrgprX2 antagonists as described herein, such as the MrgprX2 antagonists described above, such as compounds of formula I, provides a means of improving the symptoms of various inflammatory diseases and conditions and / or treating various inflammatory diseases and conditions.

[0147] For example, in one embodiment, this disclosure provides a method for treating an inflammatory condition [method 1], the method comprising administering a topical or oral composition to a subject in need, the topical or oral composition comprising a therapeutically effective amount of a MrgprX2 antagonist (e.g., a MrgprX2 antagonist according to this disclosure); and a dermatologically or orally acceptable excipient.

[0148] This disclosure further provides additional embodiments of method 1 as follows:

[0149] 1.1 Method 1, wherein the MrgprX2 antagonist is a compound according to Formula I above;

[0150] 1.2 Method 1.1, wherein the MrgprX2 antagonist is a compound according to any one of compounds 1.1-1.55 above;

[0151] 1.3 Any of the foregoing methods, wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 of this document, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof;

[0152] 1.4 Any of the foregoing methods, wherein the composition is in the form of a cream, gel, spray or ointment.

[0153] 1.5 Any of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.% based on the total weight of the composition.

[0154] 1.6 Any of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.% based on the total weight of the composition.

[0155] 1.7 Any of the foregoing methods, further comprising a skin absorption enhancer.

[0156] 1.8 Any of the foregoing methods further includes a skin absorption enhancer, said skin absorption enhancer comprising one or more of the following: mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., lauryl azone), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexanediol, polyethylene glycol, diethylene glycol), surfactants (also commonly found in dosage forms), and terpenes.

[0157] 1.9 Any of the foregoing methods, wherein the composition is applied to the patient's skin once daily.

[0158] 1.10 Any of the foregoing methods, wherein the composition is applied to the patient's skin twice daily.

[0159] 1.11 Any of the foregoing methods, wherein the composition is applied to the patient’s skin three times a day.

[0160] 1.12 Any of the foregoing methods, wherein the composition is applied to a patient suffering from an inflammatory condition.

[0161] 1.13 The aforementioned method, wherein the inflammatory condition is a skin condition.

[0162] 1.14 The aforementioned method, wherein the skin is human skin.

[0163] 1.15 Any of methods 1.12-1.14, wherein the inflammatory condition activates MrgprX2 or is caused by the activation of MrgprX2.

[0164] 1.16 The aforementioned method, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as allergy-like drug reactions, anaphylactic shock, erythematosus acne, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

[0165] 1.17 Any one of methods 1.12-1.16, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0166] 1.18 Any one of methods 1.12-1.16, wherein the inflammatory condition is atopic dermatitis.

[0167] 1.19 Any of the foregoing methods, wherein the subject is a human being.

[0168] 1.20 Any of the foregoing methods, wherein the mammalian skin is human skin.

[0169] 1.21 Any of the foregoing methods, wherein the composition is for oral administration.

[0170] In another embodiment, this disclosure provides a method [method 2] for reducing inflammation of mammalian skin, the method comprising administering an effective amount of a topical or oral composition to a subject in need of the mammalian skin, the topical or oral composition comprising a MrgprX2 antagonist according to this disclosure and a dermatologically acceptable excipient.

[0171] This disclosure further provides additional embodiments of method 2 as follows:

[0172] 2.1 Method 2, wherein the MrgprX2 antagonist is a compound according to Formula I above;

[0173] 2.2 Method 2 or 2.1, wherein the MrgprX2 antagonist is a compound according to any one of compounds 1.1-1.55 above;

[0174] 2.3 Any of the foregoing methods, wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 of this document, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof;

[0175] 2.4 Any of the foregoing methods, wherein the inflammation is caused by activation of MrgprX2;

[0176] 2.5 Any of the foregoing methods, wherein the composition is in the form of a cream, gel, spray or ointment.

[0177] 2.6 Any of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.% based on the total weight of the composition.

[0178] 2.7 Any of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.% based on the total weight of the composition.

[0179] 2.8 Any of the foregoing methods, further comprising a skin absorption enhancer.

[0180] 2.9 Any of the foregoing methods further includes a skin absorption enhancer, said skin absorption enhancer comprising one or more of the following: mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., lauryl azone), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexanediol, polyethylene glycol, diethylene glycol), surfactants (also commonly found in dosage forms), and terpenes.

[0181] 2.10 Any of the foregoing methods, wherein the composition is applied to the patient's skin once daily.

[0182] 2.11 Any of the foregoing methods, wherein the composition is applied to the patient's skin twice daily.

[0183] 2.12 Any of the foregoing methods, wherein the composition is applied to the patient’s skin three times a day.

[0184] 2.13 Any of the foregoing methods, wherein the composition is applied to a patient suffering from an inflammatory condition.

[0185] 2.14 The aforementioned method, wherein the inflammatory condition is a skin condition.

[0186] 2.15 The aforementioned method, wherein the skin is human skin.

[0187] 2.16 Any of methods 1.12-1.14, wherein the inflammatory condition activates MrgprX2 or is caused by the activation of MrgprX2.

[0188] 2.17 The aforementioned method, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as allergy-like drug reactions, anaphylactic shock, erythematosus acne, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

[0189] 2.18 Any one of methods 1.12-1.16, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0190] 2.19 Any one of methods 1.12-1.16, wherein the inflammatory condition is atopic dermatitis.

[0191] 2.20 Any of the foregoing methods, wherein the subject is a human being.

[0192] 2.21 Any of the foregoing methods, wherein the mammalian skin is human skin.

[0193] 2.22 Any of the foregoing methods, wherein the composition is for oral administration.

[0194] Another embodiment provides a method [method 3] for reducing the incidence or severity of pruritus in subjects in need, the method comprising applying a therapeutically effective amount of the topical or oral composition according to any one of compositions 1 and 1.1-1.73 to mammalian skin.

[0195] This disclosure further provides additional embodiments of method 3 as follows:

[0196] 3.1 Method 3, in which the severity of itching is reduced within 5 minutes of application.

[0197] 3.2 Method 3 or 3.1, wherein the severity of itching is reduced within 6 hours after application.

[0198] 3.3 Method 3 or 3.1, wherein the severity of itching is reduced within 12 hours after application.

[0199] 3.4 Method 3 or 3.1, wherein the severity of itching is reduced within 18 hours after application.

[0200] 3.5 Method 3 or 3.1, wherein the severity of itching is reduced within 24 hours after application.

[0201] 3.6 Any of the foregoing methods, wherein the MgrprX2 antagonist is a compound selected from the compounds listed in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0202] 3.7 Any of the foregoing methods, wherein the composition is in the form of a cream, gel, spray or ointment.

[0203] 3.8 Any of the foregoing methods, wherein the McGrprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.% based on the total weight of the composition.

[0204] 3.9 Any of the foregoing methods, wherein the McGrprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.% based on the total weight of the composition.

[0205] 3.10 Any of the foregoing methods, further comprising a skin absorption enhancer.

[0206] 3.11 The aforementioned method, wherein the skin absorption enhancer comprises one or more of the following: mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., lauryl azone), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexanediol, polyethylene glycol, diethylene glycol), surfactants (also commonly found in dosage forms), and terpenes.

[0207] 3.12 Any of the foregoing methods, wherein the composition is applied to the patient’s skin once daily.

[0208] 3.13 Any of the foregoing methods, wherein the composition is applied to the patient’s skin twice daily.

[0209] 3.14 Any of the foregoing methods, wherein the composition is applied to the patient’s skin three times a day.

[0210] 3.15 Any of the foregoing methods, wherein the composition is applied to a patient suffering from an inflammatory condition.

[0211] 3.16 Any of the foregoing methods, wherein the inflammatory condition is a skin condition.

[0212] 3.17 Any of the foregoing methods, wherein the skin is human skin.

[0213] 3.18 Any one of methods 1.12-1.14, wherein the inflammatory condition activates MrgprX2 or is caused by the activation of MrgprX2.

[0214] 3.19 The aforementioned method, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as allergy-like drug reactions, anaphylactic shock, erythematosus acne, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

[0215] 3.20 Any one of methods 1.12-1.16, wherein the inflammatory condition is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0216] 3.21 Any one of methods 1.12-1.16, wherein the inflammatory condition is atopic dermatitis.

[0217] 3.22 Any of the foregoing methods, wherein the subject is a human being.

[0218] 3.23 Any of the foregoing methods, wherein the mammalian skin is human skin.

[0219] 3.24 Any of the foregoing methods, wherein the composition is for oral administration.

[0220] Atopic dermatitis is a skin condition involving chronic inflammation, and its symptoms include red, itchy rashes. Atopic dermatitis can occur on any part of the body, but it is most common on the hands, feet, upper chest, and elbows or the creases of the knees. Other symptoms may include small raised bumps or thickened, scaly skin.

[0221] Psoriasis is a chronic skin condition associated with an overactive immune response. It can occur on the skin anywhere on the body. Symptoms include localized inflammation, peeling skin, and thick, white or red plaques.

[0222] Hair loss is an autoimmune skin disease that causes hair loss on the scalp, face, and sometimes other parts of the body. For example, in alopecia areata, T-cell lymphocytes accumulate around the affected hair follicles, leading to inflammation and subsequent hair loss.

[0223] Chronic urticaria (urticaria) is a common skin rash triggered by a variety of factors, including certain foods, medications, and stress. Symptoms may include itching, raised bumps, redness, or skin-colored swellings on the skin surface. Given the role of mast cells in chronic idiopathic urticaria, MrgprX2 plays a crucial role in mast cell activation. Human MrgprX2 is activated by antibacterial host defense peptides, neuropeptides, major basic proteins, eosinophil peroxidase, and some FDA-approved peptidergic drugs. Unique characteristics that distinguish MrgprX2 from other GPCRs include their presence at plasma membrane and intracellular sites and their selective expression in mast cells (MCs). Furthermore, small molecule inhibitors of MrgprX2 may be beneficial in treating MC-dependent allergic and inflammatory conditions, such as chronic urticaria currently treated by targeting the IgE axis of mast cell activity. However, many MC activities depend on ligand binding to MrgprX2 (Subramanian H et al., 2016, The Journal of Allergy and Clinical Immunology, 138(3), 700-710; https: / / doi.org / ). 10.1016 / j.jaci.2016.04.051This suggests that targeting MRGPRX2 may indeed be a treatment option for IgE-independent and drug-resistant chronic urticaria.

[0224] Anaphylactic shock is an extreme, often life-threatening, allergic reaction to an antigen to which the body is already highly sensitive. Activation of mast cells via MrgprB2 has attracted attention due to its IgE-independent mast cell activation and nonhistaminergic pruritus (Meixiong J. et al., 2019, *Immunity*, 50(5), 1163-1171.e5. https: / / doi.org / 10.1016 / j.immuni.2019.03.013 Activation of MrgprB2 by N-terminal peptide 9-20 (PAMP9-20), a precursor of adrenal medullaris, induced the release of multiple bioactive mediators from mast cells, subsequently activating pruritus-sensitive neurons, indicating that mast cell-specific MrgprB2 is key to mast cell degranulation and associated nonhistaminergic pruritus. Mast cell MrgprB2 and MrgrpX2 were activated by SP, compound 48 / 80, and pseudohypersensitive drugs such as atebandel (McNeil, BD et al., 2015, *Nature*, 519(7542), 237-241; https: / / doi.org / 10.1038 / nature14022 This places MrgprX2 at the center of nonhistamine mast cell activation and various allergic and non-allergic diseases, as well as pseudo-allergic reactions.

[0225] "Rhodopsin" is a condition that causes facial redness, typically presenting as small, red, pus-filled lumps. MrgrpX2 is also identified as a receptor for endogenous host defense peptides, including cathelicidin (LL-37) and β-defensin (Subramanian, H. et al., 2011, The Journal of Biological Chemistry, 286(52), 44739-44749; https: / / doi.org / ). 10.1074 / jbc.M111.277152 With Subramanian, H. et al., 2013, *Journal of Immunology* (Baltimore, Md.: 1950), 191(1), 345-352; https: / / doi.org / 10.4049 / jimmunol.1300023This increases the likelihood that MrgprX2 in mast cells will participate in antibacterial host defense. Pituitary adenylate cyclase activating peptide (PACAP), an effective mast cell degranulation agent (Baun, M. et al., 2012, *Cephalalgia: An International Journal of Headache*, 32(4), 337-345; https: / / doi.org / 10.1177 / 0333102412439354 and Seebeck, J. et al., 1998, *Annals of the New York Academy of Sciences*, 865, 141-146. https: / / doi.org / 10.1111 / j.1749- 6632.1998.tb11172.x ), has been shown to activate MrgprX2 (Tatemoto K. et al., 2006, Biochemical and Biophysical Research Communications, 349(4), 1322-1328; https: / / doi.org / 10.1016 / j.bbrc.2006.08.177; and McNeil, BD et al., 2015, Nature, 519(7542), 237-241; https: / / doi.org / 10.1038 / nature14022 These findings suggest that MrgprX2 may also play a role in innate immunity by modulating the host defense response. Given that MrgprX2 is activated by peptides such as LL-37 and the neuropeptide PACAP, both of which are closely associated with rosacea and act as triggering peptides to influence mast cell activity and vasodilation, these results collectively indicate that MrgprX2 is an emerging receptor in the pathophysiology of rosacea.

[0226] Asthma is a condition characterized by inflammation, narrowing, and swelling of the airways, leading to excessive mucus production and difficulty breathing. Mast cells (MCs), which are important effector cells of airway hyperresponsiveness and inflammation, are also present near smooth muscle cells, T cells, and leukocytes, and are key features of asthma. Even in healthy individuals with low levels of transcripts, the level of MrgprX2 transcripts is increased in severe asthma, characterized by a phenotypic shift from MCTs to MCTCs. Compared to MCTs, the mast cell MCTC population in severe asthma is expressing MrgprX2 (Fajt ML et al., 2013; The Journal of Allergy and Clinical Immunology, 131(6), 1504-1512; https: / / doi.org / 10.1016 / j.jaci.2013.01.035 and Balzar, S. et al., 2011, *American Journal of Respiratory and Critical Care Medicine*, 183(3), 299-309; https: / / doi.org / 10.1164 / rccm.201002-0295OC Given the increased SP levels in the lungs of patients with severe asthma who activate MrgprX2, treatment with small molecule antagonists would be beneficial for patients with severe asthma (van Diest, SA. et al., 2012, *Biochimica et Biophysica Acta*, 1822(1), 74-84; https: / / doi.org / ). 10.1016 / i.bbadis.2011.03.019 ).

[0227] "Mammal / mammalian" includes humans, as well as livestock such as laboratory animals and pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-livestock animals such as wild animals.

[0228] "Therapeutic effective amount" refers to the amount of the compound of the present invention that, when applied to a mammal, preferably a human, is sufficient to treat the target disease or symptom in that mammal, preferably a human. The amount of the compound of the present invention constituting a "therapeutic effective amount" will vary depending on the compound, the disease or symptom and its severity, the method of administration, and the age of the mammal to be treated, but can be conventionally determined by one of ordinary skill in the art after taking into account his or her knowledge and this disclosure. Preferably, for the purposes of the present invention, a "therapeutic effective amount" is the amount of the compound of the present invention sufficient to inhibit skin inflammation.

[0229] As used herein, “treating / treatment” encompasses the treatment of a target disease or symptom in mammals, preferably humans, and includes:

[0230] (i) To prevent the occurrence of the disease or condition in the mammal;

[0231] (ii) Inhibit the disease or symptom in the mammal, i.e., prevent its development;

[0232] (iii) Alleviating the disease or symptom in the mammal, even if the disease or symptom subsides; or

[0233] (iv) Alleviating the symptoms of the disease or condition in the mammal, i.e., alleviating the symptoms without addressing the underlying disease or condition.

[0234] As used in this article, the terms “disease,” “symptom,” and “symptom” may be used interchangeably or may be different because the causative agent of a particular disease or symptom may not yet be known (and therefore the cause is not yet determined), and therefore it is not yet considered a disease, but rather an undesirable symptom or syndrome in which a clinician has identified a more or less specific set of symptoms.

[0235] In this specification, unless otherwise indicated, the term "about" means ±20% of the indicated range, value, or structure.

[0236] In some embodiments, the MrgprX2 antagonist (e.g., the MrgprX2 antagonist according to this disclosure) is present in the topical or oral composition at a concentration of about 0.05% by weight to about 5% by weight.

[0237] In some embodiments, the pharmaceutical compositions described herein further comprise dermatologically acceptable excipients. Dermatologically acceptable excipients may be one or more solvents that dissolve and / or stabilize the active ingredient contained therein (e.g., a MrgprX2 antagonist). Dermatologically acceptable excipients may also comprise skin penetration enhancers, preservatives, thickeners, pH adjusters, film-forming agents, etc. Non-limiting examples of suitable excipients include water, PEG 200, PEG 400, ethanol, glycerin, Transcutol P (diethylene glycol monoethyl ether), propylene glycol, 1,3-dimethyl-2-imidazolinone (DMI), sodium metabisulfite, butylated hydroxytoluene (BHT), benzyl alcohol, sodium benzoate, isopropyl myristate, diisopropyl adipate, crodamolOHS (ethylhexyl hydroxystearate), mineral oil, Betadex, TWEEN 20, Brij S20 (polyoxyethylene (20) stearate ether).

[0238] The following describes some suitable excipients in more detail. As you will understand, the components of the pharmaceutical formulations described herein can have multiple functions. For example, a given substance can be used as both a thickener and an emulsifier.

[0239] The skin (especially the stratum corneum) provides a physical barrier against harmful effects from the external environment. In doing so, it can also interfere with the absorption or transdermal delivery of topical therapeutic agents. Therefore, suitable dermatologically acceptable excipients may contain one or more penetration enhancers (or permeation promoters), which are substances that facilitate the diffusion of therapeutic agents (e.g., the MrgprX2 antagonist described herein) across the skin barrier. They typically function to reduce skin impedance or resistance, thereby improving the penetration of therapeutic agents. In particular, substances that disrupt the normal structure of the stratum corneum can damage the intercellular lipid tissue, thereby reducing its effectiveness as a barrier. These substances may include any lipid material that directly affects the stratum corneum by breaking it down into lipids, or any material that indirectly perturbs proteins and causes lipid structure. Furthermore, solvents such as ethanol can remove lipids from the stratum corneum, thereby disrupting its lipid tissue and impairing its barrier function.

[0240] Examples of penetration enhancers or barrier disruptors include, but are not limited to, alcohol-based enhancers, such as alkanols having 1 to 16 carbon atoms, benzyl alcohol, butanediol, diethylene glycol, tetraethylene glycol, glycerides, glycerin / glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based enhancers, such as N-butyl-N-dodecylacetamide, clomiphene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, and urea; amino acids, such as L-α-amino acids and water-soluble proteins; azones and azone-like compounds, such as azacycloalkanes; and essential oils, such as almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, and castor oil. Sesame oil, 1-carvone, coconut oil, corn oil, cottonseed oil, eugenol, menthol, anise oil, clove oil, orange oil, peanut oil, peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil (squalene), soybean oil, sunflower oil, and walnut oil; vitamins and herbs, such as aloe vera, allantoin, black walnut extract, chamomile extract, panthenol, papain, tocopherol, and vitamin A palmitate; waxes, such as candelilla wax, carnauba wax, ceresin, beeswax, lanolin wax, jojoba oil, and petrolatum; mixtures, such as fractionated vegetable oil fatty acids with primary esters of glycerol or propylene glycol and transesterified medium-chain triglyceride oils; fatty acids and fatty acid esters, such as amyl hexanoate, butyl acetate, caprylic acid, and cetyl ester. Diethyl sebacate, dioctyl malate, ethyl octyl transoleate, ethylene palmitoyl stearate, glyceryl behenate, glucosamine glutamate, isobutyl acetate, lauryl ether-4, lauric acid, malic acid, methyl decanoate, mineral oil, myristic acid, oleic acid, palmitic acid, PEG fatty acid esters, polyoxyethylene sorbitan monooleate, polypropylene glycol, propylene glycol, sucrose distearate, salicylic acid, sodium citrate, stearic acid, soaps and hexanoic acid, caprylic acid, capric acid and lauric acid triglycerides; macrocyclic compounds, such as butylated hydroxyanisole, cyclopentadecanolactone, cyclodextrin; phospholipids and phosphate promoters, such as dialkyl phosphate, tetradecyl phosphate, lecithin, 2-pyrrolidone derivatives, for example... Examples of such agents include pyrrolidone-5-carboxylic acid alkyl esters, pyroglutamic acid esters, N-methylpyrrolidone, biodegradable soft penetration enhancers such as dioxane derivatives and dioxonane derivatives; sulfoxide enhancers such as dimethyl sulfoxide and decyl methyl sulfoxide; acid enhancers such as alginic acid, sorbic acid, and succinic acid; cyclic amines; imidazolinones; imidazoles; ketones such as acetone, polydimethylsiloxane, methyl ethyl ketone, and pentanedione; lanolin derivatives such as lanolin alcohol, PEG16 lanolin, and acetylated lanolin; oxazoline; oxazolinones; proline esters; pyrroles, urethanes; and surfactants such as nonylbenzene alcohol ethers, polysorbates, polyoxyenols, polyoxyenol fatty acid esters, sodium lauryl sulfate, and dehydrated sorbitan monostearate.

[0241] The topical compositions described herein typically contain one or more carriers, which preferably have a vapor pressure greater than or equal to 23.8 mm Hg at 25°C. Preferred concentration ranges for a single carrier or for the total concentration range of a combination of carriers can be from about 0.1 wt.% to about 10 wt.%, more preferably from about 10 wt.% to about 50 wt.%, and more specifically from about 50 wt.% to about 95 wt.% of the dermatological composition. Non-limiting examples of solvents include water (e.g., deionized water) and lower alcohols, including ethanol, 2-propanol, and n-propanol.

[0242] The dermatological compositions of the present invention may contain one or more hydrophilic cosolvents that are miscible with water and / or lower chain alcohols and preferably have a vapor pressure less than that of water (~23.8 mm Hg) at 25°C. The carrier typically has a vapor pressure greater than or equal to that of the hydrophilic cosolvent to concentrate the active ingredient (e.g., the MrgprX2 antagonist of this disclosure) on the skin. The hydrophilic cosolvent may be a glycol, particularly propylene glycol. Specifically, propylene glycol may be derived from polyethylene glycols, particularly those with a molecular weight range of 200 to 20,000. Preferably, the solvent will be a type of glycol ether. More specifically, the hydrophilic cosolvent of the present invention will be diethylene glycol monoethyl ether (Cabidol). As used herein, “diethylene glycol monoethyl ether” (“DGME”) or “Cabidol” refers to 2-(2-ethoxyethoxy)ethanol {CAS NO 001893} or ethoxydiethylene glycol. Another preferred cosolvent is 1,3-dimethyl-2-imidazolinone (DMI).

[0243] The topical compositions described herein may also contain one or more "humectants" for providing a wetting effect. Preferably, the humectant remains stable in the composition. Any suitable concentration of a single humectant or a combination of humectants may be used, provided that the resulting concentration provides the desired wetting effect. Typically, the suitable amount of humectant will depend on the specific humectant or humectant used. Preferred concentration ranges for a single humectant or for the total concentration range of a combination of humectants may be from about 0.1 wt.% to about 70 wt.%, more preferably from about 5.0 wt.% to about 30 wt.%, and more specifically from about 10 wt.% to about 25 wt.% of the dermatological composition. Non-limiting examples used herein include glycerin, polyols, and silicone oils. More preferably, the humectant is glycerin, propylene glycol, and / or cyclomethicone. Specifically, the filler will be glycerin and / or cyclomethicone.

[0244] In some embodiments, the pharmaceutical composition includes a thickener or emulsifier. A gelling agent is used to increase the viscosity of the final composition. An emulsifier is a substance that stabilizes an emulsion. A thickener can also be used as an emulsifier. Generally, the concentration and combination of thickeners will depend on the physical stability of the finished product. A preferred concentration range for thickeners can be from about 0.01 wt.% to about 20 wt.% of the dermatological composition, more preferably from about 0.1 wt.% to about 10 wt.%, and more specifically from about 0.5 wt.% to about 5 wt.%. Non-limiting examples of thickeners used herein include the classes of cellulose, acrylate polymers, and acrylate crosslinking polymers, such as hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, carbomer 980, carbomer 1342, and carbomer 940, more preferably hydroxypropyl cellulose, Pluronic PF127 carbomer 980, and carbomer 1342, and more specifically hydroxypropyl cellulose (…). EF, GF and / or HF), Pluronic PF127, Carbomer 980 and / or Carbomer 1342 ( TR-1, TR-2 and / or Examples of emulsifiers used herein include polysorbate, lauryl ether-4, and potassium hexadecyl sulfate. (ETD 2020)

[0245] The topical or oral compositions described herein may contain one or more antioxidants, free radical scavengers, and / or stabilizers, preferably in concentrations ranging from about 0.001 wt.% to about 0.1 wt.%, more preferably from about 0.1 wt.% to about 5 wt.% of the dermatological composition. Non-limiting examples used herein include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tococelen, and propyl gallate. More specifically, the antioxidant may be ascorbyl palmitate, vitamin E acetate, vitamin E-TPGS, vitamin E, or butylated hydroxytoluene.

[0246] The topical or oral compositions described herein may also contain preservatives exhibiting antibacterial and / or antifungal properties. Preservatives may be present in the gelled dermatological compositions of the present invention to minimize bacteria and / or fungi during their shelf life. A preferred concentration range of the preservative in the dermatological compositions of the present invention is from about 0.001 wt.% to about 0.01 wt.%, more preferably from about 0.01 wt.% to about 0.5 wt.%. Non-limiting examples used herein include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben. More specifically, the preservative is a combination of methylparaben and propylparaben.

[0247] The topical compositions described herein may optionally contain one or more chelating agents. As used herein, the term "chelating agent" refers to those skin-beneficial agents that can remove metal ions from the system by forming a complex, thereby preventing the metal ions from readily participating in or catalyzing chemical reactions. The chelating agents used herein are preferably formulated at a concentration of about 0.001 wt.% to about 10 wt.%, more preferably about 0.05 wt.% to about 5.0 wt.%, of the dermatological composition. Non-limiting examples used herein include EDTA, disodium edetate, dipotassium edetate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid, and potassium gluconate. Specifically, the chelating agent may be EDTA, disodium edetate, dipotassium edetate, trisodium edetate, or potassium gluconate.

[0248] The topical or oral compositions described herein may contain one or more commonly used, compatible, cosmetically acceptable adjuvants, such as colorants, fragrances, emollients, etc., as well as herbal ingredients, such as aloe vera, chamomile, witch hazel, etc.

[0249] Alternatively, other drug delivery systems can be used in the pharmaceutical compositions of the present invention. Liposomes and emulsions are well-known examples of delivery media that can be used to deliver active compounds or prodrugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used.

[0250] The topical compositions described herein can be provided in any cosmetically suitable form, preferably as a lotion, cream, or ointment, and in a sprayable liquid form (e.g., a spray containing the MrgprX2 antagonist in a matrix, mordant, or carrier that dries in a cosmetically acceptable manner and does not result in the greasy appearance associated with lotions or ointments when applied to the skin).

[0251] Any suitable amount of a MrgprX2 antagonist (e.g., a compound according to this disclosure) can be used in such dermatological compositions, provided that said amount effectively reduces local inflammation and / or vascular dysfunction and remains stable in the composition for a prolonged period. Preferably, stability lasts for a long period, such as up to about 3 years, up to 1 year, or up to about 6 months, which is typical in the manufacture, packaging, transport, and / or storage of dermatologically acceptable compositions. The compounds of this disclosure can be soluble in solution, partially soluble in solution and partially undissolved, or in a completely undissolved suspension. The compounds of this disclosure can be present in the dermatological compositions of the present invention at concentrations ranging from about 0.001 wt.% to about 80 wt.%, from about 0.001 wt.% to about 50 wt.%, from about 0.001 wt.% to about 25 wt.%, or from about 0.001 wt.% to about 6 wt.%. In one embodiment, the compounds of this disclosure may be present in a concentration range of about 0.001 wt.% to about 10 wt.%, about 0.1 wt.% to about 10 wt.%, or about 1.0 wt.% to about 5.0 wt.% of the dermatological composition.

[0252] In treating inflammatory conditions such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudohypersensory reactions triggered by small molecules, such as allergic drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions, it is preferable to apply a topical composition comprising the compounds of this disclosure directly to the affected area of ​​the skin of the person in need (e.g., itchy skin). When such compositions are used (e.g., when dermatological compositions comprising the compounds of this disclosure are used) and a dermatologically acceptable excipient is placed on the skin of the person in need, the MrgprX2 antagonist maintains continuous contact with the patient's skin, thereby achieving penetration and treatment.

[0253] When applying the pharmaceutical composition of the present invention topically, the skin of the person to be treated may optionally be pretreated (e.g., by washing the skin with soap and water or by cleaning the skin with an alcohol-based cleanser) before applying the dermatological composition of the present invention.

[0254] If desired, the pharmaceutical compositions of the present invention can be present in a packaging or dispensing device, which may contain one or more unit dosage forms containing the active compound. The topical compositions described herein can also be provided in patches, wherein the topical composition is located on the side of the patch that directly contacts the skin. Dermatologically acceptable adhesives can be used to hold the patch in place on the skin for extended periods.

[0255] Oral administration

[0256] In some embodiments, the pharmaceutical compositions provided herein are intended for oral administration. Therefore, solid, semi-solid, or liquid dosage forms for oral administration, comprising the compounds described herein, are provided according to this disclosure. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pellets, granules, powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, elixirs, syrups, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow aids, enteric coatings, membrane costing agents, modified release agents, colorants, dye migration inhibitors, sweeteners, and flavoring agents.

[0257] Binders or granulators give tablets adhesive properties to ensure that the tablets remain intact after compression. Suitable binders or granulators include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, alginate, seaweed extract, Irish moss extract, Panwar gum, Indian gum, psyllium husk adhesive, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, methylparaben, polyoxyethylene, povidone, polyvinylpyrrolidone (PVP), crosspovidone, Veegum, larch arabinogalactan, tragacanth gum powder, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methyl cellulose (HPMC); and microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, and AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose binders, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and mixtures thereof. Binders or fillers may be present in the pharmaceutical compositions provided herein in amounts from about 50% by weight to about 99% by weight.

[0258] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, trehalose, lysine, leucine, lecithin, starch, kaolin, sucrose, inositol, cellulose, mannitol, sodium chloride, dry starch, and powdered sugar. When present in sufficient quantities, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart properties to some compressed tablets that allow them to disintegrate in the mouth through chewing. Such compressed tablets can be used as chewable tablets.

[0259] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginate; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethylcellulose; cross-linked polymers, such as cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium glycolate starch; potassium polacrine; starch, such as corn starch, potato starch, cassava starch, and pregelatinized starch; clay; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% by weight or from about 1 to about 5% by weight of disintegrant.

[0260] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurylate; agar; starch; phycocyanin; silica or silica gel, for example... 200 (WR Grace Co., Baltimore, MD) and (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant.

[0261] Suitable flow aids include colloidal silica, (Cabot Co. of Boston, MA) and asbestos-free talc. Colorants include any approved, certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on hydrated alumina, as well as lakes and mixtures thereof. Lakes are combinations that produce an insoluble form of dye by adsorbing water-soluble dyes onto hydrated oxides of heavy metals. Flavorings include natural flavorings extracted from plants, such as fruits, and synthetic mixtures of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (POD). 20), Polyoxyethylene dehydrated sorbitan monooleate 80 ( 80) and triethanolamine oleate. Suspension and dispersant ingredients include sodium carboxymethyl cellulose, pectin, tragacanth gum, Veegum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methylparaben and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethanol, and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0262] It should be understood that multiple carriers and excipients can perform multiple functions, even in the same formulation.

[0263] The pharmaceutical compositions described herein may be provided in the form of compressed tablets, formulation tablets, chewable tablets, instant tablets, multi-compressed tablets, enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with sugar, which may help mask unpleasant tastes or odors and protect the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multi-compressed tablets are compressed tablets made through more than one compression cycle and include layered tablets, compressed-coated tablets, or dry-compressed-coated tablets.

[0264] Tablet dosage forms can be prepared alone from the active ingredient in powder, crystalline, or granular form, or in combination with one or more carriers or excipients described herein, said carriers or excipients comprising binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0265] The pharmaceutical compositions provided herein can be provided as soft capsules or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two parts, one sliding over the other to completely encapsulate the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms comprise solutions and suspensions of propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules can also be coated, as is known to those skilled in the art, to alter or maintain the solubility of the active ingredient.

[0266] The pharmaceutical compositions described herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed in another liquid in the form of small spheres; it can be oil-in-water or water-in-oil. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions may contain pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for convenient measurement at the time of administration.

[0267] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients described herein and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0268] The pharmaceutical compositions for oral administration described herein may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms may be prepared as described in U.S. Patent No. 6,350,458.

[0269] The pharmaceutical compositions described herein may be provided in non-effervescent or effervescent granule and powder form, reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

[0270] Colorants and flavorings can be used in all of the above dosage forms.

[0271] The pharmaceutical compositions provided herein can be formulated into immediate-release or modified-release dosage forms, including delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms. Thus, in some preferred embodiments, the active ingredient (i.e., a calcium channel blocker or L-arginine, or a combination of a calcium channel blocker and L-arginine, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof) is administered in a pharmaceutical composition that is an immediate-release oral dosage form, preferably but not necessarily containing an enteric coating. In some preferred embodiments, the active ingredient is administered in a pharmaceutical composition that is a delayed-release oral dosage form, preferably but not necessarily containing an enteric coating. In another preferred embodiment, the active ingredient is administered in a pharmaceutical composition containing an immediate-release dose and a delayed-release dose or pulsatile-release dose of a calcium channel blocker, preferably but not necessarily also containing an enteric coating. This dual-release dosage form achieves the initial release of an initial dose of the active ingredient, followed by the release of another pulsatile or sustained-release dose at a later time. Methods for preparing such dual-release dosage forms are well known in the art.

[0272] In some embodiments, the active ingredient is formulated into a controlled-release matrix tablet containing one or more polymeric matrix materials that promote sustained release, delayed release, or pulsed release profiles. Non-limiting examples of such polymeric matrix materials include cellulose materials and carbomers as described above, such as those produced by Lubrizol Corporation under the name... Those for sale, for example 71G NF, 971P NF and 974P NF polymer.

[0273] Some preferred examples of delayed-release compositions suitable for the methods and compositions of the present invention include, for example but not limited to, delayed-release compositions found in nifedipine formulations, such as Adalat. XL CR and XL; and delayed-release compositions found in diltiazem compounds, such as CD LA SR, XT and XR.

[0274] In some embodiments, this disclosure provides pharmaceutical compositions for oral administration to treat the symptoms and conditions described herein.

[0275] dose

[0276] The compositions provided herein contain therapeutically effective amounts of one or more compounds and mediators provided herein for the prevention, treatment, or improvement of one or more symptoms of the diseases or conditions described herein. Mediators suitable for administering the compounds provided herein comprise any such carriers known to those skilled in the art for a particular mode of administration, preferably topically, or orally, or via injection. Furthermore, the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients.

[0277] The amount of active compound contained in the mediator is sufficient to exert a therapeutically useful effect without causing undesirable side effects in the treated patient. Therapeuticly effective concentrations can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, from which the dosage for humans can be deduced. The human dosage is then typically fine-tuned in clinical trials and titrated based on the response.

[0278] The concentration of the active compound in the composition will depend on the absorption, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the dosage regimen and amount administered, and other factors known to those skilled in the art. For example, the amount delivered may be sufficient to improve one or more symptoms of a disease or condition as described herein.

[0279] In some embodiments, the therapeutically effective dose is from about 0.0001 mg to about 1000 mg per day. In some embodiments, the active ingredient (such as the MgrprX2 antagonist described herein) is delivered daily at a dose of 0.001-50 mg per kilogram of body weight, delivered topically, orally, or by injection as described herein. In some embodiments, the MgrprX2 antagonist is administered at a dose of up to 1500 mg / day, such as 1200 mg / day, 900 mg / day, 850 mg / day, 800 mg / day, 750 mg / day, 700 mg / day, 650 mg / day, 600 mg / day, 550 mg / day, 500 mg / day, 450 mg / day, 400 mg / day, 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 1000 mg / day, 50 mg / day, 25 mg / day, 10 mg / day, or 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.75, 0.5, 0.25, 0.10, 0.05, or 0.01 mg / day.

[0280] The active ingredient can be administered as a single dose or divided into multiple smaller doses administered at intervals. It should be understood that the precise dosage and duration of treatment vary depending on the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data or subsequent clinical testing. It should be noted that concentration and dosage values ​​may also vary depending on the severity of the symptom to be alleviated. It should be further understood that for any given subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely exemplary and not intended to limit the scope or practice of the claimed compositions.

[0281] Dosage forms or compositions containing 0.005% to 100% of the active ingredient can be prepared, with the remainder consisting of a mediator or carrier. Methods for preparing these compositions are known or will be obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th edition, 1975, or later.

[0282] Oral dosage

[0283] The oral dosage form of the present invention containing the MrgprX2 antagonist disclosed herein will generally be administered at the above-described dosage.

[0284] In some preferred embodiments, the daily dose is administered once daily. In some embodiments, the dosage form is a delayed-release composition.

[0285] In some embodiments, the daily dose is administered as a single dose. In other embodiments, the daily dose is administered multiple times a day in small increments, such as twice or three times a day, the combined amount of which is equal to the daily value described above.

[0286] In some preferred embodiments, the daily dose is administered as a single dose that provides efficacy for up to 12, 18, or 24 hours.

[0287] Local dose

[0288] In some embodiments, a local formulation comprising the compounds of this disclosure will contain an MgrprX2 antagonist at a concentration of 0.001 wt% to 20 wt% of the composition, for example, 0.001 wt% to 10 wt% of the composition, for example, 0.001 wt% to 8 wt%, for example, 0.001 wt% to 5 wt%, for example, 0.001 wt% to 4 wt%, for example, 0.001 wt% to 3 wt%, for example, 0.001 wt% to 2 wt%, for example, 0.001 wt% to 1 wt%.

[0289] The compound or its derivative may be packaged as an article containing packaging material, the compound or its derivative provided herein within the packaging material, and a label, wherein the compound or its derivative is effective in treating, preventing, or improving one or more symptoms of the aforementioned disease or condition, and the label indicates that the compound or composition or its derivative is used to treat, prevent, or improve one or more symptoms of the aforementioned disease or condition.

[0290] The articles described herein contain packaging materials. Packaging materials used to package products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for selected formulations and intended modes of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated for various treatments of any of the diseases or conditions described herein.

[0291] Those skilled in the art can use the following examples to determine the effectiveness of the compounds of the present invention in treating people with skin conditions characterized by inflammation.

[0292] Example

[0293] Example 1 - Preparation of compounds according to this disclosure

[0294] Example E01

[0295]

[0296] N-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-2-methylpropionamide

[0297] Step 1

[0298] Hydrazine carbosulfan (3000 mg, 32.3 mmol) was slowly added to a mixture of (3-fluorophenyl)acetic acid (497 g, 32.3 mmol) and sulfuric acid (8.8 mL, 0.161 mol), and the suspension was heated at 80 °C for 2 hours. The reaction mixture was then cooled to room temperature and slowly poured onto a mixture of ice and saturated aqueous NaHCO3 (50 mL). The mixture was then alkalized to pH 9 with an aqueous solution of 37% ammonia. The resulting brown solution was filtered, and the filtrate was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (30 mL) and concentrated under vacuum. The crude product was purified by FCC (KP Sil 25 g, 0-100% EtOAc / heptane, then 0-20% MeOH / EtOAc) to give 5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-amine, which was a white solid (401 mg, 5% yield, 78% purity).

[0299] Step 2

[0300] To a solution of 5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-amine (78%, 75 mg, 0.280 mmol) and N-ethyl-N-isopropyl-propan-2-amine (98 μL, 0.559 mmol) in THF (2 mL), 2-methylpropionyl chloride (35 μL, 0.335 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then, MeOH (1 mL) and 1 M NaOH (1 mL) were added, and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with brine (5 mL), extracted with EtOAc (2 x 5 mL), and the combined organic extracts were washed and concentrated under vacuum. The residue obtained was purified by column chromatography (Biotage Isolera 10 g SNAP Ultra, 0-60% EtOAc / heptane) to give the title compound as a pale yellow solid (27 mg, 34%). 1HNMR (400MHz, DMSO-d6) δ12.39 (s, 1H), 7.44-7.34 (m, 1H), 7.22-7.13 (m, 2H), 7.10 ( td, J=8.5, 2.3Hz, 1H), 4.37 (s, 2H), 2.74 (hept, J=6.9Hz, 1H), 1.09 (d, J=6.9Hz, 6H). LCMS m / z: 280.1[M+H]+, RT=2.82 (Method A)

[0301] Table 1: The following compounds were synthesized using a method similar to that used in Example E01, or using the carboxylic acid from step 2, combined with a coupling agent such as HATU.

[0302]

[0303]

[0304] Example E09

[0305]

[0306] 3-[5-[(2,3-difluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea

[0307] Step 1

[0308] A stirred solution of aqueous ethylamine (70%, 5.5 mL, 68.9 mmol) was diluted with water (5 mL), cooled to 0 °C, and a solution of (2S)-2-methylethylene oxide (1.00 g, 17.2 mmol) in water (2 mL) was added dropwise. The reaction mixture was heated to room temperature and stirred overnight. The solvent was then removed under reduced pressure to give the title compound as a pale yellow liquid (1.35 g, 90% purity, 68% yield). ¹H NMR (400 MHz, methanol-d⁴) δ 3.90–3.81 (m, 1H), 2.72–2.46 (m, 4H), 1.21–1.09 (m, 6H); no NH₄⁺ or OH⁻ was observed.

[0309] Step 2

[0310] A solution of 5-[(2,3-difluorophenyl)methyl]-1,3,4-thiadiazol-2-amine (synthesized using a method similar to E01 (step 1), 60 mg, 0.264 mmol) and pyridine (23 μL, 0.290 mmol) in anhydrous THF (1 mL) was added to a solution of (4-nitrophenyl)chloroformate (59 mg, 0.290 mmol) in anhydrous THF (1 mL), and the reaction mixture was stirred at room temperature for 20 min. Then, a solution of (2S)-1-(ethylamino)prop-2-ol (39 mg, 0.343 mmol) and N-ethyl-N-isopropyl-prop-2-amine (69 μL, 0.396 mmol) in anhydrous THF (1 mL) was added, and the reaction mixture was stirred at room temperature for 15 min. The mixture was then concentrated under reduced pressure and purified by preparative HPLC (method C) to give the title compound as a white solid (64 mg). 1H NMR (500MHz, DMSO-d6) δ10.96 (s, 1H), 7.46-7.31 (m, 1H), 7.29-7.16 (m, 2H), 5.16 (s, 1H), 4.35(s, 2H), 3.93-3.76(m, 1H), 3.53-3.35(m, 2H), 3.31-3.00(m, 2H), 1.11-0.93(m, 6H). LCMSm / z: 357.1[M+H]+, RT=2.65 (Method A)

[0311] Table 2: The following compounds were synthesized using a method similar to that used in Example E09, using commercially available amines or amino alcohols synthesized using a method similar to step 1 of Example E09.

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] Examples E50 and E51

[0324]

[0325] A single unknown enantiomer of 3-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)urea

[0326] Separation of 3-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)urea (Example E40) yielded two single enantiomers. Method: Chiralpak AD-H, 10 x 250 mm, 5 μm column, eluted with 10% IPA; 90% CO2, flow rate 15 mL / min.

[0327] Example E50 (first wash-out):

[0328] ¹H NMR (400 MHz, chloroform-d): δ 7.25–7.20 (m, ¹H), 6.98 (d, J = 7.7 Hz, ¹H), 6.89 (t, J = 7.9 Hz, 2H), 4.17 (s, 2H), 3.80 (d, J = 15.2 Hz, 1H), 3.34 (s, ¹H), 3.10 (s, 3H), 1.44 (s, 3H). LCMS m / z: 393.2 [M+H]+, RT = 2.93 (Method A).

[0329] Example E51 (second wash):

[0330] ¹H NMR (400 MHz, chloroform-d): δ 7.25–7.20 (m, ¹H), 6.98 (d, J = 7.6 Hz, ¹H), 6.90 (t, J = 8.0 Hz, 2H), 4.17 (s, 2H), 3.79 (d, J = 15.9 Hz, 1H), 3.35 (s, 1H), 3.10 (s, 3H), 1.44 (s, 3H). LCMS m / z: 393.2 [M+H]+, RT = 2.93 (Method A).

[0331] Examples E52 and E53

[0332]

[0333] A single unknown enantiomer of 1-ethyl-3-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)urea

[0334] Separation of 1-ethyl-3-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)urea (Example E42) yielded two enantiomers. Method: Chiralpak AD-H, 10x250 mm, 5 μm column, eluted with 15% IPA: 85% CO2, flow rate 15 mL / min.

[0335] Example E52 (first wash)

[0336] ¹H NMR (400 MHz, chloroform-d): δ 7.25–7.20 (m, ¹H), 6.98 (d, J = 7.7 Hz, ¹H), 6.89 (t, J = 8.2 Hz, 2H), 4.16 (s, 2H), 3.81–3.65 (m, 2H), 3.25 (d, J = 15.4 Hz, 1H), 3.07 (s, 1H), 1.48 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H). LCMS m / z: 407.2 [M+H]+, RT = 3.21 (Method A).

[0337] Example E53 (Second elution)

[0338] ¹H NMR (400 MHz, chloroform-d): δ 7.25–7.20 (m, ¹H), 6.98 (d, J = 7.6 Hz, ¹H), 6.89 (t, J = 8.3 Hz, 2H), 4.16 (s, 2H), 3.79–3.65 (m, 2H), 3.24 (d, J = 15.2 Hz, 1H), 3.07 (s, 1H), 1.48 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H). LCMS m / z: 407.3 [M+H]+, RT = 3.24 (Method A).

[0339] Example E54

[0340]

[0341] 3-[5-[(3,5-difluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0342] Step 1

[0343] (2S)-2-(trifluoromethyl)ethylene oxide (200 mg, 1.78 mmol) was added to a three-necked RBF under N2 conditions, followed by anhydrous THF (8 mL), and the stirred solution was cooled to -100 °C using an Et2O / dry ice bath. Then, 1.6 M butyllithium (1.2 mL, 1.96 mmol) was added dropwise, followed by stirring at this temperature for 10 min. Iodomethane (0.17 mL, 2.68 mmol) was then added, and the reaction mixture was stirred at this temperature for 2 h. The mixture was then heated to ~0 °C using an ice bath, and 2 M methylamine (3.6 mL, 7.14 mmol) was added. The mixture was then heated to room temperature and stirred overnight. The mixture was then quenched by adding saturated aqueous NH4Cl (5 mL), followed by removal of volatiles under reduced pressure (100 mbar). The residue was loaded onto an SCX-2 column (5 g, washed with MeOH and eluted with 3.5 N NH3 / MeOH). The MeOH fraction was concentrated under reduced pressure to give (2s)-1,1,1-trifluoro-2-methyl-3-(methylamino)prop-2-ol, which is an orange liquid (750 mg, 30% purity). ¹H NMR (500 MHz, methanol-d⁴) δ 3.38 (d, J = 13.2 Hz, 1H), 3.23 (d, J = 13.2 Hz, 1H), 2.77 (s, 3H), 1.54–1.46 (m, 3H). No NH₄⁺ or OH⁻ was observed.

[0344] Step 2

[0345] A solution of (4-nitrophenyl)chloroformate (49 mg, 0.245 mmol) in anhydrous THF (1 mL) was cooled in an ice bath. While stirring, a solution of 5-[(3,5-difluorophenyl)methyl]-1,3,4-thiadiazol-2-amine (synthesized using a method similar to that in Example E01 (step 1), 55 mg, 0.223 mmol) and pyridine (0.020 mL, 0.245 mmol) in anhydrous THF (1 mL) was added, and the reaction mixture was heated to room temperature and stirred at room temperature for 30 minutes. Then, a solution of (2S)-1,1,1-trifluoro-2-methyl-3-(methylamino)prop-2-ol (95 mg, 0.181 mmol) and N-ethyl-N-isopropyl-prop-2-amine (0.058 mL, 0.334 mmol) in anhydrous THF (1 mL) was added, and the reaction mixture was stirred at room temperature for 15 minutes. The solution was then diluted with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method C) to give the title compound as a white solid (24 mg). ¹H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.15 (tt, J = 9.4, 2.4 Hz, 1H), 7.12–7.03 (m, 2H), 6.21 (s, 1H), 4.29 (s, 2H), 4.07–3.73 (m, 1H), 3.08 (s, 3H), 1.19 (s, 3H); 1H at water peak. LCMS m / z: 411.2 [M+H]+, RT = 3.06 (Method A)

[0346] Table 3: The following compounds were synthesized using a method similar to that used in Example E54.

[0347]

[0348]

[0349] Example E58

[0350]

[0351] 5-[(3,5-difluorophenyl)methyl]-N-isopropyl-1,3,4-thiadiazole-2-carboxamide

[0352] Step 1

[0353] Hydrazine hydrate (0.64 mL, 13.0 mmol) was added to a stirred solution of ethyl 2-(3,5-difluorophenyl)acetyl (1.12 g, 5.6 mmol) in MeOH (10 mL). The reaction mixture was stirred at 70 °C for 4 hours, and then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give difluorophenyl)acetylhydrazine (1.21 g), which was a grayish-white solid.

[0354] Step 2

[0355] At 0 °C, ethyl 2-chloro-2-oxo-ethyl (800 μL, 7.16 mmol) was added dropwise to a stirred solution of 2-(3,5-difluorophenyl)acetylhydrazine (1.21 g, 6.50 mmol) and triethylamine (1.1 mL, 7.89 mmol) in anhydrous DCM (15 mL), forming a yellow solution. After 15 minutes, the ice bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (10 mL) and extracted into DCM (3 x 20 mL). A white solid was present, so the layers were filtered to obtain a white solid. The DCM layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to obtain a yellow solid. The solids were combined and dissolved in EtOAc, and the aqueous layer was further extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain 2-[2-[2-(3,5-difluorophenyl)acetyl]hydrazino]-2-oxo-ethyl acetate (1.92 g, 80% purity), which was a yellow solid.

[0356] Step 3

[0357] At 50 °C, ethyl 2-[2-[2-(3,5-difluorophenyl)acetyl]hydrazino]-2-oxo-ethyl acetate (80%, 100 mg, 0.279 mmol) and Lawson's reagent (71 mg, 0.176 mmol) were stirred for a total of 3 hours in a pressure vial containing 1 mL of THF to give a pale yellow solution. Water (4 mL) was added, and the mixture was extracted with EtOAc (4 x 3 mL). The organic compounds were combined and concentrated. The crude product was purified by FCC (Biotage SNAP KP-Sil 10 g), eluted with 0–25% EtOAc / heptane, and washed with 25–100% EtOAc / heptane to give ethyl 5-[(3,5-difluorophenyl)methyl]-1,3,4-thiadiazole-2-carboxylate (45 mg, 54% yield). ¹H NMR (500 MHz, chloroform-d) δ 6.85 (qd, J = 7.3, 2.3 Hz, 2H), 6.76 (tt, J = 8.9, 2.3 Hz, 1H), 4.53–4.48 (m, 2H), 4.47 (s, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0358] Step 4

[0359] In a septated 1.5 mL vial, ethyl 5-[(3,5-difluorophenyl)methyl]-1,3,4-thiadiazole-2-carboxylate (96%, 45 mg, 0.152 mmol) was dissolved in anhydrous methanol (0.5 mL), and propyl-2-amine (13 μL, 0.152 mmol) was added. The solution turned yellow (after 5 minutes, the reactant turned green, then yellow). The sealed reaction mixture was heated at 80 °C for 1 hour. Further propyl-2-amine (100 μL, 1.16 mmol) was added, and the reaction mixture was heated at 80 °C for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (Method D) to give the title compound (32 mg, 70% yield) as a grayish-white solid. 1H NMR (500MHz, DMSO-d6) 69.03 (d, J=8.1Hz, 1H), 7.18 (tt, J=9.6, 2.4Hz, 1H), 7.1 3 (dd, J=8.4, 2.0Hz, 2H), 4.57 (s, 2H), 4.14-4.01 (m, 1H), 1.17 (d, J=6.6Hz, 6H). LCMS m / z: 298.1[M+H]+, RT=3.11 (Method A)

[0360] Example E59

[0361]

[0362] 3-[5-[1-(3,5-difluorophenyl)-1-methyl-ethyl]-1,3,4-thiadiazol-2-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea

[0363] Step 1

[0364] Sodium hydroxide (214 mg, 5.22 mmol) was dissolved in warm water (0.3 mL). A solution of (3,5-difluorophenyl)acetonitrile (200 mg, 1.31 mmol) in DMSO (1.2 mL) was added to the warm mixture, and the mixture was stirred in a cold water bath (~10 °C). Iodomethane (0.33 mL, 5.22 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water (2 mL) was added, and the mixture was extracted into EtOAc (3 x 3 mL). The organic matter was combined and concentrated under vacuum to give 2-(3,5-difluorophenyl)-2-methylpropionitrile (275 mg).

[0365] Step 2

[0366] Sodium hydroxide (1.28 g, 31.9 mmol) was added to a stirred solution of 2-(3,5-difluorophenyl)-2-methylpropionitrile (85% purity, 2.27 g, 10.6 mmol) in methanol (2 mL) and water (5 mL). The reaction mixture was stirred overnight (~20 h) at 90 °C, and then stirred at room temperature for about 46 h. The reaction mixture was diluted with water (5 mL) and extracted into EtOAc (3 x 10 mL). The organic matter was dried over MgSO4, filtered, and concentrated under vacuum to give 2-(3,5-difluorophenyl)-2-methylpropionic acid (2.28 g).

[0367] Step 3

[0368] 5-[1-(3,5-difluorophenyl)-1-methyl-ethyl]-1,3,4-thiadiazole-2-amine was synthesized using a method similar to that used in Example E01 (step 1).

[0369] ¹H NMR (400 MHz, chloroform-d) δ 6.95–6.79 (m, 2H), 6.68 (tt, J = 8.7, 2.3 Hz, 1H), 4.97 (s, 2H), 1.78 (s, 6H).

[0370] Step 4

[0371] The title compound was synthesized using a method similar to that used in Example E09 (step 2). ¹H NMR (400 MHz, chloroform-d): δ 6.90–6.76 (m, 2H), 6.66 (tt, J = 8.7, 2.3 Hz, 1H), 4.30–4.16 (m, 1H), 3.57–3.45 (m, 1H), 3.45–3.27 (m, 3H), 1.80 (s, 6H), 1.32 (d, J = 6.3 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). LCMS m / z: 385.3 [M+H]+, RT = 2.96 (Method B).

[0372] HPLC method

[0373] Analytical LCMS

[0374] Method A

[0375] Analytical uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μM; temperature: 40 °C) with a gradient of 5–100% B (A = 0.1% formic acid in H₂O solution; B = 0.1% formic acid in ACN solution) for 5.3 min, followed by 100% B for 0.5 min. A second gradient of 100–5% B was then applied over 0.02 min at a flow rate of 0.6 mL / min for 1.18 min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector with a spectral range of 200–400 nm, and ELS data were collected and recorded using a Waters Acquity ELS detector (if assembled). Mass spectra were obtained using a Waters SQD (MSQ1) or a Waters Acquity QDA (MSQ2). Use Waters MassLynx and OpenLynx software to integrate and report data.

[0376] Method B

[0377] Using Waters Acquity uPLC system Analytical uPLC-MS was performed on a BEHTM C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40 °C) with a gradient of 5–100% (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) for 5.3 min, followed by 100% B for 0.5 min. A second gradient of 100–5% B was then applied over 0.02 min at a flow rate of 0.6 mL / min for 1.18 min. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector with a spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0378] Preparative HPLC methods

[0379] The purification method is as follows:

[0380] Method C: Acidic Method

[0381] Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) with a gradient of 10–95% B (A = 0.1% formic acid in H₂O solution; B = 0.1% formic acid in ACN solution) for 14.44 min, followed by 95% B for 2.11 min. A second gradient of 95–10% B was then applied over 0.2 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0382] Method D: Alkaline method

[0383] Purification was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) with a gradient of 30–95% B (A = 0.2% aqueous ammonium hydroxide; B = 0.2% ammonium hydroxide in ACN solution) for 11.00 min, followed by 95% B for 2.10 min. A second gradient of 95–30% B was then applied over 0.21 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0384] Example 2 - Screening of Compounds

[0385] Potent and selective hMrgpMRGPRX2 compounds were generated from those identified during high-throughput screening (HTS) activities and subsequently subjected to a structure-activity-based medicinal chemistry work cycle. These compounds were characterized as antagonists in recombinant hMrgpMRGPRX2-expressing cells, and their potency was confirmed in the human mast cell line LAD-2, where the target was endogenously expressed. Assays used to determine potency were performed using FLIPR. TM Technological observation of the functional readout of intracellular calcium mobilization. In these FLIPR assays, we tested the orthologous activity of the labeled compounds using recombinant cell systems expressing mouse MrgprB2, mouse MrgprA1, gerbil MrgpMRGPRX2 orthologs, Chinese hamster MrgpMRGPRX2 orthologs, and cynomolgus monkey MrgpMRGPRX2 orthologs.

[0386] The results are summarized in Table 4 below.

[0387] Table 4

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

Claims

1. A compound of Formula I: wherein: G1 is phenyl substituted at the 2-, 3-, 4-, or 5-position; G2 is q is 1; m is 1; n is 1; k is 1; R4 is H; R5 is H; or a stereoisomer or pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein G1 is phenyl substituted at the 3-position.

4. The compound of claim 1, wherein G1 is phenyl substituted at the 3- and 5-positions.

5. The compound of claim 1, wherein G1 is phenyl substituted at the 2- and 5-positions.

6. The compound of claim 1, wherein G1 is phenyl substituted at the 2- and 4-positions.

7. The compound of claim 1, wherein G1 is phenyl substituted at the 2- and 3-positions. R1is C 1-3 alkyl; R2is n-propyl optionally substituted with 1 to 3 R 20 groups, said R 20 independently selected from hydroxyl, di- or trihalomethyl, methoxy, halogen and cyano; R3is H or C 1-3 alkyl; 8. The compound of claim 1, wherein G1 is phenyl substituted at the 3- and 4-positions.

13. The compound of claim 1, wherein the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of: G1is phenyl optionally substituted with 1, 2, or 3 independently selected R 30 groups; G2is phenyl optionally substituted with 1, 2, or 3 independently selected R Each R 30 Independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl groups, C groups optionally substituted with halogens 1-3 Alkyl and hydroxyl groups; 14. Use of a compound of claim 1 in the manufacture of a medicament for treating an inflammatory condition mediated by MrgprX2, the use comprising administering to a subject in need thereof a topical or oral composition comprising a therapeutically effective amount of a compound of Formula I and a dermatologically or orally acceptable excipient.

2. The compound of claim 1, wherein G1is phenyl optionally having one or two R 30 groups independently selected.

15. The use of claim 14, wherein the composition is in the form of a cream, gel, spray, or ointment, or is a dosage form for oral administration.

16. The use of claim 14, wherein the compound is present at a concentration of 0.001 wt.% to 10 wt.% based on the total weight of the composition.

17. The use of claim 14, wherein the compound is present at a concentration of 0.1 wt.% to 5 wt.% based on the total weight of the composition.

18. The use of claim 14, wherein the composition further comprises a skin absorption enhancer.

19. The use of claim 14, wherein the composition further comprises a skin absorption enhancer comprising one or more of a sulfoxide, an azone, a pyrrolidone, an alcohol, a surfactant, and a terpene.

20. The use of claim 14, wherein the inflammatory condition is a skin condition.

9. The compound of claim 1, wherein each R 30 is independently selected from the group consisting of mono-, di-, or tri-halo- methyl, fluoro, chloro, methoxy, cyano, and methyl.

10. The compound of claim 1, wherein each R 30 is independently selected from difluoromethyl, trifluoromethyl, fluoro, chloro, methoxy, cyano, and methyl.

11. The compound of claim 1, wherein each R 30 is independently selected from fluoro and chloro.

12. The compound of claim 1, wherein each R 30 is fluoro.

21. The use of claim 20, wherein the skin is human skin.

22. The use of claim 14, wherein the inflammatory condition is atopic dermatitis, chronic hives, pseudoallergic reactions triggered by small molecules, anaphylactic shock, rosacea, asthma, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

23. The use of claim 14, wherein the inflammatory condition is atopic dermatitis.

24. The use of claim 14, wherein the subject is human.

25. The use of claim 20, wherein the skin is mammalian skin.

26. The use of claim 23, wherein the atopic dermatitis is Asian atopic dermatitis or European atopic dermatitis. ​ ​ ​ ​ ​ ​ ​ ​ 27. The use of claim 22, wherein the inflammatory condition is chronic urticaria.

28. The use of claim 15, wherein, Dosage forms for oral administration are tablets or capsules.

29. The use of claim 19, wherein the composition comprises one or more of mannitol, dimethyl sulfoxide (DMSO), laurocapram, 2-pyrrolidone, ethanol, decanol, propylene glycol, hexylene glycol, polyethylene glycol, or diethylene glycol.

30. The use of claim 14, wherein the inflammatory condition is atopic dermatitis.

31. The use of claim 14, wherein the inflammatory condition is cholestatic or uremic pruritus.

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