MrgprX2 Antagonists and Uses Thereof

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Application Nos. 62 / 931,186, filed November 5, 2019, 62 / 931,576, filed November 6, 2019, and 63 / 046,481, filed June 30, 2020, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Atopic dermatitis (AD) is the most common inflammatory skin disease, with an overall prevalence of 6% in US adults and 1-3% of adults and 15-20% of children worldwide. 17.8 million Americans suffer from AD. Disease onset is typically childhood, with skin manifestations present by the age of 1 year in 60% of patients. Clinical symptoms include erythematous papules and macules, exudation, crusting, hypopigmentation, and lichenification. However, the hallmark symptom of AD is intense, chronic itch lasting for more than 6 weeks. Despite the high prevalence of chronic itch in AD patients, there is no available, effective first-line treatment with a favorable safety profile. Itch has a significant impact on the quality of life of these patients, including sleep disturbances, ultimately leading to impaired work or school performance. Health-related quality of life in children is inversely correlated with disease severity. Sleep is affected by persistent nighttime itch.

[0003] Due to their sedative effects, oral antihistamines provide mild symptomatic relief without directly altering pruritus. Topical calcineurin inhibitors (TCIs) and topical corticosteroids (TCSs) can help reduce pruritus. However, side effects (skin atrophy, hypopigmentation, and telangiectasia in the case of TCSs, as well as a black box warning for TCIs regarding skin cancer malignancies) make them undesirable treatment options, especially for chronic use in young children. Therefore, there is a high medical demand among patients and their families to find new treatment options for itch. In addition, relief of chronic itch interrupts the vicious cycle of itch and scratching, which may have secondary beneficial effects, such as improving the skin barrier, leading to improvement of skin lesions and erythema.

[0004] Finding both a cure and an effective treatment for chronic itch in AD is a significant challenge. Histamine is not the primary pruritic substance in AD, and therefore histamine blockers only work in AD patients through their soothing effects, especially on nocturnal itch. Proteases released from immune and skin cells in AD patients and acting on GPCRs have been investigated as major pruritic contributors in AD. Cathepsin S has been described in the literature as a protease with high pro-inflammatory properties that induces itch. Overexpression of cathepsin S results in an AD phenotype in mice with severe chronic itch. Recently, one group reported that cathepsin S induces itch via MrgprX2. Despite this, knowledge about the major itch mediators in AD is limited, although several have been identified and postulated to play a role.

[0005] Another pruritic neuropeptide is substance P, a vasoactive neuropeptide released by neuronal and non-neuronal skin cells that acts as a pro-inflammatory and pruritogenic agent. Therefore, targeting its cognate receptor, NK1, is considered an ideal therapeutic approach, and this has been achieved using aprepitant. However, despite preclinical data in mice, the NK1R antagonist aprepitant failed to significantly block itch in humans.

[0006] MrgprX2 is a promising target due to its promiscuous ligand-binding properties to various itch mediators. Several itch mediators known or suspected to be relevant players in the pathogenesis of AD are thought to bind to the MrgprX receptor rather than its cognate receptor.

[0007] There is an unmet need for an effective treatment for AD and its symptoms. The present invention addresses that unmet need, as well as other important objectives. Summary of the Invention

[0008] overview Described herein are topical and oral compositions comprising MrgprX2 antagonists, as well as methods for using MrgprX2 antagonists for the treatment of inflammatory conditions, such as AD.

[0009] Thus, in a first aspect, the present disclosure provides compounds that are MrgprX2 antagonists.

[0010] In a second aspect, the present disclosure provides topical and oral compositions comprising an MrgprX2 antagonist and a pharmaceutically acceptable excipient.

[0011] In a third aspect, the present disclosure provides a method for treating an inflammatory disorder, comprising administering to a subject in need thereof a topical or oral composition having a therapeutically effective amount of an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) and a dermatologically or orally acceptable excipient.

[0012] In a fourth aspect, the present disclosure provides a method for reducing inflammation in mammalian skin, comprising administering to a subject in need thereof an effective amount of a topical or oral composition comprising an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) and a dermatologically or orally acceptable excipient to the mammalian skin.

[0013] In a fifth aspect, the present disclosure provides a method for reducing the occurrence or severity of itching in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a topical or oral composition comprising an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure). [The present invention 1001] A compound having formula I, TIFF0007787811000001.tif40128 During the ceremony, G 2 but, TIFF0007787811000002.tif31128 and q is 0 or 1, m is 0 or 1, n is 0, 1, or 2; k is 0 or 1, provided that k, q, and m are not all zero. provided that when m and k are each 1, q is not 0; R 1 and R 2 However, independently, H, C 1-6 Alkyl; C 3-6 Cycloalkyl; 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein each C1-6 Alkyl, C 3-6 Cycloalkyl, and 5- to 10-membered heterocycloalkyl are each selected from 1 to 3 R 20 may be substituted with a group, However, R 1 and R 2 However, on the condition that it is not H at the same time, Each R 20 are independently 1) hydroxy, 2) cyano, 3) C 1-3 Alkyl, 4) C 1-3 Alkoxy, 5)C 1-3 Haloalkyl, 6) Halogen, 7) C 1-3 Alkyl, 8) Hydroxy, Cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C optionally substituted with 1 to 3 substituents selected from haloalkyl and halogen 3-6 Cycloalkyl, and 9) hydroxy, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 a 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, optionally substituted by 1-3 substituents selected from haloalkyl, and halogen; Or, R 1 and R 2 can be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered saturated, partially saturated, or aromatic heterocycle having 1 to 3 ring heteroatoms independently selected from N, O, and S, which includes hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen; R 3 But H or C 1-3 is alkyl, Each R 4 and R 5 are independently H or C 1-3 is alkyl, G 1 But C 6-10 Aryl;C 3-7 Cycloalkyl; C 1-3 Haloalkyl;C 1-3 alkyl; and 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein said C 6-10 Aryl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, and 5- to 10-membered heteroaryl are each selected from 1, 2, or 3 independently selected R30 may be substituted with a group, Each R 30 But halogen, cyano, C 1-3 Alkyl, C 1-3 C optionally substituted with haloalkyl, halogen and hydroxy 1-3 alkoxy, The compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. [The present invention 1002] G 1 may be substituted C 6-10 1001. A compound of the present invention, which is aryl. [The present invention 1003] G 1 1001. A compound of the present invention, wherein is optionally substituted phenyl. [The present invention 1004] G 1 1001. A compound of the present invention, wherein is optionally substituted pyridyl. [The present invention 1005] G 1 may be substituted C 3-6 1001. A compound of the present invention which is cycloalkyl. [The present invention 1006] G 1 1001. A compound of the present invention wherein is optionally substituted cyclopropyl or cyclohexyl. [The present invention 1007] G 1 1001. A compound of the present invention, wherein is phenyl optionally having one or two substituents. [The present invention 1008] G 1 1001. A compound of the present invention, wherein is phenyl optionally having one or two substituents. [The present invention 1009] G 1 1001. A compound of the present invention wherein is phenyl substituted at the 3-position. [The present invention 1010] G 1 1001. A compound of the present invention wherein is phenyl substituted at the 3- and 5-positions. [The present invention 1011] G 1 1001. A compound of the present invention, wherein is phenyl substituted at the 2- and 5-positions. [The present invention 1012] G 1 1001. A compound of the present invention wherein is phenyl substituted at the 2- and 4-positions. [The present invention 1013] G 1 1001. A compound of the present invention, wherein is phenyl substituted at the 2- and 3-positions. [The present invention 1014] G 1 1001. A compound of the present invention, wherein is phenyl substituted at the 3- and 4-positions. [The present invention 1015] Each R 30 is independently selected from mono-, di-, or trihalomethyl, fluorine, chlorine, methoxy, cyano, and methyl. [The present invention 1016] Each R 30 is independently selected from difluoromethyl, trifluoromethyl, fluorine, chlorine, methoxy, cyano, and methyl. [The present invention 1017] Each R 30 is independently selected from fluorine and chlorine. [The present invention 1018] Each R 30 is fluorine. [The present invention 1019] G 1 But C 1-3 1001. A compound of the present invention which is haloalkyl. [The present invention 1020] G 1 1001. The compound of the present invention, wherein is trifluoromethyl. [The present invention 1021] Any of the preceding compounds wherein n is 1. [The present invention 1022] Any of the preceding compounds of the invention wherein n is 2. [The present invention 1023] Any of the preceding compounds of the invention, wherein m, k, and q are each 1. [The present invention 1024] Any of the preceding compounds of the invention, wherein q and m are each 1 and k is 0. [The present invention 1025] Any of the preceding compounds of the invention, wherein m is 0, and k and q are each 1. [The present invention 1026] Any of the preceding compounds of the invention, wherein k is 0, and m and q are each 1. [The present invention 1027] R 1 and R 2 Each independently has 1 to 3 R 20 C optionally substituted with a group 1-3 Any of the preceding compounds of the invention, wherein: [The present invention 1028] R 1 and R 2 is each independently one to three R independently selected from hydroxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, methoxy, halogen, and cyano; 20 C optionally substituted with a group 1-3 Any of the preceding compounds of the invention, wherein: [The present invention 1029] R 1 But H or C 1-3 alkyl, and R 2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Any of the preceding compounds of the invention optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen. [The present invention 1030] R 1 But H or C 1-3 alkyl, and R 2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is optionally substituted with one, two, or three groups selected from hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, cyano, and halogen. [The present invention 1031] R 1 But H or C 1-3 alkyl, and R 2 However, pyrrolidine, tetrahydrofuran, morpholine, piperidine, tetrahydropyran, and C 3-6 C substituted with a ring selected from cycloalkyl 1-3 any of the preceding compounds of the invention, wherein R is an alkyl, each of which is optionally substituted with one, two, or three groups selected from hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, cyano, and halogen. [The present invention 1032] R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Any of the preceding compounds of the invention optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen. [The present invention 1033] Any compound of the preceding invention, which is a compound selected from the compounds of Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. [The present invention 1034] A method for treating an inflammatory disorder, comprising administering to a subject in need thereof a topical or oral composition comprising a therapeutically effective amount of a compound of the present invention and a dermatologically or orally acceptable excipient. [This invention 1035] 1034. The method of claim 1034, wherein said composition is in the form of a cream, gel, spray, or ointment, or in a dosage form for oral administration, such as a tablet or capsule. [The present invention 1036] The method of claim 1034, wherein the MrgprX2 antagonist is present at a concentration of about 0.001% by weight to about 10% by weight, based on the total weight of the composition. [This invention 1037] The method of claim 1034, wherein the MrgprX2 antagonist is present at a concentration of about 0.1% by weight to about 5% by weight, based on the total weight of the composition. [The present invention 1038] The method of claim 1034, wherein the composition further comprises a skin absorption enhancer. [This invention 1039] The method of claim 1034, wherein the composition further comprises a skin absorption enhancer comprising one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. [The present invention 1040] 1039. The method of any of claims 1034 to 1039, wherein said composition is applied to the patient's skin once a day. [The present invention 1041] 1039. The method of any of claims 1034 to 1039, wherein said composition is applied to the patient's skin twice daily. [The present invention 1042] 1039. The method of any of claims 1034 to 1039, wherein said composition is applied to the patient's skin three times a day. [This invention 1043] 1043. The method of any of claims 1034 to 1042, wherein the composition is administered to a patient suffering from an inflammatory disorder. [This invention 1044] The method according to any one of claims 1034 to 1043, wherein the inflammatory disorder is a skin disorder. [This invention 1045] The method of any one of claims 1034 to 1044, wherein the skin is human skin. [The present invention 1046] The method of any of claims 1043 to 1045, wherein said inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2. [This invention 1047] Any of the methods of inventions 1043 to 1046, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, a pseudoallergic response caused by a small molecule, e.g., an anaphylactoid drug response, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by a systemic disease, or an adverse drug response. [This invention 1048] The method of any of claims 1043 to 1047, wherein said inflammatory disorder is atopic dermatitis (for example, Asian atopic dermatitis, European atopic dermatitis). [This invention 1049] The method of any one of claims 1043 to 1048, wherein the subject is a human. [The present invention 1050] The method of any one of claims 1043 to 1048, wherein the mammalian skin is human skin. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description Provided herein is a topical or oral composition for treating inflammatory conditions, such as skin disorders characterized by inflammation. Specifically, the pharmaceutical composition comprises a compound that is an antagonist of Mas-related G protein-coupled receptor MrgprX2.

[0015] MrgprX2 Antagonists for Use in the Compositions and Methods of the Disclosure In some embodiments, the present disclosure provides a compound [Compound 1] that is an MrgprX2 antagonist having formula I, TIFF0007787811000003.tif40128In formula, G2, TIFF0007787811000004.tif31128, q is 0 or 1, m is 0 or 1, n is 0, 1, or 2; k is 0 or 1, provided that k, q, and m are not all zero. provided that when m and k are each 1, q is not 0; R1 and R2 are each independently H, C 1-6 Alkyl, C 3-6 cycloalkyl, 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, and each C 1-6 Alkyl, C 3-6 Cycloalkyl, and 5- to 10-membered heterocycloalkyl are each selected from 1 to 3 R 20 may be substituted with a group, provided that R1 and R2 are not simultaneously H; Each R 20 are independently 1) hydroxy, 2) cyano, 3) C 1-3 Alkyl, 4) C 1-3 Alkoxy, 5)C 1-3 Haloalkyl, 6) Halogen, 7) C 1-3 Alkyl, 8) Hydroxy, Cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C optionally substituted with 1 to 3 substituents selected from haloalkyl and halogen 3-6 Cycloalkyl, and 9) hydroxy, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3a 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, optionally substituted by 1-3 substituents selected from haloalkyl, and halogen; Alternatively, R1 and R2 together with the nitrogen atom to which they are attached can form a 5- or 6-membered saturated, partially saturated, or aromatic heterocyclic ring having 1 to 3 ring heteroatoms independently selected from N, O, S, which can be hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen; R3 is H or C 1-3 is alkyl, Each R4 and R5 is independently H or C 1-3 is alkyl, G1, C 6-10 Aryl, C 3-7 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 alkyl, and 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; C 6-10 Aryl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, and 5- to 10-membered heteroaryl are each selected from 1, 2, or 3 independently selected R 30 may be substituted with a group, Each R 30 But halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, and C optionally substituted with halogen and hydroxy 1-3 independently selected from alkoxy; The present invention provides a compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0016] The present disclosure further provides the following compounds: 1.1 G1 is an optionally substituted C 6-10 Compound 1, which is an aryl; 1.2 Compound 1, wherein G1 is optionally substituted phenyl; 1.3 Compound 1, wherein G1 is optionally substituted pyridyl; 1.4 G1 is an optionally substituted C 3-6 Compound 1, which is a cycloalkyl; 1.5 Compound 1, wherein G1 is optionally substituted cyclopropyl or cyclohexyl; 1.6 Compound 1, wherein G1 is phenyl optionally having one or two substituents; 1.7 Compound 1, wherein G1 is phenyl optionally having one or two substituents; 1.8 Compound 1, wherein G1 is phenyl substituted at the 3-position; 1.9 Compound 1, wherein G1 is phenyl substituted at the 3- and 5-positions; 1.10 Compound 1, wherein G1 is phenyl substituted at the 2- and 5-positions; 1.11 Compound 1, wherein G1 is phenyl substituted at the 2- and 4-positions; 1.12 Compound 1, wherein G1 is phenyl substituted at the 2- and 3-positions; 1.13 Compound 1, wherein G1 is phenyl substituted at the 3- and 4-positions; 1.14 Each R 30 any of the preceding compounds wherein is independently selected from mono-, di-, or trihalomethyl, fluorine, chlorine, methoxy, cyano, and methyl; 1.15 each R 30 any of the preceding compounds wherein is independently selected from difluoromethyl, trifluoromethyl, fluorine, chlorine, methoxy, cyano, and methyl; 1.16 each R 30 any of the preceding compounds wherein is independently selected from fluorine and chlorine; 1.17 Each R 30 any of the preceding compounds, wherein is fluorine; 1.18 G1, C 1-3 Compound 1, which is a haloalkyl; 1.19 Compound 1, wherein G1 is trifluoromethyl; 1.20 Any of the preceding compounds wherein n is 1; 1.21 Any of the preceding compounds wherein n is 2; 1.22 Any of the preceding compounds wherein m, k, and q are each 1; 1.23 Any of the preceding compounds wherein q and m are each 1 and k is 0; 1.24 Any of the preceding compounds wherein m is 0 and k and q are each 1; 1.25 Any of the preceding compounds wherein k is 0 and m and q are each 1; 1.26 R1 and R2 each independently represent 1 to 3 R 20 C optionally substituted with a group 1-3 any of the preceding compounds which is alkyl; 1.27 R1 and R2 are each independently one to three R independently selected from hydroxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, methoxy, halogen, and cyano. 20 C optionally substituted with a group 1-3 any of the preceding compounds which is alkyl; 1.28 R1 is H or C 1-3 alkyl, and R2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Any of the preceding compounds optionally substituted with one, two, or three groups selected from haloalkyl, cyano, and halogen; 1.29 R1 is H or C 1-3any of the preceding compounds wherein R is alkyl and R2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is optionally substituted with one, two, or three groups selected from hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, cyano, and halogen; 1.30 R1 is H or C 1-3 alkyl, and R2 is selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, tetrahydropyran, and C 3-6 C substituted with a ring selected from cycloalkyl 1-3 any of the preceding compounds which is alkyl, each of which is optionally substituted with one, two, or three groups selected from hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, cyano, and halogen; 1.31 R1 and R2, together with the nitrogen atom to which they are attached, form a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Any of the preceding compounds optionally substituted with one, two, or three groups selected from haloalkyl, cyano, and halogen; 1.32 Any of the preceding compounds, wherein the compound is selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0017] Also provided herein is a topical or oral composition [Composition 1] comprising an MrgprX2 antagonist and a dermatologically or orally acceptable excipient. In some embodiments, the MrgprX2 antagonist is Compound I having Formula I above.

[0018] The present disclosure further provides the following compositions: 1.1 Composition 1, wherein the MrgprX2 antagonist is compound I having formula I above; 1.2 G1 is an optionally substituted C 6-10 Composition 1, which is aryl; 1.3 Composition 1, wherein G1 is optionally substituted phenyl; 1.4 Composition 1, wherein G1 is optionally substituted pyridyl; 1.5 G1 is an optionally substituted C 3-6 Composition 1, which is cycloalkyl; 1.6 Composition 1, wherein G1 is optionally substituted cyclopropyl or cyclohexyl; 1.7 Composition 1, wherein G1 is phenyl optionally bearing one or two substituents; 1.8 Composition 1, wherein G1 is phenyl optionally having one or two substituents; 1.9 Composition 1 wherein G1 is phenyl substituted at the 3-position; 1.10 Composition 1 wherein G1 is phenyl substituted at the 3- and 5-positions; 1.11 Composition 1 wherein G1 is phenyl substituted at the 2- and 5-positions; 1.12 Composition 1 wherein G1 is phenyl substituted at the 2- and 4-positions; 1.13 Composition 1 wherein G1 is phenyl substituted at the 2- and 3-positions; 1.14 Composition 1 wherein G1 is phenyl substituted at the 3- and 4-positions; 1.15 each R 30Any of the preceding compositions wherein is independently selected from mono-, di-, or trihalomethyl, fluorine, chlorine, methoxy, cyano, and methyl; 1.16 each R 30 Any of the preceding compositions wherein is independently selected from difluoromethyl, trifluoromethyl, fluorine, chlorine, methoxy, cyano, and methyl; 1.17 Each R 30 Any of the preceding compositions wherein is independently selected from fluorine and chlorine; 1.18 each R 30 Any of the preceding compositions wherein is fluorine; 1.19 G1, C 1-3 Composition 1, which is haloalkyl; 1.20 Composition 1 wherein G1 is trifluoromethyl; 1.21 Any of the preceding compositions wherein n is 1; 1.22 Any of the preceding compositions wherein n is 2; 1.23 Any of the preceding compositions wherein m, k, and q are each 1; 1.24 Any of the preceding compositions wherein q and m are each 1 and k is 0; 1.25 Any of the preceding compositions wherein m is 0 and k and q are each 1; 1.26 Any of the preceding compositions wherein k is 0 and m and q are each 1; 1.27 R1 and R2 each independently represent 1 to 3 R 20 C optionally substituted with a group 1-3 Any of the preceding compositions wherein is alkyl; 1.28 R1 and R2 are each independently one to three R independently selected from hydroxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, methoxy, halogen, and cyano. 20 C optionally substituted with a group 1-3 Any of the preceding compositions wherein is alkyl; 1.29 R1 is H or C 1-3alkyl, and R2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Any of the preceding compositions optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen; 1.30 R1 is H or C 1-3 Any of the preceding compositions wherein R is alkyl and R2 is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is optionally substituted with 1, 2, or 3 groups selected from hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, cyano, and halogen; 1.31 R1 is H or C 1-3 alkyl, and R2 is selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, tetrahydropyran, and C 3-6 C substituted with a ring selected from cycloalkyl 1-3 Any of the preceding compositions which is alkyl, each of which is optionally substituted with one, two, or three groups selected from hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxy, di- or trihalomethyl, e.g., difluoromethyl or trifluoromethyl, cyano, and halogen; 1.32 R1 and R2, together with the nitrogen atom to which they are attached, form a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Any of the preceding compositions optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen; 1.33 Any of the preceding compounds, wherein the compound is selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. 1.34 Any of the preceding compositions, wherein the composition is an oral dosage form. 1.35 Any of the preceding compositions, wherein the composition is in the form of a cream, gel, spray, or ointment. 1.36 Any of the preceding compositions, wherein the MrgprX2 antagonist is present in a concentration of about 0.001% to about 10% by weight, based on the total weight of the composition. 1.37 Any of the preceding compositions, wherein the MrgprX2 antagonist is present in a concentration of about 0.1% to about 5% by weight, based on the total weight of the composition. 1.38 Any of the preceding compositions further comprising a skin absorption enhancer. 1.39 Any of the preceding compositions further comprising a skin absorption enhancer, including one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 1.40 Any of the preceding compositions, wherein the composition is applied to the patient's skin once daily. 1.41 Any of the preceding compositions, wherein the composition is applied to the patient's skin twice daily. 1.42 Any of the preceding compositions, wherein the composition is applied to the patient's skin three times daily. 1.43 Any of the preceding compositions, wherein the composition is administered to a patient suffering from an inflammatory disorder. 1.44 The preceding composition, wherein the inflammatory disorder is a skin disorder. 1.45 The preceding composition, wherein the skin is human skin. 1.46 Any of compositions 1.64-1.66, wherein the inflammatory disorder activates MrgprX2 or is the result of activation of MrgprX2. 1.47 The preceding composition, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, adverse drug response. 1.48 Any of compositions 1.63-1.67, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). 1.49 Any of compositions 1.63-1.66, wherein the inflammatory disorder is atopic dermatitis. 1.50 Any of the preceding compositions wherein the subject is a human. 1.51 Any of the preceding compositions wherein the mammalian skin is human skin. 1.52 Any one of the preceding compositions, wherein the composition is for oral administration.

[0019] As used herein, a "topical composition" refers to a formulation of an invention compound with a vehicle generally accepted in the art for delivering a biologically active compound to mammalian skin, e.g., human skin. Such vehicles include all dermatologically acceptable carriers, diluents, or excipients therefor.

[0020] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds, but having different three-dimensional structures and are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0021] "Solvate" refers to a form of a compound complexed with solvent molecules.

[0022] "Tautomers" refer to two molecules that are structural isomers that readily interconvert.

[0023] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0024] "Pharmaceutically acceptable acid addition salts" are those which retain the biological effectiveness and properties of the biologically or otherwise desirable free base and are prepared from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as from, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, 10-camphor-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, acetic ... It refers to salts formed with organic acids such as guar, guar, guar- ...

[0025] "Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the biologically or otherwise desirable free acid. These salts are prepared from the addition of 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, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, 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, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0026] The compounds of the invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-. The present invention is meant 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 the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC).

[0027] "Dermatologically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, including those approved by the U.S. Food and Drug Administration as acceptable for dermatological use in humans or domestic animals, or those known or suitable for use in dermatological compositions.

[0028] "Optionally" or "optionally" means that the subsequently described circumstance event may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. When a functional group is described as "optionally substituted," and thus a substituent on the functional group is also "optionally substituted," etc., for purposes of this invention, such repetition is limited to three times.

[0029] The term "alkyl" is intended to mean a straight or branched chain carbon group containing the indicated number of carbon atoms. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, and the like.

[0030] The term "cycloalkyl" is intended to mean a saturated ring group containing the indicated number of carbon atoms. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0031] The term "haloalkyl" is intended to mean a group containing an alkyl group having the indicated number of carbon atoms, substituted with one or more halogens. For example, a C1-C6 haloalkyl may be fully substituted, in which case it has the formula C n L 2n+1where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6. When two or more halogens are present, they may be the same or different and may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkyl contains 1 to 5 carbons. In some embodiments, a haloalkyl contains 1 to 4 carbons. In some embodiments, a haloalkyl contains 1 to 3 carbons. In some embodiments, a haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like. When used without a prefix indicating the number of halo substituents, a "haloalkyl" group contains 1, 2, or 3 halogen atoms.

[0032] The term "hydroxyalkyl" is intended to mean a group comprising an alkyl group having the indicated number of carbon atoms substituted with one or more hydroxy (i.e., -OH) groups. When used without a prefix indicating the number of hydroxy substituents, the "hydroxyalkyl" group contains 1, 2, or 3 hydroxy groups.

[0033] The term "halogen" is intended to mean a fluoro, chloro, bromo, or iodo group.

[0034] The term "aryl" is intended to mean a ring system containing 6 to 10 carbon atoms and which may contain a single ring or two fused rings, in which at least one ring is aromatic. Examples include phenyl, indanyl, and naphthyl.

[0035] The term "heteroaryl" is intended to mean a ring system containing 5 to 14 ring atoms, which may contain a single ring, two fused rings, or three fused rings, in which at least one ring is aromatic and at least one ring atom is a heteroatom selected from, for example, O, S, and N. Some embodiments contain 5 to 6 ring atoms, such as, for example, furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc. Some embodiments include, for example, quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, Containing 8 to 14 ring atoms, such as isobenzofuran, 2,3-dihydrobenzofuranyl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-hydro-isoquinolinyl, 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridinyl, 7,8-dihydro-5H-[1,6]naphthyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxyl, pyrazolo[1,5-a]pyrimidinyl, and 1,2,3,4-tetrahydroquinolinyl.

[0036] The term "cyano" refers to the group --CN.

[0037] The term "alkoxy" means a radical of the formula --O-alkyl having the indicated number of carbon atoms.

[0038] As used herein, the term "heterocycloalkyl" is intended to mean a non-aromatic 3- to 6-membered heterocyclic ring, which may be fused to a 3- to 6-membered saturated, partially unsaturated, or aromatic aryl or heteroaryl ring. Examples of non-aromatic 3- to 6-membered heterocyclic rings include oxirane, azinidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyran, morpholine, piperazine, hexahydropyrimidine, hexahydropyridazine, and the like. A heterocycloalkyl group may contain one or more oxo (i.e., -C=O-) groups within the ring, and the sulfur ring heteroatom may be present as a sulfur dione. Examples of such heterocycloalkyl rings include sulfolane, tetrahydro-2H-thiopyran-1,1-dione, thiomorpholine-1,1-dioxide, 2-pyrrolidione, piperidin-2-one, piperazin-2-one, morpholin-3-one, and the like. Examples of heterocycloalkyls having fused rings include dihydroindoles, such as 1,3 dihydroindole.

[0039] The term "spiroalkyl" is intended to mean a structure of two or more rings, two of which share one common atom and at least one of which is a cycloalkyl ring containing the indicated number of carbon atoms. Examples include spirocyclopropane and spirocyclobutane.

[0040] Methods of Using the Compounds of the Invention The compounds of the invention are useful for treating inflammatory disorders, such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions caused by small molecules, such as anaphylactic drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, and adverse drug reactions.Therefore, the administration or use of the preferred MrgprX2 antagonists described herein, such as the above-mentioned MrgprX2 antagonists, for example, compounds of Formula I, provides a means of improving the symptoms and / or providing treatment for various inflammatory diseases and disorders.

[0041] For example, in one embodiment of the present disclosure, the present disclosure provides a method for treating an inflammatory disorder [Method 1], comprising administering to a subject in need thereof a topical or oral composition comprising a therapeutically effective amount of an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) and a dermatologically or orally acceptable excipient.

[0042] The present disclosure further provides additional embodiments of Method 1 as follows: 1.1 Method 1, wherein the MrgprX2 antagonist is a compound according to formula I above; 1.2 Method 1.1, wherein the MrgprX2 antagonist is a compound according to any of the above compounds 1.1 to 1.55; 1.3 Any of the preceding methods wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof; 1.4 Any of the preceding methods, wherein the composition is in the form of a cream, gel, spray, or ointment. 1.5 Any of the preceding methods, wherein the MrgprX2 antagonist is present in a concentration of about 0.001% to about 10% by weight based on the total weight of the composition. 1.6 Any of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1% to about 5% by weight based on the total weight of the composition. 1.7 Any of the preceding methods further comprising a skin absorption enhancer. 1.8 Any of the preceding methods further comprising a skin absorption enhancer, including one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 1.9 Any of the preceding methods, wherein the composition is applied to the patient's skin once daily. 1.10 Any of the preceding methods wherein the composition is applied to the patient's skin twice daily. 1.11 Any of the preceding methods wherein the composition is applied to the patient's skin three times daily. 1.12 Any of the preceding methods wherein the composition is administered to a patient suffering from an inflammatory disorder. 1.13 The preceding method, wherein the inflammatory disorder is a skin disorder. 1.14 The preceding method, wherein the skin is human skin. 1.15 Any of methods 1.12-1.14, wherein the inflammatory disorder activates MrgprX2 or is the result of activation of MrgprX2. 1.16 The preceding methods, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, or adverse drug response. 1.17 Any of methods 1.12-1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). 1.18 Any of methods 1.12-1.16, wherein the inflammatory disorder is atopic dermatitis. 1.19 Any of the preceding methods in which the subject is a human. 1.20 Any of the preceding methods in which the mammalian skin is human skin. 1.21 Any of the preceding methods, wherein the composition is for oral administration.

[0043] In another embodiment, the present disclosure provides a method for reducing inflammation in mammalian skin [Method 2], comprising administering to a subject in need thereof an effective amount of a topical or oral composition comprising an MrgprX2 antagonist according to the present disclosure and a dermatologically acceptable excipient to the mammalian skin.

[0044] The present disclosure further provides a further embodiment of Method 2 as follows: 2.1 Method 2, wherein the MrgprX2 antagonist is a compound according to formula I above; 2.2 Method 2 or 2.1, wherein the MrgprX2 antagonist is a compound according to any of compounds 1.1 to 1.55 above; 2.3 Any of the preceding methods wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof; 2.4 Any of the preceding methods, wherein the inflammation is a result of activation of MrgprX2; 2.5 Any of the preceding methods, wherein the composition is in the form of a cream, gel, spray, or ointment. 2.6 Any of the preceding methods, wherein the MrgprX2 antagonist is present in a concentration of about 0.001% to about 10% by weight based on the total weight of the composition. 2.7 Any of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1% to about 5% by weight based on the total weight of the composition. 2.8 Any of the preceding methods further comprising a skin absorption enhancer. 2.9 Any of the preceding methods further comprising a skin absorption enhancer, including one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 2.10 Any of the preceding methods, wherein the composition is applied to the patient's skin once daily. 2.11 Any of the preceding methods wherein the composition is applied to the patient's skin twice daily. 2.12 Any of the preceding methods, wherein the composition is applied to the patient's skin three times daily. 2.13 Any of the preceding methods wherein the composition is administered to a patient suffering from an inflammatory disorder. 2.14 The preceding method, wherein the inflammatory disorder is a skin disorder. 2.15 The preceding method, wherein the skin is human skin. 2.16 Any of methods 1.12-1.14, wherein the inflammatory disorder activates MrgprX2 or is the result of activation of MrgprX2. 2.17 The preceding methods, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, or adverse drug response. 2.18 Any of methods 1.12-1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). 2.19 Any of methods 1.12-1.16, wherein the inflammatory disorder is atopic dermatitis. 2.20 Any of the preceding methods in which the subject is a human. 2.21 Any of the preceding methods in which the mammalian skin is human skin. 2.22 Any of the preceding methods, wherein the composition is for oral administration.

[0045] A further embodiment provides a method [Method 3] for reducing the incidence or severity of itch, comprising administering to the skin of a mammal a therapeutically effective amount of a topical or oral composition according to any of Compositions 1 and 1.1-1.73.

[0046] The present disclosure further provides a further embodiment of Method 3 as follows: 3.1 Method 3, wherein the severity of itch is reduced within 5 minutes of administration. 3.2 Method 3 or 3.1, wherein the severity of itch is reduced over a 6 hour period following administration. 3.3 Method 3 or 3.1, wherein the severity of itch is reduced over a 12 hour period following administration. 3.4 Method 3 or 3.1, wherein the severity of itch is reduced over an 18 hour period following administration. 3.5 Method 3 or 3.1, wherein the severity of the itch is reduced over a 24 hour period following administration. 3.6 Any of the preceding methods wherein the MgrprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. 3.7 Any of the preceding methods wherein the composition is in the form of a cream, gel, spray, or ointment. 3.8 Any of the preceding methods, wherein the MgrprX2 antagonist is present in a concentration of about 0.001% to about 10% by weight based on the total weight of the composition. 3.9 Any of the preceding methods, wherein the MgrprX2 antagonist is present in a concentration of about 0.1% to about 5% by weight based on the total weight of the composition. 3.10 Any of the preceding methods further comprising a skin absorption enhancer. 3.11 The prior method, wherein the skin absorption enhancer comprises one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 3.12 Any of the preceding methods wherein the composition is applied to the patient's skin once daily. 3.13 Any of the preceding methods wherein the composition is applied to the patient's skin twice daily. 3.14 Any of the preceding methods, wherein the composition is applied to the patient's skin three times daily. 3.15 Any of the preceding methods, wherein the composition is administered to a patient suffering from an inflammatory disorder. 3.16 Any of the preceding methods, wherein the inflammatory disorder is a skin disorder. 3.17 Any of the preceding methods, wherein the skin is human skin. 3.18 Any of methods 1.12-1.14, wherein the inflammatory disorder activates MrgprX2 or is the result of activation of MrgprX2. 3.19 The preceding methods, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, or adverse drug response. 3.20 Any of methods 1.12-1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). 3.21 Any of methods 1.12-1.16, wherein the inflammatory disorder is atopic dermatitis. 3.22 Any of the preceding methods in which the subject is a human. 3.23 Any of the preceding methods in which the mammalian skin is human skin. 3.24 Any of the preceding methods, wherein the composition is for oral administration.

[0047] "Atopic dermatitis" refers to a chronic inflammatory skin condition, and symptoms of atopic dermatitis include a red, itchy rash. Atopic dermatitis can occur on the skin of any part of the body, but is most common on the hands, feet, upper chest, and elbows or knees. Additional symptoms of atopic dermatitis can include small, raised bumps or thickened, scaly skin.

[0048] "Psoriasis" is a chronic skin condition associated with an excessive immune response. Psoriasis can occur on the skin of any part of the body. Symptoms of psoriasis include localized inflammation, peeling skin, and thick white or red discolored areas of the skin.

[0049] "Alopecia" is an autoimmune skin disease that causes hair loss on the scalp, face, and possibly other areas of the body. For example, in alopecia areata, T-cell lymphocytes cluster around affected follicles, causing inflammation and subsequent hair loss.

[0050] "Chronic hives" (hives) are a common skin rash triggered by many factors, including certain foods, medications, and stress. Symptoms include itchy, raised, red, or skin-colored swellings on the skin surface. Considering the role of mast cells in chronic idiopathic urticaria, MrgprX2 plays an important role in mast cell activation. Antibacterial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and several FDA-approved peptide agonists activate human MrgprX2. Unique properties of MrgprX2 that distinguish it from other GPCRs include its presence at both plasma membrane and intracellular sites, as well as its selective expression in MCs. Furthermore, small molecule inhibitors of MrgprX2 may be beneficial for treating MC-dependent allergic and inflammatory disorders, such as chronic urticaria, which are currently treated by targeting the IgE axis of mast cell activity. However, diverse 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.2016.04.051), suggesting that targeting MRGPRX2 may indeed be a therapeutic option for IgE-independent and resistant chronic urticaria.

[0051] Anaphylactic shock is an extreme, often life-threatening, allergic response to an antigen to which the body is hypersensitive. MrgprB2-mediated mast cell activation has attracted attention for its IgE-independent mast cell activation and non-histaminergic itch (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 proadrenomedullin N-terminal peptide 9-20 (PAMP9-20) induced the release of multiple bioactive mediators from mast cells, which in turn activated itch-sensing neurons, suggesting that mast cell-specific MrgprB2 is important in mast cell degranulation and the associated nonhistaminergic itch. Mast cell MrgprB2 and MrgrpX2 are activated by pseudoallergy-inducing drugs such as SP, compound 48 / 80, and icatibant (McNeil, BD et al., 2015, Nature, 519(7542), 237-241; https: / / doi.org / 10.1038 / nature14022), and MrgprX2 plays a central role in non-histaminergic mast cell activation and various allergic and non-allergic diseases, as well as pseudoallergic responses.

[0052] Rosacea is a condition that causes redness, often small, red, pus-filled bumps on the face. MrgrpX2 has also been 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 and Subramanian, H. et al., 2013, Journal of Immunology (Baltimore, Md.: 1950), 191(1), 345-352; https: / / doi.org / 10.4049 / jimmunol.1300023), it has emerged that mast cell MrgprX2 may participate in antibacterial host defense. Pituitary adenylate cyclase-activating peptide (PACAP), a potent mast cell degranulator (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 function in innate immunity by regulating host defense responses.Considering that MrgprX2 is activated by peptides such as LL-37 and the neuropeptide PACAP, both of which are critically involved in rosacea and function as trigger peptides that influence mast cell activity and vasodilation, these findings together suggest MrgprX2 as a newly emerging receptor in the pathophysiology of rosacea.

[0053] Asthma is a condition in which human airways become inflamed, narrowed, swollen, and produce excess mucus, making breathing difficult. Mast cells (MCs), which normally reside in close proximity to smooth muscle, T cells, and leukocytes, are key effector cells in the airway hyperresponsiveness and inflammation that characterize asthma. While only low amounts of transcripts are present in healthy conditions, MrgprX2 transcript levels increase in severe asthma, characterized by a phenotypic switch from MCTs to MCTCs. In contrast to MCTs, mast cell MCTC populations in severe asthma express MrgprX2 (Fajt MLet 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 that SP levels are increased in the lungs of patients with severe asthma, which activates MrgprX2, treatment with small molecule antagonists may benefit patients with severe asthma (van Diest, SA. et al., 2012, Biochimica et Biophysica Acta, 1822(1), 74-84; https: / / doi.org / 10.1016 / j.bbadis.2011.03.019).

[0054] "Mammal" or "mammalian" includes both humans and domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0055] A "therapeutically effective amount" refers to the amount of a compound of the invention that, when administered to a mammal, preferably a human, is sufficient to achieve treatment of the desired disease or condition in a mammal, preferably a human, having the disease or condition. The amount of a compound of the invention that corresponds to a "therapeutically effective amount" will vary depending on the compound, the disease or condition and its severity, the mode of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art in light of their own knowledge and this disclosure. Preferably, for purposes of the present invention, a "therapeutically effective amount" is the amount of a compound of the invention that is sufficient to inhibit skin inflammation.

[0056] As used herein, "treating" or "treatment" encompasses the treatment of a disease or condition of interest in a mammal, preferably a human; (i) preventing a disease or condition from occurring in a mammal; (ii) inhibiting, i.e., arresting the progression of, a disease or condition in a mammal; (iii) alleviating a disease or condition in a mammal, i.e., causing regression of the disease or condition; or (iv) Alleviating the symptoms of a disease or condition in a mammal, i.e., alleviating the symptoms without addressing the underlying disease or condition.

[0057] As used herein, the terms "disease," "disorder," and "condition" may be used interchangeably or may differ in that a particular illness or condition may not have a known causative factor (and thus the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable state or syndrome, with more or less specific sets of symptoms identified by clinicians.

[0058] As used herein, the term "about" means ±20% of the indicated range, value, or structure, unless otherwise indicated.

[0059] In some embodiments, the MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) is present in the topical or oral composition at a concentration of about 0.05% to about 5% by weight.

[0060] In certain embodiments, the pharmaceutical compositions described herein further comprise a dermatologically acceptable excipient.The dermatologically acceptable excipient may be one or more solvents that solubilize and / or stabilize the active ingredient (e.g., MrgprX2 antagonist) contained in the composition.The dermatologically acceptable excipient may also include a skin penetration enhancer, a preservative, a viscosity enhancer, a pH adjuster, a film-forming agent, etc. Non-limiting examples of suitable excipients include water, PEG200, PEG400, ethanol, glycerol, Transcutol P (diethylene glycol monoethyl ether), propylene glycol, 1,3-dimethyl-2-imidazolidinone (DMI), sodium metabisulfite, butylated hydroxytoluene (BHT), benzyl alcohol, sodium benzoate, isopropyl myristate, diisopropyl adipate, Crodamol OHS (ethylhexyl hydroxystearate), mineral oil, Betadex, TWEEN 20, Brij S20 (polyoxyethylene (20) stearyl ether).

[0061] A more detailed description of certain suitable excipients is provided below. As will be understood, components of the pharmaceutical formulations described herein may have multiple functions. For example, a given substance may act as both a viscosity-increasing agent and an emulsifier.

[0062] The skin (particularly the stratum corneum) provides a physical barrier against the harmful effects of the external environment. In doing so, the skin also interferes with the absorption or transdermal delivery of topical therapeutic drugs. Therefore, suitable dermatologically acceptable excipients can include one or more penetration enhancers (or permeation enhancers), which are substances that promote the diffusion of therapeutic drugs (e.g., the MrgprX2 antagonists described herein) through the skin barrier. They typically act to reduce the barriers or resistance of the skin, allowing for improved penetration of therapeutic drugs. Specifically, substances that disrupt the normal structure of the stratum corneum can disrupt the lipid organization between cells, thus reducing its effectiveness as a barrier. These substances can include any lipid substance that will split into stratum corneum lipids, causing direct effects, or any substance that will affect proteins and cause indirect disruption of lipid structure. In addition, solvents such as ethanol can remove lipids from the stratum corneum, thus destroying its lipid organization and disrupting its barrier function.

[0063] Examples of penetration enhancers or barrier function disrupters include, but are not limited to, alcohol-based enhancers such as alkanols having 1 to 16 carbons, benzyl alcohol, butylene glycol, diethylene glycol, glycofurol, glycerides, glycerin, glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based enhancers such as N-butyl-N-dodecylacetamide, crotamiton, 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; almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, castor oil, 1-carvone, coconut oil, corn oil, cottonseed oil, eugenol, menthol, and anise oil. essential oils such as 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, allantoin, black walnut extract, chamomile extract, panthenol, papaya, tocopherol, and vitamin A palmitate; waxes such as candelilla wax, carnauba wax, ceresin wax, beeswax, lanolin wax, jojoba oil, and petrolatum; primary esters of fractionated vegetable oil fatty acids with glycerin or propylene glycol, and mixtures of interesterified medium-chain triglyceride oils; amyl caproate, butyl acetate, caprylic acid, cetyl esters, diethyl sebacate, dioctyl malate, elaidic acid, ethyl caprylate, ethyl glycol palmitostearate, glyceryl behenate beheate), glucose glutamate, isobutyl acetate, laureth-4, lauric acid, malic acid, methyl caprylate, 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, soap, and fatty acids and fatty acid esters such as caproic, caprylic, capric, and lauric triglycerides;Macrocylics such as butylated hydroxyanisole, cyclopentadecanolide, and cyclodextrin; phospholipid and phosphate enhancers such as dialkyl phosphates, ditetradecyl phosphate, and lecithin; biodegradable soft penetration enhancers such as 2-pyrrolidone derivatives such as alkylpyrrolidone-5-carboxylic acid esters, pyroglutamic acid esters, N-methylpyrrolidone, dioxane derivatives, and dioxolane derivatives; sulfoxide enhancers such as dimethyl sulfoxide and decylmethyl sulfoxide; alginic acid, sorbic acid, and succinic acid. Acid enhancers such as cyclic amines, imidazolinones, imidazoles, ketones such as acetone, dimethicone, methyl ethyl ketone, and pentanedione, lanolin derivatives such as lanolin alcohol, PEG-16 lanolin, and acetylated lanolin, oxazolines, oxazolindinones, proline esters, pyrroles, urethanes, and surfactants such as nonoxynol, polysorbates, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, sodium lauryl sulfate, and sorbitan monostearate.

[0064] The topical compositions described herein typically contain one or more carriers, preferably having a vapor pressure of 23.8 mm Hg or greater at 25°C. Preferred concentration ranges of a single carrier or total combination of carriers can be from about 0.1% to about 10%, more preferably from about 10% to about 50%, and more specifically from about 50% to about 95% by weight 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.

[0065] The dermatological compositions of the invention may contain one or more hydrophilic cosolvents that are miscible with water and / or low-chain alcohols and preferably have a vapor pressure less than that of water (approximately 23.8 mm Hg) at 25°C. The carrier typically has a vapor pressure equal to or greater than that of the hydrophilic cosolvent to concentrate the active ingredient (e.g., the MrgprX2 antagonist of the present disclosure) on the skin. The hydrophilic cosolvent may be a glycol, specifically propylene glycol. Specifically, the propylene glycol may be from the class of polyethylene glycols, specifically those in the molecular weight range of 200 to 20,000. Preferably, the solvent will be part of the glycol ether class. More specifically, the hydrophilic cosolvent of the invention will be diethylene glycol monoethyl ether (Transquitol). As used herein, "diethylene glycol monoethyl ether" ("DGME") or "Transquitol" refers to 2-(2-ethoxyethoxy)ethanol {CAS No. 001893} or ethyoxydiglycol. Another preferred co-solvent is 1,3-dimethyl-2-imidazolidinone (DMI).

[0066] The topical compositions described herein may also contain one or more "humectants" used to provide a moisturizing effect. Preferably, the humectant remains stable in the composition. Any suitable concentration of a single humectant or combination of humectants may be used, provided that the resulting concentration provides the desired moisturizing effect. Typically, the suitable amount of humectant will depend on the specific humectant or humectants used. Preferred concentrations of a single humectant or a combination of humectants may range from about 0.1% to about 70% by weight of the dermatological composition, more preferably from about 5.0% to about 30% by weight, and more specifically from about 10% to about 25% by weight. Non-limiting examples for use herein include glycerin, polyhydric alcohols, and silicone oils. More preferably, the humectant is glycerin, propylene glycol, and / or cyclomethicone. Specifically, the filler will be glycerin and / or cyclomethicone.

[0067] In certain embodiments, the pharmaceutical composition includes a viscosity-enhancing agent or emulsifier. Gelling agents are used to increase the viscosity of the final composition. Emulsifiers are substances that stabilize emulsions. Viscosity-enhancing agents may also act as emulsifiers. Typically, the concentration and combination of viscosity-enhancing agents will depend on the physical stability of the finished product. A preferred concentration range for the viscosity-enhancing agent may be about 0.01% to about 20% by weight of the dermatological composition, more preferably about 0.1% to about 10% by weight, and more specifically about 0.5% to about 5% by weight. Non-limiting examples of viscosity-increasing agents for use herein include classes of celluloses, acrylate polymers, and acrylate crosspolymers, 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, more specifically hydroxypropyl cellulose (Klucel® EF, GF, and / or HF), Pluronic PF127, carbomer 980, and / or carbomer 1342 (Pemulen® TR-1, TR-2, and / or Carbopol® ETD2020). Examples of emulsifiers for use herein include polysorbates, laureth-4, and potassium cetyl sulfate.

[0068] The topical or oral compositions described herein may contain one or more antioxidants, radical scavengers, and / or stabilizers, with preferred concentrations ranging from about 0.001% to about 0.1% by weight of the dermatological composition, more preferably from about 0.1% to about 5% by weight. Non-limiting examples for use herein include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tocophersolan, and propyl gallate. More specifically, the antioxidant may be ascorbyl palmitate, vitamin E acetate, vitamin E-TPGS, vitamin E, or butylated hydroxytoluene.

[0069] The topical or oral compositions described herein may also contain a preservative that exhibits antibacterial and / or antifungal properties. A preservative may be present in the gelling dermatological compositions of the invention to minimize bacterial and / or fungal growth over the shelf life. A preferred concentration range for the preservative in the dermatological compositions of the invention may be from about 0.001% to about 0.01% by weight of the dermatological composition, more preferably from about 0.01% to about 0.5% by weight. Non-limiting examples for use herein include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben. More specifically, the preservative may be a combination of methylparaben and propylparaben.

[0070] The topical compositions described herein may contain one or more chelating agents. As used herein, the term "chelating agent" or "chelator" refers to a skin benefit agent capable of removing metal ions from a system by forming a complex such that the metal ions cannot readily participate in or catalyze chemical reactions. Chelating agents for use herein are preferably formulated at a concentration ranging from about 0.001% to about 10% by weight of the dermatological composition, more preferably from about 0.05% to about 5.0% by weight. Non-limiting examples for use herein include EDTA, disodium edeate, dipotassium edetate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid, and potassium gluconate. Specifically, the chelating agent may be EDTA, disodium edeate, dipotassium edate, trisodium edetate, or potassium gluconate.

[0071] The topical or oral compositions described herein may contain one or more commonly used, compatible, cosmetically acceptable adjuvants, such as coloring agents, fragrances, emollients, and botanical substances, such as aloe, chamomile, witch hazel, and the like.

[0072] Alternatively, other pharmaceutical delivery systems can be used for the pharmaceutical compositions of the invention.Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds or prodrugs.Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used.

[0073] The topical compositions described herein can be provided in any cosmetically suitable form, preferably as a lotion, cream, or ointment, as well as in a sprayable liquid form (e.g., a spray containing an MrgprX2 antagonist in a base, vehicle, or carrier that, when applied to the skin, dries in a cosmetically acceptable manner without the greasy appearance that a lotion or ointment would have).

[0074] Any suitable amount of MrgprX2 antagonist (e.g., a compound according to the present disclosure) can be employed in such dermatological compositions, provided that the amount effectively reduces local inflammation and / or vascular dysfunction and remains stable in the composition for an extended period of time. Preferably, the stability is for an extended period of time typical of the manufacturing, packaging, shipping, and / or storage of dermatologically acceptable compositions, such as up to about 3 years, up to about 1 year, or up to about 6 months. The compound of the present disclosure can be present in solution, partially in solution with undissolved portions, or in a completely undissolved suspension. The compound of the present disclosure can be present in the dermatological compositions of the present invention in a concentration range of about 0.001% to about 80%, about 0.001% to about 50%, about 0.001% to about 25%, or about 0.001% to about 6% by weight of the dermatological composition. In one embodiment, the compounds of the present disclosure may be present in a concentration range of about 0.001% to about 10%, about 0.1% to about 10%, or about 1.0% to about 5.0% by weight of the dermatological composition.

[0075] In the treatment of inflammatory disorders such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, such as anaphylactic drug responses, anaphylactic shock, rosacea, asthma, systemic itching such as cholestatic or uremic itching, chronic itching caused by systemic diseases, or adverse drug reactions, topical compositions containing compounds of the present disclosure are preferably administered directly to the affected area of ​​the skin (e.g., itchy skin) of the person in need of treatment. During use of such compositions (e.g., dermatological compositions containing compounds of the present disclosure), and when dermatologically acceptable excipients are placed on the skin of the person in need of treatment, the MrgprX2 antagonist is in continuous contact with the patient's skin, thereby resulting in penetration and treatment.

[0076] When administering the pharmaceutical compositions of the invention topically, the human skin to be treated may be pretreated (such as by washing the skin with soap and water or by washing the skin with an alcohol-based cleanser) prior to administration of the dermatological compositions of the invention.

[0077] The pharmaceutical compositions of the invention can be presented in a pack or dispenser device, which can contain one or more unit dosage forms containing the active compound, if desired.The topical compositions described herein can also be provided in a patch, with the topical composition on one side of the patch that directly contacts the skin.A dermatologically acceptable adhesive can be used to attach the patch to the skin for a long period of time.

[0078] Oral administration In some embodiments, the pharmaceutical compositions herein are provided for oral administration.Accordingly, the present disclosure provides a solid, semi-solid, or liquid dosage form for oral administration, comprising the compounds described herein.Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pellets, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, 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, lubricants, enteric coatings, film costing agents, modified release agents, colorants, dye transfer inhibitors, sweeteners, and flavoring agents.

[0079] Binders or granulating agents impart cohesiveness to the tablet to ensure that it remains intact after compression. Suitable binders or granulating agents 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; gum arabic, alginic acid, alginates, Irish moss extract, Panwar gum, ghatti gum, mucilage from plantain husk, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, methyl paraben, polyalkylene oxide, povidone, polyvinylpyrrolidone (PVP), crospovidone, Veegum, larch arabogalactan. Natural and synthetic gums, such as arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and 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, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein at about 50 to about 99% by weight.

[0080] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, trehalose, lysine, leucine, lecithin, starch, kaolin, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0081] Suitable disintegrants include, but are not limited to, gelatin; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; align; 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 about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[0082] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glycerol 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 laureate, gelatin, starch, lycopodium, silica or silica gel such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

[0083] Suitable lubricants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Coloring agents include any of the approved, certified water-soluble FD&C dyes, water-insoluble FD&C dyes suspended on alumina hydrate, lake colors, and mixtures thereof. Lake colors are a combination of water-soluble dyes adsorbed onto aqueous oxides of heavy metals, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, gum arabic, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid additive, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0084] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0085] The pharmaceutical compositions provided herein may be provided as compressed tablets, powder tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammonium shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial for masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings generally impart the same characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

[0086] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in chewable tablet and lozenge formats.

[0087] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two compartments, one over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, that are plasticized by adding glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben, propylparaben, and sorbic acid. Liquid, semisolid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in 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 known to those skilled in the art to modify or maintain the solubility of the active ingredient.

[0088] The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, which may be oil-in-water or water-in-oil, in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, e.g., acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, eg, water, to be measured conveniently for administration.

[0089] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weights of the 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.

[0090] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms may be prepared as described in U.S. Patent No. 6,350,458.

[0091] The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders that can be reconstituted into liquid dosage forms.The pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents.The pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources.

[0092] Coloring and flavoring agents may be used in all of the above dosage forms.

[0093] The pharmaceutical compositions provided herein can be formulated as immediate release or modified release dosage forms, including delayed-release, sustained-release, pulse-release, controlled-release, targeted-release, and programmed-release forms.Therefore, in some preferred embodiments, the active ingredient (i.e., calcium channel blocker, or L-arginine, or a combination of calcium channel blocker and L-arginine, or their pharmaceutically acceptable salts, hydrates, solvates, and prodrugs) is administered in a pharmaceutical composition that is an immediate release oral dosage form, preferably but not necessarily including an enteric coating.In some preferred embodiments, the active ingredient is administered in a pharmaceutical composition that is an extended release oral dosage form, preferably but not necessarily including an enteric coating.In a further preferred embodiment, the active ingredient is administered in a pharmaceutical composition that contains both an immediate release dose and an extended or pulsed release dose of a calcium channel blocker, preferably but not necessarily including an enteric coating. Such dual release dosage forms achieve release of an initial dose of active ingredient followed, at a time delay, by release of another pulsed or sustained release dose. Methodologies for preparing such dual release dosage forms are well known to those skilled in the art.

[0094] In some embodiments, the active ingredient is formulated into a controlled-release matrix tablet containing one or more polymer matrix materials that promote sustained, delayed, or pulsed release profiles. Non-limiting examples of such polymer matrix materials include the above-mentioned cellulose materials, as well as carbomers, such as those sold by Lubrizol Corporation under the name Carbopol®, for example, Carbopol® 71G NF, Carbopol® 971P NF, and Carbopol® 974P NF polymers.

[0095] Some preferred examples of sustained-release compositions suitable for use in the methods and compositions of the invention include, but are not limited to, sustained-release compositions found in nifedipine formulations such as Adalat CC®, Procardia® XL, Afeditab® CR, and Nifedic® XL; and in diltiazem formulations such as Cardizem® CD, Cardizem® LA, Cardizem® SR, Cartia® XT, and Dilacor® XR.

[0096] In some embodiments, the present disclosure provides pharmaceutical compositions for oral administration for use in treating the conditions and disorders described herein.

[0097] Dosage The compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein, which are useful for preventing, treating or improving one or more symptoms of diseases or disorders described herein, and a vehicle.Vehicles suitable for administering the compounds provided herein include any carrier known by those skilled in the art to be suitable for specific administration modes, preferably topical, oral or via injection.In addition, the compound can be formulated as the only active ingredient in the composition, or can be combined with other active ingredients.

[0098] The active compound is contained in the vehicle in an amount sufficient to exert therapeutically useful effects without the presence of undesirable side effects in the treated patient.The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then human dosage can be estimated from it.Then, human dosage is typically fine-tuned in clinical trials and titrated to response.

[0099] The concentration of the active compound in the composition will depend on the absorption, inactivation and excretion rate of the active compound, the physicochemical characteristics of the compound, the dosage schedule and dosage amount, and other factors known to those skilled in the art.For example, the amount delivered is sufficient to improve one or more of the symptoms of the disease or disorder described herein.

[0100] In some embodiments, the therapeutically effective dosage should be about 0.0001 mg to about 1000 mg per day. In some embodiments, 0.001 to 50 mg of active ingredient (an MgrprX2 antagonist described herein) per kilogram of body weight per day is delivered topically, orally, or by injection as described herein. In some embodiments, the MgrprX2 antagonist is administered at a dosage of up to 1500 mg / day, e.g., 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.

[0101] Active ingredient can be administered at once, or divided into several smaller doses and administered at intervals.It is understood that the exact dosage and duration of treatment can be determined empirically according to the disease to be treated, using known test protocols, or by inference from in vivo or in vitro test data, or subsequent clinical trials.It should be noted that concentration and dosage value can also vary according to the severity of the condition to be alleviated.For any specific subject, specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person who administers or supervises administration of composition, and it is further understood that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0102] Dosage forms or compositions can be prepared containing 0.005% to 100% of the active ingredient, with the remainder consisting of a vehicle or carrier. Methods for preparing these compositions are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions.

[0103] Oral Dosage Oral dosage forms of the invention containing the MrgprX2 antagonists of the present disclosure will typically be administered in the dosages described above.

[0104] In some preferred embodiments, the daily dose is administered once daily. In some embodiments, the dosage form is a sustained release composition.

[0105] In some embodiments, the daily dose is administered in a single dose. In other embodiments, the daily dose is administered in smaller increments, given multiple times daily, for example, two or three times daily, in a combined amount equal to the above daily values.

[0106] In some preferred embodiments, the daily dose is administered in a single dose that provides up to 12 hours, up to 18 hours, or up to 24 hours of effectiveness.

[0107] Topical Dosage In some embodiments, topical formulations comprising the compounds of the present disclosure will contain the MgrprX2 antagonist at a concentration of from 0.001% to 20% by weight of the composition, for example from 0.001% to 10% by weight of the composition, for example from 0.001% to 8% by weight, for example from 0.001% to 5% by weight, for example from 0.001% to 4% by weight, for example from 0.001% to 3% by weight, for example from 0.001% to 2% by weight, for example from 0.001% to 1% by weight.

[0108] The compound or derivative may be packaged as an article of manufacture containing packaging material and, within the packaging material, a compound provided herein or a derivative thereof that is effective in treating, preventing, or ameliorating one or more symptoms of the above-mentioned diseases or disorders, and a label indicating that the compound or composition or derivative thereof is used for treating, preventing, or ameliorating one or more symptoms of the above-mentioned diseases or disorders.

[0109] The manufactured articles provided herein contain packaging materials.Packaging materials for use in product packaging are well known to those skilled in the art.For example, see 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 the selected formulation and intended administration and treatment mode.A wide range of formulations of the compounds and compositions provided herein are contemplated, as are various treatments for any disease or disorder described herein.

[0110] The following examples can be used by one skilled in the art to determine the effectiveness of compounds of the invention in treating humans with dermatological conditions characterized by inflammation. [Example]

[0111] Example 1 - Preparation of compounds according to the present disclosure Example E01 TIFF0007787811000005.tif23128N-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-2-methyl-propanamide

[0112] Step 1 To a mixture of (3-fluorophenyl)acetic acid (497 g, 32.3 mmol) and sulfuric acid (8.8 mL, 0.161 mol), hydrazinecarbothioamide (3000 mg, 32.3 mmol) was slowly added, and the suspension was heated at 80 °C for 2 h. After that, the reaction mixture was cooled to room temperature and slowly poured into a mixture of ice and saturated aqueous NaHCO (50 mL). The mixture was then basified to pH 9 with 37% ammonia in water. The resulting brown solution was filtered, and the filtrate was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were washed with brine (30 mL) and concentrated in vacuo. The crude material was purified by FCC (KP Sil 25 g, 0-100% EtOAc in heptane, then 0-20% MeOH in EtOAc) to give 5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-amine as a white solid (401 mg, 5% yield, 78% purity).

[0113] Step 2 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) was added 2-methylpropanoyl chloride (35 μL, 0.335 mmol) with stirring at room temperature for 1 h. Then, MeOH (1 mL) and 1 M NaOH (1 mL) were added, and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with brine (5 mL), extracted with EtOAc (2 × 5 mL), and the combined organic extracts were washed in vacuo. The residue thus obtained was purified by column chromatography (Biotage Isolera 10 g SNAP Ultra, 0–60% EtOAc in heptane) to give the title compound (27 mg, 34%) as a pale yellow solid. 1HNMR(400MHz,DMSO-d6)δ 12.39(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).

[0114] (Table 1) Using methods similar to those used in Example E01 or using the carboxylic acid in step 2 in combination with a coupling agent such as HATU, the following compounds were synthesized. TIFF0007787811000006.tif45166TIFF0007787811000007.tif211166TIFF0007787811000008.tif74166

[0115] Example E09 TIFF0007787811000009.tif211283-[5-[(2,3-difluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea

[0116] Step 1 A stirred aqueous solution of ethanamine (70%, 5.5 mL, 68.9 mmol) was diluted with water (5 mL), cooled to 0 °C, and a solution of (2S)-2-methyloxirane (1.00 g, 17.2 mmol) in water (2 mL) was added dropwise. The reaction mixture was allowed to warm 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); NH and OH were not observed.

[0117] Step 2 To a solution of (4-nitrophenyl)carbonochloridate (59 mg, 0.290 mmol) in anhydrous THF (1 mL) was added 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 uL, 0.290 mmol) in anhydrous THF (1 mL), and the reaction was stirred at room temperature for 20 minutes. Then, (2S)-1-(ethylamino)propan-2-ol (39 mg, 0.343 mmol) and N-ethyl-N-isopropyl-propan-2-amine (69 uL, 0.396 mmol) in anhydrous THF (1 mL) were added, and the reaction was stirred at room temperature for 15 minutes. It was then concentrated under reduced pressure and purified by preparative HPLC (Method C) to give the title compound (64 mg) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.96(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).LCMS m / z:357.1[M+H]+, RT=2.65 (Method A).

[0118] (Table 2) Using methods similar to those used in Example E09, the following compounds were synthesized using either commercially available amines or amino alcohols synthesized using methods similar to those in Example E09, Step 1. TIFF0007787811000010.tif147166TIFF0007787811000011.tif206166TIFF000 7787811000012.tif226166TIFF0007787811000013.tif221166TIFF00077878110 00014.tif216166TIFF0007787811000015.tif226166TIFF0007787811000016.t if216166TIFF0007787811000017.tif226166TIFF0007787811000018.tif236166

[0119] Example E50 and E51 TIFF0007787811000019.tif191333-A single unknown enantiomer of [5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)urea

[0120] 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) was separated to give two single enantiomers. Method: Chiralpak AD-H, 10 x 250 mm, 5 um column eluted with 10% IPA:90% CO2 at a flow rate of 15 ml / min.

[0121] Example E50 (first elution): 1H NMR(400MHz,Chloroform-d)δ 7.25-7.20(m,1H),6.98(d,J=7.7Hz,1H),6.89(t,J=7.9Hz,2H),4.17(s,2H),3.80(d,J=15.2Hz,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).

[0122] Example E51 (second elution): 1H NMR(400MHz,Chloroform-d)δ 7.25-7.20(m,1H),6.98(d,J=7.6Hz,1H),6.90(t,J=8.0Hz,2H),4.17(s,2H),3.79(d,J=15.9Hz,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).

[0123] Examples E52 and E53 TIFF0007787811000020.tif201411-Ethyl-3-[5-[(3-fluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-1-(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)urea Single unknown enantiomer

[0124] 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) was separated to give the two enantiomers. Method: Chiralpak AD-H, 10 x 250 mm, 5 um column eluted with 15% IPA:85% CO2 at a flow rate of 15 ml / min.

[0125] Example E52 (First Elution) 1HNMR(400MHz,Chloroform-d)δ 7.25-7.20(m,1H),6.98(d,J=7.7Hz,1H),6.89(t,J=8.2Hz,2H),4.16(s,2H),3.81-3.6 5(m,2H),3.25(d,J=15.4Hz,1H),3.07(s,1H),1.48(s,3H),1.13(t,J=7.0Hz,3H).LCMS m / z:407.2[M+H]+, RT=3.21 (method A).

[0126] Example E53 (Second Elution) 1HNMR(400MHz,Chloroform-d)δ 7.25-7.20(m,1H),6.98(d,J=7.6Hz,1H),6.89(t,J=8.3Hz,2H),4.16(s,2H),3.79-3.6 5(m,2H),3.24(d,J=15.2Hz,1H),3.07(s,1H),1.48(s,3H),1.13(t,J=7.0Hz,3H).LCMS m / z:407.3[M+H]+, RT=3.24 (Method A).

[0127] Example E54 TIFF0007787811000021.tif301283-[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

[0128] Step 1 To a three-necked RBF under N was added (2S)-2-(trifluoromethyl)oxirane (200 mg, 1.78 mmol), followed by anhydrous THF (8 mL), and the stirred solution was cooled to -100 °C in an EtO / dry ice bath. 1.6 M butyllithium (1.2 mL, 1.96 mmol) was then added dropwise, followed by stirring at this temperature for 10 minutes. Iodomethane (0.17 mL, 2.68 mmol) was then added, and the reaction was stirred at this temperature for 2 hours, warmed to approximately 0 °C in an ice bath, to which 2 M methanamine (3.6 mL, 7.14 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. The reaction was then quenched by adding saturated aqueous NH4Cl (5 mL), followed by removal of volatiles under reduced pressure (pressure at 100 mbar). The residue was loaded onto an SCX-2 cartridge (5 g, washed with MeOH, 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)propan-2-ol (750 mg, 30% purity) as an orange liquid. 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). NH and OH were not observed.

[0129] Step 2 A solution of (4-nitrophenyl)carbonochloridate (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 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 was allowed to warm to room temperature and stirred at room temperature for 30 minutes. Next, (2S)-1,1,1-trifluoro-2-methyl-3-(methylamino)propan-2-ol (95 mg, 0.181 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.058 mL, 0.334 mmol) in anhydrous THF (1 mL) were added, and the reaction was stirred at room temperature for 15 minutes. It 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 (24 mg) as a white solid. 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 below the water peak. LCMS m / z: 411.2 [M+H]+, RT = 3.06 (Method A).

[0130] (Table 3) The following compounds were synthesized using methods similar to those used in Example E54. TIFF0007787811000022.tif143166

[0131] Example E58 TIFF0007787811000023.tif191285-[(3,5-difluorophenyl)methyl]-N-isopropyl-1,3,4-thiadiazole-2-carboxamide

[0132] Step 1 To a stirred solution of ethyl 2-(3,5-difluorophenyl)acetate (1.12 g, 5.6 mmol) in MeOH (10 mL) was added hydrazine hydrate (0.64 mL, 13.0 mmol). The reaction was stirred at 70° C. for 4 hours and then at room temperature overnight. The reaction was concentrated in vacuo to give 2-(3,5-difluorophenyl)acetohydrazide (1.21 g) as an off-white solid.

[0133] Step 2 To a stirred solution of 2-(3,5-difluorophenyl)acetohydrazide (1.21 g, 6.50 mmol) and triethylamine (1.1 mL, 7.89 mmol) in anhydrous DCM (15 mL) was added 2-chloro-2-oxo-ethyl acetate (800 uL, 7.16 mmol) dropwise at 0 °C to form a yellow solution. After 15 minutes, the ice bath was removed and the reaction was stirred at room temperature for 30 minutes. The reaction 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 give a white solid. The DCM layers were combined, dried over MgSO, filtered, and concentrated in vacuo to give a yellow solid. The solids were combined, dissolved in EtOAc, and the aqueous solution was further extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to give ethyl 2-[2-[2-(3,5-difluorophenyl)acetyl]hydrazino]-2-oxo-acetate (1.92 g, 80% purity) as a yellow solid.

[0134] Step 3 Ethyl 2-[2-[2-(3,5-difluorophenyl)acetyl]hydrazino]-2-oxo-acetate (80%, 100 mg, 0.279 mmol) and Lawesson's reagent (71 mg, 0.176 mmol) in THF (1 mL) were stirred in a pressure vial at 50 °C for a total of 3 h to give a pale yellow solution. Water (4 mL) was added, and the mixture was extracted with EtOAc (4 × 3 mL). The organics were combined and concentrated. The crude product was purified by FCC (Biotage SNAP KP-Sil 10 g) eluting with 0–25% EtOAc in heptane, followed by flushing with 25–100% EtOAc in heptane, to give ethyl 5-[(3,5-difluorophenyl)methyl]-1,3,4-thiadiazole-2-carboxylate (45 mg, 54% yield). 1H NMR (500MHz, Chloroform-d) δ 6.85(qd,J=7.3,2.3Hz,2H),6.76(tt,J=8.9,2.3Hz,1H),4.53-4.48(m,2H),4.47(s,2H),1.44(t,J=7.1Hz,3H).

[0135] Step 4 In a 1.5 mL vial with a septum, 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 propan-2-amine (13 uL, 0.152 mmol) was added, causing the solution to turn yellow (after 5 minutes, the reaction turned green, then yellow). The sealed reaction was heated at 80° C. for 1 hour. Further propan-2-amine (100 uL, 1.16 mmol) was added, and the reaction was heated at 80° C. for 1 hour. The reaction was concentrated and purified by preparative HPLC (Method D) to give the title compound (32 mg, 70% yield) as an off-white solid. 1H NMR(500MHz,DMSO-d6)δ 9.03(d,J=8.1Hz,1H),7.18(tt,J=9.6,2.4Hz,1H),7.13(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).

[0136] Example E59 TIFF0007787811000024.tif251283-[5-[1-(3,5-difluorophenyl)-1-methyl-ethyl]-1,3,4-thiadiazol-2-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea

[0137] Step 1 Sodium hydroxide (214 mg, 5.22 mmol) was dissolved in warm water (0.3 mL). (3,5-Difluorophenyl)acetonitrile (200 mg, 1.31 mmol) in DMSO (1.2 mL) was added to the warm mixture and stirred in a cold water bath (approximately 10 °C). Iodomethane (0.33 mL, 5.22 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. Water (2 mL) was added, the mixture was extracted into EtOAc (3 × 3 mL), and the combined organics were concentrated in vacuo to give 2-(3,5-difluorophenyl)-2-methyl-propanenitrile (275 mg).

[0138] Step 2 To a stirred solution of 2-(3,5-difluorophenyl)-2-methyl-propanenitrile (85% pure, 2.27 g, 10.6 mmol) in methanol (2 mL) and water (5 mL) was added sodium hydroxide (1.28 g, 31.9 mmol). The reaction was stirred at 90° C. overnight (approximately 20 hours) and then at room temperature for approximately 46 hours. The reaction was diluted with water (5 mL), extracted into EtOAc (3×10 mL), and the organics were dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3,5-difluorophenyl)-2-methyl-propanoic acid (2.28 g).

[0139] Step 3 Using a method similar to that used in Example E01 (Step 1), 5-[1-(3,5-difluorophenyl)-1-methyl-ethyl]-1,3,4-thiadiazol-2-amine was synthesized. 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).

[0140] Step 4 The title compound was synthesized using a method similar to that used in Example E09 (Step 2). H 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).

[0141] HPLC method analyticalLCMS Method A Analytical uHPLC-MS was performed on a Waters Acquity uPLC using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μM; temperature: 40 °C) and a gradient of 5 to 100% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 5.3 min, followed by 100% B in 0.5 min. A second gradient of 100 to 5% B was then applied in 0.02 min and held for 1.18 min with an injection volume of 1 μL at a flow rate of 0.6 mL / min. UV spectra were recorded using a Waters Acquity PDA detector spectral range: 200-400 nm at 215 nm, and ELS data were collected and reported using a Waters Acquity ELS detector (if compatible). Mass spectra were obtained using a Waters SQD (MSQ1) or a Waters Acquity QDA (MSQ2). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0142] Method B Analytical uPLC-MS was performed on a Waters Acquity uPLC using a Waters UPLC® BEH™ C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40 °C) and a gradient of 5 to 100% (A = 2 mM sodium bicarbonate, buffered to pH 10, B = ACN) in 5.3 min, followed by 100% B in 0.5 min. A second gradient of 100 to 5% B was then applied in 0.02 min and held for 1.18 min with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded using a Waters Acquity photodiode array detector with a spectral range of 200-400 nm at 215 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0143] Preparative HPLC method The purification method is as follows.

[0144] Method C: Acidic method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10 to 95% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 14.44 min, followed by 95% B in 2.11 min. A second gradient of 95 to 10% B was then applied in 0.2 min with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded using a Gilson detector at 215 nm.

[0145] Method D: Basic Method 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) and a gradient of 30 to 95% B (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in ACN) in 11.00 min, followed by 95% B in 2.10 min. A second gradient of 95 to 30% B was then applied in 0.21 min with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded using a Gilson detector at 215 nm.

[0146] Example 2 - Compound Screening Potent and selective hMrgpMRGPRX2 compounds were generated from compounds identified during a high-throughput screening (HTS) campaign and followed up in an iterative structure-activity-based medicinal chemistry effort. These compounds were characterized for their antagonist activity in recombinant hMrgpMRGPRX2-expressing cells, and their potency was confirmed in the human mast cell line LAD-2, where the target is endogenously expressed. The assay used to determine potency was a functional readout using FLIPR™ technology to observe intracellular calcium mobilization. In these FLIPR assays, identified compounds were tested for orthologous activity using recombinant cell lines expressing mouse MrgprB2, mouse MrgprA1, gerbil MrgpMRGPRX2 orthologue, Chinese hamster MrgpMRGPRX2 orthologue, and cynomolgus monkey MrgpMRGPRX2 orthologue, respectively.

[0147] The results are summarized in Table 4 below.

[0148] (Table 4) TIFF0007787811000025.tif96134TIFF0007787811000026.tif229134TIFF0007787811000027.ti f190134TIFF0007787811000028.tif216134TIFF0007787811000029.tif197134TIFF00077878110 00030.tif224134TIFF0007787811000031.tif217134TIFF0007787811000032.tif207134TIFF000 7787811000033.tif227134TIFF0007787811000034.tif199134TIFF0007787811000035.tif226134

Claims

1. A compound having formula I, During the ceremony, G ２ but, and q is 1, m is 1, n is 1, k is 1, R １ and R ２ However, each independently, C １－６ Alkyl; C ３－６ cycloalkyl; 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein each C １－６ Alkyl, C ３－６ cycloalkyl, and 5- to 10-membered heterocycloalkyl are each selected from 1 to 3 R ２０ may be substituted with a group, Each R ２０ are independently selected from 1) hydroxy, 2) cyano, 3) C １－３ Alkyl, 4) C １－３ Alkoxy, 5) C １－３ Haloalkyl, 6) halogen, 7) hydroxy, cyano, C １－３ Alkyl, C １－３ Alkoxy, C １－３ C optionally substituted with 1 to 3 substituents selected from haloalkyl and halogen ３－６ 7) cycloalkyl; and 8) 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; R ３ is H or C １－３ is alkyl, R ４ is H, R ５ is H, G １ is two or three independently selected R ３０ phenyl substituted with a group; Each R ３０ But halogen, cyano, C １－３ Alkyl, C １－３ C optionally substituted with haloalkyl, halogen and hydroxy １－３ alkoxy, The compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

2. G １ The compound of claim 1 , wherein is a phenyl having two substituents.

3. G １ 2. The compound of claim 1, wherein is phenyl substituted at the 3 and 5 positions.

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

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

6. G １ 2. The compound of claim 1, wherein is phenyl substituted at the 2- and 3-positions.

7. G １ 2. The compound of claim 1, wherein is phenyl substituted at the 3 and 4 positions.

8. Each R ３０ The compound of any one of claims 1 to 7, wherein is independently selected from mono-, di-, or trihalomethyl, fluorine, chlorine, methoxy, cyano, and methyl.

9. Each R ３０ The compound of any one of claims 1 to 7, wherein is independently selected from difluoromethyl, trifluoromethyl, fluorine, chlorine, methoxy, cyano, and methyl.

10. Each R ３０ The compound of any one of claims 1 to 7, wherein is independently selected from fluorine and chlorine.

11. Each R ３０ The compound according to any one of claims 1 to 7, wherein is fluorine.

12. R １ and R ２ each independently represents 1 to 3 R ２０ C optionally substituted with a group １－３ The compound of any one of claims 1 to 11, which is alkyl.

13. R １ and R ２ is each independently 1 to 3 R independently selected from hydroxy, di- or trihalomethyl, methoxy, halogen, and cyano; ２０ C optionally substituted with a group １－３ The compound of any one of claims 1 to 11, which is alkyl.

14. R １ But C １－３ alkyl, and R ２ is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is selected from hydroxy, C １－３ Alkyl, C １－３ Alkoxy, C １－３ The compound of any one of claims 1 to 11, optionally substituted with 1, 2, or 3 groups selected from haloalkyl, cyano, and halogen.

15. R １ But C １－３ alkyl, and R ２ is a heterocycle selected from pyrrolidine, tetrahydrofuran, morpholine, piperidine, and tetrahydropyran, each of which is optionally substituted with one, two, or three groups selected from hydroxy, methyl, methoxy, di- or trihalomethyl, cyano, and halogen.

16. R １ But C １－３ alkyl, and R ２ pyrrolidine, tetrahydrofuran, morpholine, piperidine, tetrahydropyran, and C ３－６ C substituted with a ring selected from cycloalkyl １－３ The compound of any one of claims 1 to 11, which is alkyl.

17. below: or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

18. 18. A topical or oral composition for treating an inflammatory disorder in a subject, comprising a therapeutically effective amount of a compound of any one of claims 1 to 17 and a dermatologically or orally acceptable excipient.

19. 20. The composition of claim 18 in the form of a cream, gel, spray, or ointment, or in a dosage form for oral administration.

20. 19. The composition of claim 18, wherein the compound is present in a concentration of 0.001% to 10% by weight, based on the total weight of the composition.

21. 19. The composition of claim 18, wherein the compound is present in a concentration of 0.1% to 5% by weight, based on the total weight of the composition.

22. 20. The composition of claim 18, further comprising a skin absorption enhancer.

23. 20. The composition of claim 18, further comprising a skin absorption enhancer comprising one or more of mannitol, sulfoxides, azones, pyrrolidones, alcohols and alkanols, glycols, surfactants, and terpenes.

24. 24. The composition of any one of claims 18 to 23, which is applied to the skin of a subject once daily.

25. 24. The composition of any one of claims 18 to 23, which is applied to the skin of a subject twice daily.

26. 24. The composition of any one of claims 18 to 23, which is applied to the skin of a subject three times a day.

27. The composition of any one of claims 18 to 26, wherein the subject is suffering from an inflammatory disorder.

28. The composition according to any one of claims 18 to 27, wherein the inflammatory disorder is a skin disorder.

29. The composition according to any one of claims 24 to 26 and 28, wherein the skin is human skin.

30. 30. The composition of any one of claims 18 to 29, wherein the inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2.

31. 31. The composition of any one of claims 18 to 30, wherein the inflammatory disorder is atopic dermatitis, chronic urticaria, pseudoallergic response caused by a small molecule, anaphylactoid drug response, anaphylactic shock, rosacea, asthma, generalized itch, chronic itch caused by a systemic disease, or adverse drug response.

32. The composition of any one of claims 18 to 31, wherein the inflammatory disorder is atopic dermatitis.

33. The composition of any one of claims 18 to 32, wherein the subject is a human.

34. 33. The composition of claim 32, wherein the atopic dermatitis is Asian atopic dermatitis or European atopic dermatitis.

35. 32. The composition of claim 31, wherein the inflammatory disorder is chronic urticaria.

36. 32. The composition of claim 31, wherein the generalized itch is cholestatic or uremic itch.

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