MrgprX2 antagonist for treating inflammatory disorders

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 administration, comprising an MrgprX2 antagonist and a pharmaceutically or orally acceptable carrier.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 62 / 931,183, filed on November 5, 2019, U.S. Provisional Application No. 62 / 931,698, filed on November 6, 2019, and U.S. Provisional Application No. 63 / 046,461, filed on June 30, 2020, the contents of each of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Background Atopic dermatitis (AD) is the most common inflammatory skin disease, with an overall prevalence of 6% in adults in the United States, and prevalence rates of 1 - 3% in adults and 15 - 20% in children worldwide. 17.8 million Americans suffer from AD. The onset of the disease typically occurs in childhood, and skin symptoms are seen in 60% of patients by the age of 1 year. Clinical symptoms include erythematous papules and patches, exudates, crusts, hypopigmentation, and lichenification. However, the characteristic symptom of AD is intense chronic itching that lasts for more than 6 weeks. Despite the high prevalence of chronic itching in AD patients, there is no available effective first - line treatment with a good safety profile. Itching has a significant impact on the quality of life of these patients, including sleep disturbances, and ultimately leads to a decline in performance at work or school. The health - related quality of life in children is inversely correlated with the severity of the disease. Sleep is affected by persistent nocturnal pruritus.

[0003] Due to their sedative effects, oral antihistamines provide mild symptom relief without directly altering itching. Topical calcineurin inhibitors (TCIs) as well as topical corticosteroids (TCSs) can help reduce itching. However, due to side effects (skin atrophy, hypopigmentation, and telangiectasia in the case of TCSs, as well as black box warnings regarding skin cancer malignancies for TCIs), they are not preferred treatment options, especially for chronic use in young children. Therefore, the medical need to find new treatment options for itching is very high among patients and their families. Additionally, relief of chronic itching interrupts the vicious cycle of itching and scratching, which has secondary beneficial effects such as improvement of the skin barrier and can lead to improvement of skin lesions and erythema.

[0004] Finding both a cure and effective treatment for chronic itching in AD is a major challenge. Histamine is not the main pruritogen in AD, and thus, antihistamine blockers act in AD patients only through sedative effects, especially against nocturnal itching. Proteases released from immune and skin cells of AD patients and acting on GPCRs have been investigated as the main pruritogenic contributing factors in AD. Cathepsin S has been described in the literature as a highly pro-inflammatory and itch-inducing protease. Overexpression of cathepsin S results in an AD phenotype in mice with severe chronic itching. Recently, a group reported that cathepsin S induces itching via MrgprX2. Nevertheless, knowledge regarding the main itch mediators in AD is limited, although some have been identified and assumed to play a role.

[0005] Another pruritogenic neuropeptide is substance P, which is released by nerve cells and non-neural skin cells, is pro-inflammatory, and is a vasoactive neuropeptide that acts as a pruritogen. Therefore, targeting its cognate receptor NK1 is considered an ideal therapeutic approach and has been carried out using aprepitant. However, despite preclinical data in mice, aprepitant, an NK1R antagonist, was unable to significantly block itching in humans.

[0006] MrgprX2 is a promising target due to its promiscuous ligand-binding properties for various pruritus mediators. A number of pruritus mediators known or suspected as players in the pathogenesis of AD are thought to bind to MrgprX receptors rather than cognate receptors.

[0007] The need for effective treatment for AD and its symptoms remains unmet. The present invention addresses the unmet need as well as other important objectives.

Summary of the Invention

[0008] Summary Described herein are 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 disclosure provides a compound that is an MrgprX2 antagonist.

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

[0011] In a third aspect, the present disclosure provides a method for treating an inflammatory disorder, the method 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, the method 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.

[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, the method 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). [Invention 1001] a dermatologically acceptable excipient, and a compound having the following formula I, TIFF0007712922000001.tif47128 wherein, W is H, or -(L 1 ) p -A 2 and A 1 is one of the following eight systems: TIFF0007712922000002.tif164128 is a ring system selected from R A is absent or is selected from H, C 1-3 alkyl, halogen, and CN, k, q, m, and p are each independently 0 or 1, provided that when m and k are each 1, q is not 0, R 3 is H, R 1 is H; C 50 alkyl or C 1-6 cycloalkyl, which may be substituted with 1, 2, or 3 independently selected R 3-6 groups; or 3- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, which may be substituted with 1, 2, or 3 independently selected R 51 groups and may contain a -(C=O)- group or -S(=O) 2 - group within the ring, selected from each R 50 is independently hydroxy; -NR 20 N 21 ;C 1-3 haloalkyl; halogen; CN; C 25 cycloalkyl which may be substituted with 1 to 3 R 3-6 groups; C 1-3 alkoxy; C 1-3 hydroxyalkyl; and 5- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, which may be substituted with 1 or 2 independently selected R 51 groups, selected from each R 20 and R 21 are independently selected from H, C 1-6 alkyl, and -SO 2 NR 30 R 31 , each R 22 is independently C 1-6 alkyl, each R 25 is hydroxy, each R 51 is independently selected from C 1-6 alkyl, -SO 2 NR 30 R 31 , -C(=O)-O-R 32 , halogen, hydroxy, cyano, C 1-3 hydroxyalkyl, -C(=O)-NR 33 R 34 , -C(=O)-R 35 , CN, -SO 2R 22 、C 1-3 haloalkyl, NR 33 R 34 , and C 1-3 alkoxy, each R 30 and R 31 are independently selected from H and C 1-6 alkyl, each R 32 is independently selected from H and C 1-6 alkyl, each R 33 and R 34 are independently selected from H and C 1-6 alkyl, each R 35 is independently C 1-6 alkyl, R 2 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, each of which may be substituted with 1, 2, or 3 groups independently selected from hydroxy, C 1-3 haloalkyl, halogen, C 1-3 alkoxy, and CN, L 1 is O, CH 2 , -CH(C 1-3 alkyl)-, -C(=O)-NH-CH 2 -, -N(C 1-6 alkyl)-, or -NH-, A 2 is C 6-10 aryl, C 3-7 Cycloalkyl, or a 5- to 10-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein C 6-10 aryl, C 3-7 cycloalkyl, and each of the 5- to 10-membered heteroaryls may be substituted with 1, 2, or 3 independently selected R 60 groups, each R 60 is independently halogen, CN, hydroxy, C1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 haloalkyl, -C(=O)-O-R 35 , and C 1-3 alkyl which may be substituted with 1 to 3 substituents independently selected from hydroxy, CN, and C 1-3 alkoxy, a compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof, and a composition comprising the same. [Invention 1002] A 1 The composition of Invention 1001, wherein the ring system is Ring System 1. [Invention 1003] A 1 The composition of Invention 1001, wherein the ring system is Ring System 3. [Invention 1004] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted phenyl. [Invention 1005] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted pyridyl. [Invention 1006] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted pyrid-2-yl. [Invention 1007] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted pyrid-3-yl. [Invention 1008] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted pyrid-4-yl. [Invention 1009] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted pyrid-2-yl. [Invention 1010] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted cyclopentyl. [Invention 1011] A 2 The composition of Invention 1001, wherein the substituent is an optionally substituted cyclohexyl. [Invention 1012] A 2 The composition of Invention 1001, wherein the substituent is a phenyl or pyridyl substituted with one R 60 group. [Invention 1013] A 2 The composition of Invention 1001, wherein the substituent is a phenyl or pyridyl substituted with two R 60 groups. [Invention 1014] A 2 is L 1 or 1 a phenyl or pyridyl substituted with one R 60 group at the 2-position relative to the point of attachment to or A, [Invention 1015] A 2 is L 1 or 1 a phenyl or pyridyl substituted with one R 60 group at the 3-position relative to the point of attachment to or A, [Invention 1016] A 2 is L 1 or 1 a phenyl or pyridyl substituted with one R 60 group at the 4-position relative to the point of attachment to or A The composition of the present invention 1001. [The present invention 1017] A 2 is L 1 or A 1 at the 2- and 3-positions relative to the bonding point to 60 phenyl or pyridyl substituted with two R groups. The composition of the present invention 1001. [The present invention 1018] A 2 is L 1 or A 1 at the 2- and 4-positions relative to the bonding point to 60 phenyl substituted with two R groups. The composition of the present invention 1001. [The present invention 1019] A 2 is L1 or A 1 at the 2- and 5-positions relative to the bonding point to 60 phenyl substituted with two R groups. The composition of the present invention 1001. [The present invention 1020] A 2 is L 1 or A 1 at the 3- and 4-positions relative to the bonding point to 60 phenyl substituted with two R groups. The composition of the present invention 1001. [The present invention 1021] A 2 is L 1 or A 1 at the 3- and 5-positions relative to the bonding point to 60 phenyl substituted with two R groups. The composition of the present invention 1001. [The present invention 1022] A 2 is L 1 or A 1 at the 2- and 5-positions relative to the bonding point to 60 phenyl substituted with two R groups. The composition of the present invention 1001. [The present invention 1023] The R 60 group is selected from F, Cl, CN, CF 3 , methoxy, and methyl. The composition of the present invention 1001. [The present invention 1024] A 2 is L 1 or A 1 phenyl substituted with fluorine at the 3-position relative to the bonding point to The composition of the present invention 1001. [The present invention 1025] p is 1, and L 1 is O. The composition of the present invention 1001. [The present invention 1026] p is 1, and L 1 is CH 2 . The composition of the present invention 1001. [The present invention 1027] R 2 is H, methyl, ethyl, or cyclopropyl. The composition of the present invention 1001. [The present invention 1028] R 1 is OH, cyclopropyl optionally substituted with -OH, methoxy, trifluoromethyl, dimethylamino, methylsulfonyl, fluorine, and CN, independently selected from 1 or 2 R 50 groups, optionally substituted C 1-4 alkyl . The composition of the present invention 1001. [The present invention 1029] R 1 is 2-hydroxypropyl, and R 2 is methyl or ethyl. The composition of the present invention 1001. [The present invention 1030] R 1 is A heterocycloalkyl ring which is optionally substituted and is selected from pyrrolidin-3-yl, pyrrolidin-2-yl, pyrrolidin-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, azetidin-1-yl, azetidin-3-yl, morpholin-4-yl, 2-pyrrolidinone-4-yl, 2-pyrrolidinone-5-yl, piperidin-4-yl, piperidin-2-one-4-yl, tetrahydro-2H-thiopyran-1,1,-dione-4-yl, piperazin-1-yl, thiomorpholine-1,1-dioxide-4-yl, and morpholin-2-one-1-yl The composition of the present invention 1001 which is such. [The present invention 1031] Each R 51 is, -SO 2 NH 2 , methyl, t-butoxycarbonyl, fluorine, hydroxymethyl, -C(=O)NH 2 , -SO 2 CH 3 , -C(=O)CH 3 , hydroxy, and CN, and is the composition of the present invention 1001. [The present invention 1032] R 1 is An optionally substituted heterocycloalkyl ring selected from pyrrolidine, piperidine, 2-pyrrolidinone, morpholine, and tetrahydropyran and is optionally substituted with a C 1-4 alkyl which is the composition of the present invention 1001. [The present invention 1033] The composition of the present invention 1001, wherein the compound is selected from the compounds in Table 1 of this specification, or stereoisomers, solvates, tautomers, or pharmaceutically acceptable salts thereof. [The present invention 1034] A method for treating an inflammatory disorder, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of the compound of the present invention 1001 and a dermatologically or orally acceptable excipient. [The present invention 1035] The method of the present invention 1034, wherein the composition is in the form of a cream, gel, spray, ointment, or is a unit dosage form for oral administration. [The present invention 1036] The method of the present invention 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. [The present invention 1037] The method of the present invention 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 the present invention 1034, wherein the composition further comprises a skin absorption enhancer. [The present invention 1039] The method of the present invention 1034, wherein the composition further comprises a skin absorption enhancer containing one or more of mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., laurocapram), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohol and alkanol (e.g., ethanol or decanol), glycol (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactant (which is also common in dosage forms), and terpene. [The present invention 1040] The method according to any one of the present inventions 1034 to 1039, wherein the composition is applied to the skin of a patient once a day. [The present invention 1041] The method according to any one of the present inventions 1034 to 1040, wherein the composition is applied to the skin of a patient twice a day. [The present invention 1042] The method according to any one of the present inventions 1034 to 1041, wherein the composition is applied to the skin of a patient three times a day. [The present invention 1043] The method according to any one of the present inventions 1034 to 1042, wherein the composition is administered to a patient suffering from an inflammatory disorder. [The present invention 1044] The method according to any one of the present inventions 1034 to 1043, wherein the inflammatory disorder is a skin disorder. [The present invention 1045] The method according to any one of the present inventions 1034 to 1044, wherein the skin is human skin. [The present invention 1046] The method according to any one of the present inventions 1043 to 1045, wherein the inflammatory disorder activates MrgprX2 or is a result of the activation of MrgprX2. [The present invention 1047] The method according to any one of the present inventions 1043 to 1046, 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, alcohol flush, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, or drug adverse responses. [The present invention 1048] The method according to any one of the present inventions 1043 to 1047, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). [The present invention 1050] The method according to any one of the present inventions 1034 to 1048, wherein the subject is human. [The present invention 1051] The method according to any one of 1034 to 1050 of the present invention, wherein the skin is mammalian skin and is human skin.

Mode for Carrying Out the Invention

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

[0015] MrgprX2 Antagonists for Use in the Compositions and Methods of the Present Disclosure In some embodiments, the present disclosure is a compound [Compound 1], an MrgprX2 antagonist, having Formula I, TIFF0007712922000003.tif47128wherein, W is absent, or is H, or -(L1) p -A2, A1 is a ring system selected from Systems 1 - 21: TIFF0007712922000004.tif168147TIFF0007712922000005.tif151151, R A is absent, or is H, C 1-3 alkyl, -C(=O)-NH2, -C(=O)-OH, halogen, phenyl, CN, and benzyl, k, q, m, and p are each independently 0 or 1, provided that when m and k are each 1, q is not 0, R3 is H or C 1-3 alkyl, R1 is H; C 50 alkyl or C 1-6 cycloalkyl, optionally substituted with 1, 2, or 3 independently selected R 3-6 groups; or 3 - 10 membered heterocycloalkyl having 1 - 3 ring heteroatoms independently selected from N, O, and S, 1 , 2, or 3 independently selected R 51 groups, optionally substituted, and optionally containing a -(C=O)- group or a -S(=O)2- group within the ring, each R 50 is independently hydroxy; -NR 20 N 21 ;-SO2R 22 ;C 1-3 haloalkyl; halogen; -C(=O)-R 26 ;CN, C 25 cycloalkyl, optionally substituted with 1 - 3 R 3-6 groups; C 1-3 alkoxy; -C(=O)-NR 27R 28 ;C 1-3 Hydroxyalkyl; and having 1 to 3 ring heteroatoms independently selected from N, O, and S, 1 , 2, or 3 independently selected R 51 groups, and may contain a -(C=O)- group in the ring, selected from 5- to 10-membered heterocycloalkyl, each R 20 and R 21 is independently H, C 1-6 alkyl, and -SO2NR 30 R 31 selected from each R 22 is independently C 1-6 alkyl each R 25 is independently hydroxy, C 1-3 haloalkyl, and C 1-3 hydroxyalkyl selected from each R 26 is independently hydroxy, C 1-3 haloalkyl, and C 1-6 alkoxy selected from each R 27 and R 28 is independently H, hydroxy, C 1-3 haloalkyl, and C 1-3 alkoxy selected from each R 51 is independently C 1-6 alkyl, -SO2NR 30 R 31 , -C(=O)-O-R 32 , halogen, hydroxy, cyano, C 1-3 hydroxyalkyl, -C(=O)-NR 33 R 34 , -C(=O)-R 35 , CN, -SO2R 22 , C 1-3 haloalkyl, NR 33 R 34 , and C 1-3 alkoxy selected from each R 30 and R31 is independently H and C 1-6 selected from alkyl, each R 32 is independently H and C 1-6 selected from alkyl, each R 33 and R 34 is independently H and C 1-6 selected from alkyl, each R 35 is independently C 1-6 alkyl, R2 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, each being optionally substituted with one, two, or three groups selected from hydroxy, C 1-3 haloalkyl, halogen, C 1-3 alkoxy, and CN, or R2 is -SO2(C 1-6 alkyl), or or R2 and R3 together form a -CH2-CH2- group such as the ring of formula TIFF0007712922000006.tif25128, p is 0 or 1, L1 is O, CH2, -CH(C 1-3 alkyl)-, -C(=O)-NH-CH2-, -C(OH)(CH3)-, -CH(OH)-, -(C=O)-, -N(C 1-6 alkyl)-, or -NH-, A2 is C 6-10 aryl, C 3-7 cycloalkyl, or 5- to 10-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, where C 6-10 aryl, C 3-7 cycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with one, two, or three independently selected R 60 groups, each R 60 is independently halogen, CN, hydroxy, C 1-3 alkoxy, C 1-3Haloalkoxy, C 1-3 Haloalkyl, -C(=O)-O-R 35 , and hydroxy, CN, and C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from 1-3 alkyl, selected from a compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0016] The present disclosure further provides the following compounds: 1.1 Compound 1, wherein A1 is Ring System 1; 1.2 Compound 1, wherein A1 is Ring System 3; 1.3 Any of the foregoing compounds, wherein A2 is optionally substituted phenyl; 1.4 Any of the foregoing compounds, wherein A2 is optionally substituted pyridyl; 1.5 Any of the foregoing compounds, wherein A2 is optionally substituted pyrid-2-yl; 1.6 Any of the foregoing compounds, wherein A2 is optionally substituted pyrid-3-yl; 1.7 Any of the foregoing compounds, wherein A2 is optionally substituted pyrid-4-yl; 1.8 Any of the foregoing compounds, wherein A2 is optionally substituted pyrid-2-yl; 1.9 Any of the foregoing compounds, wherein A2 is optionally substituted cyclopentyl; 1.10 Any of the foregoing compounds, wherein A2 is optionally substituted cyclohexyl; 1.11 Any of the foregoing compounds, wherein A2 is substituted with one R 60 group; 1.12 Any of the foregoing compounds, wherein A2 is substituted with two R 60 groups; 1.13 Any of the foregoing compounds, wherein A2 has one R 60Any of the preceding compounds that is phenyl or pyridyl substituted with a radical; 1.14 A2 is phenyl or pyridyl substituted with one R at the 3-position relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl or pyridyl substituted with a radical; 1.15 A2 is phenyl or pyridyl substituted with one R at the 4-position relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl or pyridyl substituted with a radical; 1.16 A2 is phenyl or pyridyl substituted with two Rs at the 2- and 3-positions relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl or pyridyl substituted with a radical; 1.17 A2 is phenyl substituted with two Rs at the 2- and 4-positions relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl substituted with a radical; 1.18 A2 is phenyl substituted with two Rs at the 2- and 5-positions relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl substituted with a radical; 1.19 A2 is phenyl substituted with two Rs at the 3- and 4-positions relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl substituted with a radical; 1.20 A2 is phenyl substituted with two Rs at the 3- and 5-positions relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl substituted with a radical; 1.21 A2 is phenyl substituted with two Rs at the 2- and 5-positions relative to the point of attachment to L1 or A1 60 Any of the preceding compounds that is phenyl substituted with a radical; 1.22 R 60 Any of the preceding compounds in which the radical is selected from F, Cl, CN, CF3, methoxy, and methyl; 1.23 Any of the preceding compounds in which A2 is phenyl substituted with fluorine at the 3-position relative to the point of attachment to L1 or A1 1.24 Any of the preceding compounds, wherein p is 1 and L1 is O; 1.25 Any of the preceding compounds, wherein p is 1 and L1 is CH2; 1.26 Any of the preceding compounds, wherein R2 is H, methyl, ethyl, or cyclopropyl; 1.27 Any of the preceding compounds, wherein R1 is OH; -C(=O)-OH; cyclopropyl optionally substituted with a substituent selected from -OH, hydroxymethyl, and trifluoromethyl; methoxy; trifluoromethyl; dimethylamino; methylsulfonyl; fluorine; and CN; or 1 or 2 R groups independently selected therefrom, and is C alkyl optionally substituted with said R group(s); 50 C 1-4 alkyl; 1.28 Any of the preceding compounds, wherein R1 is 2-hydroxypropyl and R2 is methyl or ethyl; 1.29 Any of the preceding compounds, wherein R1 is an optionally substituted heterocycloalkyl ring selected from pyrrolidin-3-yl, pyrrolidin-2-yl, pyrrolidin-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, azetidin-1-yl, azetidin-3-yl, morpholin-4-yl, 2-pyrrolidinone-4-yl, 2-pyrrolidinone-5-yl, piperidin-4-yl, piperidin-2-one-4-yl, tetrahydro-2H-thiopyran-1,1-dione-4-yl, piperazin-1-yl, thiomorpholine-1,1-dioxide-4-yl, and morpholin-2-one-1-yl; 1.30 Each R 51 is selected from -SO2NH2, methyl, t-butoxycarbonyl, fluorine, hydroxymethyl, -C(=O)NH2, -SO2CH3, -C(=O)CH3, hydroxy, and CN; 1.31 Any of the preceding compounds, wherein R1 is an optionally substituted heterocycloalkyl ring selected from pyrrolidine, piperidine, 2-pyrrolidinone, morpholine, and tetrahydropyran, and is optionally substituted; C 1-4Any of the precursor compounds that is alkyl; 1.32 Any of the precursor compounds, wherein the compound is selected from the compounds of Table 1 herein, or stereoisomers, solvates, tautomers, or pharmaceutically acceptable salts thereof; 1.33 W is H, or -(L1) p -A2, and A1 is a ring system selected from the following eight systems: TIFF0007712922000007.tif165128, and R A is absent or is selected from H, C 1-3 alkyl, halogen, and CN, k, q, m, and p are each independently 0 or 1, provided that when m and k are each 1, q is not 0, R3 is H, R1 is H; C 50 alkyl optionally substituted with 1, 2, or 3 independently selected R 1-6 groups, or C 3-6 cycloalkyl; or 3- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, 1 optionally substituted with 1, 2, or 3 independently selected R 51 groups and optionally containing a -(C=O)- group or a -S(=O)2- group within the ring, and is selected from each R 50 is independently hydroxy, -NR 20 N 21 ; C 1-3 haloalkyl; halogen; CN; C 25 cycloalkyl optionally substituted with 1 to 3 R 3-6 groups; C 1-3 alkoxy; C 1-3 hydroxyalkyl; and having 1 to 3 ring heteroatoms independently selected from N, O, and S, 1 optionally substituted with 1 or 2 independently selected R 515- to 10-membered heterocycloalkyl, which may be substituted with a group, is selected from each R 20 and R 21 is independently H, C 1-6 alkyl, and -SO2NR 30 R 31 is selected from each R 22 is independently C 1-6 alkyl, each R 25 is hydroxy, each R 51 is independently C 1-6 alkyl, -SO2NR 30 R 31 , -C(=O)-O-R 32 , halogen, hydroxy, cyano, C 1-3 hydroxyalkyl, -C(=O)-NR 33 R 34 , -C(=O)-R 35 , CN, -SO2R 22 , C 1-3 haloalkyl, NR 33 R 34 , and C 1-3 alkoxy is selected from each R 30 and R 31 is independently H and C 1-6 alkyl is selected from each R 32 is independently H and C 1-6 alkyl is selected from each R 33 and R 34 is independently H and C 1-6 alkyl is selected from each R 35 is independently C 1-6 alkyl, R2 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, each of which may be substituted with 1, 2, or 3 groups selected from hydroxy, C 1-3 haloalkyl, halogen, C 1-3 alkoxy, and CN, L1 is O, CH2, -CH(C 1-3 alkyl)-, -C(=O)-NH-CH2-, -N(C 1-6 alkyl)-, or -NH-, and A2 is C 6-10 aryl, C 3-7 cycloalkyl, or 5- to 10-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein C 6-10 aryl, C 3-7 cycloalkyl, and each of the 5- to 10-membered heteroaryl may be substituted with 1, 2, or 3 independently selected R 60 groups, each R 60 is independently halogen, CN, hydroxy, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 haloalkyl, -C(=O)-O-R 35 and may be substituted with 1 to 3 substituents independently selected from hydroxy, CN, and C 1-3 alkoxy-substituted C 1-3 alkyl, selected from a compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof, of any of the foregoing compounds; 1.34 A1 is ring system 1, W is -(L1) p -A2, L1 is CH2, p is 1, R3 is H, m is 1, q is 1, k is 0, R1 is C 1-6 alkyl, or C 50 cycloalkyl which may be substituted with 1, 2, or 3 independently selected R 3-6 groups, being any of compounds 1.1 to 1.32; 1.35 A1 is ring system 1, W is -(L1) p-A2, where L1 is CH2, p is 1, R3 is H, m is 1, q is 1, k is 0, R1 has 1 to 3 ring heteroatoms independently selected from N, O, and S, at least one heteroatom is N, and the heteroatom N is unsubstituted or C 1-6 alkyl, -SO2NR 30 R 31 and -C(=O)-R 35 selected R 51 group, and is a 3- to 10-membered heterocycloalkyl, any one of Compounds 1.1 to 1.32; 1.36 A1 is Ring System 1, W is -(L1) p -A2, where L1 is O, p is 1, R3 is H, m is 1, q is 1, k is 0, R1 is C 1-6 alkyl, or C 50 optionally substituted with 1, 2, or 3 independently selected R 3-6 groups, and is a cycloalkyl, any one of Compounds 1.1 to 1.32; 1.37 A1 is Ring System 1, W is -(L1) p -A2, where L1 is O, p is 1, R3 is H, m is 1, q is 1, k is 0, R1 has 1 to 3 ring heteroatoms independently selected from N, O, and S, at least one heteroatom is N, and the heteroatom N is unsubstituted or C 1-6 alkyl, -SO2NR 30 R 31 and -C(=O)-R 35 selected R 51 group, and is a 3- to 10-membered heterocycloalkyl, any one of Compounds 1.1 to 1.32; 1.38 A1 is Ring System 1, W is -(L1) p -A2, where L1 is CH2, p is 1, R3 is H, m is 1, q is 1, k is 0, any one of Compounds 1.1 to 1.32; 1.39 A1 is ring system 1, W is -(L1) p -A2, L1 is CH2, p is 1, R3 is H, m is 1, q is 1, k is 1, any one of Compounds 1.1 to 1.32; 1.40 A1 is ring system 1, W is -(L1) p -A2, L1 is CH2, p is 1, R3 is H, m is 1, q is 1, k is 0, R1 has 1 to 3 ring heteroatoms independently selected from N, O, and S, at least one heteroatom is N, and the heteroatom N is bonded to the carbonyl group of Formula I, and it is a 3- to 10-membered heterocycloalkyl, any one of Compounds 1.1 to 1.32; 1.41 A1 is ring system 1, W is -(L1) p -A2, L1 is O, p is 1, R3 is H, m is 1, q is 1, k is 1, any one of Compounds 1.1 to 1.32; 1.42 A1 is ring system 1, W is -(L1) p -A2, L1 is O, p is 1, R3 is H, m is 1, q is 1, k is 0, R1 has 1 to 3 ring heteroatoms independently selected from N, O, and S, at least one heteroatom is N, and the heteroatom N is bonded to the carbonyl group of Formula I, and it is a 3- to 10-membered heterocycloalkyl, any one of Compounds 1.1 to 1.32; 1.43 A1 is ring system 8, R A is absent, R3 is H, W is H, m is 1, q is 1, k is 1, any one of Compounds 1.1 to 1.32; 1.44 A1 is ring system 3, W is -(L1) p -A2, L1 is O, p is 1, R3 is H, m is 1, q is 1, k is 1, any one of Compounds 1.1 to 1.32; 1.45 A1 is ring system 3, R Ais H, and W is -(L1) p -A2, L1 is CH2, p is 1, R3 is H, m is 1, q is 1, k is 0, any one of Compounds 1.1 to 1.32; 1.46 A1 is Ring System 1, and W is -(L1) p -A2, L1 is CH2, p is 1, m is 0, q is 1, k is 1, any one of Compounds 1.1 to 1.32; 1.47 A1 is Ring System 4, and W is -(L1) p -A2, L1 is CH2, p is 1, m is 0, q is 1, k is 1, any one of Compounds 1.1 to 1.32; 1.48 A1 is Ring System 14, and R A is absent, and W is -(L1) p -A2, L1 is O, p is 1, m is 0, q is 0, k is 0, any one of Compounds 1.1 to 1.32; 1.49 A1 is Ring System 18, and W is -(L1) p -A2, L1 is -C(=O)-NH-CH2-, p is 1, R3 is H, m is 1, q is 1, k is 0, any one of Compounds 1.1 to 1.32.

[0017] Also provided, according to the present disclosure, is a topical or oral composition [Composition 1] comprising a 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 Composition 1.1, wherein A1 is Ring System 1; 1.3 Any one of the preceding compositions, wherein A1 is Ring System 3; Any of the preceding compositions, wherein A2 is phenyl which may be substituted; Any of the preceding compositions, wherein A2 is pyridyl which may be substituted; Any of the preceding compositions, wherein A2 is pyridin-2-yl which may be substituted; Any of the preceding compositions, wherein A2 is pyridin-3-yl which may be substituted; Any of the preceding compositions, wherein A2 is pyridin-4-yl which may be substituted; Any of the preceding compositions, wherein A2 is pyridin-2-yl which may be substituted; Any of the preceding compositions, wherein A2 is cyclopentyl which may be substituted; Any of the preceding compositions, wherein A2 is cyclohexyl which may be substituted; 1.12 Any of the preceding compositions, wherein A2 is substituted with one R 60 group; 1.13 Any of the preceding compositions, wherein A2 is substituted with two R 60 groups; 1.14 Any of the preceding compositions, wherein A2 is phenyl or pyridyl substituted with one R 60 group at the 2-position relative to the point of attachment to L1 or A1; 1.15 Any of the preceding compositions, wherein A2 is phenyl or pyridyl substituted with one R 60 group at the 3-position relative to the point of attachment to L1 or A1; 1.16 Any of the preceding compositions, wherein A2 is phenyl or pyridyl substituted with one R 60 group at the 4-position relative to the point of attachment to L1 or A1; 1.17 Any of the preceding compositions, wherein A2 is phenyl or pyridyl substituted with two R 60 groups at the 2- and 3-positions relative to the point of attachment to L1 or A1; 1.18 A2 is phenyl substituted with two R groups at the 2- and 4-positions relative to the point of attachment to L1 or A1, any of the prior compositions; 60 ; 1.19 A2 is phenyl substituted with two R groups at the 2- and 5-positions relative to the point of attachment to L1 or A1, any of the prior compositions; 60 ; 1.20 A2 is phenyl substituted with two R groups at the 3- and 4-positions relative to the point of attachment to L1 or A1, any of the prior compositions; 60 ; 1.21 A2 is phenyl substituted with two R groups at the 3- and 5-positions relative to the point of attachment to L1 or A1, any of the prior compositions; 60 ; 1.22 A2 is phenyl substituted with two R groups at the 2- and 5-positions relative to the point of attachment to L1 or A1, any of the prior compositions; 60 ; 1.23 R 60 group is selected from F, Cl, CN, CF3, methoxy, and methyl, any of the prior compositions; 1.24 A2 is phenyl substituted with fluorine at the 3-position relative to the point of attachment to L1 or A1, any of the prior compositions; 1.25 p is 1 and L1 is O, any of the prior compositions; 1.26 p is 1 and L1 is CH2, any of the prior compositions; 1.27 R2 is H, methyl, ethyl, or cyclopropyl, any of the prior compositions; 1.28 R1 is OH; -C(=O)-OH; cyclopropyl optionally substituted with a substituent selected from -OH, hydroxymethyl, and trifluoromethyl; methoxy; trifluoromethyl; dimethylamino; methylsulfonyl; fluorine; and CN; or C 50 alkyl optionally substituted with 1 or 2 R 1-4 groups independently selected therefrom, any of the prior compositions; 1.29 Any of the prior compositions wherein R1 is 2-hydroxypropyl and R2 is methyl or ethyl; 1.30 Any of the prior compositions wherein R1 is an optionally substituted heteroalkyl ring selected from pyrrolidin-3-yl, pyrrolidin-2-yl, pyrrolidin-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, azetidin-1-yl, azetidin-3-yl, morpholin-4-yl, 2-pyrrolidone-4-yl, 2-pyrrolidone-5-yl, piperidin-4-yl, piperidin-2-one-4-yl, tetrahydro-2H-thiopyran-1,1,-dione-4-yl, piperazin-1-yl, thiomorpholin-1,1-dioxide-4-yl, and morpholin-2-one-1-yl; 1.31 Each R 51 is any of -SO2NH2, methyl, t-butoxycarbonyl, fluorine, hydroxymethyl, -C(=O)NH2, -SO2CH3, -C(=O)CH3, hydroxy, and CN, of the prior compositions; 1.32 Any of the prior compounds wherein R1 is an optionally substituted heteroalkyl ring selected from pyrrolidine, piperidine, 2-pyrrolidone, morpholine, and tetrahydropyran, optionally substituted with C 1-4 alkyl; 1.33 Any of the prior compositions wherein the compound is selected from the compounds of Table 1 herein, or stereoisomers, solvates, tautomers, or pharmaceutically acceptable salts thereof. 1.34 Any of the prior compositions wherein the composition is in the form of a cream, gel, spray, or ointment. 1.35 Any of the prior compositions wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt% to about 10 wt% based on the total weight of the composition. 1.36 Any of the prior compositions wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt% to about 5 wt% based on the total weight of the composition. Any of the prior compositions further comprising a percutaneous absorption enhancer. Any of the prior compositions further comprising a percutaneous 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 (which are also common in dosage forms), and terpenes. Any of the prior compositions, wherein the composition is applied to a patient's skin once a day. Any of the prior compositions, wherein the composition is applied to a patient's skin twice a day. Any of the prior compositions, wherein the composition is applied to a patient's skin three times a day. Any of the prior compositions, wherein the composition is administered to a patient suffering from an inflammatory disorder. The prior composition, wherein the inflammatory disorder is a skin disorder. The prior composition, wherein the skin is human skin. Any of compositions 1.42 - 1.44, wherein the inflammatory disorder is one that activates MrgprX2 or is a result of the activation of MrgprX2. The prior 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, alcohol flushing, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, drug adverse responses. Any of compositions 1.42 - 1.46, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). Any of the prior compositions, wherein the subject is human. 1.49 Any of the prior compositions, wherein the mammalian skin is human skin. 1.50 Any one of the prior compositions, wherein the composition is for oral administration.

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

[0020] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures and are non-interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers", which refer to two stereoisomers that are mirror images that cannot be superimposed on each other.

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

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

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

[0024] "Pharmaceutically acceptable acid addition salts" retain the biological and other desirable biological effectiveness and properties of the free base and include, but are not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, 10-camphorsulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0025] "Pharmaceutically acceptable basic addition salts" refer to salts that retain the biological activity and properties of the corresponding free acid, either biologically or otherwise desirable. These salts are prepared by adding an inorganic or organic base to the free acid. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including natural substituted amines, salts of cyclic amines, and bases 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, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and basic ion exchange resins such as polyamine resins. 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, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- or, for amino acids, as (D)- or (L)-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using a chiral synthon or chiral reagent or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from a suitable optically pure precursor using chiral high pressure liquid chromatography (HPLC), or resolution of a racemate (or racemate of a salt or derivative).

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

[0028] "Optional" or "may be" means that the subsequent described event or circumstance may or may not occur, and that the description includes both the case where the event or circumstance occurs and the case where it does not. When a functional group is described as "optionally substituted" and, thus, the substituents on the functional group are also "optionally substituted," etc., for the purposes of this invention, such recitations are limited to a maximum of three.

[0029] The term "alkyl" is intended to mean a straight-chain or branched 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 cyclic 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, C1-C6 haloalkyl may be fully substituted, in which case the formula C n L 2n+1It can be represented by, where 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 can be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl contains 1 to 5 carbons. In some embodiments, the haloalkyl contains 1 to 4 carbons. In some embodiments, the haloalkyl contains 1 to 3 carbons. In some embodiments, the 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, etc. When used without a prefix indicating the number of halo substituents, the "haloalkyl" group contains 1, 2, or 3 halogen atoms.

[0032] The term "hydroxyalkyl" is intended to mean a group containing 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, which may contain a single ring or two fused rings, and 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, at least one of the rings being aromatic and at least one of the ring atoms being a heteroatom selected, for example, from O, S, and N. For example, some embodiments such as furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc. contain 5 to 6 ring atoms. For example, some embodiments such as 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, 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]dioxolyl, pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, etc. contain 8 to 14 ring atoms.

[0036] The term "cyano" means a -CN group.

[0037] The term "alkoxy" means a group 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 saturated, partially unsaturated, or fused to an aromatic aryl or heteroaryl ring of 3 to 6 members. Examples of non-aromatic 3- to 6-membered heterocyclic rings include oxirane, aziridine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyran, morpholine, piperazine, hexahydropyrimidine, hexahydropyridazine, and the like. The heterocycloalkyl group may contain one or more oxo (i.e., -C=O-) groups within the ring, and the sulfur ring heteroatom may exist as a sulfur dioxide. Examples of such heterocycloalkyl rings include sulfolane, tetrahydro-2H-thiopyran-1,1-dione, thiomorpholine 1,1-dioxide, 2-pyrrolidone, piperidin-2-one, piperazin-2-one, morpholin-3-one, and the like. Examples of heterocycloalkyl having a fused ring include dihydroindole such as 1,3-dihydroindole.

[0039] The term "spiroalkyl" is intended to mean a structure of two or more rings in which two of the rings share one common atom and at least one of the rings 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 the treatment of inflammatory disorders such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudo-allergic responses caused by small molecules such as anaphylactoid drug responses, anaphylactic shock, alcohol flushing, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, and drug adverse responses. Accordingly, administration or use of a preferred MrgprX2 antagonist described herein, such as the MrgprX2 antagonists described above, such as a compound of formula I, provides a means of ameliorating and / or providing treatment for the symptoms of various inflammatory diseases and disorders.

[0041] For example, in one embodiment, the present disclosure provides a method [Method 1] for treating an inflammatory disorder, the method 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 a further embodiment 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 one of Compounds 1.1 to 1.55 above; 1.3 Any of the preceding methods, wherein the MrgprX2 antagonist is a compound selected from the compounds of 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 at a concentration of from about 0.001% to about 10% by weight based on the total weight of the composition. Any of the prior 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. Any of the prior methods, further comprising a skin absorption enhancer. Any of the prior methods, further comprising 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 (which are also common in dosage forms), and terpenes. Any of the prior methods, wherein the composition is applied to the skin of a patient once a day. Any of the prior methods, wherein the composition is applied to the skin of a patient twice a day. Any of the prior methods, wherein the composition is applied to the skin of a patient three times a day. Any of the prior methods, wherein the composition is administered to a patient suffering from an inflammatory disorder. The prior method, wherein the inflammatory disorder is a skin disorder. The prior method, wherein the skin is human skin. Any of methods 1.12 - 1.14, wherein the inflammatory disorder is caused by activation of MrgprX2 or is a result of activation of MrgprX2. The prior method, 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., anaphylactic-like drug responses, anaphylactic shock, alcohol flushing, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, or drug adverse responses. 1.17 Any one of methods 1.12 to 1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). 1.18 Any one of the preceding methods, wherein the subject is a human. 1.19 Any one of the preceding methods, wherein the mammalian skin is human skin. 1.20 Any one of the preceding methods, wherein the composition is for oral administration.

[0043] In another embodiment, the present disclosure provides a method [Method 2] for reducing inflammation in mammalian skin, the method 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 or orally acceptable excipient.

[0044] The present disclosure further provides further embodiments 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 one of Compounds 1.1 to 1.55 above; 2.3 Any one 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 one of the preceding methods, wherein the inflammation is a result of activation of MrgprX2; 2.5 Any one of the preceding methods, wherein the composition is in the form of a cream, gel, spray, or ointment. 2.6 Any one of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt% to about 10 wt% based on the total weight of the composition. 2.7 Any one of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt% to about 5 wt% based on the total weight of the composition. Any of the prior methods, further comprising a skin absorption enhancer. Any of the prior methods, further comprising 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 (which are also common in dosage forms), and terpenes. Any of the prior methods, wherein the composition is applied to the skin of a patient once a day. Any of the prior methods, wherein the composition is applied to the skin of a patient twice a day. Any of the prior methods, wherein the composition is applied to the skin of a patient three times a day. Any of the prior methods, wherein the composition is administered to a patient suffering from an inflammatory disorder. The prior method, wherein the inflammatory disorder is a skin disorder. The prior method, wherein the skin is human skin. Any of Methods 1.12 to 1.14, wherein the inflammatory disorder activates MrgprX2 or is a result of the activation of MrgprX2. The prior method, 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, alcohol flushing, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, or drug adverse responses. Any of Methods 1.12 to 1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). Any of the prior methods, wherein the subject is human. 2.20 Any of the prior methods, wherein the mammalian skin is human skin. 2.21 Any of the prior methods, wherein the composition is for oral administration.

[0045] A further embodiment provides a method [Method 3] for reducing the occurrence or severity of itching, the method [Method 3] comprising administering a therapeutically effective amount of a topical or oral composition according to Composition 1 and any of 1.1 to 1.73.

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

[0047] "Atopic dermatitis" refers to a skin condition with chronic inflammation. Symptoms of atopic dermatitis include rashes with redness and itching. Atopic dermatitis can be present on the skin of any part of the body, but is common on the hands, feet, upper chest, and the flexures of the 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 overactive immune response. Psoriasis can be present on the skin of any part of the body. Symptoms of psoriasis include local inflammation, skin peeling, and white or red thickened discolored areas of the skin.

[0049] "Alopecia" is an autoimmune skin disease that causes hair loss on the scalp, face, and in some cases 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 urticaria" (hives) is a common skin rash caused by many things, including certain foods, medications, and stress. Symptoms can include raised, red or skin-colored bumps on the skin surface that are itchy. Considering the role of mast cells in chronic idiopathic urticaria, MrgprX2 shares an important function in mast cell activation. Antibacterial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and some peptide-acting drugs approved by the FDA activate human MrgprX2. Unique properties of MrgprX2 that differ from other GPCRs include their presence in both the plasma membrane and intracellular locations, as well as their selective expression in MCs. Furthermore, small molecule inhibitors of MrgprX2 may be beneficial for the treatment of MC-dependent allergic and inflammatory disorders such as currently treated chronic urticaria by targeting the IgE axis of mast cell activity. However, diverse MC activities are dependent 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 could be a therapeutic option for IgE-independent and resistant chronic urticaria in practice.

[0051] "Anaphylactic shock" is an extreme, often life-threatening, allergic response to an antigen to which the body has become hypersensitive. Mast cell activation via MrgprB2 has attracted attention for its IgE-independent mast cell activation and non-histaminergic itching (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) induces the release of multiple bioactive mediators from mast cells, which in turn activates neurons that sense itching, suggesting that mast cell-specific MrgprB2 is important in mast cell degranulation and associated non-histaminergic itching. Mast cell MrgprB2 and MrgrpX2 are activated by pseudoallergen-inducing drugs such as SP, compound 48 / 80, and icatibant (McNeil, B.D. et al., 2015, Nature, 519(7542), 237-241; https: / / doi.org / 10.1038 / nature14022), and MrgprX2 has a central role in non-histaminergic mast cell activation, as well as in various allergic and non-allergic diseases, and pseudoallergic responses.

[0052] "Rosacea" is a condition that causes redness, often with 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 beta-defensins ((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), raising the possibility that mast cell MrgprX2 may contribute to 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, B. D. 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 them are critically involved in urticaria and function as trigger peptides that affect mast cell activity and vasodilation. Combining these findings, MrgprX2 is suggested to be a newly emerging receptor in the pathophysiology of urticaria.

[0053] "Asthma" is a condition in which the human airway becomes inflamed, narrowed, swollen, and produces excessive mucus, which makes breathing difficult. In addition, mast cells (MCs), which are in a normal state near smooth muscle, T cells, and white blood cells, are important effector cells in airway hypersensitivity and inflammation, which are characteristic phenomena of asthma. Only low levels of transcripts are present in a healthy state, but the level of MrgprX2 transcripts increases in severe asthma characterized by a phenotypic switch from MCT to MCTC. In contrast to MCT, the mast cell MCTC population in severe asthma expresses MrgprX2 (Fajt M.L. et al, 2013; The Journal of Allergy and Clinical Immunology, 131(6), 1504-1512; https: / / doi.org / 10.1016 / j.jaci.2013.01.035, and Balzar, S. et al., 2011, American Journal of Respiratory and Critical Care Medicine, 183(3), 299-309; https: / / doi.org / 10.1164 / rccm.201002-0295OC). Considering that the level of SP increases in the lungs of severe asthma patients who activate MrgprX2, treatment with small molecule antagonists would benefit severe asthma patients (van Diest, S.A. et al., 2012, Biochimica et Biophysica Acta, 1822(1), 74-84; https: / / doi.org / 10.1016 / j.bbadis.2011.03.019).

[0054] As used herein, "mammal" or "mammalian" includes both humans, as well as 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] "Therapeutically effective amount" refers to the amount of the compound of the invention that is sufficient to achieve treatment of the desired disease or condition in a mammal, preferably a human, having the disease or condition when administered to the mammal, preferably a human. The amount of the compound of the invention corresponding 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 determined in the usual manner taking into account the person skilled in the art's own knowledge and the present disclosure. Preferably, for the purposes of the present invention, a "therapeutically effective amount" is the amount of the compound of the invention that is sufficient to inhibit skin inflammation.

[0056] As used herein, "treating" or "treatment" encompasses the treatment of a desired disease or condition in a mammal, preferably a human, (i) preventing the occurrence of a disease or condition in a mammal, (ii) inhibiting a disease or condition in a mammal, i.e., arresting its progression, (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, and includes.

[0057] As used herein, the terms "disease," "disorder," and "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus, the etiology has not yet been elucidated), and thus, a condition that is not yet recognized as a disease but is only recognized as an undesirable condition or syndrome, and to the extent that a particular set of symptoms has been identified by a clinician, despite any differences in degree.

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

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

[0060] In certain embodiments, the pharmaceutical compositions described herein further comprise a dermatologically acceptable excipient. The dermatologically acceptable excipient can be one or more solvents that solubilize and / or stabilize the active ingredient (e.g., the MrgprX2 antagonist) contained in the composition. The dermatologically acceptable excipient can also include a skin penetration enhancer, a preservative, a viscosity enhancer, a pH adjuster, a film-forming agent, and the like. 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, TWEEN20, Brij S20 (polyoxyethylene (20) stearyl ether).

[0061] A more detailed description of certain specific excipients is provided below. As will be understood, the 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 emulsifying agent.

[0062] The skin (especially 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. Thus, suitable dermatologically acceptable excipients can include one or more penetration enhancers (or permeation enhancers), which are substances that promote the diffusion of therapeutic drugs (such as the MrgprX2 antagonists described herein) through the skin barrier. They typically act to reduce the obstacles or resistance of the skin so as to enable the improvement of the permeation of therapeutic drugs. Specifically, substances that would disrupt the normal structure of the stratum corneum are capable of disrupting the intercellular lipid tissue and thus reducing the effectiveness as a barrier. These substances can include any lipid substance that would partition into the stratum corneum lipids and cause a direct effect, or any substance that would affect proteins and cause an indirect disruption of the lipid structure. Furthermore, solvents such as ethanol can remove lipids from the stratum corneum and thus disrupt its lipid tissue and disintegrate its barrier function.

[0063] Examples of the penetration enhancer or barrier function disruptor include, but are not limited to, alcohol-based enhancers such as alkanols having 1 to 16 carbons, benzyl alcohol, butylene glycol, diethylene glycol, glycolfurole, glycerides, glycerin, glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based enhancers such as N-butyl-N-dodecylacetamide, crotonamide, 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; essential oils such as almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, castor oil, 1-carboxylic, coconut oil, corn oil, cottonseed oil, eugenol, menthol, anise oil, clove oil, orange oil, peanut oil, peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil (squalene), soybean oil, sunflower oil, and walnut oil; vitamins and herbs such as aloe, 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, petrolatum; mixtures such as primary esters of fractionated vegetable oil fatty acids containing glycerin or propylene glycol, and transesterified medium-chain triglyceride oil, etc.;Amyl caproate, butyl acetate, caprylic acid, cetyl ester, diethyl sebacate, dioctyl malate, ethyl capryl elaidate, ethyl glycol palmitostearate, glyceryl beheate, glucose glutamate, isobutyl acetate, laureth-4, lauric acid, malic acid, methyl caprylate, mineral oil, myristic acid, oleic acid, palmitic acid, PEG fatty acid ester, 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 acid, caprylic acid, capric acid, and triglyceride laurate; macrocyclic compounds such as butylated hydroxyanisole, cyclopentadecanolide, cyclodextrin; phospholipids and phosphate improvers such as dialkyl phosphate, ditetradecyl phosphate, lecithin, 2-pyrrolidone derivatives such as alkyl pyrrolidone-5-carboxylic acid ester, pyroglutamic acid ester, N-methylpyrrolidone, biodegradable soft penetration improvers such as dioxane derivatives and dioxolane derivatives; sulfoxide improvers such as dimethyl sulfoxide and decyl methyl sulfoxide; acid improvers such as alginic acid, sorbic acid, and succinic acid; cyclic amines; imidazolinone; imidazole; ketones such as acetone, dimethicone, methyl ethyl ketone, and pentanedione; lanolin derivatives such as lanolin alcohol, PEG16 lanolin, and acetylated lanolin; oxazoline; oxazolindinone; proline ester; pyrrole, urethane; and surfactants such as nonoxynol, polysorbate, polyoxyethylene alcohol, polyoxyethylene fatty acid ester, sodium lauryl sulfate, and sorbitan monostearate are mentioned.;

[0064] The topical compositions described herein typically, preferably, contain one or more carriers having a vapor pressure of 23.8 mm Hg or more at 25°C. The total preferred concentration range of a single carrier or combination of carriers can be from about 0.1 wt% to about 10 wt% of the dermatological composition, more preferably from about 10 wt% to about 50 wt%, more specifically from about 50 wt% to about 95 wt%. 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 can contain one or more hydrophilic co-solvents that are miscible with water and / or lower chain alcohols and preferably have a vapor pressure less than that of water (about 23.8 mm Hg) at 25°C. The carrier typically has a vapor pressure greater than that of the hydrophilic co-solvent in order to concentrate the active ingredient (e.g., the MrgprX2 antagonist of the present disclosure) in the skin. The hydrophilic co-solvent can be a glycol, specifically propylene glycol. Specifically, the propylene glycol can be from the class of polyethylene glycols having a molecular weight in the range of 200 to 20,000. Preferably, the solvent will be part of the class of glycol ethers. More specifically, the hydrophilic co-solvent of the invention will be diethylene glycol monoethyl ether (transcutol). As used herein, "diethylene glycol monoethyl ether" ("DGME") or "transcutol" refers to 2-(2-ethoxyethoxy)ethanol {CAS number 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 wetting effect. Preferably, the humectant maintains stability 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 wetting effect. Typically, the suitable amount of humectant will depend on the particular humectant or humectants used. The total preferred concentration range of a single humectant or combination of humectants can be from about 0.1% to about 70% by weight, more preferably from about 5.0% to about 30% by weight, and more specifically from about 10% to about 25% by weight of the dermatological composition. 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 enhancer or an emulsifier. A gelling agent is used to increase the viscosity of the final composition. An emulsifier is a substance that stabilizes an emulsion. A viscosity enhancer may also act as an emulsifier. Typically, the concentration and combination of viscosity enhancers will depend on the physical stability of the finished product. Preferred concentration ranges of the viscosity enhancer can be from about 0.01% to about 20% by weight, more preferably from about 0.1% to about 10% by weight, and more specifically from about 0.5% to about 5% by weight of the dermatological composition. Non-limiting examples of viscosity enhancers for use herein include hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, carbomer 980, carbomer 1342, and carbomer 940, more preferably hydroxypropyl cellulose, Pluronic PF127 carbomer 980, and carbomer 1342, and more specifically cellulose, acrylate polymers, and acrylate cross-polymers such as 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 polysorbate, 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, and the preferred concentrations range from about 0.001% to about 0.1% by weight, more preferably from about 0.1% to about 5% by weight of the dermatological composition. 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, tocopherolsolan, and propyl gallate. More specifically, the antioxidant can 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. The preservative may be present in the gelled dermatological composition of the invention to minimize bacteria and / or fungi over the shelf life. The preferred concentration range of the preservative in the dermatological composition of the invention can be from about 0.001% to about 0.01% by weight, more preferably from about 0.01% to about 0.5% by weight of the dermatological composition. Non-limiting examples for use herein include diazolidinyl urea, methylparaben, propylparaben, EDTA tetrasodium, and ethylparaben. More specifically, the preservative will 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-beneficial agent capable of removing metal ions from a system by forming a complex so that the metal ions cannot readily participate in or catalyze chemical reactions. Chelating agents for use herein are preferably formulated at a concentration in the range of about 0.001 wt% to about 10 wt%, more preferably about 0.05 wt% to about 5.0 wt% of the dermatological composition. Non-limiting examples for use herein include EDTA, disodium edetate, dipotassium edetate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid, and potassium gluconate. Specifically, the chelating agent can be EDTA, disodium edetate, dipotassium edate, trisodium edetate, or potassium gluconate.

[0071] The topical or oral compositions described herein may contain one or more conventional, compatible, cosmetically acceptable adjuvants such as colorants, fragrances, emollients, and vegetable substances such as aloe, chamomile, witch hazel, etc.

[0072] Alternatively, other pharmaceutical delivery systems may 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 the active compound or prodrug. Certain organic solvents such as dimethyl sulfoxide (DMSO) may also be used.

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

[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 maintains stability in the composition over a long period of time. Preferably, the stability is over a long period typical in the manufacture, packaging, shipping, and / or storage of dermatologically acceptable compositions, e.g., up to about 3 years, up to about 1 year, or up to about 6 months. The compounds of the present disclosure can be present in solution, in a solution with undissolved portions, partially, or in a suspension that is not completely dissolved. The compounds of the present disclosure can be present in the inventive dermatological compositions in a concentration range of about 0.001 wt% to about 80 wt%, about 0.001 wt% to about 50 wt%, about 0.001 wt% to about 25 wt%, or about 0.001 wt% to about 6 wt%. In one embodiment, the compounds of the present disclosure can be present in a concentration range of about 0.001 wt% to about 10 wt%, about 0.1 wt% to about 10 wt%, or about 1.0 wt% to about 5.0 wt% of the dermatological composition.

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

[0076] When the pharmaceutical composition of the invention is administered topically, the skin of the human to be treated may be pretreated (such as skin cleansing with soap and water, or skin cleansing with an alcohol-based cleanser, etc.) before administration of the dermatological composition of the invention.

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

[0078] Oral administration In some embodiments, the pharmaceutical compositions herein are provided for oral administration. Accordingly, provided in accordance with the present disclosure are solid, semi-solid, or liquid dosage forms for oral administration comprising a compound described herein. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, 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, glidants, enteric coatings, film formers, modified release agents, colorants, color migration inhibitors, sweeteners, and flavoring agents.

[0079] Binders or granulating agents impart cohesiveness to the tablets so that the tablets are securely maintained as such even 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., STARCH1500); gelatin; saccharides such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of tobacco husk, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, methyl paraben, polyalkylene oxide, povidone, polyvinyl pyrrolidone (PVP), crospovidone, Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein in an amount of about 50 wt% to about 99 wt%.

[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, dried starch, and powdered sugar. Certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart to some compressed tablets the property of enabling disintegration 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 sponges; 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 celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; align, as well as mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily recognizable to those skilled in the art. The pharmaceutical compositions provided herein can contain from about 0.5 to about 15% by weight or from 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 glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; gelatin; starch; Japanese ivy; silica or silica gel such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5 weight % of a lubricant.

[0083] Suitable lubricants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable colorants include approved and certified water-soluble FD&C dyes, water-insoluble FD&C dyes suspended in aluminum hydroxide, lake pigments, and any of their mixtures. Lake pigments are a combination by adsorbing water-soluble dyes onto heavy metal aqueous oxides, resulting in dyes in insoluble form. Suitable flavoring agents include natural flavors extracted from plants such as fruits, as well as synthetic blends of compounds that produce pleasant taste sensations such as peppermint and methyl salicylate. Suitable sweeteners include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone. Suitable preservatives include glycerin, methyl and propyl parabens, benzoic acid additives, sodium benzoate, and alcohol. Suitable wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Suitable organic acids include citric acid and tartaric acid. Suitable sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

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

[0085] The pharmaceutical compositions provided herein can be provided as compressed tablets, powder tablets, chewable troches, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets that are coated with a material that resists the action of gastric acid but dissolves or disintegrates in the intestine, and thus protect 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, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating that can be useful for covering unpleasant tastes or odors and protecting the tablets 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, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings generally impart the same characteristics as sugar coatings. Multiple compressed tablets are compressed tablets produced by two or more compression cycles, including layered tablets and pre-coated or dry-coated tablets.

[0086] Tablet dosage forms can be prepared from the active ingredient in powder form, crystalline form, or granule 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 agents and sweetening agents are particularly useful in the form of chewable tablets and troches.

[0087] The pharmaceutical compositions provided herein can be provided as soft or hard capsules that can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry filled capsules (DFC), consist of two compartments, one placed over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft spherical shells, such as gelatin shells, that are plasticized by adding glycerin, sorbitol, or similar polyols. The soft gelatin shell can contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated within a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oil, 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 can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system that can be oil-in-water or water-in-oil, in which one liquid is dispersed in small spherical form throughout another liquid. Emulsions can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifying agent, and a preservative. Suspensions can contain a pharmaceutically acceptable suspending agent and a preservative. Examples of aqueous alcohol solutions include pharmaceutically acceptable acetals such as di(lower alkyl) acetals of lower alkyl aldehydes, for example, acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups such as propylene glycol and ethanol. An elixir is a clear, sweetened, aqueous alcoholic solution. A syrup is a concentrated aqueous solution of sugar, for example, sucrose, and may also contain a preservative. In liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to be conveniently metered for administration.

[0089] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients provided herein, as well as 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 weight of the polyethylene glycol. These formulations may further contain 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 dithiocarbamate.

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

[0091] The pharmaceutical compositions provided herein may be provided as granules and powders, non-foaming or foaming, which are reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-foaming granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in foaming granules or powders can include organic acids and a source of carbon dioxide.

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

[0093] The pharmaceutical compositions provided herein may be formulated as immediate-release or modified-release dosage forms, including sustained-release, extended-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms. Thus, in some preferred embodiments, the active ingredient (i.e., a calcium channel blocker, or L-arginine, or a combination of a calcium channel blocker and L-arginine, or a pharmaceutically acceptable salt, hydrate, solvate, and prodrug thereof) is administered in a pharmaceutical composition that is an immediate-release oral dosage form that preferably includes but does not necessarily include an enteric coating. In some preferred embodiments, the active ingredient is administered in a pharmaceutical composition that is a sustained-release oral dosage form that preferably includes but does not necessarily include an enteric coating. In further preferred embodiments, the active ingredient is administered in a pharmaceutical composition that preferably includes but does not necessarily include an enteric coating and contains both an immediate-release dose and a sustained-release dose or a pulsatile-release dose of a calcium channel blocker. Such a dual-release dosage form achieves the release of an initial dose of the active ingredient, followed by the release of another pulsatile-release or sustained-release dose at a later time. Methodologies for preparing such dual-release dosage forms are well known to those of skill in the art.

[0094] In some embodiments, the active ingredient is formulated into a controlled-release matrix tablet containing one or more polymeric matrix materials that promote a sustained-release, slow-release, or pulsatile release profile. Non-limiting examples of such polymeric matrix materials include the cellulose materials described above, as well as carbomers, such as those sold under the name Carbopol® by Lubrizol Corporation, such as 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, for example, but not limited to, sustained-release compositions found in nifedipine formulations such as Adalat CC®, Procardia® XL, Afeditab® CR, and Nifedical® 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 a pharmaceutical composition for oral administration for use in the treatment of the conditions and disorders described herein.

[0097] Dosage The compositions provided herein contain a therapeutically effective amount of one or more of the compounds provided herein, which are useful for preventing, treating, or ameliorating one or more of the symptoms of the diseases or disorders described herein, and a vehicle. Suitable vehicles for administration of the compounds provided herein include, preferably, any such carrier known to those skilled in the art that is suitable for a particular mode of administration, preferably via topical, oral, or injection. In addition, the compounds can be formulated as the sole active ingredient in the composition or can be combined with other active ingredients.

[0098] The active compound is contained in a vehicle in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the patient being treated. 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 the dosage for humans can be estimated therefrom. The human dosage is then typically fine-tuned and titrated against the response in clinical trials.

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

[0100] In some embodiments, the therapeutically effective dosage should be from about 0.0001 mg to about 1000 mg per day. In some embodiments, from 0.001 to 50 mg of the active ingredient (the MgrprX2 antagonist described herein) per kilogram of body weight per day is delivered by topical, oral, or injection as described herein. In some embodiments, the MgrprX2 antagonist is administered at a dosage of up to 1500 mg / day, such as 1200 mg / day, 900 mg / day, 850 mg / day, 800 mg / day, 750 mg / day, 700 mg / day, 650 mg / day, 600 mg / day, 550 mg / day, 500 mg / day, 450 mg / day, 400 mg / day, 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 1000 mg / day, 50 mg / day, 25 mg / day, 10 mg / day, or 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.75, 0.5, 0.25, 0.10, 0.05, or 0.01 mg / day.

[0101] The active ingredient can be administered once or divided into several smaller doses and administered at time intervals. It is understood that the exact dosage and duration of treatment can be determined empirically using known test protocols, or by extrapolation from in vivo or in vitro test data, or subsequent clinical trials, depending on the disease being treated. It should be noted that the concentration and dosage values can also vary depending on the severity of the condition being alleviated. For any particular subject, a specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or managing the administration of the composition, and it is further understood that the concentration ranges described herein are merely illustrative and are not intended to limit the scope or practice of the claimed composition.

[0102] Dosage forms or compositions can be prepared that contain active ingredients in the range of 0.005% to 100%, 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 The oral dosage forms of the invention comprising the MrgprX2 antagonist of the present disclosure will typically be administered at the dosages described above.

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

[0105] In some embodiments, the daily dose is administered as a single dose. In other embodiments, the daily dose is administered in smaller increments, multiple times a day, e.g., twice or three times a day, in a combined amount equal to the above daily value.

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

[0107] Topical dosage In some embodiments, topical formulations containing a compound of the disclosure will contain the MgrprX2 antagonist at a concentration of from 0.001% to 20% by weight of the composition, such as from 0.001% to 10% by weight of the composition, such as from 0.001% to 8% by weight, such as from 0.001% to 5% by weight, such as from 0.001% to 4% by weight, such as from 0.001% to 3% by weight, such as from 0.001% to 2% by weight, such as from 0.001% to 1% by weight.

[0108] The compound or derivative may be packaged as a manufactured article containing a packaging material, the compound or derivative provided herein within the packaging material that is effective for the treatment, prevention, or amelioration of one or more symptoms of the above-described disease or disorder, and a label indicating that the compound or composition or derivative thereof is used for the treatment, prevention, or amelioration of one or more symptoms of the above-described disease or disorder.

[0109] The manufactured articles provided herein contain a packaging material. Packaging materials for use in packaging the products are well known to those of skill in the art. See, for example, U.S. Pat. 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 mode of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated, as well as the various treatments for any of the diseases or disorders described herein.

[0110] The following examples can be used by those of skill in the art to determine the efficacy of the inventive compounds in the treatment of humans having dermatological conditions characterized by inflammation.

Example

[0111] Example 1 - Synthesis Example The following exemplary compounds are prepared according to the procedure described below.

[0112] Compound E001 TIFF0007712922000008.tif16128N-[5-[(4-Fluorophenyl)methyl]thiazol-2-yl]-4-methyl-tetrahydropyran-4-carboxamide 4-Methyloxane-4-carboxylic acid (47.0 mg, 0.33 mmol) was dissolved in DCM (2 mL), and N-ethyl-N-isopropyl-propan-2-amine (0.17 mL, 0.98 mmol) was added, followed by 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (124.0 mg, 0.33 mmol). After stirring for 10 minutes, 5-(4-fluorobenzyl)-1,3-thiazol-2-amine (68.0 mg, 0.33 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NaHCO3, passed through a TELOS phase separator, concentrated under reduced pressure, and purified by preparative HPLC (Method D) to obtain the title compound as a colorless gum (77 mg). 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.35 - 7.27 (m, 2H), 7.25 (s, 1H), 7.18 - 7.09 (m, 2H), 4.07 (s, 2H), 3.64 (ddd, J = 11.5, 4.1, 4.1 Hz, 2H), 3.37 (ddd, J = 11.8, 9.3, 2.7 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.48 (ddd, J = 13.3, 9.1, 3.7 Hz, 2H), 1.23 (s, 3H). LCMS: m / z 335.1 [M+H]+, (ESI+), RT = 3.17 (Method A).

[0113] (Table 1) The following compounds were synthesized using a method similar to that used for Compound E001. TIFF0007712922000009.tif140166TIFF0007712922000010.tif213166TIFF0007712922000011.tif228166TIFF0007712922000012.tif228166TIFF0007712922000013.tif221166TIFF0007712922000014.tif221166TIFF0007712922000015.tif221166TIFF0007712922000016.tif206166TIFF0007712922000017.tif221166TIFF0007712922000018.tif221166TIFF0007712922000019.tif221166TIFF0007712922000020.tif213166TIFF0007712922000021.tif221166TIFF0007712922000022.tif228166TIFF0007712922000023.tif221166TIFF0007712922000024.tif191166

[0114] Compounds E048 and E049 TIFF0007712922000025.tif19128The unknown single enantiomer of N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide (Compound E015, 62 mg, 0.194 mmol) was chiral separated using a method with a 70:30 heptane:IPA, Chiralpak AS 25 cm column at 18 ml / min to obtain two enantiomers: Compound E048 (the first eluate) 27 mg and Compound 049 (the second eluate) 29 mg.

[0115] Compounds E050 and E051 TIFF0007712922000026.tif18128Unknown single enantiomer of N-[5-[(3-chlorophenyl)methyl]thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide N-[5-[(3-chlorophenyl)methyl]thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide (Compound E033, 56 mg, 0.166 mmol) was chiral separated using a method with a 70:30 heptane:IPA and a Cellulose-4 25 cm column at 18 ml / min to obtain two enantiomers: Compound E050 (the first eluate) 21 mg and Compound E051 (the second eluate) 22 mg.

[0116] Compounds E052 and E053 TIFF0007712922000027.tif24128Unknown single enantiomer of N-[5-[(3,5-difluorophenyl)methyl]thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide N-[5-[(3,5-difluorophenyl)methyl]thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide (Compound E046, 64 mg, 0.189 mmol) was chiral separated using a method with a 90:10 heptane:IPA and a Chiralpak AS column at 15 ml / min to obtain two enantiomers; Compound E052 (the first eluate) 28 mg and Compound E053 (the second eluate) 27 mg.

[0117] Compound E054 TIFF0007712922000028.tif20128(2R)-N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]-1-methyl-pyrrolidine-2-carboxamide Step 1: To tert-butyl (2R)-2-[[5-[(3-fluorophenyl)methyl]thiazol-2-yl]carbamoyl]pyrrolidine-1-carboxylate (Compound E035, 697 mg, 1.67 mmol) was added 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol), and the mixture was stirred at room temperature for 1 hour. Then, it was concentrated under vacuum and oven-dried to obtain (2R)-N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide hydrochloride (Intermediate I01) as an off-white solid (725 mg, 1.63 mmol, 98% yield, 77% purity). 1H NMR (500 MHz, DMSO-d6) δ 9.92 - 9.78 (m, 1H), 8.85 - 8.70 (m, 1H), 7.42 - 7.31 (m, 2H), 7.15 - 7.00 (m, 3H), 4.44 - 4.36 (m, 1H), 4.18 - 4.10 (m, 2H), 3.29 - 3.20 (m, 2H), 2.39 - 2.30 (m, 1H), 2.00 - 1.86 (m, 3H) (NH amide not observed). LCMS: m / z 306.1 [M+H]+, (ESI+), RT = 1.68 (Method A).

[0118] Step 2: (2R)-N-[5-[(3-Fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide hydrochloride (Intermediate I01, 77%, 100 mg, 0.225 mmol) was converted to the free base (SCX-2 cartridge, washed with MeOH, eluted with 7N NH3 / MeOH), and formaldehyde (37%, 34 μL, 0.338 mmol) and acetic acid (1.3 μL, 0.0225 mmol) in DCE (2 mL) were added. This was stirred for 1 h, then sodium triacetoxyborohydride (72 mg, 0.338 mmol) was added and the resulting mixture was stirred at 70 °C overnight. Further, sodium triacetoxyborohydride (95.5 mg, 2 eq) was added and stirred at 70 °C for 1 h. This was concentrated under reduced pressure, MeOH (2 mL) and sodium triacetoxyborohydride (95.5 mg, 2 eq) were added thereto and stirred at room temperature for 2 h. Then, sodium borohydride (43 mg, 1.13 mmol) was added and the mixture was stirred at room temperature overnight. Then, the reaction was treated again with triacetoxyborohydride (95.5 mg, 2 eq) and stirred at room temperature for 1 h. Upon completion, the reaction mixture was washed with NaHCO3, passed through a TELOS phase separator cartridge and concentrated under reduced pressure. It was then purified by preparative HPLC (Method E). The relevant fractions were combined, concentrated to dryness under reduced pressure and subsequently dried in a vacuum oven to give the title compound as a yellow oil (11 mg, 0.0344 mmol, 15% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.31 (m, 1H), 7.30-7.27 (m, 1H), 7.14-7.02 (m, 3H), 4.14-4.10 (m, 2H), 3.19-3.01 (m, 2H), 2.36-2.26 (m, 4H), 2.17-2.09 (m, 1H), 1.83-1.71 (m, 3H) (amide NH peak was observed but not investigated). LCMS: m / z 320.2 [M+H]+, (ESI+), RT = 1.66 (Method A).

[0119] Compound E055 TIFF0007712922000029.tif25128(2R)-1-Acetyl-N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide To a cold (0 °C) solution of (2R)-N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide, hydrochloride (Intermediate I01, 77%, 70 mg, 0.158 mmol) in DCM (1 mL) was added acetic anhydride (21 μL, 0.222 mmol), followed by N-ethyl-N-isopropyl-propan-2-amine (72 μL, 0.412 mmol), and the mixture was stirred at 0 °C for 5 minutes and then at room temperature for 10 minutes. The reaction was washed with water (10 mL), extracted with DCM (10 mL), filtered, and concentrated under reduced pressure to give the title compound as an off-white solid (43 mg, 0.122 mmol, 78% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.34 - 11.96 (m, 1H), 7.39 - 7.32 (m, 1H), 7.31 - 7.26 (m, 1H), 7.13 - 7.01 (m, 3H), 4.62 - 4.42 (m, 1H), 4.13 - 4.08 (m, 2H), 3.62 - 3.34 (m, 2H), 2.33 - 2.07 (m, 1H), 1.97 (s, 3H), 1.96 - 1.78 (m, 3H). LCMS: m / z 348.1 [M+H]+, (ESI+), RT = 2.66 (Method A).

[0120] Compound E056 TIFF0007712922000030.tif25128(2R)-N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]-1-methylsulfonyl-pyrrolidine-2-carboxamide (2R)-N-[5-[(3-Fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide hydrochloride (Intermediate I01, 61 mg, 0.178 mmol) and DIPEA (93 μL, 0.533 mmol) were dissolved in DCM (3 mL), to which methanesulfonyl chloride (16 μL, 0.213 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated again with methanesulfonyl chloride (7 μL, 0.089 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated again with methanesulfonyl chloride (7 μL, 0.089 mmol) and stirred at room temperature for 30 minutes. Then, it was washed with water, passed through a TELOS cartridge, concentrated under reduced pressure, and purified by preparative HPLC (Method E) to obtain the title compound as an off-white solid (20.5 mg, 29%). 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.38 - 7.33 (m, 1H), 7.31 - 7.27 (m, 1H), 7.13 - 7.08 (m, 2H), 7.08 - 7.02 (m, 1H), 4.43 - 4.38 (m, 1H), 4.13 - 4.09 (m, 2H), 3.48 - 3.42 (m, 1H), 3.39 - 3.34 (m, 1H), 2.98 - 2.93 (m, 3H), 2.29 - 2.18 (m, 1H), 1.96 - 1.83 (m, 3H). LCMS: m / z 384.2 [M+H]+, (ESI+), RT = 2.94 (Method A).

[0121] Compound E057 TIFF0007712922000031.tif26128(2R)-N-[5-[(3-Fluorophenyl)methyl]thiazol-2-yl]-1-sulfamoyl-pyrrolidine-2-carboxamide (2R)-N-[5-[(3-Fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide hydrochloride (Intermediate I01, 77%, 70 mg, 0.158 mmol), N-ethyl-N-isopropyl-propan-2-amine (30 μL, 0.172 mmol), and diamide sulfate (26 mg, 0.271 mmol) were stirred in anhydrous 1,4-dioxane (1 mL) at 95 °C for 24 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative HPLC (Method E) to give the title compound as a dark yellow solid (18 mg, 0.0458 mmol, 29% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.38 - 7.33 (m, 1H), 7.30 - 7.28 (m, 1H), 7.13 - 7.08 (m, 2H), 7.07 - 7.02 (m, 1H), 6.92 (s, 2H), 4.29 - 4.23 (m, 1H), 4.11 (s, 2H), 3.41 - 3.35 (m, 1H), 3.29 - 3.24 (m, 1H), 2.19 - 2.10 (m, 1H), 1.95 - 1.79 (m, 3H). LCMS: m / z 385.1 [M+H]+, (ESI+), RT = 2.74 (Method A).

[0122] Compound E058 TIFF0007712922000032.tif20128(2S)-N-[5-[(3-Fluorophenyl)methyl]thiazol-2-yl]-1-methyl-pyrrolidine-2-carboxamide Synthesized using a method similar to that used for Compound E054. 1H NMR (500 MHz, DMSO-d6) δ 7.40 - 7.33 (m, 1H), 7.30 (s, 1H), 7.14 - 7.03 (m, 3H), 4.12 (s, 2H), 3.24 - 3.04 (m, 2H), 2.45 - 2.31 (m, 4H), 2.23 - 2.10 (m, 1H), 1.84 - 1.73 (m, 3H). LCMS: m / z 320.2 [M+H]+, (ESI+), RT = 1.68 (Method A).

[0123] Compound E059 TIFF0007712922000033.tif 181281 - Acetyl - N - [5 - [(2 - fluorophenyl)methyl]thiazol - 2 - yl] - 4 - methyl - piperidine - 4 - carboxamide It was synthesized from Compound E018 using a method similar to that used for Compound E055. 1H NMR (500 MHz, DMSO - d6) δ 11.81 (s, 1H), 7.37 (td, J = 8.0, 6.2 Hz, 1H), 7.30 (s, 1H), 7.15 - 7.09 (m, 2H), 7.06 (td, J = 8.4, 2.3 Hz, 1H), 4.11 (s, 2H), 3.82 - 3.71 (m, 1H), 3.59 - 3.49 (m, 1H), 3.23 - 3.13 (m, 1H), 3.06 - 2.94 (m, 1H), 2.14 (d, J = 14.2 Hz, 1H), 2.06 (d, J = 14.0 Hz, 1H), 1.97 (s, 3H), 1.52 - 1.42 (m, 1H), 1.40 - 1.31 (m, 1H), 1.24 (s, 3H). LCMS: m / z 376.2 [M + H]+, (ESI+), RT = 2.91 (Method A).

[0124] Compound E060 TIFF0007712922000034.tif 18128 N - [5 - [(2 - fluorophenyl)methyl]thiazol - 2 - yl] - 4 - methyl - 1 - methylsulfonyl - piperidine - 4 - carboxamide It was synthesized from Compound E018 using a method similar to that used for Compound E056. 1H NMR (500 MHz, DMSO - d6) δ 11.83 (s, 1H), 7.36 (td, J = 8.0, 6.2 Hz, 1H), 7.29 (s, 1H), 7.15 - 7.08 (m, 2H), 7.05 (td, J = 8.4, 2.3 Hz, 1H), 4.10 (s, 2H), 3.31 - 3.24 (m, 2H), 2.88 - 2.74 (m, 5H), 2.30 - 2.18 (m, 2H), 1.54 (ddd, J = 13.8, 10.1, 3.8 Hz, 2H), 1.24 (s, 3H). LCMS: m / z 412.2 [M + H]+, (ESI+), RT = 3.20 (Method A).

[0125] Compound E061 TIFF0007712922000035.tif16128(2R)-N-[5-[(3-Fluorophenyl)methyl]thiazol-2-yl]-2-methyl-pyrrolidine-2-carboxamide To tert-butyl (2R)-2-[[5-[(3-fluorophenyl)methyl]thiazol-2-yl]carbamoyl]-2-methyl-pyrrolidine-1-carboxylate (Compound E037, 91%, 120 mg, 0.259 mmol) in dioxane was added 4 M HCl in dioxane (0.90 mL, 3.60 mmol), and the mixture was stirred at room temperature for 1 h. It was then concentrated in vacuo and converted to the free base (SCX-2 cartridge, washed with MeOH, eluted with 7 N NH3 / MeOH) to give the title compound as a white solid (69.6 mg, 80%). 1H NMR (500 MHz, DMSO-d6) δ 7.38 - 7.33 (m, 1H), 7.27 (s, 1H), 7.12 - 7.02 (m, 3H), 4.11 (s, 2H), 3.06 - 2.99 (m, 1H), 2.82 - 2.75 (m, 1H), 2.12 - 2.05 (m, 1H), 1.76 - 1.67 (m, 1H), 1.63 - 1.52 (m, 2H), 1.36 - 1.32 (m, 3H). LCMS: m / z 320.2 [M+H]+, (ESI+), RT = 1.68 (Method A).

[0126] (Table 2) The following compounds were synthesized using a method similar to that used for Compound E057. TIFF0007712922000036.tif52166TIFF0007712922000037.tif213166TIFF0007712922000038.tif221166TIFF0007712922000039.tif177166

[0127] Compound E070 TIFF0007712922000040.tif16128N-[5-(3-Fluorophenoxy)thiazol-2-yl]-4-methyl-tetrahydropyran-4-carboxamide Step 1: 5-Bromothiazol-2-amine hydrobromide (1.00 g, 3.85 mmol) and cesium carbonate (3.13 g, 9.61 mmol) were suspended in acetonitrile (5 mL), and the mixture was warmed to 70 °C. A solution of 3-fluorophenol (462 μL, 5.10 mmol) in acetonitrile (25 mL) was added dropwise over 15 minutes. Upon completion of the addition, the mixture was stirred at 70 °C for 1 hour and then at 60 °C for 16 hours overnight. The mixture was diluted with MeOH (20 mL), and the remaining solids were filtered off and discarded. The crude mixture was pre-absorbed on silica (silica was added to the filtrate and concentrated to dryness under vacuum), and purified by chromatography (100 g KP-Sil cartridge, 0 - 20% MeOH in DCM gradient), followed by preparative HPLC (Method E) to give 5-(3-fluorophenoxy)thiazol-2-amine (90.0%) as a pale pink solid (46 mg, 0.197 mmol, 5.1% yield).

[0128] Step 2: 5-(3-Fluorophenoxy)thiazol-2-amine (45 mg, 0.214 mmol) was dissolved in DCM (2 mL), and 4-methyloxane-4-carboxylic acid (35 mg, 0.243 mmol), followed by DIPEA (75 μL, 0.429 mmol), and finally HATU (98 mg, 0.258 mmol) were added. The mixture was stirred at room temperature for a total of 20 hours and then warmed to 35 °C for 4 hours. Water (2 mL) was added, and the organic layer was separated using a Telos phase separator cartridge. The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC (Method F) to give the title compound as a pale yellow gum (40 mg, 0.117 mmol, 54% yield). 1H NMR (250 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.49 - 7.35 (m, 1H), 7.31 (s, 1H), 7.08 - 6.92 (m, 3H), 3.76 - 3.58 (m, 2H), 3.47 - 3.38 (m, 2H), 2.16 - 2.00 (m, 2H), 1.60 - 1.42 (m, 2H), 1.27 (s, 3H). LCMS: m / z 337.1 [M + H]+, (ESI+), RT = 3.30 (Method A).

[0129] (Table 3) The following compounds were synthesized using a method similar to that used for Compound E070. TIFF0007712922000041.tif52166TIFF0007712922000042.tif213166TIFF0007712922000043.tif221166TIFF0007712922000044.tif228166TIFF0007712922000045.tif104166

[0130] Compounds E083 and E084 TIFF0007712922000046.tif19128Unknown single enantiomer of N-[5-(3-fluorophenoxy)thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide N-[5-(3-fluorophenoxy)thiazol-2-yl]-3-methyl-tetrahydrofuran-3-carboxamide (Compound E078, 105 mg, 0.326 mmol) was chiral separated using a method of using a 50:50 ethanol:methanol, Amylose-2 25 cm column at 18 ml / min to obtain two enantiomers; Compound E083 (the first eluate) 48 mg and Compound E084 (the second eluate) 44 mg.

[0131] Compound E085 TIFF0007712922000047.tif16128(2R)-N-(5-phenoxythiazol-2-yl)pyrrolidine-2-carboxamide tert-Butyl (2R)-2-[(5-phenoxythiazol-2-yl)carbamoyl]pyrrolidine-1-carboxylate (Compound E082, 180 mg, 0.462 mmol) was dissolved in 4 M HCl (1.4 mL, 5.55 mmol) in dioxane, and the reaction mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, and the residue was loaded onto an SCX-2 cartridge (2 g, washed with MeOH, eluted with 7 N NH3 / MeOH) to afford the title compound as an orange glass (120 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.34 (m, 2H), 7.21 (s, 1H), 7.18 - 7.06 (m, 3H), 3.84 (dd, J = 8.7, 5.6 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.12 - 1.99 (m, 1H), 1.85 - 1.74 (m, 1H), 1.73 - 1.61 (m, 2H); NH not observed. LCMS: m / z 290.1 [M+H]+, (ESI+), RT = 1.60 (Method A).

[0132] Compound E086 TIFF0007712922000048.tif27128(2R)-N-(5-Phenoxythiazol-2-yl)-1-sulfamoyl-pyrrolidine-2-carboxamide Synthesized using a method similar to that used for Compound E057. 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.47 - 7.34 (m, 2H), 7.26 (s, 1H), 7.22 - 7.06 (m, 3H), 6.94 (s, 2H), 4.28 (dd, J = 8.8, 4.6 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.29 - 3.25 (m, 1H), 2.24 - 2.10 (m, 1H), 2.00 - 1.75 (m, 3H). LCMS: m / z 369.1 [M+H]+, (ESI+), RT = 2.78 (Method A).

[0133] Compound E087 TIFF0007712922000049.tif24128(2R)-N-[5-(4-Cyanophenoxy)thiazol-2-yl]-1-methyl-pyrrolidine-2-carboxamide It was synthesized using a method similar to that used for Compound E054. 1H NMR (500 MHz, DMSO-d6) δ 7.91 - 7.84 (m, 2H), 7.37 (s, 1H), 7.32 - 7.25 (m, 2H), 3.16 - 3.11 (m, 1H), 3.09 - 3.01 (m, 1H), 2.36 - 2.32 (m, 1H), 2.31 (s, 3H), 2.18 - 2.07 (m, 1H), 1.85 - 1.71 (m, 3H). LCMS: m / z 329.1 [M+H]+, (ESI+), RT = 2.97 (Method B).

[0134] Compound E088 TIFF0007712922000050.tif28128(2R)-N-[5-(4-Cyanophenoxy)thiazol-2-yl]-1-ethyl-pyrrolidine-2-carboxamide It was synthesized using a method similar to that used for Compound E054. 1H NMR (500 MHz, Chloroform-d) δ 7.65 - 7.59 (m, 2H), 7.18 - 7.12 (m, 3H), 3.31 - 3.24 (m, 2H), 2.77 - 2.68 (m, 1H), 2.68 - 2.59 (m, 1H), 2.45 (ddd, J = 10.6, 9.2, 6.0 Hz, 1H), 2.24 (dtd, J = 13.2, 10.7, 7.6 Hz, 1H), 2.02 - 1.95 (m, 1H), 1.90 - 1.82 (m, 1H), 1.81 - 1.71 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H). LCMS: m / z 343.1 [M+H]+, (ESI+), RT = 1.60 (Method A).

[0135] Compound E089 TIFF0007712922000051.tif25128(2R)-N-[5-(4-Fluorophenoxy)thiazol-2-yl]-1-sulfamoyl-pyrrolidine-2-carboxamide It was synthesized using a method similar to that used for Compound E057. 1H NMR (500 MHz, Chloroform-d) δ 10.07 (s, 1H), 7.10 - 6.97 (m, 5H), 5.28 (s, 2H), 4.42 (dd, J = 8.0, 4.4 Hz, 1H), 3.58 (ddd, J = 10.9, 7.1, 3.8 Hz, 1H), 3.45 (td, J = 9.3, 6.7 Hz, 1H), 2.37 - 2.21 (m, 2H), 2.09 - 1.99 (m, 1H), 1.99 - 1.88 (m, 1H). LCMS: m / z 387.1 [M+H]+, (ESI+), RT = 2.80 (Method A).

[0136] Compound E090 TIFF0007712922000052.tif31128(2R)-N-[5-(3-Cyano-5-fluoro-phenoxy)thiazol-2-yl]-1-sulfamoyl-pyrrolidine-2-carboxamide It was synthesized using a method similar to that used for Compound E057. 1H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 7.19 (s, 1H), 7.18 - 7.16 (m, 1H), 7.16 - 7.12 (m, 1H), 7.08 (dt, J = 9.5, 2.3 Hz, 1H), 5.01 (s, 2H), 4.43 (dd, J = 8.9, 3.4 Hz, 1H), 3.69 - 3.55 (m, 1H), 3.46 (td, J = 9.5, 6.6 Hz, 1H), 2.46 - 2.23 (m, 2H), 2.15 - 1.89 (m, 2H). LCMS: m / z 412.2 [M+H]+, (ESI+), RT = 2.49 (Method A).

[0137] Compound E091 TIFF0007712922000053.tif29128(2R)-N-[5-(4-Cyanophenoxy)thiazol-2-yl]-1-sulfamoyl-pyrrolidine-2-carboxamide It was synthesized using a method similar to that used for Compound E057. 1H NMR (500 MHz, Chloroform-d) δ 9.89 (s, 1H), 7.66 - 7.61 (m, 2H), 7.17 - 7.12 (m, 3H), 4.97 (s, 2H), 4.40 (dd, J = 9.0, 3.3 Hz, 1H), 3.61 (ddd, J = 10.3, 7.1, 3.6 Hz, 1H), 3.44 (td, J = 9.5, 6.7 Hz, 1H), 2.41 - 2.33 (m, 1H), 2.33 - 2.24 (m, 1H), 2.11 - 2.02 (m, 1H), 2.00 - 1.87 (m, 1H). LCMS: m / z 394.1 [M+H]+, (ESI+), RT = 2.54 (Method A).

[0138] Compound E092 TIFF0007712922000054.tif23128N-[5-[(2,5-Difluorophenyl)methyl]thiazol-2-yl]-4-methyl-tetrahydropyran-4-carboxamide Step 1: 2,5-Difluorobenzaldehyde (0.23 mL, 2.15 mmol) was dissolved in THF-anhydrous (10 mL), and the reaction mixture was cooled to -78 °C. Then, 1.6 M butyllithium (1.7 mL, 2.69 mmol) was added dropwise, and after stirring at -78 °C for 15 minutes, tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (500 mg, 1.79 mmol) was added, and the reaction mixture was stirred at this temperature for an additional 30 minutes. Further, 1.6 M butyllithium (1.7 mL, 2.69 mmol) was added, and the reaction was stirred at -78 °C for 1 hour. Then, it was quenched by the addition of saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (50 g SiO2 column, 0 - 60% EtOAc in heptane) to give tert-butyl N-[5-[(2,5-difluorophenyl)-hydroxy-methyl]thiazol-2-yl]carbamate as an off-white solid (225 mg). 1H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.37 (ddd, J = 9.0, 5.6, 3.2 Hz, 1H), 7.27 - 7.15 (m, 2H), 7.13 (s, 1H), 6.39 (d, J = 4.6 Hz, 1H), 6.08 (d, J = 4.6 Hz, 1H), 1.45 (s, 9H).

[0139] Step 2: tert-Butyl N-[5-[(2,5-difluorophenyl)-hydroxy-methyl]thiazol-2-yl]carbamate (225 mg, 0.644 mmol) was suspended in DCM (5 mL), 2,2,2-trifluoroacetic acid (0.69 mL, 9.02 mmol) (the solution became homogeneous at this point), followed by addition of triethylsilane (0.82 mL, 5.15 mmol), and the reaction was stirred at room temperature over the weekend. The solvent was then removed under reduced pressure, and the crude residue was purified by preparative HPLC (Method E) to afford 5-[(2,5-difluorophenyl)methyl]thiazol-2-amine as a white crystalline solid (80 mg). 1H NMR (500 MHz, DMSO-d6) δ 7.22 (ddd, J = 9.1, 9.1, 4.6 Hz, 1H), 7.17 - 7.07 (m, 2H), 6.74 (s, 2H), 6.70 (s, 1H), 3.91 (s, 2H).

[0140] Step 3: 4-Methyloxane-4-carboxylic acid (25 mg, 0.177 mmol) was dissolved in DCM (2 mL), and N-ethyl-N-isopropyl-propan-2-amine (0.09 mL, 0.53 mmol) was added, followed by 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (67 mg, 0.177 mmol). After stirring for 10 minutes, 5-[(2,5-difluorophenyl)methyl]thiazol-2-amine (40 mg, 0.177 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous NaHCO3, passed through a TELOS phase separator, concentrated under reduced pressure, and purified by preparative HPLC (Method D) to give the title compound as a pale pink gum (26 mg). 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.34 - 7.19 (m, 3H), 7.19 - 7.09 (m, 1H), 4.10 (s, 2H), 3.65 (ddd, J = 11.5, 4.1, 4.1 Hz, 2H), 3.37 (ddd, J = 11.8, 9.3, 2.7 Hz, 2H), 2.13 - 2.03 (m, 2H), 1.48 (ddd, J = 13.3, 9.2, 3.7 Hz, 2H), 1.24 (s, 3H). LCMS: m / z 353.1 [M+H]+, (ESI+), RT = 3.21 (Method A).

[0141] (Table 4) Using a method similar to that used for Compound E092, the following compounds were synthesized. TIFF0007712922000055.tif169166TIFF0007712922000056.tif155166

[0142] Compound 098 TIFF0007712922000057.tif211283-[5-[(3-Chlorophenyl)methyl]thiazol-2-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea Step 1: The stirred aqueous ethylamine solution (70%, 2.1 mL, 25.8 mmol) was 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 warmed to room temperature and stirred overnight. The reaction mixture was then evaporated to dryness to give (2S)-1-(ethylamino)propan-2-ol (Intermediate I02) as a colorless liquid (1.55 g). 1H NMR (250 MHz, Methanol-d4) δ 4.00 - 3.72 (m, 1H), 2.78 - 2.29 (m, 4H), 1.23 - 0.98 (m, 6H).

[0143] Step 2: To a cooled (0 °C) solution of (4-nitrophenyl)carbonochloridate (49 mg, 0.245 mmol) in anhydrous THF (1 mL) was added a solution of 5-[(3-chlorophenyl)methyl]thiazol-2-amine (50 mg, 0.223 mmol) and pyridine (20 μL, 0.245 mmol) in anhydrous THF (2 mL). The reaction was warmed to room temperature and stirred at this temperature for 1 hour. Then, (2S)-1-(ethylamino)propan-2-ol (31 mg, 0.289 mmol) and N-ethyl-N-isopropyl-propan-2-amine (58 μL, 0.334 mmol) were added, and the reaction was stirred at room temperature for 15 minutes. The solvent was then removed under reduced pressure, and the residue was purified by preparative HPLC (Method D) to give the title compound as a pale yellow solid (56 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.38 - 7.26 (m, 3H), 7.25 - 7.19 (m, 1H), 7.10 (s, 1H), 5.34 (s, 1H), 4.02 (s, 2H), 3.91 - 3.76 (m, 1H), 3.27 (dd, J = 14.9, 3.3 Hz, 1H), 3.18 (dd, J = 14.9, 7.7 Hz, 1H), 1.06 (d, J = 6.3 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H); CH2 below the peak of water. LCMS: m / z 354.2 [M + H]+, (ESI+), RT = 3.11 (Method A).

[0144] Using the same method as that used for compound E098 in (Table 5), or any of the amino alcohols synthesized using the same method as that used for the synthesis of intermediate I02, the following compounds were synthesized. TIFF0007712922000058.tif74166TIFF0007712922000059.tif228166TIFF0007712922000060.tif228166TIFF0007712922000061.tif228166TIFF0007712922000062.tif221166TIFF0007712922000063.tif228166TIFF0007712922000064.tif213166TIFF0007712922000065.tif228166TIFF0007712922000066.tif221166TIFF0007712922000067.tif213166TIFF0007712922000068.tif221166TIFF0007712922000069.tif221166TIFF0007712922000070.tif221166TIFF0007712922000071.tif228166TIFF0007712922000072.tif228166TIFF0007712922000073.tif228166TIFF0007712922000074.tif228166TIFF0007712922000075.tif221166TIFF0007712922000076.tif45166

[0145] Compound 147 TIFF0007712922000077.tif251283-[5-(4-Cyanophenoxy)thiazol-2-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea A solution of (4-nitrophenyl)carbonochloridate (64 mg, 0.315 mmol) in anhydrous THF (1 mL) cooled to 0 °C was added to a solution of 4-(2-aminothiazol-5-yl)oxybenzonitrile (70 mg, 0.287 mmol) and pyridine (25 μL, 0.315 mmol) in anhydrous THF (2 mL). The reaction mixture was warmed to room temperature and stirred at this temperature for 1 hour. Then, (2S)-1-(ethylamino)propan-2-ol (Intermediate I02, 64 mg, 0.373 mmol) and N-ethyl-N-isopropyl-propan-2-amine (75 μL, 0.430 mmol) were added, and the reaction mixture was stirred at room temperature for 15 minutes. It was then diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method D) to give the title compound as a yellowish-brown solid (69 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.94 - 7.79 (m, 2H), 7.31 - 7.22 (m, 2H), 7.20 (s, 1H), 4.76 (s, 0H), 4.48 (s, 0H), 3.97 - 3.78 (m, 1H), 3.48 - 3.35 (m, 2H), 3.29 - 3.26 (m, 1H), 3.21 (dd, J = 15.2, 7.7 Hz, 1H), 1.08 (d, J = 6.3 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H); OH broad, not integrated. LCMS: m / z 347.1 [M+H]+, (ESI+), RT = 2.76 (Method A).

[0146] (Table 6) Using the same method as that used for Compound E147, or using any of the commercially available amines or amino alcohols synthesized using the same method as that used for the synthesis of Intermediate I02, the following compounds were synthesized. TIFF0007712922000078.tif221166TIFF0007712922000079.tif221166TIFF0007712922000080.tif228166TIFF0007712922000081.tif228166TIFF0007712922000082.tif228166TIFF0007712922000083.tif228166TIFF0007712922000084.tif228166TIFF0007712922000085.tif228166TIFF0007712922000086.tif228166TIFF0007712922000087.tif228166TIFF0007712922000088.tif221166TIFF0007712922000089.tif221166TIFF0007712922000090.tif228166TIFF0007712922000091.tif228166TIFF0007712922000092.tif213166TIFF0007712922000093.tif213166TIFF0007712922000094.tif228166TIFF0007712922000095.tif228166TIFF0007712922000096.tif226166TIFF0007712922000097.tif228166TIFF0007712922000098.tif213166

[0147] Compound E215 TIFF0007712922000099.tif281283-[2-(3,5-Difluorophenoxy)thiazol-5-yl]-1-ethyl-1-[(2S)-2-hydroxypropyl]urea Step 1: To a solution of cesium carbonate (1.46 g, 4.47 mmol) and 3,5-difluorophenol (400 mg, 2.98 mmol) in DMF-anhydrous (10 mL) was added ethyl 2-chloro-1,3-thiazole-5-carboxylate (629 mg, 3.28 mmol), and the reaction was stirred at 80 °C for 1 h. Water (50 mL) was added to the reaction, which caused a solid precipitate to form. This was isolated by vacuum filtration and dried in an oven for 1.5 h to give ethyl 2-(3,5-difluorophenoxy)thiazole-5-carboxylate as an orange solid (892 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.04 - 8.02 (m, 1H), 7.40 - 7.34 (m, 2H), 7.34 - 7.28 (m, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.30 - 1.25 (m, 3H).

[0148] Step 2: To a solution of ethyl 2-(3,5-difluorophenoxy)thiazole-5-carboxylate (850 mg, 2.98 mmol) in THF (23.4 mL) was added 2 M LiOH (3.0 mL, 5.96 mmol), and the reaction mixture was stirred at 40 °C for 3 h and then at room temperature overnight. The reaction was concentrated under reduced pressure, and water (20 mL) was added thereto. The reaction mixture was acidified with 2 M HCl and extracted with EtOAc (3 × 20 mL), and concentrated under reduced pressure to give 2-(3,5-difluorophenoxy)thiazole-5-carboxylic acid as a yellow solid (685.7 mg). 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.38 - 7.32 (m, 2H), 7.32 - 7.26 (m, 1H). (OH was not observed).

[0149] Step 3: To a solution of 2-(3,5-difluorophenoxy)thiazole-5-carboxylic acid (100 mg, 0.389 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.15 mL, 0.855 mmol) in 1,4-dioxane-anhydrous (5 mL) was added DPPA (0.10 mL, 0.467 mmol), and the reaction was stirred at room temperature for 1 h. To the reaction mixture was added (2S)-1-(ethylamino)propan-2-ol (Intermediate I02, 88%, 91 mg, 0.778 mmol), and the reaction was stirred at 100 °C for 16 h. The reaction was diluted with EtOAc (20 mL). The organic portion was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. This was purified by column chromatography (Biotage SNAP cartridge KP-Sil 10 g, 0-100% EtOAc in heptane) and preparative HPLC (Method D) to afford the title compound as a yellow gum (12 mg, 8%). 1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.18 - 7.04 (m, 3H), 6.90 (s, 1H), 4.96 (s, 1H), 3.83 (s, 1H), 3.43 - 3.34 (m, 2H), 3.29 - 3.22 (m, 1H), 3.16 - 3.10 (m, 1H), 1.09 - 1.03 (m, 6H). LCMS: m / z 358.1 [M+H]+, (ESI+), RT = 2.98 (Method A).

[0150] Compound E216 TIFF0007712922000100.tif15128N-[2-[(3-Fluorophenyl)methyl]thiazol-5-yl]-2-methyl-propanamide Step 1: To a solution of 3-fluorophenylacetonitrile (1.00 g, 7.40 mmol) in stirred DMF-anhydrous (10 mL) was added dichloromagnesium (719 mg, 7.40 mmol), followed by sodium hydrosulfide hydrate (1:1) (1.11 g, 14.8 mmol). The mixture was stirred at room temperature for a total of 21 h. The reaction mixture was washed with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with water, brine, dried (hydrophobic filter), and concentrated to dryness under reduced pressure. Purification (silica gel 60, 25 g cartridge, eluent: ethyl acetate - heptane 0 - 40%) gave 2-(3-fluorophenyl)thioacetamide as a colorless solid (1.16 g). 1H NMR (500 MHz, Chloroform-d) δ 7.62 (s, 1H), 7.36 (td, J = 7.9, 6.0 Hz, 1H), 7.10 - 7.06 (m, 1H), 7.06 - 6.99 (m, 2H), 6.67 (s, 1H), 4.09 (s, 2H).

[0151] Step 2: A solution of 2-(3-fluorophenyl)thioacetamide (300 mg, 1.77 mmol) and ethyl 2-chloro-3-oxopropanoate (320 mg, 2.13 mmol) in stirred 1,4-dioxane (6 mL) was heated to 100 °C for a total of 21 h. The reaction mixture was concentrated to dryness under reduced pressure and purified (silica gel 60, 10 g cartridge, eluent: acetone - heptane 0 - 20%) to give ethyl 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylate as an orange liquid (265 mg). 1H NMR (500 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.32 (td, J = 7.9, 6.0 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.05 - 6.96 (m, 2H), 4.33 (q, J = 7.2 Hz, 4H), 1.35 (t, J = 7.1 Hz, 3H).

[0152] Step 3: To a solution of ethyl 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylate (265 mg, 0.999 mmol) in stirred THF (2.5 mL) was added 2 M aqueous lithium hydroxide solution (1.0 mL, 2.00 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine, dried (hydrophobic filter), and concentrated to dryness under reduced pressure to give 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylic acid as a yellow solid (147 mg, yield 50%, purity about 80%). 1H NMR (500 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.24 (s, 1H), 7.44 - 7.37 (m, 1H), 7.25 - 7.18 (m, 2H), 7.12 (td, J = 9.2, 8.7, 2.3 Hz, 1H), 4.41 (s, 2H).

[0153] Step 4: To a solution of 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylic acid (146 mg, 0.615 mmol) in stirred tert-butanol (1.5 mL) was added triethylamine (257 μL, 1.85 mmol), followed by [azido(phenoxy)phosphoryl]oxybenzene (133 μL, 0.615 mmol), and the reaction mixture was heated to 90 °C for 2.5 h. Further, [azido(phenoxy)phosphoryl]oxybenzene (53 μL, 0.246 mmol) and triethylamine (103 μL, 0.738 mmol) were added, and the mixture was stirred for an additional 2.5 h. The reaction mixture was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic layers were dried (hydrophobic filter) and concentrated to dryness under reduced pressure. Purification (silica gel 60, 10 g cartridge, eluent: ethyl acetate - heptane 30 - 40%) gave tert-butyl N-[2-[(3-fluorophenyl)methyl]thiazol-5-yl]carbamate as a brown syrup (83 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 7.9 Hz, 1H), 7.02 - 6.91 (m, 3H), 4.20 (s, 2H), 1.49 (s, 9H).

[0154] Step 5: tert-Butyl N-[2-[(3-fluorophenyl)methyl]thiazol-5-yl]carbamate (83 mg, 0.269 mmol) was dissolved in 4 M 1,4-dioxane hydrochloride (3.4 mL, 13.5 mmol) and stirred for 24 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (hydrophobic filter), and concentrated to dryness under reduced pressure to give 2-[(3-fluorophenyl)methyl]thiazol-5-amine as a brown syrup (44 mg, yield 59%, purity 75%). 1H NMR (500 MHz, Chloroform-d) δ 7.32 - 7.23 (m, 2H), 7.06 (d, J = 7.7 Hz, 1H), 7.00 - 6.89 (m, 4H), 4.14 (s, 2H).

[0155] Step 6: To a solution of 2-[(3-fluorophenyl)methyl]thiazol-5-amine (22 mg, 0.106 mmol) in stirred THF-anhydrous (1 mL) were added N,N-dimethylpyridin-4-amine (1.3 mg, 0.0106 mmol) and N-ethyl-N-isopropyl-propan-2-amine (37 μL, 0.211 mmol), followed by 2-methylpropanoyl 2-methylpropanoate (26 μL, 0.158 mmol), and the reaction mixture was heated to 80 °C for 3.5 h. The reaction mixture was concentrated to dryness and purified (silica gel 60, 10 g cartridge, eluent: ethyl acetate - heptane 60%) to afford the title compound as a brown syrup (8 mg, 27%). 1H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 1H), 7.34 (s, 1H), 7.29 - 7.22 (m, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.98 (dt, J = 9.7, 1.9 Hz, 1H), 6.93 (td, J = 8.4, 2.3 Hz, 1H), 4.22 (s, 2H), 2.54 (hept, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H). LCMS: m / z 279.1 [M+H]+, (ESI+), RT = 2.84 (Method A).

[0156] Compound E217 TIFF0007712922000101.tif151285-[(3-fluorophenyl)methyl]-N-isopropyl-thiazole-2-carboxamide Step 1: To a solution of 5-methyl-1,3-thiazole-2-carboxylic acid (500 mg, 3.49 mmol) in stirred DMF-anhydrous (10 mL), potassium carbonate (965 mg, 6.99 mmol) was added, followed by iodoethane (309 μL, 3.84 mmol), and the suspension was stirred at 40 °C for 4 h. The reaction mixture was then diluted with water and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 0 - 50% EtOAc in heptane) to give ethyl 5-methylthiazole-2-carboxylate (Intermediate I03) as a colorless oil (390 mg). 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 1.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.54 (d, J = 1.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0157] Step 2: To a solution of ethyl 5-methylthiazole-2-carboxylate (335 mg, 1.96 mmol) in stirred DCE (6 mL), 1-bromopyrrolidine-2,5-dione (383 mg, 2.15 mmol) was added, followed by benzoylbenzenecarboperoxoate (75%, 1.3 mg, 3.91 μmol), and the reaction was heated to 75 °C for 1.5 h. It was then cooled to room temperature, washed with water, and the aqueous layer was extracted with DCM. The combined organic extracts were passed through a TELOS phase separator, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 0 - 15% EtOAc in heptane) to give ethyl 5-(bromomethyl)thiazole-2-carboxylate as a colorless oil (340 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 5.10 (d, J = 0.6 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0158] Step 3: (3-Fluorophenyl)boronic acid (180 mg, 1.29 mmol), ethyl 5-(bromomethyl)thiazole-2-carboxylate (70%, 400 mg, 1.12 mmol), and Na2CO3 (475 mg, 4.48 mmol) were suspended in dioxane (8 mL), and the mixture was degassed with N2 for 5 minutes. Then, Pd(PPh3)4 (129 mg, 0.112 mmol) was added, and the reaction mixture was stirred in a sealed tube at 100 °C for 16 hours. It was then cooled to room temperature, diluted with EtOAc and water, and filtered through celite. The organic layer was separated, and the aqueous solution was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (50 g SiO2 column, 0 - 25% EtOAc in heptane) to give ethyl 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (t, J = 0.9 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.21 - 7.13 (m, 2H), 7.11 - 7.04 (m, 1H), 4.38 - 4.32 (m, 2H), 4.32 - 4.31 (m, 2H), 1.34 - 1.26 (m, 3H).

[0159] Step 4: To a solution of ethyl 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylate (60%, 315 mg, 0.712 mmol) in THF (5 mL) was added 2 M LiOH (0.71 mL, 1.42 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure, and water (5 mL) was added thereto. The reaction mixture was acidified to pH 1 - 2 with 2 M HCl, and a precipitate of a gray solid formed. This was filtered, washed with 2 M HCl, and air-dried to give 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylic acid as a gray solid (125 mg). 1H NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 7.89 (s, 1H), 7.43 - 7.33 (m, 1H), 7.20 - 7.12 (m, 2H), 7.12 - 7.03 (m, 1H), 4.30 (s, 2H).

[0160] Step 5: To a solution of 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylic acid (95%, 40 mg, 0.160 mmol) and HATU (73 mg, 0.192 mmol) in stirred DMF (1.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (84 μL, 0.481 mmol), followed by propan-2-amine (21 μL, 0.240 mmol), and the resulting reaction mixture was stirred at room temperature for 1 h. Then water (10 mL) was added and the formation of a precipitate occurred. This was filtered, washed with water, and purified by flash column chromatography (10 g SiO2 column, 0 - 60% EtOAc in heptane) to afford the title compound as a beige solid (29 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.4 Hz, 1H), 7.81 - 7.79 (m, 1H), 7.44 - 7.31 (m, 1H), 7.20 - 7.11 (m, 2H), 7.11 - 7.02 (m, 1H), 4.27 (s, 2H), 4.13 - 3.96 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H). LCMS: m / z 279.1 [M+H]+, (ESI+), RT = 3.36 (Method A).

[0161] Compound E218 TIFF0007712922000102.tif161285-[(3-fluorophenyl)methyl]-N-isopropyl-N-methyl-thiazole-2-carboxamide Synthesized using a method similar to that used for Compound E217. 1H NMR (400 MHz, DMSO-d6) δ 7.86 - 7.67 (m, 1H), 7.45 - 7.29 (m, 1H), 7.20 - 6.99 (m, 3H), 5.03 (s, 1H), 4.26 (s, 2H), 1.18 (d, J = 6.7 Hz, 6H). LCMS: m / z 293.1 [M+H]+, (ESI+), RT = 3.59 (Method A).

[0162] Compound E219 TIFF0007712922000103.tif171282-methyl-N-[5-(1-phenylethyl)thiazol-2-yl]propanamide Step 1: Thiouronium (1 g, 13.14 mmol) was suspended in EtOH (20 mL), and 1,1-dimethoxy-N,N-dimethylmethanamine (2.1 mL, 15.81 mmol) was added. The mixture was heated to reflux at 90 °C for 2 h with stirring. After cooling to room temperature, the resulting precipitate was filtered off, washed with diethyl ether (2×5 mL), and dried in a vacuum oven to give dimethylaminomethylene thiourea as a pale yellow crystalline solid (1.48 g, 86% yield). 1H NMR (250 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 3.13 (s, 3H), 3.02 - 2.95 (m, 3H).

[0163] Step 2: Dimethylaminomethylene thiourea (250 mg, 1.91 mmol) and 2-bromo-1-phenylethanone (380 mg, 1.91 mmol) were combined in ethanol (10 mL), and triethylamine (266 μL, 1.91 mmol) was added. The mixture was heated to reflux at 90 °C for 16 h overnight. The mixture was concentrated under vacuum, and the residue was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. It was then loaded onto an SCX column (5 g) and eluted with 7N NH3 in MeOH. This was concentrated under reduced pressure to give 5-benzoyl-1,3-thiazol-2-amine as a brown solid (376 mg).

[0164] Step 3: N-(5-benzoyl-1,3-thiazol-2-yl)-2-methylpropanamide. To a solution of 5-benzoyl-1,3-thiazol-2-amine (376 mg, 1.10 mmol) in DCM (3 mL) was added DIPEA (385 μL, 2.21 mmol), followed by 2-methylpropanoyl chloride (127 μL, 1.22 mmol). The reaction mixture was stirred at room temperature for 1 h. Upon completion, it was washed with water, passed through a TELOS phase separator, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (Biotage SNAP cartridge KP-Sil 100 g; 0 - 100% EtOAc in heptane) to afford N-(5-benzoyl-1,3-thiazol-2-yl)-2-methylpropanamide (319 mg). 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.09 (s, 1H), 7.89 - 7.79 (m, 2H), 7.72 - 7.64 (m, 1H), 7.58 (t, J = 7.7 Hz, 2H), 2.81 (hept, J = 6.8 Hz, 1H), 1.16 (d, J = 6.9 Hz, 6H).

[0165] Step 4: N-[5-(1-Hydroxy-1-phenyl-ethyl)thiazol-2-yl]-2-methyl-propanamide. To a stirred solution of N-(5-benzoylthiazol-2-yl)-2-methyl-propanamide (100 mg, 0.365 mmol) in anhydrous THF (2 mL) at 0 °C was added MeMgBr (0.46 mL, 0.73 mmol). This was stirred for 1 h, then further MeMgBr (0.46 mL, 0.73 mmol) was added and the mixture was left stirring for 16 h. Upon completion, the reaction mixture was quenched with saturated NH4Cl (5 mL), stirred for 30 min, and then water was added. The mixture was extracted with EtOAc (3 × 10 mL), the combined organic layers were washed with brine and dried over anhydrous Na2SO4. This was concentrated under reduced pressure and purified by preparative HPLC (method G) to give N-[5-(1-hydroxy-1-phenyl-ethyl)thiazol-2-yl]-2-methyl-propanamide (44 mg). 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.49 - 7.43 (m, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.25 - 7.19 (m, 2H), 6.08 (s, 1H), 2.68 (hept, J = 13.7, 6.8 Hz, 1H), 1.86 (s, 3H), 1.07 (dd, J = 6.8, 4.6 Hz, 6H).

[0166] Step 5: N-[5-(1-Hydroxy-1-phenyl-ethyl)thiazol-2-yl]-2-methyl-propanamide (37 mg, 0.127 mmol) was dissolved in 2,2,2-trifluoroacetic acid (1.0 mL, 13.5 mmol), and the reaction mixture was heated to 80 °C for 5 minutes. The solvent was removed under reduced pressure, and the resulting residue was dissolved in IPA (5 mL). Ammonium formate (80 mg, 1.27 mmol) and palladium on carbon (10%) (14 mg, 0.0127 mmol) were added, and the reaction mixture was heated to 80 °C for 16 hours. It was then cooled to room temperature, filtered through a Celite pad, concentrated under reduced pressure, and purified by preparative HPLC (Method D) to obtain the title compound as a white solid (3 mg). 1H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.35 - 7.19 (m, 6H), 4.32 (q, J = 7.1 Hz, 1H), 2.74 - 2.64 (m, 1H), 1.60 (d, J = 7.1 Hz, 3H), 1.06 (d, J = 6.8 Hz, 6H). LCMS: m / z 275.1 [M+H]+, (ESI+), RT = 3.36 (Method A).

[0167] Compound E220 TIFF0007712922000104.tif191284-Fluoro-5-[(4-fluorophenyl)methyl]-N-isopropyl-thiazole-2-carboxamide A suspension of ethyl 5-methylthiazole-2-carboxylate (Intermediate I03, 90%, 2.22 g, 11.7 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor, 4.138 g, 11.7 mmol) in anhydrous acetonitrile (30 mL) was stirred at 80 °C for 6 h and then at room temperature overnight. Further, Selectfluor (4.138 g, 11.7 mmol) was added, then heated to reflux for 10 h and then left at room temperature overnight. Brine (20 mL) and EtOAc (20 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic extracts were washed with brine (20 mL) and concentrated in vacuo. The residue thus obtained was purified by column chromatography (KP Sil 25 g, gradient heptane / EtOAc 0 - 40%) to give ethyl 4-fluoro-5-methyl-thiazole-2-carboxylate as a yellow free-flowing oil (455 mg, yield 20%, purity 95%). 1H NMR (500 MHz, DMSO-d6) δ 4.35 (q, J = 7.1 Hz, 2H), 2.40 (d, J = 1.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0168] Using a method similar to that used for Compound E217, this compound was further reacted to give the title compound as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.10 (m, 2H), 7.09 - 6.92 (m, 2H), 6.92 - 6.70 (m, 1H), 4.27 - 4.13 (m, 1H), 4.05 (s, 2H), 1.25 (d, J = 6.6 Hz, 6H). LCMS: m / z 297.1 [M+H]+, (ESI+), RT = 3.66 (Method A).

[0169] Compound E221 TIFF0007712922000105.tif 191285-[(3,5-difluorophenyl)methyl]-N-isopropyl-isoxazole-3-carboxamide It was synthesized from ethyl 5-(hydroxymethyl)-1,2-oxazole-3-carboxylate using a method similar to that used for Compound E217. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J = 7.9 Hz, 1H), 7.16 (tt, J = 9.4, 2.3 Hz, 1H), 7.11 - 7.04 (m, 2H), 6.57 (s, 1H), 4.25 (s, 2H), 4.11 - 3.99 (m, 1H), 1.13 (d, J = 6.6 Hz, 6H). LCMS: m / z 281.1 [M+H]+, (ESI+), RT = 3.19 (Method A).

[0170] Compound E222 TIFF0007712922000106.tif121286 - phenoxy - 2-(propan - 2 - yl)-1H - 1,3 - benzodiazole A solution of 4-phenoxybenzene-1,2-diamine (50 mg, 0.250 mmol) and DIPEA (0.087 mL, 0.499 mmol) in DCM (3 mL) at room temperature was added dropwise to a solution of isobutyryl chloride (0.027 mL, 0.258 mmol) in DCM (2 mL), and the mixture was stirred for 1 h. The reaction mixture was washed with saturated NaHCO3 solution (5 mL), dried over sodium sulfate, filtered, and evaporated to dryness to afford a brown solid. The solid was suspended in AcOH (3 mL) and heated to 90 °C with stirring for 2 h. The reaction mixture was evaporated to dryness. It was then evaporated from MeOH (2 × 5 mL) to give a dark brown gum. This was dissolved in MeOH (3 mL), loaded onto an Isolute SCX-2 cartridge (1 g), and subsequently dissolved in MeOH (10 mL). The product was eluted with 7N ammonia in MeOH solution (10 mL) and evaporated to dryness. Purification by preparative HPLC (method E) followed by lyophilization gave the title compound as a yellow solid (33 mg, 52%). 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.14 - 7.00 (m, 2H), 6.97 - 6.89 (m, 2H), 6.85 (dd, J = 8.6, 2.3 Hz, 1H), 3.12 (hept, J = 6.9 Hz, 1H), 1.33 (d, J = 7.0 Hz, 6H). LCMS: m / z 253.1 [M+H]+, (ESI+), RT = 1.72 (method A).

[0171] Compound E223 TIFF0007712922000107.tif21128N-Benzyl-4-(2-methylpropanoylamino)thiophene-2-carboxamide Step 1: 4-Aminothiophene-2-carboxylic acid (100.0 mg, 0.7 mmol), 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (265.6 mg, 0.7 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.24 mL, 1.40 mmol) were mixed in acetonitrile (4 mL), followed by mixing in phenylmethanamine (0.23 mL, 2.1 mmol), and stirred overnight at room temperature. The solvent was removed in vacuo, and the crude reaction mixture was purified using preparative HPLC (Method G) to afford 4-amino-N-benzyl-thiophene-2-carboxamide as a yellow oil (110 mg).

[0172] Step 2: 4-Amino-N-benzyl-thiophene-2-carboxamide (85.0 mg, 0.18 mmol) was dissolved in THF (5 mL), and mixed with N-ethyl-N-isopropyl-propan-2-amine (0.064 mL, 0.366 mmol), N,N-dimethylpyridin-4-amine (22 mg, 0.183 mmol), and 2-methylpropanoyl 2-methylpropanoate (43 mg, 0.274 mmol), and stirred in a sealed vial at 80 °C for 18 h. Upon completion, the solvent was removed in vacuo, and the crude material was purified using preparative HPLC (Method E) to afford the title compound as an off-white solid (32 mg, 58% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.10 (t, J = 6.0 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.41 - 7.12 (m, 5H), 4.43 (d, J = 6.0 Hz, 2H), 2.59 - 2.53 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H). LCMS: m / z 303.1 [M+H]+, (ESI+), RT = 2.76 (Method B).

[0173] HPLC method: Analytical LCMS Method A: Analytical uHPLC-MS was performed on a Waters Acquity uPLC using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40 °C), and a gradient of 5–100% B (A = 0.1% formic acid in H2O, B = 0.1% formic acid in ACN) for 5.3 minutes, followed by 100% B for 0.5 minute. Then, a second gradient of 100–5% B was applied for 0.02 minute and held for 1.18 minutes at a flow rate of 0.6 mL / min with an injection volume of 1 μL. The Waters Acquity PDA detector spectral range: 200–400 nm was used at 215 nm to record the UV spectrum, and the Waters Acquity ELS detector (if applicable) was used to collect and report the ELS data. A mass spectrum was obtained using a Waters SQD (MSQ1) or Waters Acquity QDA (MSQ2). The data was integrated and reported using Waters MassLynx and OpenLynx software.

[0174] Method B: Analytical uPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH C18 column (2.1 mm × 100 mm, 1.7 μm column; temperature: 40 °C), and a gradient of 5–100% (A = 2 mM sodium bicarbonate, buffered to pH 10, B = ACN) for 5.3 minutes, followed by 100% B for 0.5 minute. Then, a second gradient of 100–5% B was applied for 0.02 minute and held for 1.18 minutes at an injection volume of 1 μL and a flow rate of 0.6 mL / min. The Waters Acquity photodiode array detector spectral range: 200–400 nm was used at 215 nm to record the UV spectrum. A mass spectrum was obtained using a Waters Quattro Premier XE mass detector. The data was integrated and reported using Waters MassLynx and OpenLynx software.

[0175] Method C: Analytical HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm × 50 mm, 5 μm; temperature: 40 °C), and a gradient of 5 - 100% B (A = 0.1% formic acid in H2O, B = 0.1% formic acid in ACN) for 1.2 minutes, followed by 100% B for 0.1 minute. Then, a second gradient of 100 - 5% B was applied for 0.01 minute at an injection volume of 3 μL and a flow rate of 1.2 mL / min. The UV spectrum was recorded using an SPD-M20A photodiode array detector with a spectral range of 200 - 400 nm at 215 nm. A 2010EV detector was used to obtain the mass spectrum. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0176] HPLC method: Preparative HPLC method The purification method is as follows.

[0177] Method D: Acidic early method: Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature), and a gradient of 10 - 95% B (A = 0.1% formic acid in H2O, B = 0.1% formic acid in ACN) for 14.44 minutes, followed by 95% B for 2.11 minutes. Then, a second gradient of 95 - 10% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.2 minute. The UV spectrum was recorded using a Gilson detector at 215 nm.

[0178] Method E: Basic early method: Purification was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature), and a gradient of 10 - 95% B (A = 0.2% ammonium hydroxide in H2O, B = 0.2% ammonium hydroxide in ACN) for 14.44 minutes, followed by 95% B for 2.11 minutes. Then, a second gradient of 95 - 10% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.2 minute. The UV spectrum was recorded using a Gilson detector at 215 nm.

[0179] Method F: Standard method for acidic substances: Purification was carried out using a Gilson LC system with a Waters Sunfire C18 column (30 mm × 10 mm, 10 μm; temperature: room temperature), and a gradient of 30 - 95% B (A = 0.1% formic acid in water, B = 0.1% formic acid in ACN) for 11.00 minutes, followed by 95% B for 2.10 minutes. Then, a second gradient of 95 - 30% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.2 minutes. The Gilson detector was used at 215 nm to record the UV spectrum.

[0180] Method G: Standard method for basic substances: Purification was carried out using a Gilson LC system with a Waters X - Bridge C18 column (30 mm × 10 mm, 10 μm; temperature: room temperature), and a gradient of 30 - 95% B (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in ACN) for 11.00 minutes, followed by 95% B for 2.10 minutes. Then, a second gradient of 95 - 30% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.21 minutes. The Gilson detector was used at 215 nm to record the UV spectrum.

[0181] Example 2 - Screening of Compounds Potent and selective hMrgpMRGPRX2 compounds were generated from compounds identified during a high-throughput screening (HTS) campaign and followed up in a cycle of the power of structure-activity-based pharmaceutical science. 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, which endogenously expresses the target. The assay used to determine potency was a functional readout by observing intracellular calcium mobilization using FLIPR™ technology. In these FLIPR assays, recombinant cell lines expressing mouse MrgprB2, mouse MrgprA1, the Syrian hamster MrgpMRGPRX2 ortholog, the Chinese hamster MrgpMRGPRX2 ortholog, and the cynomolgus monkey MrgpMRGPRX2 ortholog were used to test the identified compounds for ortholog activity, respectively.

[0182] The results are summarized in Table 1 below.

[0183] (Table 1) Results of the selected compounds TIFF0007712922000108.tif65149TIFF0007712922000109.tif215149TIFF0007712922000110.tif200149TIFF0007712922000111.tif200149TIFF0007712922000112.tif200149TIFF0007712922000113.tif200149TIFF0007712922000114.tif200149TIFF0007712922000115.tif200149TIFF0007712922000116.tif200149TIFF0007712922000117.tif200149TIFF0007712922000118.tif200149TIFF0007712922000119.tif200149TIFF0007712922000120.tif249149TIFF0007712922000121.tif200149TIFF0007712922000122.tif203149TIFF0007712922000123.tif200149TIFF0007712922000124.tif200149TIFF0007712922000125.tif219149TIFF0007712922000126.tif200149TIFF0007712922000127.tif200149TIFF0007712922000128.tif199149TIFF0007712922000129.tif199149TIFF0007712922000130.tif200149TIFF0007712922000131.tif200149TIFF0007712922000132.tif200149TIFF0007712922000133.tif200149TIFF0007712922000134.tif200149TIFF0007712922000135.tif200149TIFF0007712922000136.tif200149TIFF0007712922000137.tif200149TIFF0007712922000138.tif200149TIFF0007712922000139.tif200149TIFF0007712922000140.tif200149TIFF0007712922000141.tif200149TIFF0007712922000142.tif200149TIFF0007712922000143.tif200149TIFF0007712922000144.tif200149TIFF0007712922000145.tif200149TIFF0007712922000146.tif200149TIFF0007712922000147.tif200149TIFF0007712922000148.tif200149TIFF0007712922000149.tif200149TIFF0007712922000150.tif200149TIFF0007712922000151.tif200149TIFF0007712922000152.tif200149TIFF0007712922000153.tif81149.

Claims

1. A compound having the following formula I, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof: In the formula, W is -(L １ ) ｐ -A ２ and A １ is as follows: is a ring system of, R Ａ is selected from H, C １－３ alkyl, halogen, and CN, k, q, m, and p are each 1, R ３ is H, and R １ is C alkyl or C cycloalkyl which may be substituted with H; 1, 2 or 3 independently selected R groups; or 3- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, which may be substituted with 1, 2 or 3 independently selected R groups and may contain a -(C=O)- group or a -S(=O)- group in the ring, selected from: ５０ alkyl optionally substituted with １－６ or C ３－６ cycloalkyl; or 3- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, which may be substituted with 1, 2 or 3 independently selected R groups and may contain a -(C=O)- group or a -S(=O)- group in the ring, ５１ optionally substituted with 1, 2 or 3 independently selected R groups and containing a -(C=O)- group or a -S(=O)- group in the ring, ２ selected from Each R ５０ independently is hydroxy; -NR ２０ R ２１ ; C １－３ haloalkyl; halogen; CN; C optionally substituted with 1 to 3 R ２５ groups cycloalkyl; C ３－６ alkoxy; C １－３ hydroxyalkyl; and 5- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1 or 2 independently selected R １－３ groups, is selected from ５１ and Each R ２０ and R ２１ are each independently H, C １－６ alkyl, and -SO ２ NR ３０ R ３１ selected from, Each R ２２ is independently C １－６ alkyl, and Each R ２５ is hydroxy, Each R ５１ is independently C １－６ alkyl, -SO ２ NR ３０ R ３１ , -C(=O)-O-R ３２ , halogen, hydroxy, cyano, C １－３ hydroxyalkyl, -C(=O)-NR ３３ R ３４ , -C(=O)-R ３５ , -SO ２ R ２２ , C １－３ haloalkyl, NR ３３ R ３４ , and C １－３ alkoxy, and is selected from Each R ３０ and R ３１ is independently selected from H and C １－６ alkyl Each R ３２ is independently selected from H and C １－６ alkyl Each R ３３ and R ３４ are each independently selected from H and C １－６ alkyl Each R ３５ is independently C １－６ alkyl, and R ２ is H, C １－６ alkyl, or C ３－６ cycloalkyl, each of which may be substituted with one, two, or three groups selected from hydroxy, C １－３ haloalkyl, halogen, C １－３ alkoxy, and CN L １ is O, CH ２ , -CH(C １－３ alkyl)-, -C(=O)-NH-CH ２ -, -N(C １－６ alkyl)-, or -NH-, and A ２ is C ６－１０ aryl, C ３－７ cycloalkyl, or heteroaryl having 1 to 3 ring heteroatoms independently selected from N, where C ６－１０ aryl, C ３－７ cycloalkyl, and each of the heteroaryl having 6 members is independently optionally substituted with 1, 2, or 3 R ６０ groups, provided that when L1 is CH2, A2 is not a C6-10 aryl optionally substituted with 1, 2, or 3 independently selected R60 groups, Each R ６０ is independently selected from halogen, CN, hydroxy, C １－３ alkoxy, C １－３ haloalkoxy, C １－３ haloalkyl, -C(=O)-O-R ３５ , and C which may be substituted with 1 to 3 substituents independently selected from hydroxy, CN, and C １－３ alkoxy. １－３ Alkyl is selected from.

2. A ２ The compound according to claim 1, wherein A is phenyl which may be substituted.

3. A ２ The compound according to claim 1, wherein A is a pyridyl which may be substituted.

4. A ２ The compound according to claim 1, wherein A is pyrid-2-yl which may be substituted.

5. A ２ The compound according to claim 1, wherein A is pyrid-3-yl which may be substituted.

6. A ２ The compound according to claim 1, wherein A is a pyrid-4-yl which may be substituted.

7. A ２ The compound according to claim 1, wherein A is cyclopentyl which may be substituted.

8. A ２ The compound according to claim 1, wherein A is cyclohexyl which may be substituted.

9. A ２ is substituted with one R ６０ group, the compound according to claim 1.

10. A ２ is substituted with two R ６０ groups, the compound according to claim 1.

11. A ２ is phenyl or pyridyl substituted with one R １ group at the 2-position relative to the attachment point to L ６０ The compound according to claim 1.

12. A ２ is phenyl or pyridyl substituted at the 3-position with one R １ group relative to the point of attachment to L ６０ The compound according to claim 1

13. A ２ is phenyl or pyridyl substituted with one R １ group at the 4-position relative to the attachment point to L ６０ The compound according to claim 1

14. A ２ is phenyl or pyridyl substituted at the 2- and 3-positions with two R １ groups relative to the point of attachment to L ６０ The compound according to claim 1

15. A ２ is phenyl substituted at the 2- and 4-positions relative to the point of attachment to L １ with two R ６０ groups, the compound according to claim 1.

16. A ２ is phenyl substituted with two R １ groups at the 2- and 5-positions relative to the point of attachment to L ６０ The compound according to claim 1.

17. A ２ is phenyl substituted with two R １ groups at the 3- and 4-positions relative to the point of attachment to L ６０ The compound according to claim 1

18. A ２ is phenyl substituted with two R １ groups at the 3- and 5-positions relative to the point of attachment to L ６０ The compound according to claim 1

19. The foregoing R ６０ group is selected from F, Cl, CN, CF ３ , methoxy, and methyl, the compound according to claim 1.

20. A ２ is phenyl substituted with fluorine at the 3-position relative to the point of attachment to L １ The compound according to claim 1

21. L １ The compound according to claim 1, wherein L is O.

22. L １ is CH ２ The compound according to claim 1, wherein it is

23. R ２ The compound according to claim 1, wherein R is H, methyl, ethyl, or cyclopropyl.

24. R １ wherein one or two Rs are independently selected from cyclopropyl, methoxy, trifluoromethyl, dimethylamino, methylsulfonyl, fluorine, and CN, which may be substituted with OH, -OH ５０ is C １－４ alkyl optionally substituted with a group, and the compound according to claim 1

25. R １ is 2-hydroxypropyl, and R ２ is methyl or ethyl, the compound according to claim 1.

26. R １ is an optionally substituted heterocycloalkyl ring selected from pyrrolidin-3-yl, pyrrolidin-2-yl, pyrrolidin-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, azetidin-1-yl, azetidin-3-yl, morpholin-4-yl, 2-pyrrolidinone-4-yl, 2-pyrrolidinone-5-yl, piperidin-4-yl, piperidin-2-one-4-yl, tetrahydro-2H-thiopyran-1,1,-dione-4-yl, piperazin-1-yl, thiomorpholin-1,1-dioxide-4-yl, and morpholin-2-one-1-yl, the compound according to claim 1.

27. Each R ５１ is selected from -SO ２ NH ２ , methyl, t-butoxycarbonyl, fluorine, hydroxymethyl, -C(=O)NH ２ , -SO ２ CH ３ , -C(=O)CH ３ , hydroxy, and CN, and is the compound according to claim 1.

28. R １ is C alkyl optionally substituted with an optionally substituted heterocycloalkyl ring selected from pyrrolidine, piperidine, 2-pyrrolidinone, morpholine, and tetrahydro- pyran １－４ The compound according to claim 1

29. The following: A compound selected from, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 29, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof, and an excipient.

31. The composition according to Claim 30 for treating an inflammatory disorder in a subject.

32. The composition according to Claim 30 or 31 for oral administration.

33. The composition according to Claim 30 or 31 for topical administration.

34. The composition according to any one of Claims 30 to 33, which is in the form of a cream, gel, spray, or ointment, or is in a unit dosage form for oral administration.

35. The composition according to Claim 31, wherein the compound is present at a concentration of about 0.001% to about 10% by weight based on the total weight of the composition.

36. The composition according to Claim 31, wherein the compound is present at a concentration of about 0.1% to about 5% by weight based on the total weight of the composition.

37. The composition according to Claim 31, further comprising a skin absorption enhancer.

38. The composition according to Claim 31, further comprising a skin absorption enhancer comprising one or more of mannitol, sulfoxide, azone, pyrrolidone, alcohols and alkanols, glycols, surfactants, and terpenes.

39. The composition according to any one of Claims 31, and 33 to 38, which is applied to the skin of the subject once a day.

40. The composition according to any one of claims 31 and 33 to 38, which is applied to the skin of the subject twice a day.

41. The composition according to any one of claims 31 and 33 to 38, which is applied to the skin of the subject three times a day.

42. The composition according to any one of claims 31 to 41, wherein the inflammatory disorder is a skin disorder.

43. The composition according to any one of claims 39 to 42, wherein the skin is human skin.

44. The composition according to any one of claims 31 to 43, wherein the subject suffers from an inflammatory disorder.

45. The composition according to any one of claims 31 to 44, wherein the inflammatory disorder activates MrgprX2 or is a result of the activation of MrgprX2.

46. The composition according to any one of claims 31 to 45, wherein the inflammatory disorder is atopic dermatitis, chronic urticaria, pseudo-allergic responses caused by small molecules, anaphylaxis-like drug responses, anaphylactic shock, alcohol flush, asthma, systemic itching, chronic itching caused by systemic diseases, or drug adverse responses.

47. The composition according to any one of claims 31 to 46, wherein the inflammatory disorder is atopic dermatitis.

48. The composition according to any one of claims 31 to 47, wherein the subject is human.

49. The unit dosage form for oral administration according to claim 34, wherein the unit dosage form is a tablet, capsule, pill, troche, pellet, granule, bulk powder, effervescent or non-effervescent powder or granule, solution, emulsion, suspension, wafer, sprinkle, elixir, or syrup.

50. The composition according to claim 47, wherein the atopic dermatitis is Asian atopic dermatitis or European atopic dermatitis.

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