MrgprX2 Antagonists and Uses Thereof

Abstract

To provide compounds for the treatment of inflammatory conditions such as atopic dermatitis (AD), compositions comprising the compounds, and methods for treating inflammatory disorders.SOLUTION: The present disclosure is directed to the use of MrgprX2 antagonists in the treatment of inflammatory disorders, for example, inflammatory disorders of the skin, and provides a compound having the following formula I as a compound which is a MrgprX2 antagonist. (In the formula, Q represents a nitrogen atom as a part of a heterocyclic ring or a nitrogen atom substituted with an organic group, and G1 to G5 each independently represent a nitrogen atom or a substituted carbon atom).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Application Nos. 62 / 931,174, filed November 5, 2019, 62 / 931,627, filed November 6, 2019, and 63 / 046,476, filed June 30, 2020, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

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

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

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

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

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

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

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

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

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

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

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

[0013] In a fifth aspect, the present disclosure provides a method for reducing the occurrence or severity of itching in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a topical or oral composition comprising an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) to the skin of a mammal. [The present invention 1001] A compound having formula I: TIFF0007827911000001.tif33128In formula, Q is, TIFF0007827911000002.tif38128, Z is -C(=O)-(CR 20 R 21 ) n or -S(=O)2-, R1 is H or C 1-3 is alkyl, n is 0 or 1, Each R 20 and R 21 are independently H or C 1-3 is alkyl, G1, G2, G3, G4, and G5 are each independently N or -C-L1-M1, provided that at least one of G1, G2, G3, G4, and G5 is N; Each L1 is independently a bond, O, -C(=O), -C(=O)-NH-, -CH2- -O-(CH2) w - (wherein w is 1, 2, or 3), or -N(R 90 )-, or any two L1-M groups on adjacent carbon atoms together form a group of the formula -O-(CH2) v -O- (where v is 1 or 2) group, Each R 90 are independently H or C 1-3 is alkyl, Each M1 is independently H, -OH, halogen, cyano, C 6-10 Aryl; 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; C 1-6 Alkyl; C 3-6 Cycloalkyl: -NR 50 R 51 4-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein each C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-6 cycloalkyl, and 4- to 10-membered heterocycloalkyl are each selected from halogen, cyano, —OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and -C(=O)-N(R 91 )(R 92 and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: Each R 91 and R 92 but independently, H and C 1-3 is selected from the group consisting of alkyl, Each R 50 and R 51 However, independently, H, C 1-3 Alkyl, and C6-10 aryl; A is -L2-M2, L2 is a bond and -(CR 60 R 61 ) k - selected from R 60 and R 61 C, each of which is optionally substituted with H, or 1, 2, or 3 substituents independently selected from —OH and halogen; 1-3 is alkyl, k is 1, 2, or 3; M2, C 1-6 Alkyl; C 3-6 Cycloalkyl; C 5-10 spiroalkyl; 4- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; -N(R 81 )(R 82 ); and C 6-10 aryl, where each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 spiroalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 Each aryl is selected from 1, 2, 3, or 4 independently selected R 200 may be substituted with a group, Each R 200 But independently, C 1-6 Alkyl; C 1-6 Hydroxyalkyl;C 3-6 Cycloalkyl; 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; C 1-6 Mono-, di-, or trihaloalkyl; halogen; cyano; -OH; C 1-6 Alkoxy; S(=O)2NR 502 R 503 and C 6-10 aryl; Each R 81 and R 82 However, independently, H, C 1-6Alkyl and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl and C 3-6 The cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OH and halogen; R 500 and R 501 but independently, does not exist or C 1-6 is alkyl, R 502 and R 503 are independently H or C 1-6 is alkyl, The compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. [The present invention 1002] 1001. A compound of the present invention, wherein G1 is N. [The present invention 1003] 1001. A compound of the present invention, wherein G2 is N. [The present invention 1004] 1001. The compound of the present invention, wherein G1 and G4 are N. [The present invention 1005] 1001. The compound of the present invention, wherein G1 and G2 are N. [The present invention 1006] 1001. A compound of the present invention, wherein G1 and G5 are N. [The present invention 1007] 1001. A compound of the present invention, wherein G3 is -C-L1-M1. [The present invention 1008] 1001. A compound of the present invention, wherein G4 is -C-L1-M1. [The present invention 1009] 1001. A compound of the present invention, wherein G2 is -C-L1-M1. [The present invention 1010] The compound of any one of claims 1001 to 1009, wherein L1 is O. [The present invention 1011] The compound of any one of claims 1001 to 1009, wherein L1 is -CH2-. [The present invention 1012] The compound of any one of claims 1001 to 1009, wherein L1 is a bond. [The present invention 1013] The compound of any one of claims 1001 to 1009, wherein L1 is -C(=O). [The present invention 1014] The compound of any one of claims 1001 to 1009, wherein L1 is -C(=O)-NH-. [The present invention 1015] L1 is -N(R 90 )-. [The present invention 1016] Any of the preceding compounds of the present invention wherein R1 is H. [The present invention 1017] 1001. A compound of any preceding invention wherein n is 0. [The present invention 1018] The compound of any one of claims 1001 to 1015, wherein n is 1. [The present invention 1019] Any of the preceding compounds of the present invention, wherein M1 is selected from C6 aryl; C6 heteroaryl having 1 or 2 ring heteroatoms independently selected from N and O; C5 or C6 heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N and O; and 5 to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, each of which is optionally substituted. [The present invention 1020] Any of the preceding compounds of the invention, wherein M1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or dihydroynediol, each of which is optionally substituted. [The present invention 1021] Any of the preceding compounds of the invention, wherein the substituents of M1 are independently selected from halogen, CN, -OH, -C(=O)-NH2, CF3, and -OCH3. [The present invention 1022] Any of the preceding compounds of the invention wherein M1 is optionally substituted phenyl. [The present invention 1023] The compound of any one of claims 1001 to 1021, wherein said phenyl is substituted at the 4-position. [The present invention 1024] The compound of any one of claims 1001 to 1021, wherein said phenyl is substituted at the 3- and 4-positions. [The present invention 1025] The compound of any one of claims 1001 to 1021, wherein said phenyl is substituted at the 3- and 5-positions. [The present invention 1026] Any of the preceding compounds of the invention wherein M1 is optionally substituted pyridyl. [The present invention 1027] Any of the preceding compounds of the invention wherein M1 is an optionally substituted pyridyl-4-yl. [The present invention 1028] Any of the preceding compounds of the invention wherein M1 is an optionally substituted pyridyl-3-yl. [The present invention 1029] Any of the preceding compounds of the invention wherein said pyridyl is substituted at the carbon that is ortho (ie, adjacent) to the nitrogen of said pyridyl. [The present invention 1030] Any of the preceding compounds of the invention wherein said pyridyl is substituted at the carbon that is meta to the nitrogen of said pyridyl. [The present invention 1031] Compounds of any one of claims 1001 to 1029, wherein said pyridyl is substituted at the carbon that is meta to the nitrogen of said pyridyl. [The present invention 1032] Any of the preceding compounds of the invention wherein M1 is an optionally substituted heterocycloalkyl. [The present invention 1033] Any of the preceding compounds of the invention wherein M1 is optionally substituted pyrrolidinyl. [The present invention 1034] The compound of any one of claims 1001 to 1018, wherein M1 is optionally substituted pyrrolidin-1-yl. [This invention 1035] The compound of any one of claims 1001 to 1018, wherein M1 is optionally substituted tetrahydropyranyl. [The present invention 1036] The compound of any one of claims 1001 to 1018, wherein M1 is optionally substituted tetrahydropyran-4-yl. [This invention 1037] The compound of any one of claims 1001 to 1018, wherein M1 is optionally substituted cycloalkyl. [The present invention 1038] M1 is optionally substituted C 1-6 The compound of any one of 1001 to 1018 of the present invention, which is alkyl. [This invention 1039] M1 is -NR 50 R 51 The compound of any one of 1001 to 1018 of the present invention, [The present invention 1040] Any of the preceding compounds of the invention, wherein L2 is a bond. [This invention 1041] L2 is -(CR 60 R 61 ) k Any of compounds 1001 to 1039 of the present invention, wherein [The present invention 1042] M2 is optionally substituted C 1-6 Any of the preceding compounds of the invention, wherein: [This invention 1043] Any of the preceding compounds of the invention wherein M2 is optionally substituted isopropyl. [This invention 1044] M2 is optionally substituted C 3-6 The compound of any one of claims 1001 to 1041, which is cycloalkyl. [This invention 1045] The compound of any one of claims 1001 to 1041, wherein M2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 methyl groups. [The present invention 1046] Any of compounds 1001 to 1041 of the present invention, wherein M2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or two substituents independently selected from methyl, halogen, mono-, di- or trihalomethyl, cyano, hydroxymethyl, and hydroxy. [This invention 1047] The compound of any one of claims 1001 to 1041, wherein M2 is cyclopropyl optionally substituted with 1 to 4 methyl groups, halogen or trihalomethyl. [This invention 1048] The compound of any one of claims 1001 to 1041, wherein M2 is heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy. [This invention 1049] Any of the compounds of claims 1001 to 1041, wherein M2 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or morpholine, each of which may be substituted with one or two groups independently selected from methyl and hydroxy. [The present invention 1050] M2 is -N(R 81 )(R 82 ) any of the compounds of the preceding invention. [This invention 1051] R 81 and R 82 But independently, C 1-3 Alkyl and C 3-4 cycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from -OH and halogen. [This invention 1052] A compound of any of the preceding inventions selected from a compound in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. [This invention 1053] A composition comprising a dermatologically or orally acceptable excipient and any of the preceding compounds of the invention. [This invention 1054] A method for treating an inflammatory disorder, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of the present invention and a dermatologically or orally acceptable excipient. [This invention 1055] 1054. The method of claim 1054, wherein said composition is in the form of a cream, gel, spray, ointment, or oral unit dosage form. [This invention 1056] 1054. The method of claim 1054, wherein the MrgprX2 antagonist is present in a concentration of about 0.001% by weight to about 10% by weight, based on the total weight of the composition. [This invention 1057] The method of claim 1054, wherein the MrgprX2 antagonist is present in a concentration of about 0.1% by weight to about 5% by weight, based on the total weight of the composition. [This invention 1058] The method of claim 1054, wherein the composition further comprises a skin absorption enhancer. [This invention 1059] The method of claim 1054, wherein the composition further comprises a skin absorption enhancer comprising one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. [The present invention 1060] 1059. The method of any of claims 1054 to 1059, wherein said composition is applied to the patient's skin once a day. [The present invention 1061] 1059. The method of any of claims 1054 to 1059, wherein said composition is applied to the patient's skin twice daily. [The present invention 1062] 1059. The method of any of claims 1054 to 1059, wherein said composition is applied to the patient's skin three times a day. [The present invention 1063] 1063. The method of any of claims 1054 to 1062, wherein said composition is administered to a patient suffering from an inflammatory disorder. [The present invention 1064] The method according to any one of claims 1054 to 1063, wherein the inflammatory disorder is a skin disorder. [This invention 1065] The method of any one of claims 1054 to 1064, wherein the skin is human skin. [The present invention 1066] The method of any of claims 1063 to 1065, wherein said inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2. [This invention 1067] Any of the methods of inventions 1063 to 1066, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, a pseudoallergic response caused by a small molecule, e.g., an anaphylactoid drug response, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by a systemic disease, or an adverse drug response. [The present invention 1068] The method of any of claims 1063 to 1067, wherein said inflammatory disorder is atopic dermatitis (for example, Asian atopic dermatitis, European atopic dermatitis). [The present invention 1069] The method of any one of claims 1054 to 1068, wherein the subject is a human. [The present invention 1070] The method of any one of claims 1054 to 1068, wherein the mammalian skin is human skin. [This invention 1071] The method of any of the preceding inventions, wherein said composition is for oral administration. DETAILED DESCRIPTION OF THE INVENTION

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

[0015] MrgprX2 Antagonists for Use in the Compositions and Methods of the Disclosure In some embodiments, the present disclosure provides a compound [Compound 1] that is an MrgprX2 antagonist having formula I, TIFF0007827911000003.tif38128In formula, Q is, TIFF0007827911000004.tif38128, Z is -C(=O)-(CR 20 R 21 ) n or -S(=O)2-, R1 is H or C 1-3 is alkyl, n is 0 or 1, Each R 20 and R 21 are independently H or C 1-3 is alkyl, G1, G2, G3, G4, and G5 are each independently N or -C-L1-M1, provided that at least one of G1, G2, G3, G4, and G5 is N; Each L1 is independently a bond, O, -C(=O), -C(=O)-NH-, -CH2- -O-(CH2) w - (wherein w is 1, 2, or 3), or -N(R 90 )-, or any two L1-M groups on adjacent carbon atoms together form a group of the formula -O-(CH2) v -O- (where v is 1 or 2) group, Each R 90 are independently H or C 1-3 is alkyl, Each M1 is independently H, -OH, halogen, cyano, C 6-10Aryl; 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; C 1-6 Alkyl; C 3-6 Cycloalkyl: -NR 50 R 51 4-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein each C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-6 cycloalkyl, and 4- to 10-membered heterocycloalkyl are each selected from halogen, cyano, —OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and -C(=O)-N(R 91 )(R 92 and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: Each R 91 and R 92 but independently, H and C 1-3 is selected from the group consisting of alkyl, Each R 50 and R 51 However, independently, H, C 1-3 Alkyl, and C 6-10 aryl; A is -L2-M2, L2 is a bond and -(CR 60 R 61 ) k - selected from R 60 and R 61 C, each of which is optionally substituted with H, or 1, 2, or 3 substituents independently selected from —OH and halogen; 1-3 is alkyl, k is 1, 2, or 3; M2, C 1-6 Alkyl; C 3-6 Cycloalkyl; C 6-10spiroalkyl; 4- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; -N(R 81 )(R 82 ); and C 6-10 aryl, where each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 spiroalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 Each aryl is selected from 1, 2, 3, or 4 independently selected R 200 may be substituted with a group, Each R 200 But independently, C 1-6 Alkyl; C 1-6 Hydroxyalkyl;C 3-6 Cycloalkyl; 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; C 1-6 Mono-, di-, or trihaloalkyl; halogen; cyano; -OH; C 1-6 Alkoxy; S(=O)2NR 502 R 503 and C 6-10 aryl; R 70 and R 71 are each independently H or C 1-3 is alkyl, Each R 81 and R 82 However, independently, H, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OH and halogen; R 500 and R 501 but independently, does not exist or C 1-6 is alkyl, R 502 and R 503 are independently H or C1-6 is alkyl, Provided is the compound [Compound 1], or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0016] The present disclosure further provides the following compounds: 1.1 Compound 1, wherein G1 is N; 1.2 Compound 1 or 1.1, wherein G2 is N; 1.3 Compound 1 or 1.1, wherein G1 and G4 are N; 1.4 Compound 1 or 1.1, wherein G1 and G2 are N; 1.5 Compound 1 or 1.1, wherein G1 and G5 are N; 1.6 Any of the preceding compounds wherein G3 is -C-L1-M1; 1.7 Any of the preceding compounds wherein G4 is -C-L1-M1; 1.8 Any of the preceding compounds wherein G2 is -C-L1-M1; 1.9 Any of the preceding compounds wherein L1 is O; 1.10 Any of the preceding compounds wherein L1 is -CH2-; 1.11 Any of the preceding compounds wherein L1 is a bond. 1.12 Any of the preceding compounds wherein L1 is -C(=O); 1.13 Any of the preceding compounds wherein L1 is -C(=O)-NH-; 1.14 L1 is -N(R 90 any of the preceding compounds, wherein 1.15 Any of the preceding compounds wherein R1 is H; 1.16 Any of the preceding compounds wherein n is 0. 1.17 Any of the preceding compounds wherein n is 1. 1.18 Any of the preceding compounds wherein M1 is selected from C6 aryl; C6 heteroaryl having 1 or 2 ring heteroatoms independently selected from N and O; C5 or C6 heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N and O; and 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, each of the foregoing being optionally substituted. 1.19 Any of the preceding compounds wherein M1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or dihydroynediol, each of which is optionally substituted; 1.20 Compound 1.19, wherein the substituents of M1 are independently selected from halogen, CN, —OH, —C(═O)—NH2, CF3, and —OCH3; 1.21 Any of the preceding compounds wherein M1 is optionally substituted phenyl. 1.22 Compound 1.21, in which the phenyl is substituted at the 4-position. 1.23 Compound 1.21, in which phenyl is substituted at the 3- and 4-positions. 1.24 Compound 1.21, in which phenyl is substituted at the 3- and 5-positions. 1.25 Any of the preceding compounds wherein M1 is optionally substituted pyridyl; 1.26 Any of the preceding compounds, wherein M1 is optionally substituted pyridyl-4-yl. 1.27 Any of the preceding compounds, wherein M1 is optionally substituted pyridyl-3-yl. 1.28 Compound 1.26, in which the pyridyl is substituted at the carbon ortho (i.e., adjacent) to the pyridyl nitrogen. 1.29 Compound 1.27, where the pyridyl is substituted at the carbon that is meta to the pyridyl nitrogen. 1.30 Compound 1.27, in which the pyridyl is substituted at the carbon ortho (i.e., adjacent) to the pyridyl nitrogen. 1.31 Compound 1.26, in which the pyridyl is substituted at the carbon that is meta to the pyridyl nitrogen. 1.32 Any of the preceding compounds wherein M1 is optionally substituted heterocycloalkyl; 1.33 Any of the preceding compounds, wherein M1 is optionally substituted pyrrolidinyl. 1.34 Any of the preceding compounds, wherein M1 is optionally substituted pyrrolidin-1-yl. 1.35 Any of the preceding compounds, wherein M1 is optionally substituted tetrahydropyranyl. 1.36 Any of the preceding compounds, wherein M1 is optionally substituted tetrahydropyran-4-yl. 1.37 Any of the preceding compounds wherein M1 is optionally substituted cycloalkyl; 1.38 M1 is an optionally substituted C 1-6 any of the preceding compounds, wherein 1.39 M1, -NR 50 R 51 any of the preceding compounds, 1.40 Any of the preceding compounds wherein L2 is a bond. 1.41 L2 is -(CR 60 R 61 ) k any of the preceding compounds, 1.42 M2 is optionally substituted C 1-6 any of the preceding compounds, wherein 1.43 Any of the preceding compounds wherein M2 is optionally substituted isopropyl. 1.44 M2 is optionally substituted C 3-6 Any of the preceding compounds which is cycloalkyl; 1.45 Any of the preceding compounds wherein M2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 methyl groups; 1.46 Any of the preceding compounds wherein M2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or two substituents independently selected from methyl, halogen, mono-, di- or trihalomethyl, cyano, hydroxymethyl, and hydroxy; 1.47 Any of the preceding compounds wherein M2 is cyclopropyl optionally substituted with 1 to 4 methyl groups, halogen, or trihalomethyl; 1.48 Any of the preceding compounds wherein M2 is heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy. 1.49 Any of the preceding compounds wherein M2 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or morpholine, each of which is optionally substituted with one or two groups independently selected from methyl and hydroxy; 1.50 M2 is -N(R 81 )(R 82 any of the preceding compounds, 1.51 R 81 and R 82 But independently, C 1-3 Alkyl and C 3-4 Any of the preceding compounds is selected from cycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from -OH and halogen; 1.52 A compound selected from the compounds of Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof, any of the preceding compounds.

[0017] The present disclosure also provides a topical or oral composition [Composition 1] comprising an MrgprX2 antagonist and a dermatologically or orally acceptable excipient. In some embodiments, the MrgprX2 antagonist is compound I having the above formula I.

[0018] The present disclosure further provides the following compositions: 1.1 Composition 1, in which the MrgprX2 antagonist is compound I having formula I above, 1.2 Composition 1.1, wherein G1 is N; 1.3 Composition 1.1, wherein G2 is N; 1.4 Composition 1.1, wherein G1 and G4 are N; 1.5 Composition 1.1, wherein G1 and G2 are N; 1.6 Composition 1.1, wherein G1 and G5 are N; 1.7 Composition 1.1, wherein G3 is -C-L1-M1; 1.8 Composition 1.1, wherein G4 is -C-L1-M1; 1.9 Composition 1.1, wherein G2 is -C-L1-M1; 1.10 Any of the preceding compositions wherein L1 is O. 1.11 Any of the preceding compositions wherein L1 is -CH2-; 1.12 Any of the preceding compositions, wherein L1 is a bond. 1.13 Any of the preceding compositions wherein L1 is —C(═O); 1.14 Any of the preceding compositions wherein L1 is —C(═O)—NH—; 1.15 L1 is -N(R 90 Any of the preceding compositions, wherein 1.16 Any of the preceding compositions wherein R1 is H. 1.17 Any of the preceding compositions wherein n is 0. 1.18 Any of the preceding compositions wherein n is 1. 1.19 Any of the preceding compositions wherein M1 is selected from C6 aryl; C6 heteroaryl having 1 or 2 ring heteroatoms independently selected from N and O; C5 or C6 heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N and O; and 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, each of the foregoing being optionally substituted. 1.20 Any of the preceding compositions wherein M1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or dihydroynediol, each of which is optionally substituted; 1.21 Composition 1.20, wherein the substituents of M1 are independently selected from halogen, CN, —OH, —C(═O)—NH2, CF3, and —OCH3; 1.22 Any of the preceding compositions wherein M1 is optionally substituted phenyl. 1.23 Composition 1.22, wherein phenyl is substituted at the 4-position. 1.24 Composition 1.22, wherein phenyl is substituted in the 3- and 4-positions. 1.25 Composition 1.22, wherein phenyl is substituted in the 3- and 5-positions. 1.26 Any of the preceding compositions wherein M1 is optionally substituted pyridyl. 1.27 Any of the preceding compositions, wherein M1 is optionally substituted pyridyl-4-yl. 1.28 Any of the preceding compositions, wherein M1 is optionally substituted pyridyl-3-yl. 1.29 Composition 1.27 wherein the pyridyl is substituted at the carbon ortho (i.e., adjacent) to the nitrogen of the pyridyl. 1.30 Composition 1.27 wherein the pyridyl is substituted at the carbon meta to the pyridyl nitrogen. 1.31 Composition 1.28 wherein the pyridyl is substituted at the carbon ortho (i.e., adjacent) to the nitrogen of the pyridyl. 1.32 Composition 1.28 wherein the pyridyl is substituted at the carbon that is meta to the pyridyl nitrogen. 1.33 Any of the preceding compositions wherein M1 is an optionally substituted heterocycloalkyl. 1.34 Any of the preceding compositions wherein M1 is optionally substituted pyrrolidinyl. 1.35 Any of the preceding compositions, wherein M1 is optionally substituted pyrrolidin-1-yl. 1.36 Any of the preceding compositions wherein M1 is optionally substituted tetrahydropyranyl. 1.37 Any of the preceding compositions wherein M1 is optionally substituted tetrahydropyran-4-yl. 1.38 Any of the preceding compositions wherein M1 is optionally substituted cycloalkyl. 1.39 M1 is an optionally substituted C 1-6 Any of the preceding compositions, wherein: 1.40 M1, -NR 50 R 51 Any of the preceding compositions, 1.41 Any of the preceding compositions wherein L2 is a bond. 1.42 L2 is -(CR 60 R 61 ) k any of the preceding compositions, 1.43 M2 is optionally substituted C 1-6 Any of the preceding compositions, wherein: 1.44 Any of the preceding compositions wherein M2 is optionally substituted isopropyl. 1.45 M2 is optionally substituted C 3-6 Any of the preceding compositions, wherein is cycloalkyl; 1.46 Any of the preceding compositions wherein M2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 methyl groups. 1.47 Any of the preceding compositions wherein M2 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, halogen, mono-, di- or trihalomethyl, cyano, hydroxymethyl, and hydroxy; 1.48 Any of the preceding compositions wherein M2 is cyclopropyl optionally substituted with 1 to 4 methyl groups, halogen, or trihalomethyl. 1.49 Any of the preceding compositions wherein M2 is heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy. 1.50 Any of the preceding compositions wherein M2 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or morpholine, each of which is optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy. 1.51 M2 is -N(R 81 )(R 82 any of the preceding compositions, 1.52 R 81 and R 82 But independently, C 1-3 Alkyl and C 3-4 Any of the preceding compositions is selected from cycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from —OH and halogen; 1.53 Any of the preceding compositions wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof; 1.54 Any of the preceding compositions, wherein the composition is in the form of a cream, gel, spray, or ointment. 1.55 Any of the preceding compositions, wherein the MrgprX2 antagonist is present in a concentration of about 0.001% to about 10% by weight, based on the total weight of the composition. 1.56 Any of the preceding compositions, wherein the MrgprX2 antagonist is present in a concentration of about 0.1% to about 5% by weight, based on the total weight of the composition. 1.57 Any of the preceding compositions further comprising a skin absorption enhancer. 1.58 Any of the preceding compositions further comprising a skin absorption enhancer, including one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 1.59 Any of the preceding compositions, wherein the composition is applied to the patient's skin once daily. 1.60 Any of the preceding compositions, wherein the composition is applied to the patient's skin twice daily. 1.61 Any of the preceding compositions, wherein the composition is applied to the patient's skin three times daily. 1.62 Any of the preceding compositions, wherein the composition is administered to a patient suffering from an inflammatory disorder. 1.63 The preceding composition, wherein the inflammatory disorder is a skin disorder. 1.64 The preceding composition, wherein the skin is human skin. 1.65 Any of compositions 1.64-1.66, wherein the inflammatory disorder activates or is a result of activation of MrgprX2. 1.66 The preceding composition, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, adverse drug response. 1.67 Any of compositions 1.63-1.67, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). 1.68 Any of the preceding compositions, wherein the subject is a human. 1.69 Any of the preceding compositions wherein the mammalian skin is human skin. 1.70 Any one of the preceding compositions, wherein the composition is for oral administration.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0035] The term "heteroaryl" is intended to mean a ring system containing 5 to 14 ring atoms, which may contain a single ring, two fused rings, or three fused rings, in which at least one ring is aromatic and at least one ring atom is a heteroatom selected from, for example, O, S, and N. Some embodiments, such as furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like, contain 5 to 6 ring atoms. For example, quinolizinyl, 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 Some embodiments, such as -dihydrobenzofuranyl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-hydro-isoquinolinyl, 1,4,6,7-tetrahydro-imidazo[4,5-c]-pyridinyl, 7,8-dihydro-5H-[1,6]naphthyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxyl, pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, contain 8 to 14 ring atoms.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0050] "Chronic hives" (hives) are a common skin rash triggered by many factors, including certain foods, medications, and stress. Symptoms include itchy, raised, red, or skin-colored swellings on the skin surface. Considering the role of mast cells in chronic idiopathic urticaria, MrgprX2 plays an important role in mast cell activation. Antibacterial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and several FDA-approved peptide agonists activate human MrgprX2. Unique properties of MrgprX2 that distinguish it from other GPCRs include its presence at both plasma membrane and intracellular sites, as well as its selective expression in MCs. Furthermore, small molecule inhibitors of MrgprX2 may be beneficial for the treatment of MC-dependent allergic and inflammatory disorders, such as chronic urticaria, which are currently treated by targeting the IgE axis of mast cell activity. However, diverse MC activities depend on ligand binding to MrgprX2 (Subramanian H et al., 2016, The Journal of Allergy and Clinical Immunology, 138(3), 700-710; https: / / doi.org / 10.1016 / j.jaci.2016.04.051), suggesting that targeting MRGPRX2 may indeed be a therapeutic option for IgE-independent and resistant chronic urticaria.

[0051] Anaphylactic shock is an extreme, often life-threatening, allergic response to an antigen to which the body is hypersensitive. MrgprB2-mediated mast cell activation has attracted attention for its IgE-independent mast cell activation and non-histaminergic itch (Meixiong J. et al., 2019, Immunity, 50(5), 1163-1171.e5. https: / / doi.org / 10.1016 / j.immuni.2019.03.013). Activation of MrgprB2 by proadrenomedullin N-terminal peptide 9-20 (PAMP9-20) induced the release of multiple bioactive mediators from mast cells, which in turn activated itch-sensing neurons, suggesting that mast cell-specific MrgprB2 is important in mast cell degranulation and the associated nonhistaminergic itch. Mast cell MrgprB2 and MrgrpX2 are activated by pseudoallergy-inducing drugs such as SP, compound 48 / 80, and icatibant (McNeil, BD et al., 2015, Nature, 519(7542), 237-241; https: / / doi.org / 10.1038 / nature14022), and MrgprX2 plays a central role in non-histaminergic mast cell activation and various allergic and non-allergic diseases, as well as pseudoallergic responses.

[0052] Rosacea is a condition that causes redness, often small, red, pus-filled bumps on the face. MrgrpX2 has also been identified as a receptor for endogenous host defense peptides, including cathelicidin (LL-37) and □-defensin (Subramanian, H. et al., 2011, The Journal of Biological Chemistry, 286(52), 44739-44749; https: / / doi.org / 10.1074 / jbc.M111.277152, and Subramanian, H. et al., 2013, Journal of Immunology (Baltimore, Md.: 1950), 191(1), 345-352; https: / / doi.org / 10.4049 / jimmunol.1300023), it has emerged that mast cell MrgprX2 may participate in antibacterial host defense. Pituitary adenylate cyclase-activating peptide (PACAP), a potent mast cell degranulator (Baun, M. et al., 2012, Cephalalgia: An International Journal of Headache, 32(4), 337-345; https: / / doi.org / 10.1177 / 0333102412439354, and Seebeck, J. et al., 1998, Annals of the New York Academy of Sciences, 865, 141-146. https: / / doi.org / 10.1111 / j.1749-6632.1998.tb11172.x) has been shown to activate MrgprX2 (Tatemoto K. et al., 2006, Biochemical and Biophysical Research Communications, 349(4), 1322-1328; https: / / doi.org / 10.1016 / j.bbrc.2006.08.177, and McNeil, BD et al., 2015, Nature, 519(7542), 237-241; https: / / doi.org / 10.1038 / nature14022). These findings suggest that MrgprX2 may also function in innate immunity by regulating host defense responses.Considering that MrgprX2 is activated by peptides such as LL-37 and the neuropeptide PACAP, both of which are critically involved in rosacea and function as trigger peptides that influence mast cell activity and vasodilation, these findings together suggest MrgprX2 as a newly emerging receptor in the pathophysiology of rosacea.

[0053] Asthma is a condition in which human airways become inflamed, narrowed, swollen, and produce excess mucus, making breathing difficult. Mast cells (MCs), which normally reside in close proximity to smooth muscle, T cells, and leukocytes, are key effector cells in airway hyperresponsiveness and inflammation, hallmarks of asthma. While only low amounts of transcripts are present in healthy conditions, MrgprX2 transcript levels increase in severe asthma, characterized by a phenotypic switch from MCTs to MCTCs. In contrast to MCTs, mast cell MCTC populations in severe asthma express MrgprX2 (Fajt MLet al, 2013; The Journal of Allergy and Clinical Immunology, 131(6), 1504-1512; https: / / doi.org / 10.1016 / j.jaci.2013.01.035 and Balzar, S. et al., 2011, American Journal of Respiratory and Critical Care Medicine, 183(3), 299-309; https: / / doi.org / 10.1164 / rccm.201002-0295OC). Given that SP levels are increased in the lungs of patients with severe asthma, which activates MrgprX2, treatment with small molecule antagonists may benefit patients with severe asthma (van Diest, SA. et al., 2012, Biochimica et Biophysica Acta, 1822(1), 74-84; https: / / doi.org / 10.1016 / j.bbadis.2011.03.019).

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

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

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

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

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

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

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

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

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

[0063] Examples of penetration enhancers or barrier function disrupting agents include, but are not limited to, alcohol-based enhancers, such as alkanols having 1 to 16 carbons, benzyl alcohol, butylene glycol, diethylene glycol, glycofurol, glycerides, glycerin, glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based agents, such as N-butyl-N-dodecylacetamide, crotamiton, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide; amino acids, e.g., L-α-amino acids and water-soluble proteins; azones and azone-like compounds, e.g., azacycloalkanes; essential oils, e.g., almond oil, amylbutyric acid, apricot kernel oil, avocado oil, camphor, castor oil, 1-carvone, coconut oil, corn oil, cottonseed oil, eugenol, menthol, anise oil, clove oil, orange oil, peanut oil, peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil (squalene), soybean oil, sunflower oil, walnut oil; vitamins and herbs, e.g., aloe vera, allantoin, black walnut extract , chamomile extract, panthenol, papain, tocopherol, vitamin A palmitate; waxes, such as candela wax, carnuba wax, ceresin wax, beeswax, lanolin wax, jojoba oil, petrolatum; mixtures, such as mixtures of fractionated vegetable oil fatty acids with glycerin or propylene glycol and interesterified medium-chain triglyceride oils; fatty acids and fatty acid esters, such as amyl caproate, butyl acetate, caprylic acid, cetyl esters, diethyl sebacate, dioctyl malate, elaidyl Ethyl Caprylate, Ethylene 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-4 Fatty Acid Esters, Polyoxyethylene Sorbitan Monooleate, Polypropylene Glycol, Propylene Glycol, Sucrose Distearate, Salicylic Acid, Sodium Citrate, Stearic Acid, Soap, and Caproic, Caprylic, Capric, and Lauric Triglycerides;Macrocyclics, such as butylated hydroxyanisole, cyclopentadecanolide, cyclodextrin; phospholipids and phosphate enhancers, such as dialkyl phosphates, ditetradecyl phosphate, lecithin, 2-pyrrolidone derivatives, such as alkylpyrrolidone-5-carboxylate esters, pyroglutamic acid esters, N-methylpyrrolidone, biodegradable soft penetration enhancers, such as dioxane derivatives and dioxolane derivatives; sulfoxide enhancers, such as dimethyl sulfoxide and decyl methyl sulfoxide; acid enhancers, such as alginic acid, sorbitol, Examples of suitable surfactants include carboxylic acids, carboxylic acids, and succinic acids; cyclic amines; imidazolinones; imidazoles; ketones such as acetone, dimethicone, methyl ethyl ketone, and pentanedione; lanolin derivatives such as lanolin alcohol, PEG-16 lanolin, and acetylated lanolin; oxazolines; oxazolindinones; proline esters; pyrroles, urethanes; and surfactants such as nonoxynol, polysorbates, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, sodium lauryl sulfate, and sorbitan monostearate.

[0064] The topical compositions described herein typically contain one or more carriers, preferably having a vapor pressure of 23.8 mm Hg or greater at 25°C. Preferred concentration ranges for a single carrier or total combination of carriers can be from about 0.1% to about 10%, more preferably from about 10% to about 50%, and more specifically from about 50% to about 95% by weight of the dermatological composition. Non-limiting examples of solvents include water (e.g., deionized water) and lower alcohols, including ethanol, 2-propanol, and n-propanol.

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

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

[0067] In certain embodiments, the pharmaceutical composition includes a viscosity-enhancing agent or emulsifier. Gelling agents are used to increase the viscosity of the final composition. Emulsifiers are substances that stabilize emulsions. Viscosity-enhancing agents may also act as emulsifiers. Typically, the concentration and combination of viscosity-enhancing agents will depend on the physical stability of the finished product. A preferred concentration range for the viscosity-enhancing agent may be about 0.01% to about 20% by weight of the dermatological composition, more preferably about 0.1% to about 10% by weight, and more specifically about 0.5% to about 5% by weight. Non-limiting examples of viscosity-increasing agents for use herein include cellulose, acrylate polymer, and acrylate crosspolymer classes such as hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, Carbomer 980, Carbomer 1342, and Carbomer 940, more preferably hydroxypropyl cellulose, Pluronic PF127, Carbomer 980, and Carbomer 1342, more specifically hydroxypropyl cellulose (Klucel® EF, GF, and / or HF), Pluronic PF127, Carbomer 980, and / or Carbomer 1342 (Pemulen® TR-1, TR-2, and / or Carbopol® ETD2020). Examples of emulsifiers for use herein include polysorbates, laureth-4, and potassium cetyl sulfate.

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

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

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

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

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

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

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

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

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

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

[0078] Oral administration In some embodiments, the pharmaceutical compositions herein are provided for oral administration.Accordingly, the present disclosure provides solid, semi-solid, or liquid dosage forms for oral administration, including the compounds described herein.Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, pellets, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, lubricants, enteric coatings, film costing agents, modified release agents, colorants, dye transfer inhibitors, sweeteners, and flavoring agents.

[0079] Binders or granulating agents impart cohesiveness to the tablet to ensure that it remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; gum arabic, alginic acid, alginates, Irish moss extract, Panwar gum, ghatti gum, mucilage from plantain husk, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, methyl paraben, polyalkylene oxide, povidone, polyvinylpyrrolidone (PVP), crospovidone, Veegum, larch arabogalactan. Natural and synthetic gums, such as arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein at about 50% to about 99% by weight.

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

[0081] Suitable disintegrants include, but are not limited to, gelatin; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; align; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[0082] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glycerol behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, zinc stearate, ethyl oleate, ethyl laureate, gelatin, starch, lycopodium, silica or silica gel such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

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

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

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

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

[0087] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two compartments, one over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, that are plasticized by adding glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben, propylparaben, and sorbic acid. Liquid, semisolid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules can also be coated as known to those skilled in the art to modify or maintain the solubility of the active ingredient.

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

[0089] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0109] The manufactured articles provided herein contain packaging materials.Packaging materials for use in product packaging are well known to those skilled in the art.For example, see U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252.Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended administration and treatment mode.A wide range of formulations of the compounds and compositions provided herein are contemplated, as are various treatments for any disease or disorder described herein.

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

[0111] Example 1 - Preparation of compounds according to the present disclosure Compound E001 TIFF0007827911000005.tif231282-Cyano-N-[5-(3-fluorophenoxy)-2-pyridyl]-2-methyl-propanamide

[0112] Step 1 5-Bromo-2-nitro-pyridine (750 mg, 3.69 mmol), cesium carbonate (2.4 g, 7.39 mmol), and 3-fluorophenol (335 μL, 3.69 mmol) were mixed in DMSO (7.5 mL), purged with nitrogen, and stirred at 50 °C in a sealed vial for 4 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts were dried over MgSO, filtered, concentrated under reduced pressure, and purified by column chromatography [Biotage SNAP cartridge KP-Sil 50 g; 0–50% EtOAc in heptane]. The mixed fraction was further purified by preparative HPLC (Method F) to give 5-(3-fluorophenoxy)-2-nitro-pyridine as an off-white solid (361 mg, 42% yield). 1H NMR(500MHz,DMSO-d6)δ 8.46(d,J=2.8Hz,1H),8.35(d,J=8.9Hz,1H),7.73(dd,J=9.0,2.9Hz,1H),7.54(td,J=8.3,6.8Hz ,1H),7.22(dt,J=10.0,2.4Hz,1H),7.17(tdd,J=8.6,2.5,0.7Hz,1H),7.10(dd,J=8.2,2.2Hz,1H)

[0113] Step 2: 5-(3-fluorophenoxy)pyridin-2-amine To a solution of 5-(3-fluorophenoxy)-2-nitro-pyridine (361 mg, 1.54 mmol) in ethanol (5 mL) was added 10% Pd / C (164 mg, 0.154 mmol), and the reaction mixture was placed under a balloon of hydrogen and stirred at room temperature for 4 hours. It was then filtered through Celite, washed with EtOAc, and concentrated under reduced pressure to give 5-(3-fluorophenoxy)pyridin-2-amine as an off-white solid (300 mg, 95% yield). 1H NMR(500MHz,DMSO-d6)δ 7.78(d,J=2.9Hz,1H),7.41-7.30(m,1H),7.24(dd,J=8.9,3.0Hz,1H),6.87(tdd ,J=8.6,2.2,0.9Hz,1H),6.77-6.68(m,2H),6.51(d,J=8.9Hz,1H),5.93(s,2H).

[0114] Step 3 To a solution of 5-(3-fluorophenoxy)pyridin-2-amine (50 mg, 0.245 mmol) and 2-cyano-2-methylpropanoic acid (28 mg, 0.245 mmol) in ethyl acetate (2 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.13 mL, 0.735 mmol) and T3P (50% in EtOAc) (0.22 mL, 0.367 mmol), and the reaction was stirred at 70° C. for 6 h. It was then cooled to room temperature, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method F) to give the title compound (39 mg) as a pale yellow oil. 1H NMR(500MHz,DMSO-d6)δ 10.75(s,1H),8.25(d,J=2.9Hz,1H),8.04(d,J=9.0Hz,1H),7.63(dd,J=9.0,3.0Hz,1H),7.43(ddd,J= 8.3,8.3,7.0Hz,1H),7.04-6.95(m,1H),6.96-6.92(m,1H),6.89-6.81(m,1H),1.68(s,6H).LCMS:m / z 300.2[M+H]+,(ESI+),RT=3.35(Method A)

[0115] (Table 1) The following compounds were synthesized using a method similar to that used for compound E001. TIFF0007827911000006.tif37166TIFF0007827911000007.tif221166TIFF0007827911000008.tif225166TIFF0007827911000009.tif216166TIFF0007 827911000010.tif216166TIFF0007827911000011.tif225166TIFF0007827911000012.tif225166TIFF0007827911000013.tif225166TIFF00078279110 00014.tif212166TIFF0007827911000015.tif220166TIFF0007827911000016.tif221166TIFF0007827911000017.tif220166TIFF0007827911000018.tif225166TIFF0007827911000019.tif220166TIFF0007827911000020.tif212166TIFF0007827911000021.tif153166*E075 was formed as a by-product in the synthesis of E042. **E076 was formed as a by-product in the synthesis of E063.

[0116] Compound E078 TIFF0007827911000022.tif17128(1R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]-2,2-dimethyl-cyclopropanecarboxamide

[0117] This product was synthesized from compound E029 using chiral separation under the following conditions: Chiralpak AD-H column (20 x 250 mm, 5 μm) with a methanol mobile phase (9 mL / min) to give a colorless oil as the second eluting component. Comparison with compound E043 confirmed the absolute stereochemistry. The product was further purified by column chromatography (10 g Biotage snap cartridge, gradient 0-40% ethyl acetate in heptane) to give the title compound as a colorless gum. 1H NMR (400 MHz, DMSO-d6) δ 10.67(s,1H),8.14(dd,J=3.0,0.5Hz,1H),8.12(d,J=9.1Hz,1H),7.53(dd,J= 9.1,3.0Hz,1H),7.44(dt,J=10.5,9.2Hz,1H),7.23(ddd,J=11.8,6.8,3.0Hz,1 H),6.87(dtt,J=8.4,3.2,1.8Hz,1H),1.87(dd,J=7.9,5.5Hz,1H),1.14(d,J= 3.0Hz,6H),0.99(dd,J=5.3,3.9Hz,1H),0.80(dd,J=7.9,3.8Hz,1H).LCMS:m / z 319.2[M+H]+,(ESI+),RT=3.82(Method A)

[0118] Compound E079 TIFF0007827911000023.tif241282,2,3,3-Tetramethyl-N-[5-(methylamino)-2-pyridyl]cyclopropanecarboxamide

[0119] Step 1 5-Bromo-2-nitro-pyridine (250 mg, 1.23 mmol), cesium carbonate (803 mg, 2.46 mmol), and N-methyl-1-phenyl-methanamine (0.16 mL, 1.23 mmol) were combined in DMSO (6.25 mL), purged with nitrogen, and stirred at 50 °C for 3 h in a RBF. The reaction temperature was raised to 80 °C, and the reaction continued to stir for 3 h. The reaction mixture was diluted with water (50 mL). The mixture was extracted with EtOAc (3 × 25 mL). The combined organics were dried (hydrophobic frit) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (50 g SiO column, 0–80% EtOAc in heptane) to afford N-benzyl-N-methyl-6-nitro-pyridin-3-amine (60 mg, 0.230 mmol, 19% yield) as a yellow oil. 1HNMR(400MHz,DMSO-d6)δ 8.14(d,J=9.2Hz,1H),8.06(d,J=3.1Hz,1H),7.36(ddd,J=7.5,6.3,1.2Hz,2H),7.31-7.20(m,4H),4.82(s,2H),3.25(s,3H).

[0120] Step 2 To a solution of N-benzyl-N-methyl-6-nitro-pyridin-3-amine (60 mg, 0.230 mmol) in 3:1 EtOH / HO (4 mL) was added iron (128 mg, 2.30 mmol) and ammonium chloride (123 mg, 2.30 mmol). The reaction mixture was heated to 70 °C for 2 h. The reaction mixture was then cooled, filtered through a pad of Celite, and washed with EtOAc (2 × 25 mL). The filtrate was diluted with water (25 mL), the layers were separated, and the aqueous layer was extracted twice with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine, dried (hydrophobic frit), and concentrated under reduced pressure to give N5-benzyl-N5-methyl-pyridine-2,5-diamine (90.0%) (52 mg, 0.219 mmol, 95% yield) as a black oil. 1H NMR(400MHz,DMSO-d6)δ 7.51(d,J=2.7Hz,1H),7.31(ddd,J=9.7,4.4,2.4Hz,2H),7.22(td,J=5.2,4.7,2.2Hz,3H),7. 10(dd,J=8.9,3.1Hz,1H),6.39(dd,J=8.8,0.6Hz,1H),5.21(s,2H),4.30(s,2H),2.76(s,3H).

[0121] Step 3 To a solution of N5-benzyl-N5-methyl-pyridine-2,5-diamine (90%, 52 mg, 0.219 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.077 mL, 0.439 mmol) in THF-anhydrous (3 mL) was added 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (42 mg, 0.263 mmol) with stirring at room temperature for 2 hours. Then, MeOH (1 mL) and 1 M NaOH (1 mL) were added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was resuspended in brine (15 mL) and EtOAc (15 mL). The organic layer was separated, and the aqueous solution was further extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo to give N-[5-[benzyl(methyl)amino]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92.0%) (75 mg, 0.203 mmol, 93% yield) as a reddish-brown oil. 1H NMR (400MHz, chloroform-d)δ 7.91(d,J=9.1Hz,1H),7.76(s,1H),7.70(d,J=3.1Hz,1H),7.24(t,J=7.3Hz,2H),7.16(d,J=7.4Hz,1H),7.13( d,J=7.1Hz,2H),7.01(dd,J=9.1,3.1Hz,1H),4.41(s,2H),2.92(s,3H),1.23(s,6H),1.12(s,6H),0.93(s,1H).

[0122] Step 4 A stirred solution of N-[5-[benzyl(methyl)amino]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92%, 75 mg, 0.203 mmol) in ethyl acetate (10 mL) was placed under a hydrogen balloon and stirred at room temperature for 16 hours. An additional portion of 10% palladium on carbon (4.3 mg, 0.0406 mmol) was added, and the mixture was placed under a hydrogen balloon and stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite, and the Celite was washed with additional dioxane (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was dissolved in methanol (5 mL). The solution was passed through an H-Cube flow hydride equipped with a 10% Pd / C cartridge at a flow rate of 1 mL / min at a reaction temperature of 80 °C. The generated hydrogen was fed to the flow at 80 bar. The crude mixture was then passed through H-cube two more times under the same conditions, but with the addition of acetic acid (5% (v / v)) to the reaction mixture. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Method E), followed by an SCX cartridge (1 g) eluting with methanol (3 CV) and then 2 M ammonia in methanol (3 CV). The ammonia-containing fractions were then combined and concentrated to give the title compound (5.4 mg, 0.0214 mmol, 11% yield) as a light brown solid. 1HNMR(500MHz,DMSO-d6)δ 9.90(s,1H),7.77(d,J=8.8Hz,1H),7.62(d,J=2.8Hz,1H),6.91(dd,J=8.9,3.0Hz,1H),5.5 6(d,J=5.2Hz,1H),2.68(d,J=5.1Hz,3H),1.44(s,1H),1.23(s,6H),1.15(s,6H).LCMS:m / z 248.2[M+H]+,(ESI+),RT=1.83(Method A)

[0123] Compound E080 TIFF0007827911000024.tif27128N-[5-(2-hydroxy-2-methyl-propoxy)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0124] Synthesized using a method similar to that used for compound E079, starting from 2-methyl-2-(phenylmethoxy)-1-propanol. 1H NMR (500 MHz, chloroform-d) δ 8.11 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.9 Hz, 1H), 7.89 (s, 1H), 7.26-7.22 (m, 1H), 3.80 (s, 2H), 2.18 (s, 1H), 1.35 (s, 6H), 1.31 (s, 6H), 1.21 (s, 6H), 1.00 (s, 1H). LCMS: m / z 307.5 [M+H]+, (ESI+), RT = 2.73 (Method A).

[0125] Compound E081 TIFF0007827911000025.tif241282-Methyl-N-(5-pyrrolidin-1-yl-2-pyridyl)propanamide

[0126] Step 1 A suspension of 5-bromo-2-nitro-pyridine (1 g, 4.93 mmol) in pyrrolidine (2.1 mL, 24.6 mmol) was heated to 120 °C in a microwave reactor with stirring for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. Purification by flash chromatography (50 g Biotage KP-Sil cartridge, 10–60% EtOAc in heptane) afforded 2-nitro-5-pyrrolidin-1-yl-pyridine as a yellow solid (486 mg, 2.52 mmol, 51% yield). 1H NMR (250 MHz, chloroform-d) δ 8.15 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 9.0, 2.5 Hz, 1H), 6.25 (d, J = 9.0 Hz, 1H), 3.56-3.26 (m, 4H), 2.10-1.85 (m, 4H).

[0127] Step 2 To a degassed suspension of 2-nitro-5-pyrrolidin-1-yl-pyridine (486 mg, 2.52 mmol) in ethanol (10 mL) at room temperature, 10% palladium on carbon (50 mg, 0.470 mmol) was added and stirred under a hydrogen atmosphere for 4 h. The reaction mixture was filtered through Celite (5 g) and evaporated to dryness to give 5-pyrrolidin-1-ylpyridin-2-amine (466 mg, 2.31 mmol, 92% yield) as a brown solid. H NMR (500 MHz, DMSO-d6) δ 7.35 (d, J = 2.9 Hz, 1H), 6.84 (dd, J = 8.8, 3.0 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.01 (s, 2H), 3.14-3.04 (m, 4H), 1.96-1.84 (m, 4H).

[0128] Step 3 To a stirred solution of 5-pyrrolidin-1-ylpyridin-2-amine (58 mg, 0.288 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.10 mL, 0.573 mmol) in DCM (5 mL) was added a solution of 2-methylpropanoyl chloride (0.060 mL, 0.573 mmol) in DCM (1 mL) at room temperature and stirred for 2 hours. The reaction mixture was washed with saturated NaHCO (2 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in MeOH (3 mL) and 1N NaOH solution (2 mL) and stirred at room temperature for 1 hour, then evaporated in vacuo. Purification by preparative HPLC (Method H) followed by lyophilization afforded the title product as a white solid (31 mg, 0.132 mmol, 46% yield). 1H NMR(250MHz,DMSO-d6)δ 9.95(s,1H),7.88(d,J=8.9Hz,1H),7.63(d,J=2.8Hz,1H),6.96(dd,J=9.0,3.1Hz,1H),3 .28-3.15(m,4H),2.77-2.58(m,1H),2.01-1.88(m,4H),1.06(d,J=6.8Hz,6H).LCMS:m / z 234.1[M+H]+,(ESI+),RT=1.49(Method A)

[0129] Compound E082 TIFF0007827911000026.tif22128N-[5-(2-hydroxyethoxy)pyridin-2-yl]-2,2,3,3-tetramethylcyclopropane-1-carboxamide

[0130] Synthesized using a method similar to that used for compound E078, except starting from benzyloxyethanol and using sodium hydride as the base and DMF as the solvent in step 1. H NMR (500 MHz, chloroform-d) δ 8.13 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.87 (s, 1H), 7.28-7.25 (m, 1H), 4.15-4.09 (m, 2H), 4.02-3.96 (m, 2H), 2.04 (s, 1H), 1.34 (s, 6H), 1.23 (s, 6H), 1.03 (s, 1H). LCMS: m / z 279.0 [M+H]+, (ESI+), RT = 2.26 (Method A).

[0131] (Table 2) The following compounds were synthesized using a method similar to that used for compound E001, except that sodium hydride was used as the base and DMF was used as the solvent in step 1. TIFF0007827911000027.tif167166TIFF0007827911000028.tif221166*Compounds E089 and E090 were isolated as products from the same reaction.

[0132] Compound E093 TIFF0007827911000029.tif271282,2,3,3-Tetramethyl-N-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]cyclopropanecarboxamide

[0133] Step 1 To a stirred mixture of 6-aminopyridin-3-ol (150 mg, 1.36 mmol) and cesium carbonate (0.67 g, 2.04 mmol) in anhydrous DMF (3.6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.22 mL, 1.50 mmol) dropwise. After stirring at room temperature for 6 h, the mixture was concentrated to dryness under reduced pressure. To the residue were added EtOAc (20 mL) and water (20 mL). The organics were separated, and the aqueous solution was further extracted with EtOAc (2 × 20 mL). The organics were combined, dried (MgSO), and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO, 25 g, eluting with 20–100% EtOAc in heptane) to afford 5-(2,2,2-trifluoroethoxy)pyridin-2-amine (60 mg, 22% yield) as a brown solid. 1H NMR(500MHz,DMSO-d6)δ 7.74(d,J=3.0Hz,1H),7.22(dd,J=8.9,3.1Hz,1H),6.43(d,J=8.9Hz,1H),5.65(s,2H),4.62(q,J=9.0Hz,2H)

[0134] Step 2 To a solution of 5-(2,2,2-trifluoroethoxy)pyridin-2-amine (60 mg, 0.309 mmol) and N-ethyl-N-isopropyl-propan-2-amine (108 μL, 0.618 mmol) in THF-anhydrous (2.5 mL) was added 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (60 mg, 0.371 mmol) with stirring at room temperature for 16 hours, after which time MeOH (1 mL), 1 M NaOH (1 mL) were added and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with brine (10 mL) and extracted with EtOAc (3 × 10 mL), and the combined organic extracts were concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50 g, 0-30% EtOAc in heptane) followed by preparative HPLC (Method G) to give the title compound (8.2 mg, 0.0259 mmol, 8.4% yield) as a colorless solid. 1H NMR (500 MHz, chloroform-d) δ 8.18 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 2.9 Hz, 1H), 7.87 (s, 1H), 7.31 (dd, J = 9.1, 3.0 Hz, 1H), 4.38 (q, J = 8.0 Hz, 2H), 1.34 (s, 6H), 1.24 (s, 6H), 1.03 (s, 1H). LCMS: m / z 317.2 [M+H]+, (ESI+), RT = 3.78 (Method A).

[0135] Compound E094 TIFF0007827911000030.tif20128N-(5-anilino-2-pyridyl)-2-methyl-propanamide

[0136] Step 1 To a stirred solution of isobutyric anhydride (359 μL, 2.17 mmol) and 5-bromopyridin-2-amine (250 mg, 1.45 mmol) in THF (15.453 mL), N-ethyl-N-isopropyl-propan-2-amine (505 μL, 2.89 mmol) was added, followed by N,N-dimethylpyridin-4-amine (18 mg, 0.145 mmol), and the mixture was stirred at 80 °C for 2 h in a sealable pressure tube. The reaction mixture was then evaporated to dryness. Purification by flash chromatography (50 g KP-Sil Biotage SNAP cartridge, 10–100% EtOAc in heptane) afforded N-(5-bromo-2-pyridyl)-2-methyl-propanamide (330 mg, 1.34 mmol, 93% yield) as a white solid. 1H NMR (250 MHz, chloroform-d) δ 8.30 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.90 (s, 1H), 7.79 (dd, J = 8.9, 2.4 Hz, 1H), 2.55 (hept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H).

[0137] Step 2 To a mixture of N-(5-bromo-2-pyridyl)-2-methyl-propanamide (70 mg, 0.285 mMol) and sodium tert-butoxide (41 mg, 0.428 mMol), toluene (3 mL) was added. Aniline (29 mg, 0.314 mMol) was then added, and the mixture was degassed under nitrogen at room temperature for 10 minutes. Pd2(dba)3 (26 mg, 0.0283 mMol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (40.8 mg, 0.0855 mMol) were then added to the mixture, and the reaction vessel was sealed and heated to 100 °C with stirring for 4 hours, then cooled to room temperature. The reaction mixture was filtered through Celite with EtOAc (30 mL). It was then washed with saturated NaHCO (30 mL), followed by brine (30 mL), dried over sodium sulfate, filtered and evaporated to dryness. Purification by preparative HPLC (Method F) gave the title compound as a white solid (3.6 mg, 5%). 1H NMR(500MHz,DMSO-d6)δ 10.18(s,1H),8.13(s,1H),8.08(d,J=2.4Hz,1H),7.98(d,J=8.9Hz,1H),7.51(dd,J=8.9,2.9Hz,1H),7.25-7.19(m,2H) ),6.99(dd,J=8.6,1.0Hz,2H),6.81(tt,J=7.4,1.1Hz,1H),2.71(hept,J=6.8Hz,1H),1.08(d,J=6.8Hz,6H).LCMS:m / z 256.2[M+H]+,(ESI+),RT=2.30(Method A)

[0138] Compound E095 TIFF0007827911000031.tif22128N-(5-indolin-1-yl-2-pyridyl)-2-methyl-propanamide

[0139] Synthesized using a method similar to that used for compound E094. 1H NMR(250MHz,DMSO-d6)δ 10.28(s,1H),8.24(d,J=2.4Hz,1H),8.08(d,J=9.4Hz,1H),7.70(dd,J=9.2,3.0Hz,1H),7.18(d,J=7.4Hz,1H),7.10-6.94(m ,2H),6.77-6.68(m,1H),3.93(t,J=8.6Hz,2H),3.10(t,J=8.6Hz,2H),2.77(m,J=1.9Hz,1H),1.09(d,J=6.8Hz,6H).LCMS:m / z 282.2[M+H]+,(ESI+),RT=3.02(Method A)

[0140] Compound E096 TIFF0007827911000032.tif241282-Methyl-N-[5-(N-methylanilino)-2-pyridyl]propanamide

[0141] Step 1 To a solution of 5-bromo-2-nitro-pyridine (200 mg, 0.985 mmol) and Pd(dba) (45 mg, 0.0493 mmol) in DME (5 mL) was added cesium carbonate (482 mg, 1.48 mmol) and degassed under nitrogen at room temperature for 10 minutes. To this was added N-methylaniline (0.13 mL, 1.18 mmol) and (R)-BINAP (61 mg, 0.0985 mmol). The reaction vessel was sealed and heated to 100 °C with stirring for 4 hours, then cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was then extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness to give N-methyl-6-nitro-N-phenyl-pyridin-3-amine as a dark yellow solid (187.7 mg, 83.1%). 1H NMR(500MHz,DMSO-d6)δ 8.15(d,J=9.2Hz,1H),7.97(d,J=3.0Hz,1H),7.55-7.50(m,2H),7.38-7.34(m,3H),7.21(dd,J=9.2,3.0Hz,1H),3.43(s,3H).

[0142] Step 2 To a solution of N-methyl-6-nitro-N-phenyl-pyridin-3-amine (188 mg, 0.819 mmol) in ethanol (5 mL) was added 10% Pd / C (87 mg, 0.0819 mmol), and the reaction mixture was placed under a balloon of hydrogen and stirred at room temperature for 4 h. It was then filtered through Celite, washed with EtOAc, and concentrated under reduced pressure to give N5-methyl-N5-phenyl-pyridine-2,5-diamine as a colorless oil (138 mg, 85%). 1H NMR(500MHz,DMSO-d6)δ 7.76(dd,J=2.7,0.6Hz,1H),7.22(dd,J=8.7,2.7Hz,1H),7.15-7.10(m,2H) ,6.68-6.60(m,3H),6.49(dd,J=8.7,0.7Hz,1H),5.88(s,2H),3.13(s,3H).

[0143] Step 3 To a stirred solution of N-ethyl-N-isopropyl-propan-2-amine (140 μL, 0.803 mmol) and N,N-dimethylpyridin-4-amine (4.9 mg, 0.0402 mmol) in THF-anhydrous (2.5 mL) was added isobutyric anhydride (100 μL, 0.602 mmol) followed by N-methyl-N-phenyl-pyridine-2,5-diamine (80 mg, 0.402 mmol) and stirred in a sealable pressure tube at 80° C. for 48 h. The reaction mixture was then evaporated to dryness and purified by column chromatography (Biotage SNAP cartridge KP-Sil 10 g, 0-100% EtOAc in heptane) to afford the title compound (57.3 mg, 53%) as a light brown solid. 1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.09-8.01(m,2H),7.49(dd,J=8.9,2.9Hz,1H),7.30-7.20(m,2H),6.97 -6.84(m,3H),3.25(s,3H),2.73(hept,J=6.8Hz,1H),1.08(d,J=6.8Hz,6H).LCMS:m / z 270.2[M+H]+,(ESI+),RT=2.59(Method A)

[0144] (Table 3) The following compounds were synthesized using a method similar to that used for compound E096. TIFF0007827911000033.tif207166

[0145] Compound E102 TIFF0007827911000034.tif211283-[5-(3,4-difluorophenoxy)-2-pyridyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0146] Step 1 5-Bromo-2-nitro-pyridine (2.00 g, 9.85 mmol), cesium carbonate (6.42 g, 19.7 mmol), and 3,4-difluorophenol (1.28 g, 9.85 mmol) were mixed in DMSO (25 mL), purged with nitrogen, and stirred at 50 °C for 2 h in a RBF. The reaction mixture was cooled and diluted with water (75 mL), forming a beige / gray precipitate. This was filtered, washed with water, and purified by FCC (Biotage SNAP KP-Sil 25 g, 0–50% EtOAc in heptane) to give 5-(3,4-difluorophenoxy)-2-nitro-pyridine (2.09 g, 81% yield) as an off-white solid. 1H NMR (400MHz, chloroform-d)δ 8.33(d,J=2.8Hz,1H),8.27(d,J=8.9Hz,1H),7.44(dd,J=8.9,2.8Hz,1H),7.3 2-7.21(m,1H),7.00(ddd,J=9.9,6.5,2.9Hz,1H),6.88(dq,J=8.6,3.1Hz,1H).

[0147] Step 2 To a solution of 5-(3,4-difluorophenoxy)-2-nitro-pyridine (2 g, 8 mmol) in EtOH (50 mL) and HO (10 mL) was added ammonium chloride (4.43 g, 82.9 mmol). The reaction mixture was heated to 50 °C, and iron (4.63 g, 82.9 mmol) was added. The reaction was then stirred at 70 °C for 25 minutes. The reaction mixture was then cooled, filtered through a pad of Celite, and washed with EtOH (50 mL) and EtOAc (150 mL). The filtrate was diluted with water (100 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (75 mL), dried over MgSO, and concentrated under reduced pressure to provide 5-(3,4-difluorophenoxy)pyridin-2-amine (Intermediate I01, 1.87 g, quantitative yield) as a brown oil. 1H NMR (500MHz, chloroform-d)δ 7.89(d,J=2.8Hz,1H),7.18(dd,J=8.8,2.9Hz,1H),7.11-7.03(m,1H),6.75(ddd,J=11 .5,6.6,3.0Hz,1H),6.64(dtt,J=8.3,3.2,1.8Hz,1H),6.55-6.50(m,1H),4.43(s,2H).

[0148] Step 3 To 2 M ethanamine (4.0 mL, 8.03 mmol) in THF was added (2R)-2-(trifluoromethyl)oxirane (0.23 mL, 2.68 mmol), and the reaction was stirred at room temperature overnight. The solvent was then removed under reduced pressure to give (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol as a dark yellow solid (Intermediate I02, 530 mg, 94%, 75% purity). This was used directly in the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 3.98-3.91 (m, 1H), 2.99-2.93 (m, 1H), 2.87-2.81 (m, 1H), 2.77-2.64 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H). (OH and NH were not observed.)

[0149] Step 4 A solution of pyridine (40 μL, 0.495 mmol) and 5-(3,4-difluorophenoxy)pyridin-2-amine (100 mg, 0.450 mmol) in THF-anhydrous (3 mL) was added to a stirred solution of (4-nitrophenyl)carbonochloridate (100 mg, 0.495 mmol) in THF-anhydrous (3 mL). The reaction mixture was stirred at room temperature for 4.5 hours. A solution of (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (92 mg, 0.585 mmol) and N-ethyl-N-isopropyl-propan-2-amine (118 μL, 0.675 mmol) in THF-anhydrous (3 mL) was added to the reaction mixture and stirred at room temperature overnight. The product was purified by silica flash column chromatography (0-40% EtOAc in heptane) followed by preparative HPLC (Method G) to afford the title compound (77 mg, 0.189 mmol, 42% yield) as a clear glass. 1H NMR(400MHz,DMSO-d6)δ 9.02(s,1H),8.09(d,J=2.9Hz,1H),7.83(d,J=9.1Hz,1H),7.55-7.37(m,2H),7.24-7.14(m,1H),7.01(s,1H),6.89 -6.79(m,1H),4.34-4.22(m,1H),3.59(dd,J=14.9,2.6Hz,1H),3.50-3.38(m,3H),1.11(t,J=7.0Hz,3H).LCMS:m / z 406.2[M+H]+,(ESI+),RT=3.61(Method B)

[0150] (Table 4) The following compounds were synthesized using methods similar to those used for compound E102, using either commercially available amines or amino alcohols synthesized according to compound E102, step 3. TIFF0007827911000035.tif216166TIFF0007827911000036.tif225166TIFF0007827911 000037.tif220166TIFF0007827911000038.tif225166TIFF0007827911000039.tif22016 6TIFF0007827911000040.tif220166TIFF0007827911000041.tif207166TIFF0007827911 000042.tif225166TIFF0007827911000043.tif225166TIFF0007827911000044.tif73166

[0151] Compound E139 TIFF0007827911000045.tif181283-[5-(3,4-difluorophenoxy)-2-pyridyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0152] Step 1 To a three-necked RBF under N was added (2R)-2-(trifluoromethyl)oxirane (200 mg, 1.78 mmol), followed by anhydrous THF (8 mL), and the stirred solution was cooled to 100 °C in an EtO / dry ice bath. 1.6 M butyllithium (1.2 mL, 1.96 mmol) was then added dropwise, followed by stirring at this temperature for 10 minutes. Iodomethane (0.17 mL, 2.68 mmol) was then added, and the reaction was stirred at this temperature for 2 hours, warmed to approximately 0 °C in an ice bath, to which 2 M methanamine (3.6 mL, 7.14 mmol) was added, and the reaction was allowed to warm to room temperature, stirred overnight, and left over the weekend. The solvent was then removed under reduced pressure to give (2R)-1,1,1-trifluoro-2-methyl-3-(methylamino)propan-2-ol (1.10 g) as an orange viscous gum. 1H NMR (500 MHz, methanol-d4) δ 2.82 (d, J = 12.3 Hz, 1H), 2.70-2.64 (m, 1H), 2.44 (s, 3H), 1.38-1.35 (m, 3H).

[0153] Step 2 To a solution of 4-nitrophenyl carbonochloridate (47 mg, 0.233 mmol) in anhydrous THF (1.5 mL) was added 5-[(3,4-difluorophenoxy)pyridin-2-amine (Intermediate I01, 50 mg, 0.212 mmol) and pyridine (19 μL, 0.233 mmol) in anhydrous THF (1 mL), and the reaction was stirred at room temperature for 3 h. Next, (2R)-1,1,1-trifluoro-2-methyl-3-(methylamino)propan-2-ol (25% purity, 133 mg, 0.212 mmol) and N-ethyl-N-isopropyl-propan-2-amine (55 μL, 0.317 mmol) in anhydrous THF (1.5 mL) were added, and the reaction was stirred at room temperature for 45 min. It was then concentrated under reduced pressure and purified by preparative HPLC (Method G) to give the title compound (25 mg, 29% yield) as a pale yellow solid. 1H NMR, (500 MHz, chloroform-d) δ 8.05-7.99 (m, 2H), 7.47 (s, 1H), 7.36 (dd, J = 9.0, 3.0 Hz, 1H), 7.12 (q, J = 9.0 Hz, 1H), 6.81 (ddd, J = 11.1, 6.5, 3.0 Hz, 1H), 6.73-6.66 (m, 1H), 5.66 (s, 1H), 3.77-3.60 (m, 2H), 3.18 (s, 3H), 1.39 (s, 3H). LCMS: m / z 406.2 [M+H]+, (ESI+), RT = 3.37 (Method A).

[0154] Compound E140 TIFF0007827911000046.tif191283-[5-(3,5-difluorophenoxy)-2-pyridyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0155] Synthesized using a method similar to that used for compound E139. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 9.1, 3.0 Hz, 1H), 6.98 (tt, J = 9.3, 2.3 Hz, 1H), 6.78-6.68 (m, 2H), 3.72 (d, J = 13.9 Hz, 1H), 3.46 (d, J = 14.4 Hz, 1H), 3.06 (s, 3H), 1.30 (s, 3H). LCMS: m / z 406.3 [M+H]+, (ESI+), RT = 3.64 (Method B).

[0156] Compound E141 TIFF0007827911000047.tif241283-[5-(2,4-difluorophenoxy)-2-pyridyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0157] Synthesized using a method similar to that used for compound E139. H NMR (500 MHz, chloroform-d) δ 8.02-7.98 (m, 2H), 7.43 (s, 1H), 7.30 (dd, J = 9.1, 3.0 Hz, 1H), 7.06 (td, J = 9.0, 5.4 Hz, 1H), 7.01-6.95 (m, 1H), 6.91-6.85 (m, 1H), 5.79 (s, 1H), 3.74 (d, J = 15.3 Hz, 1H), 3.64 (d, J = 15.3 Hz, 1H), 3.19 (s, 3H), 1.40 (s, 3H). LCMS: m / z 404.2 [M-H]-, (ESI-), RT = 3.30 (Method A).

[0158] Compound E142 TIFF0007827911000048.tif271281-Ethyl-3-(5-pyrazol-1-yl-2-pyridyl)-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0159] Step 1 5-Fluoro-2-nitropyridine (250 mg, 1.76 mmol) and 1H-pyrazole (126 mg, 1.85 mmol) were mixed in anhydrous DMF (3.5 mL), and the reaction mixture was cooled to 0° C. before adding sodium hydride (60%, 106 mg, 2.64 mmol) in small portions. The reaction was then stirred at room temperature for 2 hours. Upon completion, the reaction mixture was diluted with water (10 mL), forming a pale yellow precipitate. This was filtered, washed with water (50 ml), and dried to give 2-nitro-5-pyrazol-1-yl-pyridine (235 mg, 1.17 mmol, 67% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 9.23-9.16(m,1H),8.81(d,J=2.4Hz,1H),8.63(dd,J=8.9,2.6Hz,1H),8.51-8.45(m,1H),7.97(d,J=1.6Hz,1H),6.73(dd,J=2.6,1.7Hz,1H).

[0160] Step 2 To a stirred solution of 2-nitro-5-pyrazol-1-yl-pyridine (235 mg, 1.24 mmol) in 1,4-dioxane (10 mL) and methanol (5 mL) was added 10% Pd / C (53 mg, 0.25 mmol), and the reaction mixture was placed under a balloon of hydrogen and stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the Celite was washed with additional dioxane (50 mL). The filtrate was concentrated under reduced pressure to give 5-pyrazol-1-ylpyridin-2-amine (188 mg, 90% yield) as a sandy brown solid. 1H NMR(400MHz,DMSO-d6)δ 8.32(d,J=2.5Hz,1H),8.25(d,J=2.1Hz,1H),7.78(dd,J=8.8,2.8Hz,1H),7 .66(d,J=1.5Hz,1H),6.54(d,J=8.9Hz,1H),6.49-6.43(m,1H),6.10(s,2H).

[0161] Step 3 To a solution of (4-nitrophenyl) carbonochloridate (66 mg, 0.326 mmol) in anhydrous THF (2 mL) was added a solution of 5-pyrazol-1-ylpyridin-2-amine (50 mg, 0.297 mmol) and pyridine (0.026 mL, 0.297 mmol) in anhydrous THF (2 mL), and the reaction was stirred at room temperature for 1 hour. Then, (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 71 mg, 0.386 mmol) and N-ethyl-N-isopropyl-propan-2-amine (78 uL, 0.445 mmol) in anhydrous THF (2 mL) were added, and the reaction was stirred at room temperature for 1 hour. Then, it was concentrated under reduced pressure and purified by preparative HPLC (Method G) to give the title compound (47 mg, 0.133 mmol, 45% yield) as a pale yellow solid. 1HNMR(400MHz,chloroform-d)δ 8.58(s,1H),8.11(d,J=9.0Hz,1H),7.99-7.91(m,1H),7.86(d,J=2.2Hz,1H),7.76-7.71(m,1H),6.50(t,J=1.9Hz,1H),5.74(s,1H) ,4.26-4.14(m,1H),3.80(dd,J=15.2,8.7Hz,1H),3.59-3.47(m,2H),3.41(dq,J=14.8,7.3Hz,1H),1.31(t,J=7.1Hz,3H).LCMS:m / z 344.3[M+H]+,(ESI+),RT=2.48(Method A).

[0162] Compound E143 TIFF0007827911000049.tif23128N-[4-(3,5-difluorophenoxy)-2-pyridyl]-2-methyl-propanamide

[0163] Step 1 To a solution of 4-chloropyridin-2-amine (300 mg, 2.33 mmol) and 3,5-difluorophenol (395 mg, 3.03 mmol) in NMP (5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.82 mL, 4.67 mmol) at room temperature. The reaction mixture was stirred at 160° C. for 18 hours. It was then cooled to room temperature and diluted with EtOAc (30 mL) and water / brine (1:1, 30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method F) to give 4-(3,5-difluorophenoxy)pyridin-2-amine as a light brown solid (85 mg). 1H NMR(400MHz,DMSO-d6)δ 7.86(d,J=5.8Hz,1H),7.13(tt,J=9.4,2.3Hz,1H),7.03-6.85(m,2H),6.20(dd,J=5.8,2.3Hz,1H),6.02(s,2H),5.95(d,J=2.2Hz,1H).

[0164] Step 2 To a solution of 4-(3,5-difluorophenoxy)pyridin-2-amine (40 mg, 0.180 mmol) in DCM (1 mL) was added N-ethyl-N-isopropyl-propan-2-amine (63 μL, 0.360 mmol), followed by 2-methylpropanoyl chloride (32 μL, 0.306 mmol), and the reaction was stirred at room temperature for 0.5 h. The solvent was then removed under a steady stream of nitrogen, the residue was dissolved in MeOH (1 mL), 1 M NaOH (1 mL) was added, and the reaction mixture was stirred at room temperature for 0.5 h. The MeOH was removed under a steady stream of nitrogen, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography (10 g SiO column, 0–60% EtOAc in heptane) to give the title compound (39 mg) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.56(s,1H),8.24(d,J=5.7Hz,1H),7.75(d,J=2.3Hz,1H),7.21(tt,J=9.4,2.3Hz,1H),7.12-7. 00(m,2H),6.77(dd,J=5.7,2.4Hz,1H),2.72(hept,J=6.8Hz,1H),1.05(d,J=6.8Hz,6H).LCMS:m / z 292.8[M+H]+,(ESI+),RT=3.02(Method A).

[0165] Compound E144 TIFF0007827911000050.tif22128N-[4-(3,5-difluorophenoxy)-2-pyridyl]cyclopropanecarboxamide

[0166] Synthesized using a method similar to that used for compound E143. H NMR (500 MHz, DMSO-d) δ 10.92 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.20 (tt, J = 9.4, 2.3 Hz, 1H), 7.12-6.97 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 1.98 (tt, J = 6.2, 6.2 Hz, 1H), 0.78 (d, J = 6.2 Hz, 4H). LCMS: m / z 291.1 [M+H]+, (ESI+), RT = 2.83 (Method A).

[0167] Compound E145 TIFF0007827911000051.tif181282-Methyl-N-(4-phenoxy-2-pyridyl)propanamide

[0168] Step 1 To a solution of 4-chloropyridin-2-amine (500 mg, 3.89 mmol) in THF (5 mL) at room temperature, N-ethyl-N-isopropyl-propan-2-amine (1.4 mL, 7.78 mmol) was added, followed by isobutyric anhydride (0.97 mL, 5.83 mmol) and N,N-dimethylpyridin-4-amine (48 mg, 0.389 mmol). The reaction vial was sealed and heated to 70 °C for 4 h, then cooled to room temperature. The reaction mixture was evaporated to dryness. Purification by flash chromatography (50 g KP-SilBiotage SNAP cartridge, 5–40% EtOAc in heptane) afforded a white solid, which was dissolved in DCM (30 mL) and washed with 1 N NaOH solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give N-(4-chloro-2-pyridyl)-2-methyl-propanamide (546 mg, 69% yield) as a white solid. 1H NMR (250 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.22 (dd, J = 5.4, 2.0 Hz, 1H), 2.75 (hept, J = 6.8 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H).

[0169] Step 2 To a solution of N-(4-chloro-2-pyridyl)-2-methyl-propanamide (100 mg, 0.498 mmol) and phenol (47 mg, 0.498 mmol) in DMSO (1 mL) at room temperature was added potassium tert-butoxide (67 mg, 0.598 mmol). The reaction mixture was stirred at 160° C. for 3 h and cooled to room temperature. The mixture was diluted with EtOAc (20 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. Purification by preparative HPLC (Method F), followed by concentration and lyophilization, afforded the title compound as an off-white solid (56 mg, 0.218 mmol, 44% yield). 1H NMR(250MHz,DMSO-d6)δ 10.44(s,1H),8.18(d,J=5.7Hz,1H),7.68(d,J=2.3Hz,1H),7.57-7.41(m,2H),7.37-7.25(m,1H), 7.23-7.10(m,2H),6.67(dd,J=5.7,2.4Hz,1H),2.77-2.60(m,1H),1.03(d,J=6.8Hz,6H).LCMS:m / z 257.1[M+H]+,(ESI+),RT=2.33(Method A)

[0170] Compound E146 TIFF0007827911000052.tif221282,2,3,3-Tetramethyl-N-(4-pyrrolidin-1-yl-2-pyridyl)cyclopropanecarboxamide

[0171] Step 1 To a stirred solution of 4-chloropyridin-2-amine (200 mg, 1.56 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.54 mL, 3.09 mmol) in DCM (3 mL) at room temperature, a solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (497 mg, 3.10 mmol) in DCM (1 mL) was added and stirred for 2 h. The reaction mixture was washed with saturated NaHCO (2 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in MeOH (5 mL) and 1 N NaOH solution (3 mL). After stirring at room temperature for 1 h, the solvent was evaporated in vacuo, and the residue was washed with brine (15 mL), extracted with EtOAc (3 × 15 mL), and concentrated under reduced pressure. Purification by flash column chromatography (Biotage SNAP KP-Sil 50 g, heptane:ethyl acetate, 0-20%) afforded N-(4-chloro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (150 mg, 35% yield) as a white solid. H NMR (400 MHz, chloroform-d) δ 8.29 (d, J = 1.8 Hz, 1H), 8.15-8.09 (m, 2H), 6.99 (dd, J = 5.4, 1.9 Hz, 1H), 1.32 (s, 6H), 1.22 (s, 6H), 1.02 (s, 1H).

[0172] Step 2 A mixture of N-(4-chloro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (70 mg, 0.260 mmol) and pyrrolidine (0.11 mL, 1.30 mmol) in NMP (2 mL) was heated under microwave irradiation at 225 °C for 30 minutes. The mixture was washed with ethyl acetate (20 mL), extracted with water (2 × 30 mL), and the combined organics were dried using a hydrophobic filter and evaporated under reduced pressure. The crude reaction mixture was concentrated and purified by preparative HPLC (Method E) to give the title compound (28 mg, 37% yield) as an off-white solid. 1H NMR (500MHz, chloroform-d)δ 8.68(s,1H),7.63(d,J=6.8Hz,1H),7.54(d,J=2.4Hz,1H),6.18(dd,J=6.8,2.5Hz,1H), 3.43-3.45(m,4H),2.08-2.01(m,4H),1.40(s,1H),1.30(s,6H),1.24(s,6H).LCMS:m / z 288.2[M+H]+,(ESI+),RT=2.10(Method A).

[0173] Compound E147 TIFF0007827911000053.tif22128N-[4-[(5-fluoro-3-pyridyl)oxy]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0174] Step 1 To a solution of 4-fluoropyridin-2-amine (300 mg, 2.62 mmol) and N-ethyl-N-isopropyl-propan-2-amine (916 μL, 5.25 mmol) in THF-anhydrous (15 mL) was added 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (506 mg, 3.15 mmol) with stirring at room temperature for 16 hours, after which time MeOH (5 mL), 1 M NaOH (5 mL) were added and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with brine (25 mL) and extracted with EtOAc (3×25 mL), and the combined organic extracts were washed and concentrated in vacuo. The crude product was purified by flash column chromatography (50 g silica cartridge, 0–20% EtOAc in heptane) to give N-(4-fluoro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (302 mg, 46% yield) as a colorless solid. H NMR (400 MHz, chloroform-d) δ 8.21 (dd, J = 8.6, 5.7 Hz, 1H), 8.10 (s, 1H), 8.01 (dd, J = 11.4, 2.4 Hz, 1H), 6.75 (ddd, J = 7.9, 5.7, 2.4 Hz, 1H), 1.34 (s, 6H), 1.24 (s, 6H), 1.03 (s, 1H).

[0175] Step 2 To a stirred solution of 5-fluoropyridin-3-ol (48 mg, 0.422 mmol) in anhydrous DMF (3 mL) was added sodium hydride (60% dispersion in oil) (24 mg, 0.603 mmol). After gas evolution ceased, N-(4-fluoro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (100 mg, 0.402 mmol) was added, and the reaction mixture was heated to 100 °C. The reaction mixture was then heated to 120 °C for 16 h. The reaction mixture was washed with water (30 mL) and extracted with diethyl ether (2 × 20 mL). The combined organic layers were dried (hydrophobic filter) and concentrated to dryness under reduced pressure. Purification (10 g Biotage SNAP KP-Sil cartridge, 0–35% EtOAc in heptane) followed by lyophilization afforded the title product as a colorless solid (37 mg, 27% yield). 1H NMR (500MHz, chloroform-d)δ 8.36(d,J=2.4Hz,1H),8.30(d,J=2.2Hz,1H),8.17(d,J=5.7Hz,1H),8.07(s,1H),7.92(d,J=2.3Hz,1H),7 .16(dt,J=9.1,2.4Hz,1H),6.58(dd,J=5.7,2.3Hz,1H),1.29(s,6H),1.21(s,6H),1.01(s,1H).LCMS:m / z 330.3[M+H]+,(ESI+),RT=3.16(Method A)

[0176] Compound E148 TIFF0007827911000054.tif22128N-[4-[(6-fluoro-3-pyridyl)oxy]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0177] Step 1 6-Fluoropyridin-3-ol (270 mg, 2.39 mmol) and N,N-dimethylglycine hydrochloride (1:1) (178 mg, 1.27 mmol) were suspended in anhydrous 1,4-dioxane (8 mL), and the reaction mixture was degassed with N for 5 minutes. 4-Iodopyridin-2-amine (350 mg, 1.59 mmol) was added, and the reaction was stirred for 10 minutes. After that, copper(I) iodide (121 mg, 0.636 mmol) and cesium carbonate (1296 mg, 3.98 mmol) were added, and the mixture was heated to 90 °C in a microwave reactor for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc (15 mL), filtered through a pad of Celite, and washed with EtOAc (30 mL). The mixture was then washed with water (15 mL), extracted with EtOAc (2 × 20 mL), dried, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (Biotage Sfar Duo 50 g cartridge, 0–10% MeOH in EtOAc) to give 4-[(6-fluoro-3-pyridyl)oxy]pyridin-2-amine (33 mg, 87% purity, 8.7% yield) as an off-white solid. H NMR (500 MHz, chloroform-d) δ 8.05 (dd, J = 2.8, 1.4 Hz, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7.53 (ddd, J = 9.3, 6.4, 3.0 Hz, 1H), 6.99 (dd, J = 8.7, 3.4 Hz, 1H), 6.26 (dd, J = 5.9, 2.2 Hz, 1H), 5.95 (d, J = 2.1 Hz, 1H), 4.49 (s, 2H).

[0178] Step 2 To a solution of tetramethylcyclopropane-1-carbonyl chloride (22 mg, 0.138 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.024 mL, 0.138 mmol) in THF-anhydrous (1.5 mL), 4-[(6-fluoro-3-pyridyl)oxy]pyridin-2-amine (87%, 33 mg, 0.138 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Tetramethylcyclopropane-1-carbonyl chloride (10 mg, 0.2 equiv.) and DIPEA (12 μL, 0.2 equiv.) were further added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then concentrated to dryness, and the residue was washed with water (30 mL) and extracted with EtOAc (2×25 mL). The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified using column chromatography (Biotage Sfar Duo 25 g cartridge, eluent: 0-100% EtOAc in heptane) to afford the title compound (27 mg, 56% yield) as a white solid. 1H NMR (500MHz, chloroform-d)δ 8.12(d,J=5.7Hz,1H),8.04(dd,J=2.8,1.4Hz,1H),7.97(s,1H),7.85(d,J=2.3Hz,1H),7.54(ddd,J=9.1,6.4,3.0 Hz,1H),6.99(dd,J=8.8,3.5Hz,1H),6.51(dd,J=5.7,2.4Hz,1H),1.29(s,6H),1.21(s,6H),1.00(s,1H).LCMS:m / z 330.2[M+H]+,(ESI+),RT=3.29(Method A).

[0179] Compound E149 TIFF0007827911000055.tif211282,2,3,3-Tetramethyl-N-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]cyclopropanecarboxamide

[0180] Step 1 Boc anhydride (1090 mg, 5.00 mmol), N,N-dimethylpyridin-4-amine (12 mg, 0.102 mmol), and triethylamine (1.3 mL, 9.08 mmol) were added to a stirred suspension of 2-aminopyridin-4-ol (500 mg, 4.54 mmol) in MeCN (10 mL). The reaction was stirred at 40° C. overnight. Water (5 mL) was added and the mixture was concentrated to remove MeCN. Trituration with water (5 mL) gave a gum. The crude material was suspended in DMF (3 ml) and dipotassium carbonate (500 mg, 3.62 mmol) was added, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (390 uL, 2.71 mmol), and the reaction was stirred at 80° C. for 2 hours.

[0181] Additional dipotassium carbonate (100 mg, 0.724 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (140 μL, 0.972 mmol) were added, and the mixture was stirred at 80° C. for 1 h. The reaction was allowed to cool and added dropwise to stirred water (30 mL). The mixture was extracted into EtOAc (3×10 mL), dried over MgSO4, and concentrated onto silica. The crude product was purified by FCC (Biotage SNAP KP-Sil 25 g, 0–100% EtOAc in heptane) to give tert-butyl N-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]carbamate (70.0%) (160 mg, 70% purity, 8% yield). 1H NMR (400 MHz, chloroform-d) δ 8.27 (s, 1H), 8.13 (d, J = 5.8 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 5.8, 2.4 Hz, 1H), 4.43 (q, J = 8.0 Hz, 2H), 1.54 (s, 9H).

[0182] Step 2 tert-Butyl N-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]carbamate (70%, 160 mg, 0.383 mmol) was stirred in 4 M hydrogen chloride in dioxane (1.0 mL, 4.00 mmol) for 2 hours and then allowed to stand overnight. The reaction was concentrated in vacuo and purified by preparative HPLC (Method F) to give 4-(2,2,2-trifluoroethoxy)pyridin-2-amine (38 mg, 50% yield). 1H NMR (500 MHz, chloroform-d) δ 7.95 (d, J = 5.9 Hz, 1H), 6.28 (dd, J = 5.9, 2.3 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 4.53 (s, 2H), 4.33 (q, J = 8.0 Hz, 2H).

[0183] Step 3 2,2,3,3-Tetramethylcyclopropanecarbonyl chloride (62 mg, 0.384 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-(2,2,2-trifluoroethoxy)pyridin-2-amine (38 mg, 0.192 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.074 mL, 0.422 mmol) in THF (1 mL), and the reaction was stirred at room temperature for 3.5 hours. The reaction was concentrated in vacuo and then diluted with MeOH (2 mL), and 1 M sodium hydroxide (1.0 mL, 1.00 mmol) was added. The reaction was stirred at room temperature for a total of 72 hours, then 2 M sodium hydroxide (1.0 mL, 2.00 mmol) was added, and the reaction was stirred at 60 °C for 3 hours. The methanol was removed in vacuo, and the mixture was extracted with EtOAc (4 × 5 mL). The reaction was dried over MgSO, concentrated, and purified by preparative HPLC (Method G) to give the title compound (47 mg, 77% yield) as an off-white solid. H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 5.8 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 5.8, 2.5 Hz, 1H), 4.42 (q, J = 8.0 Hz, 2H), 1.32 (s, 6H), 1.22 (s, 6H), 1.02 (s, 1H). LCMS: m / z 317.5 [M+H], (ESI), RT = 2.97 (Method A).

[0184] Compound E150 TIFF0007827911000056.tif201283-[4-(3,4-difluorophenoxy)-2-pyridyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0185] Step 1 To a solution of 4-fluoropyridin-2-amine (250 mg, 2.19 mmol) and 3,4-difluorophenol (370 mg, 2.84 mmol) in NMP (3 mL) at room temperature was added N-ethyl-N-isopropyl-2-amine (0.76 mL, 4.37 mmol). The reaction mixture was stirred at 180 °C for 8 hours. It was then cooled to room temperature and diluted with EtOAc (30 mL) and water / brine (1:1, 30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO column, 0-100% EtOAc in heptane) to give 4-(3,4-difluorophenoxy)pyridin-2-amine (260 mg, 86% purity, 46% yield) as a beige solid. 1H NMR(500MHz,DMSO-d6)δ 7.82(d,J=5.8Hz,1H),7.53(ddd,J=10.5,9.2,9.2Hz,1H),7.39(ddd,J=11.5,6.9,2.9Hz,1H),7.02 (dddd,J=8.8,3.6,3.5,1.8Hz,1H),6.14(dd,J=5.8,2.3Hz,1H),5.97(s,2H),5.85(d,J=2.3Hz,1H).

[0186] Step 2 4-(3,4-Difluorophenoxy)pyridin-2-amine (86%, 40 mg, 0.155 mmol) was dissolved in DCM-anhydrous (1 mL) and CDI (33 mg, 0.201 mmol) was added. The reaction mixture was stirred at room temperature for 22 h. A solution of (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 32 mg, 0.201 mmol) in DCM-anhydrous (1 mL) was added, and the mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with water, passed through a hydrophobic frit, and concentrated. The product was purified by preparative HPLC (Method E) followed by an SCX cartridge (2 g) eluting first with MeOH (3 CV) and then with 2 M ammonia in MeOH (3 CV). The ammonia fractions were combined and concentrated to give the title compound as an off-white solid (8.6 mg, 0.0212 mmol, 14% yield). 1H NMR(500MHz,DMSO-d6)δ 9.03(s,1H),8.13(d,J=5.7Hz,1H),7.59-7.51(m,1H),7.48-7.39(m,2H),7.10-6.96(m,2H),6.60(dd,J= 5.7,2.4Hz,1H),4.29-4.20(m,1H),3.57-3.50(m,1H),3.45-3.38(m,3H),1.07(t,J=7.0Hz,3H).LCMS:m / z 406.3[M+H]+,(ESI+),RT=3.57(Method B)

[0187] (Table 5) Using intermediate 102 or compound E139, amino alcohols synthesized according to step 1, the following compounds were synthesized using a method similar to that used for compound E150. TIFF0007827911000057.tif82166TIFF0007827911000058.tif220166TIFF0007827911000059.tif216166TIFF0007827911000060.tif73166

[0188] Compound E162 TIFF0007827911000061.tif201281-Ethyl-3-[4-[(5-fluoro-3-pyridyl)oxy]-2-pyridyl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0189] Step 1 To a solution of 4-fluoropyridin-2-amine (100 mg, 0.874 mmol) and 5-fluoropyridin-3-ol (129 mg, 1.14 mmol) in NMP (2 mL) at room temperature was added N-ethyl-N-isopropyl-propan-2-amine (0.31 mL, 1.75 mmol). The reaction mixture was stirred at 180° C. for 5 hours. It was then cooled to room temperature and diluted with EtOAc (30 mL) and water / brine (1:1, 30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (hydrophobic frit), concentrated under reduced pressure, washed with MeOH (5 CV), and purified on a 5 g SCX-2 cartridge eluting with 7N NH / MeOH (5 CV) to give 4-[(5-fluoro-3-pyridyl)oxy]pyridin-2-amine (180 mg, 85% purity, 85% yield) as a brown oil. H NMR (500 MHz, chloroform-d) δ 8.39 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.05-8.00 (m, 1H), 7.20 (dt, J = 9.1, 2.4 Hz, 1H), 6.34 (dd, J = 5.9, 2.2 Hz, 1H), 6.06 (d, J = 2.1 Hz, 1H), 4.57 (s, 2H).

[0190] Step 2 To a solution of bis(trichloromethyl)carbonate (30 mg, 0.0994 mmol) in anhydrous DCM (2 mL) was added dropwise over 10 minutes a solution of 4-[(5-fluoro-3-pyridyl)oxy]pyridin-2-amine (85%, 60 mg, 0.249 mmol) and pyridine (20 μL, 0.249 mmol) in anhydrous DCM (2 mL). The reaction was stirred at −78° C. for 5 minutes. (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 51 mg, 0.323 mmol) and N-ethyl-N-isopropyl-propan-2-amine (65 μL, 0.373 mmol) in anhydrous DCM (2 mL) were then added, and the reaction was stirred at −78° C. for 5 minutes, then in an ice bath for 1 hour. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (Method G) to give the title compound (7.9 mg, 7.9% yield) as a yellow solid. 1HNMR(500MHz,chloroform-d)δ 8.43(d,J=2.4Hz,1H),8.35(d,J=2.1Hz,1H),8.15(s,1H),8.09(d,J=5.9Hz,1H),7.74(d,J=2.0Hz,1H),7.24(dt,J=8.9,2.3H z,1H),6.63(dd,J=5.9,2.3Hz,1H),4.23-4.12(m,1H),3.88-3.77(m,1H),3.60-3.38(m,3H),1.30(t,J=7.2Hz,3H).LCMS:m / z 389.1[M+H]+,(ESI+),RT=2.08(Method A).

[0191] Compound E163 TIFF0007827911000062.tif261283-[4-(3,5-difluorophenoxy)-2-pyridyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0192] Synthesized using a method similar to that used to synthesize compound E162. H NMR (500 MHz, chloroform-d) δ 8.08 (d, J = 5.5 Hz, 1H), 7.67 (s, 1H), 6.70 (tt, J = 8.8, 2.3 Hz, 1H), 6.67-6.62 (m, 2H), 6.60 (dd, J = 5.8, 2.2 Hz, 1H), 4.23-4.13 (m, 1H), 3.82 (dd, J = 15.3, 8.8 Hz, 1H), 3.57-3.44 (m, 2H), 3.39 (dq, J = 14.6, 7.1 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H). LCMS: m / z 406.1 [M+H]+, (ESI+), RT = 2.77 (Method A).

[0193] Compound E164 TIFF0007827911000063.tif251282-Methyl-N-(5-phenyl-2-pyridyl)propanamide

[0194] Step 1 To a stirred solution of isobutyric anhydride (719 μL, 4.34 mmol) and 5-bromopyridin-2-amine (500 mg, 2.89 mmol) in THF (15.5 mL), N-ethyl-N-isopropyl-propan-2-amine (1009 μL, 5.78 mmol) was added, followed by N,N-dimethylpyridin-4-amine (35 mg, 0.289 mmol), and the mixture was stirred at 80 °C for 2 h in a sealable pressure tube. The reaction mixture was then evaporated to dryness. Purification by flash chromatography (Biotage 50 g KP-Sil SNAP cartridge, 10–100% EtOAc in heptane) afforded N-(5-bromo-2-pyridyl)-2-methyl-propanamide (502 mg, 71% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.57(s,1H),8.42(d,J=2.5Hz,1H),8.08(d,J=8.9Hz,1H),7.98(dd,J=8.9,2.5Hz,1H),2.74(hept,J=6.8Hz,1H),1.08(d,J=6.8Hz,6H).

[0195] Step 2 N-(5-Bromo-2-pyridyl)-2-methyl-propanamide (70 mg, 0.288 mmol) and phenylboronic acid (39 mg, 0.317 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) and 2 M NaCO (0.29 mL, 0.576 mmol), and the reaction mixture was degassed with N for 5 minutes. Pd(dppf)Cl (11 mg, 0.0144 mmol) was then added, and the reaction was heated to 110 °C for 2 hours. It was then washed with water, extracted with ethyl acetate, cooled to room temperature, concentrated under reduced pressure, and purified by preparative HPLC (Method F) to give the title compound as a light brown solid (19.6 mg). 1H NMR(250MHz,DMSO-d6)δ 10.50(s,1H),8.63(dd,J=2.5,0.8Hz,1H),8.19(dd,J=8.7,0.8Hz,1H),8.08(dd,J=8.7,2.5Hz,1H),7.75- 7.66(m,2H),7.54-7.43(m,2H),7.42-7.34(m,1H),2.76(h,J=6.8Hz,1H),1.10(d,J=6.8Hz,6H).LCMS:m / z 241.2[M+H]+,(ESI+),RT=2.93(Method A).

[0196] (Table 6) The following compounds were synthesized using methods similar to those used in Example E164. TIFF0007827911000064.tif177170TIFF0007827911000065.tif169170

[0197] Compound E177 TIFF0007827911000066.tif23128N-(5-Cyclopentyl-2-pyridyl)-2-methyl-propanamide

[0198] To a solution of N-[5-(cyclopenten-1-yl)-2-pyridyl]-2-methylpropanamide (synthesized using a method similar to that used for compound E164, 43 mg, 0.188 mmol) in ethanol (5 mL) was added 10% Pd / C (3.9 mg, 0.0363 mmol), and the reaction mixture was placed under a balloon of hydrogen and stirred at room temperature for 2 h. It was then filtered through Celite, washed with EtOAc, concentrated under reduced pressure, and purified by flash chromatography (Biotage Isolera, C18 12 g Ultra SNAP cartridge) eluting with a solution of water (+0.1% CHO) in MeCN (+0.1% CHO) (10-100%) to give the title compound as a light brown solid (10.7 mg, 24.3%). 1H NMR (500MHz, chloroform-d)δ 8.24(s,1H),8.17(d,J=8.6Hz,1H),8.09(d,J=2.3Hz,1H),7.59(dd,J=8.6,2.4Hz,1H),3.00-2.92(m,1H),2.56 (hept,J=6.9Hz,1H),2.11-2.04(m,2H),1.86-1.65(m,4H),1.61-1.50(m,2H),1.26(d,J=6.9Hz,6H).LCMS:m / z 233.2[M+H]+,(ESI+),RT=2.43(Method A).

[0199] Compound E178 TIFF0007827911000067.tif351282-Cyano-N-[5-(3,5-difluorophenyl)-2-pyridyl]-2-methyl-propanamide

[0200] Step 1 5-Bromopyridin-2-amine (1.00 g, 5.78 mmol) and (3,5-difluorophenyl)boronic acid (913 mg, 5.78 mmol) were dissolved in anhydrous 1,4-dioxane (55 mL) and 2 M NaCO (6.0 mL, 12.0 mmol), and the reaction mixture was degassed with N for 5 minutes. Pd(dppf)Cl (212 mg, 0.289 mmol) was added to the reaction, and the reaction was heated to 110 °C for 2.5 hours. It was then cooled to room temperature and concentrated under reduced pressure to 20 mL, and the reaction was washed with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by SCX-2 cartridge (washed with MeOH and eluted with 7 N NH / MeOH). The mixture was concentrated under reduced pressure to give 5-(3,5-difluorophenyl)pyridin-2-amine (Intermediate I03, 947 mg, 74%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ 8.37-8.28 (m, 1H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.38-7.29 (m, 2H), 7.12-7.02 (m, 1H), 6.51 (dd, J = 8.7, 0.7 Hz, 1H), 6.23 (s, 2H).

[0201] Step 2 A solution of 2-cyano-2-methylpropanoic acid (42 mg, 0.373 mmol), HATU (142 mg, 0.373 mmol), and DIPEA (0.18 mL, 1.02 mmol) in anhydrous acetonitrile (3 mL) was stirred at room temperature for 1 hour. To the solution was added 5-(3,5-difluorophenyl)pyridin-2-amine (70 mg, 0.339 mmol), and the reaction was stirred at 70 °C for 4 hours, then at 80 °C for 2 hours. The reaction was retreated with HATU (142 mg, 0.373 mmol) and 2-cyano-2-methylpropanoic acid (42 mg, 0.373 mmol) and stirred at 80 °C overnight. It was then washed with water, extracted with EtOAc (30 mL), dried over NaSO, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method E) to give the title compound (12.6 mg, 12%) as an off-white solid. H NMR (500 MHz, DMSO-d) δ 10.86 (s, 1H), 8.82 (dd, J = 2.6, 0.7 Hz, 1H), 8.25 (dd, J = 8.7, 2.6 Hz, 1H), 8.09 (dd, J = 8.7, 0.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.30-7.23 (m, 1H), 1.70 (s, 6H). LCMS: m / z 302.2 [M+H], (ESI), RT = 3.45 (Method A).

[0202] (Table 7) The following compounds were synthesized using methods similar to those used in Example E178. TIFF0007827911000068.tif78170TIFF0007827911000069.tif234170*Compound E186 was isolated as a by-product from the synthesis of E187.

[0203] Compound E189 TIFF0007827911000070.tif281282,2,3,3-Tetramethyl-N-[5-(2-methyltriazol-4-yl)-2-pyridyl]cyclopropanecarboxamide

[0204] Step 1 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (100 mg, 0.454 mmol) and 4-bromo-2-methyl-triazole (81 mg, 0.500 mmol) were dissolved in anhydrous 1,4-dioxane (2.15 mL). 2 M Na2CO3 (0.47 mL, 0.949 mmol) was added to the reaction mixture, which was then degassed with nitrogen for 5 minutes. Palladium-triphenylphosphane (1:4) (26 mg, 0.0227 mmol) was then added, the mixture was degassed for another 5 minutes, and stirred at 110 °C for 1.5 hours. The reaction mixture was concentrated, and EtOAc was added. The resulting precipitate was filtered off and purified on an SCX cartridge (2 g) eluting first with MeOH (3 CV) and then with 2 M ammonia in MeOH (3 CV). The ammoniacal fractions were concentrated to give 5-(2-methyltriazol-4-yl)pyridin-2-amine (60.0%) (EV-PGN001-228-002) (45 mg, 60% purity, 34% yield) as a green solid. LCMS: m / z 175.8 [M+H]+, (ESI+), RT = 0.25 (Method D).

[0205] Step 2 To a solution of 5-(2-methyltriazol-4-yl)pyridin-2-amine (60%, 45 mg, 0.154 mmol) in anhydrous THF (1.2889 mL) was added tetramethylcyclopropane-1-carbonyl chloride (27 mg, 0.170 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.054 mL, 0.308 mmol). The reaction mixture was stirred at room temperature for 4.5 h. Water (2 mL) was added to the reaction mixture and extracted with EtOAc (3 × 2 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica flash column chromatography (0–40% EtOAc in heptane) followed by purification on an SCX cartridge (2 g) eluting first with MeOH (3 CV) and then with 2 M ammonia in MeOH (3 CV). The crude product was then further purified by silica flash column chromatography (0-100% EtOAc in heptane) to give the title compound (4.5 mg, 8.8% yield) as a white solid. H NMR (400 MHz, DMSO-d) δ 10.50 (s, 1H), 8.74 (t, J = 1.6 Hz, 1H), 8.53 (s, 1H), 8.14 (d, J = 1.6 Hz, 2H), 4.10 (s, 3H), 1.57 (s, 1H), 1.26 (s, 6H), 1.18 (s, 6H). LCMS: m / z 300.2 [M+H]+, (ESI+), RT = 3.10 (Method B).

[0206] Compound E190 TIFF0007827911000071.tif281282,2,3,3-Tetramethyl-N-[5-(1-methyltriazol-4-yl)-2-pyridyl]cyclopropanecarboxamide

[0207] Synthesized using a method similar to that used for compound E189. 1H NMR (500 MHz, chloroform-d) δ 8.71 (dd, J = 2.3, 0.7 Hz, 1H), 8.28-8.22 (m, 1H), 8.08 (dd, J = 8.6, 2.3 Hz, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 4.16 (s, 3H), 1.33 (s, 6H), 1.23 (s, 6H), 1.04 (s, 1H). LCMS: m / z 300.2 [M+H]+, (ESI+), RT = 3.10 (Method B).

[0208] Compound E191 TIFF0007827911000072.tif311283-[5-(3,5-difluorophenyl)-2-pyridyl]-1-[(2S)-2-hydroxypropyl]-1-methyl-urea

[0209] A solution of 5-(3,5-difluorophenyl)pyridin-2-amine (Intermediate I03, 50 mg, 0.242 mmol) and pyridine (25 μL, 0.310 mmol) in THF (2 mL) was added to a solution of (4-nitrophenyl)carbonochloridate (54 mg, 0.268 mmol) in THF (1 mL), and the mixture was stirred at room temperature for 1 h. (2S)-1-(methylamino)propan-2-ol; hydrochloride (46 mg, 0.366 mmol) and N-ethyl-N-isopropyl-propan-2-amine (128 μL, 0.733 mmol) were added, and the mixture was stirred at room temperature for an additional 1 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method F) followed by FCC (10 g Biotage SNAP cartridge, gradient of 0 to 100% EtOAc in heptane) to give the title compound (17 mg, 22% yield) as a white solid.

[0210] (Table 8) The following compounds were synthesized using a method similar to that used for compound E191 using aminopyridines synthesized according to the method for intermediate I03 or from commercial sources. TIFF0007827911000073.tif217170

[0211] Compound E197 TIFF0007827911000074.tif261281-Ethyl-3-(5-oxazol-2-yl-2-pyridyl)-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0212] Step 1 5-Bromo-2-nitropyridine (300 mg, 1.48 mmol) and palladium-triphenylphosphane (1:4) (200 mg, 0.173 mmol) were stirred in anhydrous toluene (4 mL) and degassed with nitrogen for 5 minutes. 2-(tributylstannanyl)-1,3-oxazole (0.79 mL, 2.58 mmol) was then added, and the reaction was degassed, then sealed, and stirred at 90 °C for 18 hours. The reaction was cooled to room temperature and treated with aqueous KF (ca. 8 M) (5 mL) and MeOH (5 mL) and stirred vigorously for 30 minutes. The mixture was then filtered through a pad of Celite and washed with EtOAc (20 mL). The filtrate was washed with water (15 mL), and the layers were separated, after which the aqueous solution was extracted again with EtOAc (20 mL). The organics were combined, washed with brine (15 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified using a normal-phase Biotage™ (Sfar Duo, 100 g, eluent: EtOAc in heptane, 0–100%) to give 2-(6-nitro-3-pyridyl)oxazole (139 mg, 92% purity, 45% yield) as a pale yellow solid. H NMR (400 MHz, DMSO-d) δ 9.22 (dd, J = 2.2, 0.6 Hz, 1H), 8.73 (dd, J = 8.5, 2.2 Hz, 1H), 8.47 (dd, J = 7.7, 0.7 Hz, 2H), 7.59 (d, J = 0.7 Hz, 1H).

[0213] Step 2 A stirred solution of 2-(6-nitro-3-pyridyl)oxazole (92%, 139 mg, 0.667 mmol) in EtOAc (10 mL) and 1,4-dioxane (3 mL) was evacuated and filled with nitrogen three times, 10% palladium on carbon (14 mg, 0.133 mmol) was added, and the reaction mixture was placed under a balloon of hydrogen and stirred at room temperature. Upon completion, the reaction mixture was filtered through a Celite pad and the filter cake was washed with ethyl acetate (25 mL). The filtrate was concentrated to dryness under reduced pressure to afford 5-oxazol-2-ylpyridin-2-amine (Intermediate I04, 110 mg, 95% purity, 97% yield) as a pale yellow solid. 1H NMR,(400MHz,DMSO-d6)δ 8.51(dd,J=2.4,0.6Hz,1H),8.07(d,J=0.8Hz,1H),7.88(dd,J=8.7,2.4Hz,1H),7.25(d,J=0.8Hz,1H),6.55-6.53(m,2H),6.52(d,J=0.7Hz,1H).

[0214] Step 3 To a solution of 4-nitrophenyl carbonochloridate (72 mg, 0.357 mmol) in anhydrous THF (1.5 mL) was added a solution of 5-oxazol-2-ylpyridin-2-amine (95%, 55 mg, 0.324 mmol) and pyridine (29 μL, 0.357 mmol) in anhydrous THF (1 mL), and the reaction was stirred at room temperature for 3 minutes. Next, (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 51 mg, 0.324 mmol) and N-ethyl-N-isopropyl-propan-2-amine (85 μL, 0.486 mmol) in anhydrous THF (1 mL) were added, and the reaction was stirred at room temperature for 45 minutes. It was then concentrated under reduced pressure and purified using preparative HPLC (Method H) to give the title compound (32 mg, 28% yield) as a white solid. 1H NMR, (500 MHz, chloroform-d) δ 8.89 (d, J = 1.8 Hz, 1H), 8.29 (dd, J = 8.9, 2.3 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.24 (d, J = 0.7 Hz, 1H), 4.27-4.18 (m, 1H), 3.77 (dd, J = 15.2, 8.8 Hz, 1H), 3.63-3.53 (m, 2H), 3.48 (dq, J = 14.6, 7.0 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H). No OH or NH observed. LCMS: m / z 345.1 [M+H]+, (ESI+), RT = 2.47 (Method A).

[0215] Compound E198 TIFF0007827911000075.tif271282,2,3,3-Tetramethyl-N-(5-oxazol-2-yl-2-pyridyl)cyclopropanecarboxamide

[0216] Compound E093 was synthesized from intermediate I04 using a method similar to that used in Step 2. 1H NMR (400 MHz, chloroform-d) δ 8.92 (dd, J = 2.0, 1.0 Hz, 1H), 8.34-8.23 (m, 2H), 8.06 (s, 1H), 7.72 (d, J = 0.6 Hz, 1H), 7.25-7.23 (m, 1H), 1.33 (s, 6H), 1.24 (s, 6H), 1.04 (s, 1H). LCMS: m / z 286.2 [M+H]+, (ESI+), RT = 3.64 (Method B).

[0217] Compound E199 TIFF0007827911000076.tif271282,2,3,3-Tetramethyl-N-(5-pyrazol-1-yl-2-pyridyl)cyclopropanecarboxamide

[0218] Step 1 5-Iodopyridin-2-amine (250 mg, 1.14 mmol), copper(I) iodide (22 mg, 0.114 mmol), tripotassium phosphate (734 mg, 3.41 mmol), and 1H-pyrazole (85 mg, 1.25 mmol) were added to a sealed tube. After purging with nitrogen, anhydrous 2-propanol (5 mL) was added, followed by ethane-1,2-diol (6.3 μL, 0.114 mmol). The reaction mixture was again purged with nitrogen, and then the tube was sealed and heated to 110 °C for 15 h. The reaction mixture was then cooled to room temperature, filtered through a pad of Celite, and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (25 g SiO column, 0–15% MeOH in DCM) to give the title compound as a beige solid (145 mg, 50% purity).

[0219] Step 2 To a solution of 5-pyrazol-1-ylpyridin-2-amine (140 mg, 0.874 mmol) and N-ethyl-N-isopropyl-propan-2-amine (305 uL, 1.75 mmol) in anhydrous THF (2 mL) was added 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (211 mg, 1.31 mmol) and stirred at room temperature for 30 minutes. The solvent was then removed under a steady stream of nitrogen, and MeOH (2 mL) and 1 M NaOH (2 mL) were added, and the reaction mixture was stirred at room temperature for 1 hour. The MeOH was then removed under a steady stream of nitrogen, forming a beige precipitate. This was filtered, washed with water, and the solid was purified by preparative HPLC (Method F) to give the title compound as a white solid (62 mg). 1H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),8.81-8.73(m,1H),8.48(dd,J=2.5,0.5Hz,1H),8.22-8.07(m,2H),7.76(dd,J= 1.8,0.5Hz,1H),6.56(dd,J=2.5,1.8Hz,1H),1.55(s,1H),1.25(s,6H),1.17(s,6H).LCMS:m / z 285.2[M+H]+,(ESI+),RT=3.58(Method B)

[0220] Compound E200 TIFF0007827911000077.tif22128N-(5-Iodo-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0221] The title compound was isolated as a by-product from the synthesis of compound E199. 1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.47 (dd, J = 2.3, 0.6 Hz, 1H), 8.03 (dd, J = 8.8, 2.3 Hz, 1H), 7.98-7.87 (m, 1H), 1.53 (s, 1H), 1.22 (s, 6H), 1.15 (s, 6H). LCMS: m / z 345.2 [M+H]+, (ESI+), RT = 4.27 (Method B).

[0222] Compound E201 TIFF0007827911000078.tif27128N-[5-(dimethylamino)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0223] To a solution of N5,N5-dimethylpyridine-2,5-diamine (100 mg, 0.729 mmol) and N-ethyl-N-isopropyl-propan-2-amine (255 µL, 1.46 mmol) in THF-anhydrous (5 mL) was added 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (117 mg, 0.729 mmol), and the reaction mixture was stirred at room temperature for 1 h. Further 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (39 mg, 0.243 mmol) was added, and the mixture was stirred for an additional 0.5 h. The solvent was then removed under a steady stream of nitrogen, and MeOH (4 mL) and 1 M NaOH (4 mL) were added. The reaction mixture was stirred at 45 °C for 4 h and at room temperature for 16 h. The methanol was removed under reduced pressure, and the precipitate was filtered, washed with water (10 mL), and purified by flash column chromatography (10 g SiO column, 0–60% EtOAc in heptane) to give the title compound as an off-white solid (125 mg). H NMR (500 MHz, DMSO-d) δ 9.99 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.14 (dd, J = 9.1, 3.2 Hz, 1H), 2.86 (s, 6H), 1.46 (s, 1H), 1.22 (s, 6H), 1.15 (s, 6H). LCMS: m / z 262.3 [M+H]+, (ESI+), RT = 2.10 (Method A).

[0224] (Table 9) The following compounds were synthesized using methods similar to those used in Example E201. TIFF0007827911000079.tif61170TIFF0007827911000080.tif217170TIFF0007827911000081.tif230170

[0225] Compound E217 TIFF0007827911000082.tif181282-Methyl-N-(5-phenoxypyrazin-2-yl)propanamide

[0226] Step 1 5-Bromopyrazin-2-amine (300 mg, 1.72 mmol), phenol (178 mg, 1.90 mmol), and cesium carbonate (1.12 g, 3.45 mmol) were suspended in anhydrous 1,4-dioxane (4 mL), and the reaction mixture was degassed with N for 5 minutes. N,N-Dimethylglycine hydrochloride (1:1) (24 mg, 0.172 mmol) was added, followed by copper(I) iodide (33 mg, 0.172 mmol), and the reaction was heated to 115 °C in a sealed tube for 2.5 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc and water, and filtered. The organic phase was then separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO column, 0–70% EtOAc in heptane) to give 5-phenoxypyrazin-2-amine (Intermediate I05) as a pale yellow oil that solidified upon standing (205 mg). 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 1.4 Hz, 1H), 7.41–7.28 (m, 2H), 7.14–7.05 (m, 1H), 7.00–6.93 (m, 2H), 6.22 (s, 2H).

[0227] Step 2 5-Phenoxypyrazin-2-amine (50 mg, 0.267 mmol) was dissolved in DCM (2 mL) and N-ethyl-N-isopropyl-propan-2-amine (70 μL, 0.401 mmol) was added, followed by 2-methylpropanoyl chloride (31 μL, 0.294 mmol). The reaction was stirred at room temperature for 15 minutes. Further N-ethyl-N-isopropyl-propan-2-amine (70 μL, 0.401 mmol) and 2-methylpropanoyl chloride (31 μL, 0.294 mmol) were added, and the reaction was stirred at room temperature for 15 minutes. The reaction mixture was washed with saturated NaHCO3, passed through a TELOS phase separator, and concentrated under reduced pressure. The residue was dissolved in MeOH (1 mL) and 1 M aqueous NaOH (1 mL) and stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative HPLC (Method E) to give the title compound as a white solid (57 mg). H NMR (250 MHz, DMSO-d ) δ 10.66 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 7.50-7.34 (m, 2H), 7.29-7.08 (m, 3H), 2.74 (h, J = 6.9 Hz, 1H), 1.10 (d, J = 6.8 Hz, 6H). LCMS: m / z 258.3 [M+H], (ESI), RT = 2.99 (Method A).

[0228] (Table 10) The following compounds were synthesized using methods similar to those used in Example E217. TIFF0007827911000083.tif138170TIFF0007827911000084.tif155170

[0229] compound 226 TIFF0007827911000085.tif30128N-[5-(2,5-difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide

[0230] Step 1 5-Bromopyrazin-2-amine (300 mg, 1.72 mmol) and (2,5-difluorophenyl)boronic acid (275 mg, 1.74 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL) and 2 M Na2CO3 (1.8 mL, 3.60 mmol), and the reaction mixture was degassed with N2 for 5 minutes. Pd(dppf)Cl2 (63 mg, 0.0862 mmol) was added to the reaction, and the reaction was heated to 110 °C for 2.5 hours. It was then cooled to room temperature, diluted with water (20 mL) and EtOAc (20 mL), and filtered through Celite. The layers in the filtrate were separated, and the aqueous solution was extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO column, 0–100% EtOAc in heptane) to give 5-(2,5-difluorophenyl)pyrazin-2-amine (Intermediate I06) as a yellow solid (295 mg). H NMR (400 MHz, DMSO-d) δ 8.37 (dd, J = 2.3, 1.6 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.62 (ddd, J = 9.6, 6.1, 3.3 Hz, 1H), 7.33 (ddd, J = 10.8, 9.1, 4.6 Hz, 1H), 7.26–7.08 (m, 1H), 6.78 (s, 2H).

[0231] Step 2 To a stirred solution of 2,2-dimethylcyclopropanecarboxylic acid (43 mg, 0.380 mmol) in ethyl acetate (2.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.19 mL, 1.09 mmol) and T3P (50% in EtOAc) (0.32 mL, 0.543 mmol), and the reaction was stirred for 10 minutes. To this was added 5-(2,5-difluorophenyl)pyrazin-2-amine (75 mg, 0.362 mmol), and the reaction was stirred at 80 °C for 20 hours. It was then cooled to room temperature, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (10 g SiO2 column, 0-50% EtOAc in heptane) to give the title compound (39 mg) as an off-white solid. 1H NMR(500MHz,DMSO-d6)δ 11.13(s,1H),9.45(d,J=1.5Hz,1H),8.92-8.67(m,1H),7.73(ddd,J=9.3,6.0,3.3Hz,1H),7.44(ddd,J=10.5,9.2,4.5Hz,1H),7.40-7 .30(m,1H),1.94(dd,J=7.8,5.5Hz,1H),1.17(s,3H),1.16(s,3H),1.05(dd,J=5.3,4.0Hz,1H),0.89(dd,J=7.8,3.9Hz,1H).LCMS:m / z 304.2[M+H]+,(ESI+),RT=3.81(Method A)

[0232] (Table 11) The following compounds were synthesized using methods similar to those used in Example E226. TIFF0007827911000086.tif159170

[0233] Compounds E231 and E232 TIFF0007827911000087.tif31128Unknown single enantiomer of N-[5-(3,5-difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide

[0234] Chiral separation of N-[5-(3,5-difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide (compound E228) to yield an unknown single enantiomer. Method: Cellulose-4 column, 21.2 x 250 mm, 5 μm, 90:10 heptane:ethanol, 18 mL / min flow rate.

[0235] Compound E231 (first elution): 1H NMR(500MHz,DMSO-d6)δ 11.12(s,1H),9.40(d,J=1.4Hz,1H),9.08(d,J=1.4Hz,1H),7.90-7.76(m,2H),7.32(tt,J=9.1,2.2Hz,1H),1.94(d d,J=7.8,5.5Hz,1H),1.17(s,3H),1.17(s,3H),1.05(dd,J=5.3,4.1Hz,1H),0.89(dd,J=7.8,3.9Hz,1H).LCMS:m / z 304.2[M+H]+,(ESI+),RT=3.93(Method A).

[0236] Compound E232 (second elution): 1H NMR(500MHz,DMSO-d6)δ 11.12(s,1H),9.40(d,J=1.5Hz,1H),9.08(d,J=1.5Hz,1H),7.90-7.76(m,2H),7.32(tt,J=9.2,2.3Hz,1H),1. 94(dd,J=7.8,5.5Hz,1H),1.17(s,3H),1.17(s,3H),1.08-1.03(m,1H),0.89(dd,J=7.8,3.9Hz,1H).LCMS:m / z 304.2[M+H]+,(ESI+),RT=3.93(Method A).

[0237] Compound E233 TIFF0007827911000088.tif271282,2,3,3-Tetramethyl-N-(5-pyrrolidin-1-ylpyrazin-2-yl)cyclopropanecarboxamide

[0238] Step 1 5-Bromopyrazin-2-amine (200 mg, 1.15 mmol) was suspended in pyrrolidine (0.30 mL, 3.59 mmol), and the mixture was stirred in a Biotage initiator microwave at 180 °C for a total of 4 h. The reaction was concentrated in vacuo and purified by FCC (Biotage SNAP KP-Sil 10 g, 50-100% EtOAc in heptane) to give 5-pyrrolidin-1-ylpyrazin-2-amine (100 mg, 50% yield). 1H NMR (400 MHz, chloroform-d) δ 7.66 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 3.86 (s, 2H), 3.45-3.35 (m, 4H), 2.07-1.94 (m, 4H).

[0239] Step 2 2,2,3,3-Tetramethylcyclopropanecarbonyl chloride (54 mg, 0.335 mmol) in THF (1 mL) was added dropwise to a stirred solution of 5-pyrrolidin-1-ylpyrazin-2-amine (50 mg, 0.304 mmol) and N-ethyl-N-isopropyl-propan-2-amine (120 μL, 0.670 mmol) in THF (1 mL). The reaction was stirred at room temperature for approximately 20 hours. Further N-ethyl-N-isopropyl-propan-2-amine (58 μL, 0.335 mmol) and 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (20 mg, 0.125 mmol) in THF (0.5 mL) were added, and the reaction was stirred for 1 hour. The reaction was diluted with water (5 mL), extracted into EtOAc (3 × 5 mL), and the organics were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method G) to give the title compound (22 mg, 25% yield) as a tan solid. H NMR (500 MHz, chloroform-d) δ 8.91 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 3.51-3.45 (m, 4H), 2.09-2.00 (m, 4H), 1.33 (s, 6H), 1.23 (s, 6H), 1.04 (s, 1H). LCMS: m / z 289.2 [M+H], (ESI), RT = 3.45 (Method A).

[0240] Compound E234 TIFF0007827911000089.tif181283-[5-(3,5-difluorophenoxy)pyrazin-2-yl]-1-isopropyl-1-methyl-urea

[0241] To a solution of (4-nitrophenyl)carbonochloridate (50 mg, 0.246 mmol) in anhydrous THF (2 mL) was added a solution of 5-[(3,5-difluorophenoxy)pyrazine-2-amine (prepared using a method similar to Intermediate I05, 50 mg, 0.224 mmol) and pyridine (20 μL, 0.246 mmol) in anhydrous THF (2 mL), and the reaction was stirred at room temperature for 1.5 minutes. Next, N-methylpropan-2-amine (30 μL, 0.291 mmol) and N-ethyl-N-isopropyl-propan-2-amine (59 μL, 0.336 mmol) in anhydrous THF (2 mL) were added, and the reaction was stirred at room temperature for 2.5 minutes. It was then concentrated under reduced pressure and purified by preparative HPLC (Method E) followed by flash column chromatography (SNAP KP-Sil, 10 g, 0-55% EtOAc in heptane) to give the title compound (29 mg, 40% yield) as a white solid. H NMR, (400 MHz, chloroform-d) δ 9.01 (d, J = 1.4 Hz, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.03 (s, 1H), 6.70-6.60 (m, 3H), 4.64-4.50 (m, 1H), 2.89 (s, 3H), 1.19 (d, J = 6.8 Hz, 6H). LCMS: m / z 323.2 [M+H], (ESI), RT = 3.27 (Method A).

[0242] (Table 12) Using intermediates I02, I05, I06 and compound E139, precursors synthesized using a method similar to that used for compound E234 in Step 1, the following compounds were synthesized: TIFF0007827911000090.tif190170TIFF0007827911000091.tif221170TIFF0007827911000092.tif204170 TIFF0007827911000093.tif212170TIFF0007827911000094.tif217170TIFF0007827911000095.tif243170

[0243] Compound E265 TIFF0007827911000096.tif201283-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0244] Step 1 tert-Butyl N-(5-bromopyrazin-2-yl)carbamate (500 mg, 1.70 mmol) and dichloro(1,3-bis(diphenylphosphino)propane)nickel (92 mg, 0.170 mmol) were suspended in anhydrous 1,4-dioxane (4.7 mL), and the reaction mixture was degassed with N at room temperature for 5 minutes. 0.5 M bromo-[(3,5-difluorophenyl)methyl]zinc (14 mL, 6.79 mmol) was then added slowly, and the reaction was stirred at 60 °C for 2 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc (25 mL), aqueous NaHCO (25 mL), and brine (15 mL). The aqueous layer was separated and extracted with EtOAc (25 mL). The combined organics were washed with brine (15 mL), dried over MgSO, filtered, and concentrated. The crude material was then purified by normal-phase flash column chromatography (Sfar Duo, 100 g, eluent: EtOAc in heptane, 0–60%) to afford tert-butyl N-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]carbamate (424 mg, 75% yield) as a white solid. 1H NMR, (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.94 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H), 7.11–6.94 (m, 3H), 4.09 (s, 2H), 1.47 (s, 9H).

[0245] Step 2 To tert-butyl N-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]carbamate (424 mg, 1.28 mmol) was added 4 M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol) and stirred at room temperature for 3 hours. Further 4 M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol) was added, and the mixture was stirred at room temperature for 7 hours. It was then concentrated in vacuo and passed through an SCX-2 column (5 g) (flushed with MeOH (2 CV), then 7 N NH3 in MeOH (2.5 CV)) to give 5-[(3,5-difluorophenyl)methyl]pyrazin-2-amine (264 mg, 88% yield) as a brown solid. 1H NMR,(500MHz,DMSO-d6)δ 7.84(dd,J=33.4,1.4Hz,2H),7.03(tt,J=9.4,2.4Hz,1H),6.98-6.90(m,2H),6.27(s,2H),3.90(s,2H).

[0246] Step 3 The urea was formed using a similar method to that used for compound E191 to give the title compound (36 mg, 34% yield) as a white solid. 1H NMR,(500MHz,chloroform-d)δ 9.26(d,J=1.4Hz,1H),8.04(d,J=1.4Hz,1H),7.47(s,1H),6.81-6.74(m,2H),6.67(tt,J=9.0,2.3Hz,1H),4.82(s,1H),4.20(s, 1H),4.08(s,2H),3.81(dd,J=15.3,8.7Hz,1H),3.56-3.46(m,2H),3.40(dq,J=14.7,7.2Hz,1H),1.32(t,J=7.2Hz,3H).LCMS:m / z 405.2[M+H]+,(ESI+),RT=3.42(Method A).

[0247] (Table 13) The following compounds were synthesized using a method similar to that used for compound E265. TIFF0007827911000097.tif124170

[0248] Compound E269 TIFF0007827911000098.tif211282-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide

[0249] Step 1 Starting from methyl 2-aminopyridine-4-carboxylate (200 mg, 1.31 mmol), a similar method to compound E199 (Step 2) was used to obtain 2-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid (260 mg, 90% purity, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.61-8.51 (m, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.45 (dd, J = 5.1, 1.3 Hz, 1H), 1.57 (s, 1H), 1.24 (s, 6H), 1.17 (s, 6H), OH not observed.

[0250] Step 2 2-[(2,2,3,3-Tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid (50 mg, 0.172 mmol) was dissolved in anhydrous DMF (1.5 mL) and N-ethyl-N-isopropyl-propan-2-amine (90 μL, 0.515 mmol) was added, followed by HATU (98 mg, 0.257 mmol). After stirring for 10 minutes, 2,2,2-trifluoroethanamine (20 μL, 0.257 mmol) was added, and the reaction was stirred at room temperature overnight. It was then diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL), and the combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method F) to give the title compound (48 mg) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.59(s,1H),9.42-9.22(m,1H),8.49-8.37(m,2H),7.40(dd,J=5.1,1.6Hz,1H ),4.08(td,J=9.6,5.6Hz,2H),1.57(s,1H),1.25(s,6H),1.17(s,6H).LCMS:m / z 344.3[M+H]+,(ESI+),RT=3.30(Method A).

[0251] Compound E270 TIFF0007827911000099.tif211282,2,3,3-Tetramethyl-N-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]cyclopropanecarboxamide

[0252] To a stirred solution of N-(5-formyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (step 2), 100 mg, 0.406 mmol) in DCE (2 mL) was added pyrrolidine (41 uL, 0.487 mmol), followed by acetic acid (2.3 uL, 0.0406 mmol). After 4 hours, sodium triacetoxyborohydride (172 mg, 0.812 mmol) was added. The reaction mixture was washed with saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (hydrophobic filter), and concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (Biotage 11 g SNAP-KPNH cartridge, 0-25% EtOAc in heptane) followed by further chromatography (C18 silica gel, 12 g SNAP Ultra cartridge, eluent: 0.1% formic acid in acetonitrile-0.1% formic acid in water, 15-30%). The crude product was then washed with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 × 20 mL). Final purification by flash chromatography (Biotage 11 g SNAP-KPNH cartridge, 0-20% EtOAc in heptane) afforded the title product as a colorless solid (15 mg, 12% yield). 1H NMR (500MHz, chloroform-d)δ 8.17(d,J=1.9Hz,1H),8.11(d,J=8.5Hz,1H),7.96(s,1H),7.64(dd,J=8.5,2.2Hz,1H),3.56(s,2H),2.53-2.43(m,4H),1.82 1.74(m,4H),1.32(s,6H),1.21(s,6H),1.02(s,1H).LCMS:m / z 302.4[M+H]+,(ESI+),RT=1.79(Method A).

[0253] Compound E271 TIFF0007827911000100.tif271282,2,3,3-Tetramethyl-N-[5-(1,2,4-oxadiazol-3-yl)-2-pyridyl]cyclopropanecarboxamide

[0254] Step 1 To a solution of N-(5-cyano-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (step 2), 247 mg, 0.934 mmol) in ethanol (5.8974 mL) was added hydroxylamine (50%, 0.50 mL, 0.934 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. To the mixture were added DCM (10 ml) and water (10 ml). The colorless precipitate was isolated by filtration to give N-[5-(N-hydroxycarbamidoyl)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (176 mg, 67% yield) as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),9.64(s,1H),8.55(dd,J=2.3,0.7Hz,1H),8.08-8.01(m,1H),7. 96(dd,J=8.8,2.4Hz,1H),5.87(s,2H),1.56(s,1H),1.24(s,6H),1.17(s,6H).

[0255] Step 2 To a stirred solution of N-[5-(N-hydroxycarbamidoyl)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (100%, 50 mg, 0.181 mmol) in trimethoxymethane (3.0 mL, 0.181 mmol) was added a catalytic amount of 2,2,2-trifluoroacetic acid (0.0013 mL). The reaction was stirred at room temperature for 5 minutes and then at 60° C. for 30 minutes. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method G) to afford the title compound (39 mg, 75% yield) as a colorless solid. 1H NMR(400MHz,chloroform-d)δ 9.02-8.99(m,1H),8.79(s,1H),8.38-8.35(m,2H),8.17(s,1H),1.36(s,6H),1.26(s,6H),1.08(s,1H).LCMS:m / z 287.2[M+H]+,(ESI+),RT=3.50(Method A).

[0256] Compound E272 TIFF0007827911000101.tif331282,2,3,3-Tetramethyl-N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-pyridyl]cyclopropanecarboxamide

[0257] Synthesized using a method similar to that used for compound E271. 1H NMR (400 MHz, chloroform-d) δ 8.97-8.92 (m, 1H), 8.36-8.29 (m, 2H), 8.15 (s, 1H), 2.68 (s, 3H), 1.36 (s, 6H), 1.26 (s, 6H), 1.07 (s, 1H). LCMS: m / z 301.2 [M+H]+, (ESI+), RT = 3.78 (Method B).

[0258] Compound E273 TIFF0007827911000102.tif281282,2,3,3-Tetramethyl-N-(5-oxazol-5-yl-2-pyridyl)cyclopropanecarboxamide

[0259] Step 1 To a mixture of 1-(isocyanomethylsulfonyl)-4-methyl-benzene (320 mg, 1.64 mmol) and dipotassium carbonate (226 mg, 1.64 mmol) in methanol (4.5 mL) was added 6-aminopyridine-3-carbaldehyde (200 mg, 1.64 mmol). The reaction mixture was refluxed for 2.5 h, then cooled, concentrated under reduced pressure, and partitioned between MTBE (35 mL) and water (25 mL). After separation of the layers, the aqueous layer was extracted twice with EtOAc (2 x 30 mL). The combined organics were dried (MgSO), filtered, and concentrated to give 5-oxazol-5-ylpyridin-2-amine (199 mg, 35% purity) as a yellow oil that was used directly in the next step without further purification. H NMR, (500 MHz, DMSO-d) δ 8.31 (s, 1H), 8.30-8.27 (m, 1H), 7.46-7.44 (m, 1H), 7.40 (s, 1H), 6.52 (dd, J = 8.7, 0.7 Hz, 1H), 6.31 (s, 2H).

[0260] Step 2 Starting from 5-oxazol-5-ylpyridin-2-amine (65 mg, 35% purity), a similar method to compound E199 (Step 2) was used to obtain the title compound (6.1 mg, 15% yield) as a white solid. H NMR (500 MHz, chloroform-d) δ 8.56 (dd, J = 2.3, 0.6 Hz, 1H), 8.29-8.24 (m, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.90 (dd, J = 8.7, 2.3 Hz, 1H), 7.34 (s, 1H), 1.33 (s, 6H), 1.23 (s, 6H), 1.04 (s, 1H). LCMS: m / z 286.2 [M+H]+, (ESI+), RT = 3.25 (Method A).

[0261] Compound E274 TIFF0007827911000103.tif27128N-(5-Isoxazol-5-yl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0262] Step 1 N-(5-acetyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (step 2), 90 mg, 0.346 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (1.0 mL, 7.53 mmol). The reaction mixture was stirred at 110° C. for 16 h. After completion of the reaction, excess volatiles were removed under reduced pressure to afford N-[5-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (109 mg, 85% purity) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.72 (d, J = 1.4 Hz, 1H), 8.17-8.12 (m, 2H), 8.10 (dd, J = 8.7, 2.2 Hz, 1H), 7.76 (d, J = 12.2 Hz, 1H), 5.58 (d, J = 12.3 Hz, 1H), 3.27 (d, J = 6.9 Hz, 3H), 2.21 (d, J = 9.2 Hz, 3H), 1.26 (s, 6H), 1.15 (s, 6H), 0.98 (s, 1H).

[0263] Step 2 N-[5-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (85%, 109 mg, 0.294 mmol) and hydroxylamine hydrochloride (1:1) (24 mg, 0.352 mmol) were dissolved in ethanol (2 mL), and the reaction was heated to 80° C. with stirring for 1 h. After this time, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Method G) to afford the title compound (14 mg, 16% yield) as a pale yellow solid. 1H NMR (500MHz, chloroform-d)δ 8.72(d,J=1.8Hz,1H),8.35-8.31(m,2H),8.10(s,1H),8.06(dd,J=8.8,2.3Hz ,1H),6.54(d,J=1.9Hz,1H),1.36(s,6H),1.26(s,6H),1.08(s,1H).LCMS:m / z 286.2[M+H]+,(ESI+),RT=3.55(Method A).

[0264] Compound E275 TIFF0007827911000104.tif28128N-(5-Isoxazol-3-yl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0265] Step 1 N-(5-formyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (step 2), 90 mg, 0.345 mmol) and hydroxylamine hydrochloride (1:1) (36 mg, 0.518 mmol) were dissolved in water (9 mL) and methanol (4 mL). To the reaction mixture was slowly added disodium carbonate (66 mg, 0.621 mmol). The reaction mixture was stirred at room temperature for 5 h. An additional portion of hydroxylamine hydrochloride (1:1) (36 mg, 0.518 mmol) and disodium carbonate (66 mg, 0.621 mmol) was added along with THF (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added water (20 ml) and EtOAc (20 ml). The organics were separated and the aqueous solution was further extracted with EtOAc (2 x 20 ml). The combined organics were dried (hydrophobic frit) and concentrated under reduced pressure to give N-[5-[hydroxyiminomethyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92 mg, 0.316 mmol, 92% yield) as a colorless solid. 1H NMR (500 MHz, chloroform-d) δ 8.31 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.85 (dd, J = 8.7, 2.2 Hz, 1H), 7.75 (s, 1H), 1.25 (s, 6H), 1.14 (s, 6H), 0.96 (s, 1H).

[0266] Step 2 N-[5-[hydroxyiminomethyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92 mg, 0.351 mmol), calcium ethyndide (70%, 225 mg, 2.46 mmol), and 1-chloropyrrolidine-2,5-dione (59 mg, 0.439 mmol) were dissolved in benzene (1 mL) and DCM (1 mL). The resulting solution was stirred until the oxime dissolved. Water (1.1475 mL) was then added, and the reaction was stirred at room temperature overnight. The reaction mixture was filtered, and the solid was washed with chloroform (2 × 10 ml). The aqueous solution was then separated, and the organics were dried (hydrophobic frit). The organics were concentrated under reduced pressure and purified by preparative HPLC (Method H) to give the title compound (8.4 mg, 7.5% yield) as an off-white solid. 1H NMR (400MHz, chloroform-d)δ 8.75-8.70(m,1H),8.51(d,J=1.7Hz,1H),8.32(d,J=8.7Hz,1H),8.12(dd,J=8.7,2.3Hz, 1H),8.07(s,1H),6.68(d,J=1.7Hz,1H),1.36(s,6H),1.26(s,6H),1.07(s,1H).LCMS:m / z 286.2[M+H]+,(ESI+),RT=3.50(Method A).

[0267] Compound E276 TIFF0007827911000105.tif18128N-[5-[(3-fluorophenyl)methyl]-2-pyridyl]-2-methyl-propanamide

[0268] Step 1 To a solution of 5-bromopyridin-2-amine (1.00 g, 5.78 mmol), N,N-dimethylpyridin-4-amine (71 mg, 0.578 mmol), and triethylamine (1.6 mL, 11.6 mmol) in DCM (20 mL) at 0 °C, Boc anhydride (2.78 g, 12.7 mmol) was added portionwise and stirred at room temperature overnight. The reaction mixture was evaporated to dryness. Purification by flash chromatography (Biotage Isolera, 100 g KP-Sil SNAP cartridge, 2–20% EtOAc in heptane) afforded tert-butyl N-(5-bromo-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (1.98 g, 90% purity, 83% yield) as a white solid. To a solution of tert-butyl N-(5-bromo-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (90%, 1.00 g, 2.41 mmol) in methanol (10 mL) was added 1 M sodium hydroxide (2.5 mL, 2.53 mmol), stirred at 50° C. for 2 hours, and cooled to room temperature. It was then concentrated in vacuo, neutralized with 1 N HCl solution, extracted with DCM (2×50 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give tert-butyl N-(5-bromo-2-pyridyl)carbamate (99.0%) (EV-PIJ001-088-001) (630 mg, 95% yield) as a white solid. 1H NMR (250 MHz, chloroform-d) δ 8.61 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 9.0, 2.5 Hz, 1H), 1.55 (s, 9H).

[0269] Step 2 To a stirred solution of tert-butyl N-(5-bromo-2-pyridyl)carbamate (630 mg, 2.28 mmol) in anhydrous THF (10 mL) under nitrogen at 0 °C was added a suspension of potassium hydride (30%, 0.42 mL, 4.57 mmol) in THF (5 mL). After 10 min, the reaction mixture was cooled to -78 °C. 3-Fluorobenzaldehyde (0.29 mL, 2.74 mmol) was added and stirred for 10 min, after which 1.6 M butyllithium (2.9 mL, 4.57 mmol) was added in one portion. The reaction mixture was stirred for 1 h, then allowed to warm to room temperature and slowly quenched with saturated NH4Cl solution (3 mL). The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL), then brine (30 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The solid was then adsorbed onto silica gel and purified by flash chromatography (Biotage 100 g KP-Sil SNAP cartridge, 10-80% EtOAc in heptane) to give tert-butyl N-[5-[(3-fluorophenyl)-hydroxymethyl]-2-pyridyl]carbamate (396 mg, 52% yield) as an off-white solid. 1H NMR (250 MHz, chloroform-d) δ 8.29-8.20 (m, 1H), 7.98-7.78 (m, 2H), 7.68-7.56 (m, 1H), 7.39-7.27 (m, 1H), 7.17-7.04 (m, 2H), 7.04-6.89 (m, 1H), 5.81 (s, 1H), 2.41 (d, J = 3.2 Hz, 1H), 1.51 (s, 9H).

[0270] Step 3 To a solution of tert-butyl N-[5-[(3-fluorophenyl)-hydroxy-methyl]-2-pyridyl]carbamate (396 mg, 1.19 mmol) in DCE (10 mL) was added 2,2,2-trifluoroacetic acid (3.0 mL, 40.4 mmol), followed by triethylsilane (3.0 mL, 18.8 mmol), and the mixture was stirred at 50 °C overnight. The reaction mixture was then cooled to room temperature and evaporated to dryness. Purification by flash chromatography (Biotage C18 30 g KP-Ultra SNAP cartridge, eluting with 10–100% water (+0.1% NH4OH) in MeCN (+0.1% NH4OH) afforded 5-[(3-fluorophenyl)methyl]pyridin-2-amine (196 mg, 80% yield) as a beige solid. 1H NMR (250 MHz, chloroform-d) δ 7.94 (d, J = 1.9 Hz, 1H), 7.28-7.15 (m, 2H), 6.99-6.79 (m, 3H), 6.45 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.82 (s, 2H).

[0271] Step 4 A similar method to compound E164 (step 1) was used, starting from 5-[(3-fluorophenyl)methyl]pyridin-2-amine (50 mg, 0.242 mmol), to give the title compound (49 mg, 74% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ 10.34(s,1H),8.22(d,J=2.0Hz,1H),8.01(d,J=8.5Hz,1H),7.62(dd,J=8.5,2.4Hz,1H),7.37-7.29(m,1H) ),7.11-7.05(m,2H),7.05-6.98(m,1H),3.93(s,2H),2.78-2.66(m,1H),1.06(d,J=6.8Hz,6H).LCMS:m / z 273.1[M+H]+,(ESI+),RT=2.85(Method A).

[0272] Compound E277 TIFF0007827911000106.tif19128(2R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]-1-sulfamoyl-pyrrolidine-2-carboxamide

[0273] Step 1 To tert-butyl (2R)-2-[[5-(3,4-difluorophenoxy)-2-pyridyl]carbamoyl]pyrrolidine-1-carboxylate (synthesized using a similar method as E001 (Step 3), 90% purity, 446 mg, 0.957 mmol) was added 4 M hydrogen chloride in dioxane (2.9 mL, 11.5 mmol) and stirred at room temperature for 1 hour. It was then concentrated in vacuo, washed with MeOH, and purified on an SCX-2 cartridge eluting with 7N NH3 / MeOH to give (2R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]pyrrolidine-2-carboxamide (285 mg, 90% purity, 84% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ 10.35(s,1H),8.16(dd,J=6.0,2.6Hz,2H),7.59(dd,J=9.1,2.9Hz,1H),7.45(dt,J=10. 4,9.2Hz,1H),7.24(ddd,J=11.8,6.8,3.0Hz,1H),6.88(dtt,J=8.5,3.2,1.8Hz,1H),3.7 7(dd,J=9.1,5.4Hz,1H),3.18(s,1H),2.95(dt,J=10.2,6.7Hz,1H),2.84(dt,J=10.2,6 .4Hz,1H),2.07(ddt,J=12.5,8.9,7.3Hz,1H),1.86-1.74(m,1H),1.65(p,J=6.5Hz,2H).

[0274] Step 2 (2R)—N-[5-(3,4-difluorophenoxy)-2-pyridyl]pyrrolidine-2-carboxamide (90%, 47 mg, 0.132 mmol) and sulfuric acid diamide (22 mg, 0.225 mmol) in anhydrous 1,4-dioxane (0.9 mL) were stirred at 95° C. for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative HPLC (Method F) to give the title compound (18 mg, 0.0457 mmol, 35% yield) as an off-white solid. 1HNMR(400MHz,DMSO-d6)δ 9.81(s,1H),8.20-8.16(m,1H),8.13(d,J=9.3Hz,1H),7.60(dd,J=9.0,3. 0Hz,1H),7.46(dt,J=10.4,9.2Hz,1H),7.26(ddd,J=11.8,6.8,3.0Hz,1H) ,7.05(s,2H),6.93-6.85(m,1H),4.28(dd,J=8.7,4.4Hz,1H),3.45-3.36( m,2H),2.21-2.09(m,1H),2.07-2.01(m,1H),1.93-1.75(m,2H).LCMS:m / z 399.2[M+H]+,(ESI+),RT=3.03(Method B)

[0275] Compound E278 TIFF0007827911000107.tif19128(2R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]-1-methyl-pyrrolidine-2-carboxamide

[0276] The title compound was synthesized from intermediate I01 using a method similar to that used for compound E001 (Step 3) to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.94(s,1H),8.17(s,1H),8.17-8.14(m,1H),7.60(dd,J=8.9,3.0Hz,1H),7. 46(dt,J=10.5,9.2Hz,1H),7.25(ddd,J=11.8,6.8,3.0Hz,1H),6.88(ddq,J= 8.4,3.4,1.8Hz,1H),3.18-3.10(m,1H),3.03(dd,J=9.8,5.1Hz,1H),2.42-2 .35(m,4H),2.20(ddd,J=17.0,11.6,7.8Hz,1H),1.85-1.70(m,3H).LCMS:m / z 334.2[M+H]+,(ESI+),RT=3.89(Method B)

[0277] (Table 14) The following compounds were synthesized using a method similar to that used for compound E277. TIFF0007827911000108.tif231170

[0278] Compound E284 TIFF0007827911000109.tif241281-[5-(3,4-difluorophenoxy)-2-pyridyl]-4,4-dimethyl-pyrrolidin-2-one

[0279] Step 1 A mixture of 6-chloropyridin-3-ol (500 mg, 3.86 mmol), (3,4-difluorophenyl)boronic acid (0.91 g, 5.79 mmol), copper(II) diacetate (729 mg, 4.01 mmol), triethylamine (2.7 mL, 19.3 mmol), and powdered activated 4 Å molecular sieves in anhydrous DCM (38 mL) was stirred under air for 23 h. Further copper(II) diacetate (145 mg, 0.2 equiv.) and anhydrous DCM (10 mL) were added, and the mixture was stirred for 17 h. The suspension was diluted with dichloromethane, filtered twice through Celite, and washed with water (40 mL) and saturated aqueous Rochelle's salt solution (50 mL). The organics were washed with brine (30 mL), dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by FCC (Biotage KP-Sil 100 g, eluent: 0–100% DCM in heptane) to give 2-chloro-5-(3,4-difluorophenoxy)pyridine (426 mg, 45% yield) as a light brown oil. H NMR (500 MHz, chloroform-d) δ 8.15 (dd, J = 2.9, 0.6 Hz, 1H), 7.33–7.26 (m, 2H), 7.22–7.12 (m, 1H), 6.88 (ddd, J = 10.8, 6.5, 2.9 Hz, 1H), 6.75 (dtd, J = 9.0, 3.2, 1.9 Hz, 1H).

[0280] Step 2 A solution of potassium carbonate (90 mg, 0.649 mmol), 2-chloro-5-(3,4-difluorophenoxy)pyridine (80 mg, 0.324 mmol) in anhydrous toluene (2.5 mL) was degassed under nitrogen at room temperature for 15 minutes, and then 4,4-dimethylpyrrolidin-2-one (37 mg, 0.324 mmol) and XPhos Pd G3 (14 mg, 0.0162 mmol) were added. The reaction vessel was sealed and heated to 90 °C with stirring for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL). The aqueous layer was then extracted with EtOAc (3 × 20 mL). The organic extracts were combined, dried through a hydrophobic filter, and evaporated to dryness. The crude compound was purified using flash column chromatography (Biotage Sfar Duo 10 g, 0-80% DCM in heptane followed by 0-40% MeOH in EtOAc) to afford the title compound (20 mg, 19% yield) as an orange solid. 1H NMR,(400MHz,Chloroform-d)δ 8.43(d,J=9.1Hz,1H),8.11(d,J=2.9Hz,1H),7.37(dd,J=9.1,2.9Hz,1H),7.12(q,J=9.1Hz,1H),6.8 2(ddd,J=11.1,6.6,3.0Hz,1H),6.73-6.66(m,1H),3.82(s,2H),2.49(s,2H),1.24(s,6H).LCMS:m / z 319.2[M+H]+,(ESI+),RT=3.89(Method A)

[0281] Compound E285 TIFF0007827911000110.tif181281-[5-(3,4-difluorophenoxy)-2-pyridyl]-3,3-dimethyl-pyrrolidin-2-one

[0282] Synthesized using a method similar to that used for compound E284. H NMR (400 MHz, chloroform-d) δ 8.46 (d, J = 9.1 Hz, 1H), 8.13 (d, J = 2.9 Hz, 1H), 7.37 (dd, J = 9.1, 3.0 Hz, 1H), 7.12 (q, J = 9.0 Hz, 1H), 6.82 (ddd, J = 11.1, 6.6, 2.9 Hz, 1H), 6.74-6.66 (m, 1H), 4.03-3.97 (m, 2H), 2.03-1.96 (m, 2H), 1.27 (s, 6H). LCMS: m / z 319.2 [M+H]+, (ESI+), RT = 3.93 (Method A).

[0283] Compound E286 TIFF0007827911000111.tif201285-(3,4-Difluorophenoxy)-2-[[ethyl-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]sulfamoyl]amino]pyridine

[0284] Step 1 To a solution of ice-cold DCM (3 mL) was added sulfurisocyanatideyl chloride (58 μL, 0.662 mmol). 2-Chloroethanol (44 μL, 0.662 mmol) was then added via syringe over 1 minute, maintaining the internal temperature below 2°C. The reaction mixture was stirred for 1 hour, after which N-ethyl-N-isopropyl-propan-2-amine (347 μL, 1.98 mmol) was added. A solution of 5-(3,4-difluorophenoxy)pyridin-2-amine (Intermediate I01, 150 mg, 0.662 mmol) in DCM (3 mL) was added dropwise over 5 minutes, then stirred at 0°C for an additional 16 hours and allowed to warm to room temperature overnight. The reaction was quenched by the addition of 0.2 M HCl (10 mL) and DCM (15 mL). The organic layer was separated and concentrated in vacuo. The residue was triturated with water (2 mL) and then diluted with 3 mL of DCM to form a white solid which was filtered to give N-[5-(3,4-difluorophenoxy)-2-pyridyl]-2-oxo-oxazolidine-3-sulfonamide (83 mg, 32% yield) as a white solid. 1H NMR,(500MHz,chloroform-d)δ 7.84(d,J=2.6Hz,1H),7.51(dd,J=9.4,2.9Hz,1H),7.27(s,1H),7.25(s,1H),7.17(q,J=9.0Hz,1H),6.88( ddd,J=10.7,6.5,3.0Hz,1H),6.77-6.70(m,1H),4.40(dd,J=8.7,7.0Hz,2H),4.16(dd,J=8.7,7.1Hz,2H).

[0285] Step 2 N-[5-(3,4-Difluorophenoxy)-2-pyridyl]-2-oxo-oxazolidine-3-sulfonamide (40 mg, 0.102 mmol), (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (80%, 26 mg, 0.133 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.18 mL, 1.02 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated to 130 °C for 1 h using microwave heating. After cooling to room temperature, it was diluted with EtOAc (10 mL) and washed with saturated aqueous ammonium chloride (10 mL) followed by saturated aqueous sodium bicarbonate (2 × 10 mL). The organic layer was separated and concentrated in vacuo. The crude material was purified using FCC (Biotage SNAP KP-Sil 10 g, 0-100% EtOAc in heptane) to give the title compound (4.0 mg, 8.4% yield) as a light brown glass. 1H NMR, (500 MHz, chloroform-d) δ 8.07 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 8.8, 2.9 Hz, 1H), 7.16 (q, J = 9.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.85 (ddd, J = 10.8, 6.5, 2.9 Hz, 1H), 6.75-6.71 (m, 1H), 4.31 (dqd, J = 9.6, 6.8, 2.9 Hz, 1H), 3.67 (dd, J = 15.2, 9.9 Hz, 1H), 3.58 (dd, J = 15.2, 2.8 Hz, 1H), 3.40 (dq, J = 14.4, 7.2 Hz, 1H), 3.28 (dq, J = 14.3, 7.1 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H). NH and OH were not observed. LCMS: m / z 442.2 [M+H]+, (ESI+), RT = 3.48 (Method A).

[0286] Compound E287 TIFF0007827911000112.tif18128N-[5-(3-fluorophenoxy)-3-hydroxy-2-pyridyl]-2-methyl-propanamide

[0287] Step 1 5-Chloro-2-nitropyridin-3-ol (300.0 mg, 1.72 mmol), cesium carbonate (616.02 mg, 1.89 mmol), and chloromethylbenzene (239.33 mg, 1.89 mmol) were mixed in DMF (4.5 mL), purged with nitrogen, and stirred at room temperature in a sealed vial for 18 hours. Additional cesium carbonate (616 mg, 1.89 mmol) was added to the reaction mixture and stirred at room temperature for an additional 24 hours. The reaction mixture was filtered, and the crude product was purified using preparative HPLC (Method F) to afford 3-benzyloxy-5-chloro-2-nitro-pyridine (330 mg, 73% yield) as an off-white solid.

[0288] Step 2 3-Benzyloxy-5-chloro-2-nitro-pyridine (330 mg, 1.25 mmol), cesium carbonate (406.26 mg, 1.25 mmol), and 3-fluorophenol (139.78 mg, 1.25 mmol) were combined in DMSO (5 mL), purged with nitrogen, and stirred for 18 h in a sealed vial at 50° C. Upon completion, the reaction mixture was filtered and the crude product was purified using preparative HPLC (Method F) to afford 3-benzyloxy-5-(3-fluorophenoxy)-2-nitro-pyridine (225 mg, 53% yield) as a yellow solid.

[0289] Step 3 3-Benzyloxy-5-(3-fluorophenoxy)-2-nitro-pyridine (112.0 mg, 0.33 mmol) was dissolved in methanol (20 mL) and hydrogenated using an H-cube (room temperature, 3 hours, 2 mL / min, recirculation mode, 10% Pd / C cartridge). Upon completion, the material was dried in vacuo and mixed with N-ethyl-N-isopropyl-propan-2-amine (0.11 mL, 0.658 mmol) and anhydrous isopropyl (52 mg, 0.329 mmol) in THF (4 mL) and stirred at 80° C. for 18 hours in a sealed vial. Upon completion, the solvent was removed in vacuo and the crude material was purified using preparative HPLC (Method E) to afford the title compound (44 mg, 46% yield) as an off-white solid. 1H NMR(500MHz,DMSO-d6)δ 10.76(s,1H),10.53(s,1H),7.74(d,J=2.5Hz,1H),7.44(td,J=8.3,6.9Hz,1H),7.06-6.94(m ,3H),6.89(dd,J=8.2,2.2Hz,1H),2.86(sept,J=6.8Hz,1H),1.13(d,J=6.8Hz,6H).LCMS:m / z 291.2[M+H]+,(ESI+),RT=3.33(Method A).

[0290] Compound E288 TIFF0007827911000113.tif22128N-[6-[(5-fluoro-3-pyridyl)oxy]pyridazin-3-yl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0291] Synthesized using a method similar to that used for compound E217, starting from 6-bromopyridazin-3-amine. 1H NMR (500 MHz, chloroform-d) δ 8.67 (s, 1H), 8.60 (d, J = 9.5 Hz, 1H), 8.40 (d, J = 14.0 Hz, 2H), 7.42 (dt, J = 9.2, 2.3 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 1.35 (s, 6H), 1.22 (s, 6H), 1.18 (s, 1H). LCMS: m / z 331.5 [M+H]+, (ESI+), RT = 3.44 (Method A).

[0292] Compound E289 TIFF0007827911000114.tif201283-[6-[(3,4-difluorophenoxy)pyrimidin-4-yl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0293] Step 1 6-Chloropyrimidin-4-amine (250 mg, 1.93 mmol), cesium carbonate (1.26 g, 3.86 mmol), and 3,4-difluorophenol (251 mg, 1.93 mmol) were mixed in DMSO (5 mL), purged with nitrogen, and stirred in a sealed tube at 50° C. for 3 h, followed by 80° C. for 14 h and 100° C. for 2.5 h. The reaction mixture was then cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO column, 25–100% EtOAc in heptane) to give 6-(3,4-difluorophenoxy)pyrimidin-4-amine (180 mg, 70% purity) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ 8.07(d,J=0.8Hz,1H),7.48(ddd,J=10.6,9.2,9.2Hz,1H),7.39(ddd,J=11.6,6.9,2. 8Hz,1H),7.03(dddd,J=9.0,3.7,2.9,1.8Hz,1H),6.90(s,2H),5.80(d,J=0.9Hz,1H).

[0294] Step 2 Using a similar method as for compound E191, starting from 6-(3,4-difluorophenoxy)pyrimidin-4-amine (70%, 85 mg, 0.267 mmol), the title compound (48 mg, 44% yield) was obtained as a white solid. 1H NMR(500MHz,DMSO-d6)δ 9.57(s,1H),8.43(d,J=0.8Hz,1H),7.59-7.44(m,2H),7.35(s,1H),7.26-6.73(m,2H),4 .40-4.21(m,1H),3.68-3.54(m,1H),3.54-3.38(m,3H),1.10(t,J=7.0Hz,3H).LCMS:m / z 407.2[M+H]+,(ESI+),RT=3.31(Method A).

[0295] Compound E290 TIFF0007827911000115.tif201281-Ethyl-3-[6-(2-fluorophenoxy)pyrimidin-4-yl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0296] Synthesized using a method similar to that used for compound E289. H NMR (500 MHz, DMSO-d ) δ 9.58 (s, 1H), 8.39 (d, J = 0.9 Hz, 1H), 7.46-7.30 (m, 4H), 7.30-7.23 (m, 1H), 7.13 (s, 1H), 4.39-4.20 (m, 1H), 3.65-3.54 (m, 1H), 3.54-3.37 (m, 3H), 1.10 (t, J = 7.0 Hz, 3H). LCMS: m / z 389.1 [M+H]+, (ESI+), RT = 3.19 (Method A).

[0297] Compound E291 TIFF0007827911000116.tif201281-Ethyl-3-[6-(3-fluorophenoxy)pyrimidin-4-yl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0298] Synthesized using a method similar to that used for compound E289. H NMR (400 MHz, DMSO-d) δ 9.55 (s, 1H), 8.42 (d, J = 0.9 Hz, 1H), 7.53-7.44 (m, 1H), 7.33 (s, 1H), 7.20-7.09 (m, 2H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 4.34-4.20 (m, 1H), 3.62-3.41 (m, 5H), 1.09 (t, J = 7.0 Hz, 3H). LCMS: m / z 389.2 [M+H]+, (ESI+), RT = 3.33 (Method A).

[0299] HPLC method analyticalLCMS Method A Analytical uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μM; temperature: 40 °C) and a gradient of 5 to 100% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 5.3 min, followed by 100% B in 0.5 min. A second gradient of 100 to 5% B was then applied in 0.02 min and held for 1.18 min with an injection volume of 1 μL at a flow rate of 0.6 mL / min. UV spectra were recorded using a Waters Acquity PDA detector spectral range: 200-400 nm at 215 nm. ELS data were collected and reported using a Waters Acquity ELS detector (if compatible). Mass spectra were obtained using a Waters SQD (MSQ1) or a Waters Acquity QDA (MSQ2). Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0300] Method B Analytical uPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40 °C) and a gradient of 5 to 100% (A = 2 mM sodium bicarbonate, buffered to pH 10, B = ACN) in 5.3 min, followed by 100% B in 0.5 min. A second gradient of 100 to 5% B was then applied in 0.02 min and held for 1.18 min with an injection volume of 1 μL and a flow rate of 0.6 mL / min. UV spectra were recorded using a Waters Acquity photodiode array detector with a spectral range of 200-400 nm at 215 nm. Mass spectra were acquired using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0301] Method C Analytical HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40 °C) and a gradient of 5 to 100% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 1.2 min, followed by 100% B in 0.1 min. A second gradient of 100 to 5% B was then applied in 0.01 min with an injection volume of 3 μL at a flow rate of 1.2 mL / min. UV spectra were recorded using an SPD-M20A photodiode array detector with a spectral range of 200-400 nm at 215 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0302] Method D Analytical uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm x 30 mm, 1.7 μm column; temperature: 40 °C) and a gradient of 5 to 100% B (A: 2 mM ammonium bicarbonate, buffered to pH 10; B: ACN) in 0.75 min, followed by 100% B in 0.1 min. A second gradient of 100 to 5% B was then applied in 0.05 min and held for 0.1 min with an injection volume of 1 μL and a flow rate of 1 mL / min. UV spectra were recorded at 215 nm on a Waters Acquity PDA with a spectral range of 200-400 nm. Mass spectra were acquired using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0303] Preparative HPLC method The purification method is as follows.

[0304] Method E: Acidic Early Method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient from 10 to 95% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 14.44 min, followed by 95% B in 2.11 min. A second gradient from 95 to 10% B, 1500 μL injection volume, and 40 mL / min flow rate was then applied in 0.2 min. UV spectra were recorded using a Gilson detector at 215 nm.

[0305] Method F: Basic Early Method Purification was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10 to 95% B (A = 0.2% ammonium hydroxide in HO, B = 0.2% ammonium hydroxide in ACN) in 14.44 min, followed by 95% B in 2.11 min. A second gradient of 95 to 10% B was then applied in 0.2 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded using a Gilson detector at 215 nm.

[0306] Method G: Acidic Standard Method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) and a gradient of 30 to 95% B (A = 0.1% formic acid in water, B = 0.1% formic acid in ACN) in 11.00 min, followed by 95% B in 2.10 min. A second gradient of 95 to 30% B, 1500 μL injection volume, and 40 mL / min flow rate was then applied in 0.2 min. UV spectra were recorded using a Gilson detector at 215 nm.

[0307] Method H: Basic Standard Method Purification was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) and a gradient of 30 to 95% B (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in ACN) in 11.00 min, followed by 95% B in 2.10 min. A second gradient of 95 to 30% B, 1500 μL injection volume, and 40 mL / min flow rate was then applied in 0.21 min. UV spectra were recorded using a Gilson detector at 215 nm.

[0308] Example 2 - Compound Screening Potent and selective hMrgpMRGPRX2 compounds were generated from compounds identified during a high-throughput screening (HTS) campaign and followed up with a structure-activity-based medicinal science power cycle. These compounds were characterized for their antagonist activity in recombinant hMrgpMRGPRX2-expressing cells, and their potency was confirmed in the human mast cell line LAD-2, where the target is endogenously expressed. The assay used to determine potency was a functional readout using FLIPR™ technology to observe intracellular calcium mobilization. In these FLIPR assays, identified compounds were tested for orthologous activity using recombinant cell lines expressing mouse MrgprB2, mouse MrgprA1, gerbil MrgpMRGPRX2 orthologue, Chinese hamster MrgpMRGPRX2 orthologue, and cynomolgus monkey MrgpMRGPRX2 orthologue, respectively.

[0309] The results are summarized in Table 15 below.

[0310] (Table 15) TIFF0007827911000117.tif184139TIFF0007827911000118.tif206139TIFF0007827911000119.tif223139TIFF0007827911000120.tif190139TIFF0007827911000121.tif192139TIFF0007827911000122.tif202139TIFF0007827911000123.tif219139TIFF0007827911000124.tif209139TIFF0007827911000125.tif195139TIFF0007827911000126.tif217139TIFF0007827911000127.tif211139TIFF0007827911000128.tif189139TIFF0007827911000129.tif167139TIFF0007827911000130.tif207139TIFF0007827911000131.tif210139TIFF0007827911000132.tif193139TIFF0007827911000133.tif198139TIFF0007827911000134.tif218139TIFF0007827911000135.tif189139TIFF0007827911000136.tif203139TIFF0007827911000137.tif207139TIFF0007827911000138.tif210139TIFF0007827911000139.tif213139TIFF0007827911000140.tif213139TIFF0007827911000141.tif188139TIFF0007827911000142.tif205139TIFF0007827911000143.tif200139TIFF0007827911000144.tif203139TIFF0007827911000145.tif221139TIFF0007827911000146.tif214139TIFF0007827911000147.tif214139TIFF0007827911000148.tif192139TIFF0007827911000149.tif194139TIFF0007827911000150.tif192139TIFF0007827911000151.tif189139TIFF0007827911000152.tif208139TIFF0007827911000153.tif199139TIFF0007827911000154.tif222139TIFF0007827911000155.tif187139TIFF0007827911000156.tif205139TIFF0007827911000157.tif177139TIFF0007827911000158.tif220139TIFF0007827911000159.tif194139TIFF0007827911000160.tif225139TIFF0007827911000161.tif187139TIFF0007827911000162.tif220139TIFF0007827911000163.tif225139TIFF0007827911000164.tif168139TIFF0007827911000165.tif194139TIFF0007827911000166.tif213139TIFF0007827911000167.tif190139TIFF0007827911000168.tif191139TIFF0007827911000169.tif193139TIFF0007827911000170.tif190139TIFF0007827911000171.tif198139TIFF0007827911000172.tif192139TIFF0007827911000173.tif170139TIFF0007827911000174.tif209139TIFF0007827911000175.tif195139TIFF0007827911000176.tif193139TIFF0007827911000177.tif182139.

Claims

1. A compound having the following formula I: During the ceremony, Q is, and Z is —C(═O), R １ is H or C １－３ is alkyl, G １ , G ２ , G ３ , G ４ and G ５ are each independently N or -CL １ -M １ where G １ , G ２ , G ３ , G ４ and G ５ is N; Each L １ are independently a bond, O, —C(═O), —C(═O)—NH—, or —CH ２ -, or -O-(CH ２ ) ｗ - (wherein w is 1, 2 or 3), L １ is a bond, M １ is H, L １ is O, -C(=O), -C(=O)-NH-, -CH ２ -, or -O-(CH ２ ) ｗ -, then each M １ is a C6 aryl or a 5-6 membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, wherein each of said C6 aryl or 5-6 membered heteroaryl is selected from halogen, cyano, —OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and —C(═O)—N(R ９１ ) (R ９２ and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: Each R ９１ and R ９２ independently H and C １－３ is selected from the group consisting of alkyl, A is -L ２ -M ２ and L ２ is a bond, M ２ But -N(R ８１ ) (R ８２ ); C ３－６ Cycloalkyl; C ５－１０ spiroalkyl; 4-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; or C ６－１０ aryl, wherein each C ３－６ Cycloalkyl, C ６－１０ spiroalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C ６－１０ Each aryl is selected from 1, 2, 3, or 4 independently selected R ２００ may be substituted with a group, Each R ２００ But independently, C １－６ Alkyl; C １－６ Hydroxyalkyl; C ３－６ cycloalkyl; 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; C １－６ Mono-, di-, or trihaloalkyl; halogen; cyano; —OH; C １－６ Alkoxy; S(=O) ２ NR ５０２ R ５０３ and C ６－１０ aryl; Each R ８１ and R ８２ However, independently, H, C １－６ Alkyl and C ３－６ cycloalkyl, wherein said C １－６ Alkyl and C ３－６ The cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OH and halogen; R ５０２ and R ５０３ are independently H or C １－６ is alkyl, The compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

2. G １ and G ４ The compound of claim 1 , wherein is N.

3. G １ and G ２ The compound of claim 1 , wherein is N.

4. G １ and G ５ The compound of claim 1 , wherein is N.

5. G １ The compound of claim 1 , wherein is N.

6. G ２ The compound of claim 1 , wherein is N.

7. G ３ But -C-L １ -M １ 2. The compound of claim 1, wherein:

8. G ４ But -C-L １ -M １ 2. The compound of claim 1, wherein:

9. G ２ But -C-L １ -M １ 2. The compound of claim 1, wherein:

10. L １ The compound according to any one of claims 1 to 9, wherein is O.

11. L １ But -CH ２ The compound according to any one of claims 1 to 9, wherein

12. L １ The compound of any one of claims 1 to 9, wherein is a bond.

13. L １ The compound of any one of claims 1 to 9, wherein is -C(=O).

14. L １ The compound according to any one of claims 1 to 9, wherein is -C(=O)-NH-.

15. R １ The compound of any one of claims 1 to 14, wherein is H.

16. M １ But C ６ aryl; and 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N and O, each of the foregoing being optionally substituted.

17. M １ The compound of any one of claims 1 to 16, wherein is phenyl or pyridyl, each of which is optionally substituted.

18. Said M １ The substituents are independently selected from halogen, CN, —OH, —C(═O)—NH ２ , C.F. ３ , and -OCH ３ The compound according to any one of claims 1 to 17, selected from:

19. M １ The compound of any one of claims 1 to 18, wherein is optionally substituted phenyl.

20. 20. The compound of claim 19, wherein the phenyl is substituted at the 4-position.

21. 20. The compound of claim 19, wherein the phenyl is substituted at the 3 and 4 positions.

22. 20. The compound of claim 19, wherein the phenyl is substituted at the 3 and 5 positions.

23. M １ The compound of any one of claims 1 to 18, wherein is optionally substituted pyridyl.

24. M １ The compound of any one of claims 1 to 18, wherein is optionally substituted pyridyl-4-yl.

25. M １ The compound of any one of claims 1 to 18, wherein is optionally substituted pyridyl-3-yl.

26. 26. The compound of any one of claims 23-25, wherein the pyridyl is substituted at the carbon that is ortho (ie, adjacent) to the nitrogen of the pyridyl.

27. 26. The compound of any one of claims 23-25, wherein the pyridyl is substituted at the carbon that is meta to the nitrogen of the pyridyl.

28. M ２ is optionally substituted C ３－６ The compound of any one of claims 1 to 27, which is cycloalkyl.

29. M ２ The compound of any one of claims 1 to 27, wherein is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 methyl groups.

30. M ２ is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or two substituents independently selected from methyl, halogen, mono-, di- or trihalomethyl, cyano, hydroxymethyl, and hydroxy.

31. M ２ The compound of any one of claims 1 to 27, wherein is cyclopropyl optionally substituted with one to four methyl groups, halogen or trihalomethyl.

32. M ２ The compound of any one of claims 1 to 27, wherein is heterocycloalkyl optionally substituted with one or two groups independently selected from methyl and hydroxy.

33. M ２ is tetrahydrofuran, pyrrolidine, tetrahydropyran, or morpholine, each of which is optionally substituted with one or two groups independently selected from methyl and hydroxy.

34. M ２ But -N(R ８１ ) (R ８２ 28. The compound according to any one of claims 1 to 27, wherein

35. R ８１ and R ８２ But independently, C １－３ Alkyl and C ３－４ cycloalkyl, each of which is optionally substituted with one or two substituents independently selected from -OH and halogen.

36. below:

2. The compound of claim 1 selected from:

37. A composition comprising a dermatologically or orally acceptable excipient and a compound according to any one of claims 1 to 36.

38. 37. A composition for treating an inflammatory disorder in a subject, comprising a therapeutically effective amount of a compound of any one of claims 1 to 36 and a dermatologically or orally acceptable excipient.

39. 39. The composition of claim 38 in the form of a cream, gel, spray, ointment, or oral unit dosage form.

40. 39. The composition of claim 38, wherein the compound is present in a concentration of 0.001% to 10% by weight, based on the total weight of the composition.

41. 39. The composition of claim 38, wherein the compound is present in a concentration of 0.1% to 5% by weight, based on the total weight of the composition.

42. 39. The composition of claim 38, further comprising a skin absorption enhancer.

43. 39. The composition of claim 38, further comprising a skin absorption enhancer comprising one or more of mannitol, sulfoxides, azones, pyrrolidones, alcohols and alkanols, glycols, surfactants, and terpenes.

44. 44. The composition of any one of claims 38 to 43, which is applied to the skin of a subject once daily.

45. 44. The composition of any one of claims 38 to 43, which is applied to the skin of a subject twice daily.

46. 44. The composition of any one of claims 38 to 43, which is applied to the skin of a subject three times daily.

47. The composition of any one of claims 38 to 46, wherein the subject is suffering from an inflammatory disorder.

48. The composition of any one of claims 38 to 47, wherein the inflammatory disorder is a skin disorder.

49. The composition of any one of claims 44 to 46 and 48, wherein the skin is human skin.

50. 50. The composition of any one of claims 38 to 49, wherein the inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2.

51. 51. The composition of any one of claims 38 to 50, wherein the inflammatory disorder is atopic dermatitis, chronic urticaria, pseudoallergic response caused by a small molecule, anaphylactoid drug response, anaphylactic shock, rosacea, asthma, generalized itch, chronic itch caused by a systemic disease, or adverse drug response.

52. The composition of any one of claims 38 to 51, wherein the inflammatory disorder is atopic dermatitis.

53. 53. The composition of claim 52, wherein the atopic dermatitis is Asian atopic dermatitis or European atopic dermatitis.

54. 52. The composition of claim 51, wherein the inflammatory disorder is chronic urticaria.

55. 52. The composition of claim 51, wherein the generalized itch is cholestatic or uremic itch.

56. The composition of any one of claims 38 to 55, wherein the subject is a human.

57. The composition of any one of claims 38 to 56, which is for oral administration.

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