MrgprX2 antagonists and uses thereof

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Application No. 62 / 931,174, filed November 5, 2019, No. 62 / 931,627, filed November 6, 2019, and No. 63 / 046,476, filed June 30, 2020, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

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

[0003] Oral antihistamines, due to their sedative effects, provide mild symptomatic relief without directly altering pruritus. Topical calcineurin inhibitors (TCIs) as well as 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 unfavorable treatment options for chronic use, especially in young children. Thus, the medical demand to find new treatment options for itch is very high among patients and their families. In addition, relief of chronic itch interrupts the vicious cycle of itch and scratching, which may have secondary beneficial effects such as improved skin barrier, resulting in improved 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 main pruritogen in AD, and therefore histamine blockers act in AD patients only through a sedative effect, especially for nocturnal itch. Proteases released from immune and skin cells in AD patients and acting on GPCRs have been investigated as major pruritic contributors in AD. Cathepsin S has been described in the literature as a protease that is highly proinflammatory and causes itch. Overexpression of cathepsin S leads to AD phenotypes in mice with severe chronic itch. Recently, a group reported that cathepsin S induces itch via MrgprX2. Nevertheless, knowledge of the main itch mediators in AD is limited, although some have been identified and assumed to play a role.

[0005] Another pruritic neuropeptide is substance P, a vasoactive neuropeptide released by neuronal and non-neuronal skin cells that is proinflammatory and acts as a pruritogen. Therefore, targeting its cognate receptor NK1 is considered an ideal therapeutic approach and has been done with 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 that are known or suspected to be relevant players in the pathogenesis of AD are thought to bind to the MrgprX receptor rather than to their cognate receptors.

[0007] There is an unmet need for an effective treatment for AD and its symptoms. The present invention is directed to 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 pharma- ceutically 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 itch 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 the following formula I: TIFF0007645256000001.tif33128 During the ceremony, Q, TIFF0007645256000002.tif38128 and Z is -C(=O)-(CR 20 R 21 ) n or -S(=O) 2 - and R 1 But 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, 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 At least one of is N, Each L 1 are independently a bond, O, -C(=O), -C(=O)-NH-, -CH 2 - -O-(CH 2 ) w -(wherein w is 1, 2 or 3), or -N(R 90 )-, or any two L on adjacent carbon atoms 1 The -M groups, taken together, represent a compound of the formula -O-(CH 2 ) v -O- (where v is 1 or 2) group, Each R 90 are independently H or C 1-3 is alkyl, Each M 1 are 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 of said C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-10 membered heterocycloalkyl are each independently 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 R50 and R 51 However, independently, H, C 1-3 Alkyl, and C 6-10 aryl; A is -L 2 -M 2 and L 2 However, bonds and -(CR 60 R 61 ) k - selected from R 60 and R 61 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; M 2 But, C 1-6 Alkyl;C 3-6 Cycloalkyl;C 5-10 spiroalkyl; 4-10 membered heterocycloalkyl having 1-3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and C 6-10 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 500 and R 501 is not present or C 1-6 is alkyl, R 502 and R 503 are independently H or C 1-6 is alkyl, A compound, or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof. [The present invention 1002] G 1 The compound of the present invention 1001, wherein is N. [The present invention 1003] G 2 The compound of the present invention 1001, wherein is N. [The present invention 1004] G 1 and G 4 The compound of the present invention 1001, wherein is N. [The present invention 1005] G 1 and G 2 The compound of the present invention 1001, wherein is N. [The present invention 1006] G 1 and G 5 The compound of the present invention 1001, wherein is N. [The present invention 1007] G 3 But -CL 1 -M 1 The compound of the present invention 1001, [The present invention 1008] G 4 But -CL 1 -M 1 The compound of the present invention 1001, [The present invention 1009] G 2 But -CL 1 -M 1 The compound of the present invention 1001, [The present invention 1010] L 1 The compound of any one of 1001 to 1009 according to the present invention, wherein [The present invention 1011] L 1 But -CH 2 Any of the compounds of 1001 to 1009 of the present invention, [The present invention 1012] L 1 The compound of any one of 1001 to 1009 according to the present invention, wherein is a bond. [The present invention 1013] L 1 The compound according to any one of claims 1001 to 1009, wherein is -C(=O). [The present invention 1014] L 1 Any of the compounds of 1001 to 1009 according to the present invention, wherein is -C(=O)-NH-. [The present invention 1015] L 1 But -N(R 90 )-, any one of the compounds of the present invention 1001 to 1009. [The present invention 1016] R 1 is H. [The present invention 1017] The compound of any of the preceding inventions 1001, wherein n is 0. [The present invention 1018] The compound of any one of 1001 to 1015 of the present invention, wherein n is 1. [The present invention 1019] M 1 But, C 6 Aryl; C having 1 or 2 ring heteroatoms independently selected from N and O 6 Heteroaryl; C having 1 or 2 ring heteroatoms independently selected from N and O 5 or C 6 heterocycloalkyl; and 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, each of the foregoing being optionally substituted. [The present invention 1020] M 1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or dihydroynediol, each of which is optionally substituted. [The present invention 1021] Said M 1 The substituents are independently halogen, CN, -OH, -C(=O)-NH 2 , C.F. 3 , and -OCH 3 Any of the compounds of the preceding inventions is selected from: [The present invention 1022] M 1 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] M 1 is an optionally substituted pyridyl. [The present invention 1027] M 1 is an optionally substituted pyridyl-4-yl. [The present invention 1028] M 1 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 according to 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] M 1 Any of the preceding compounds of the invention, wherein is an optionally substituted heterocycloalkyl. [The present invention 1033] M 1 is an optionally substituted pyrrolidinyl. [The present invention 1034] M 1 is optionally substituted pyrrolidin-1-yl. [The present invention 1035] M 1 is optionally substituted tetrahydropyranyl. [The present invention 1036] M 1 is optionally substituted tetrahydropyran-4-yl. [The present invention 1037] M 1 The compound of any of the present invention 1001 to 1018, wherein is optionally substituted cycloalkyl. [The present invention 1038] M 1 may be substituted C 1-6 The compound of any one of 1001 to 1018, which is alkyl. [The present invention 1039] M 1 But -NR 50 R 51 The compound of any one of claims 1001 to 1018, [The present invention 1040] L 2 Any of the preceding compounds of the invention, wherein is a bond. [The present invention 1041] L 2 But -(CR 60 R 61 ) k Any of the compounds of 1001 to 1039 of the present invention, [The present invention 1042] M 2 may be substituted C 1-6 Any of the compounds of the preceding invention, wherein: [The present invention 1043] M 2 Any of the preceding compounds of the invention, wherein is optionally substituted isopropyl. [The present invention 1044] M 2 may be substituted C 3-6 The compound of any one of 1001 to 1041 according to the present invention, which is cycloalkyl. [The present invention 1045] M 2 is cyclopropyl or cyclobutyl, each of which may be substituted with 1 to 4 methyl groups. [The present invention 1046] 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. [The present invention 1047] M 2 is cyclopropyl optionally substituted with 1 to 4 methyl groups, halogen or trihalomethyl. [The present invention 1048] M 2 is heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy. [The present invention 1049] M 2 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or morpholine, each of which may be substituted with 1 or 2 groups independently selected from methyl and hydroxy. [The present invention 1050] M 2 But -N(R 81 )(R 82 ). [The present 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. [The present invention 1052] A compound of any of the preceding inventions selected from a compound in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof. [The present invention 1053] A composition comprising a dermatologically or orally acceptable excipient and any of the preceding compounds of the present invention. [The present 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. [The present invention 1055] The method of claim 1054, wherein said composition is in the form of a cream, gel, spray, ointment, or oral unit dosage form. [The present invention 1056] 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. [The present 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. [The present invention 1058] The method of claim 1054, wherein the composition further comprises a skin absorption enhancer. [The present 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] The method of any of claims 1054 to 1059, wherein the composition is applied to the patient's skin once a day. [The present invention 1061] The method of any of claims 1054 to 1059, wherein the composition is applied to the patient's skin twice a day. [The present invention 1062] The method of any of claims 1054 to 1059, wherein the composition is applied to the patient's skin three times a day. [The present invention 1063] The method of any of claims 1054 to 1062, wherein the 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. [The present invention 1065] The method according to 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 the inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2. [The present invention 1067] Any of the methods of claims 1063 to 1066, 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 a systemic disease, or adverse drug response. [The present invention 1068] The method according to any one of claims 1063 to 1067, wherein said inflammatory disorder is atopic dermatitis (eg, Asian atopic dermatitis, European atopic dermatitis). [The present invention 1069] The method according to 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. [The present invention 1071] The method of any of the preceding inventions, wherein said composition is for oral administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 present disclosure In some embodiments, the present disclosure provides a compound that is an MrgprX2 antagonist having formula I [Compound 1], TIFF0007645256000003.tif38128In formula, Q, TIFF0007645256000004.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 represent 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, where each C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-10 membered heterocycloalkyl are each independently 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 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 6-10 spiroalkyl; 4-10 membered heterocycloalkyl having 1-3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and C 6-10 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 1-3is alkyl, Each R 81 and R 82 However, independently, H, C 1-6 Alkyl and C 3-6 cycloalkyl, where 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 is not present or C 1-6 is alkyl, R 502 and R 503 are independently H or C 1-6 is alkyl, Provided is the compound [Compound 1], or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof.

[0016] The 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, 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 that is 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 that is 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 an 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 an 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 an 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, 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 in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharma- ceutically 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 formula I above.

[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, 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 at the 3- and 4-positions. 1.25 Composition 1.22, wherein phenyl is substituted at 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 that is ortho (i.e., adjacent) to the nitrogen of the pyridyl. 1.30 Composition 1.27, wherein the pyridyl is substituted at the carbon that is meta to the pyridyl nitrogen. 1.31 Composition 1.28, wherein the pyridyl is substituted at the carbon that is 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 an 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 an 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 an 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, 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 pharma- ceutically 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% by weight 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 the 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 responses. 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 vehicles include all dermatologically acceptable carriers, diluents, or excipients therefor.

[0020] "Stereoisomers" refers to compounds composed of the same atoms linked 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 refers 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 salt" includes both acid and base addition salts.

[0024] "Pharmaceutically acceptable acid addition salts" are those which retain the biological effectiveness and properties of the biologically or otherwise desirable free base and are selected from the group consisting of inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, 10-camphor-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, tauric ... It refers to salts formed with organic acids such as glycerol, glycerol, glycerol, glycerol, lauric, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthalene-1,5-disulfonic, naphthalene-2-sulfonic, 1-hydroxy-2-naphthoic, nicotinic, oleic, orotic, oxalic, palmitic, pamoic, propionic, pyroglutamic, pyruvic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, tartaric, thiocyanic, p-toluenesulfonic, trifluoroacetic, and undecylenic acids.

[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 the 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 pharma- ceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be de?ned in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-. The present invention is meant to include 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, for example, chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using 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 carbon group containing the indicated number of carbon atoms. Some embodiments contain 1-5 carbons. Some embodiments contain 1-4 carbons. Some embodiments contain 1-3 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 3-6 carbons. Some embodiments contain 3-5 carbons. Some embodiments contain 5-7 carbons. Some embodiments contain 3-4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0031] The term "haloalkyl" is intended to mean a group that includes 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 the group 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 1-5 carbons. In some embodiments, a haloalkyl contains 1-4 carbons. In some embodiments, a haloalkyl contains 1-3 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 that contains 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 one, two, or three 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 and which may contain a single ring, 2 fused rings, or 3 fused rings, in which at least one ring is aromatic and at least one ring atom is a heteroatom selected, for example, from O, S, and N. Some embodiments, such as, for example, 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, and 1,2,3,4-tetrahydroquinolinyl, contain from 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 that 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. Heterocycloalkyl groups 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, where two of the rings share one common atom and at least one of the rings is a cycloalkyl ring containing the indicated number of carbon atoms. Examples include spirocyclopropane and spirocyclobutane.

[0040] Methods of Using the Compounds of the Invention The compounds of the present invention are useful for treating 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 itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, adverse drug responses.Therefore, administration or use of the preferred MrgprX2 antagonists described herein, such as the MrgprX2 antagonists described above, such as the compounds of formula I, provides a means of improving 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 [Method 1] for treating an inflammatory disorder, comprising administering to a subject in need thereof a topical or oral composition comprising a therapeutically effective amount of an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) and a dermatologically or orally acceptable excipient.

[0042] The present disclosure further provides a further embodiment of Method 1 as follows: 1.1 Method 1, wherein the MrgprX2 antagonist is a compound according to formula I above; 1.2 Method 1.1, wherein the MrgprX2 antagonist is a compound according to any 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 pharma- ceutically acceptable salt thereof; 1.4 Any of the preceding methods, wherein the composition is in the form of a cream, gel, spray, or ointment. 1.5 Any of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001% by weight to about 10% by weight based on the total weight of the composition. 1.6 Any of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1% to about 5% by weight based on the total weight of the composition. 1.7 Any of the preceding methods further comprising a skin absorption enhancer. 1.8 Any of the preceding methods further comprising a skin absorption enhancer, including one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 1.9 Any of the preceding methods, wherein the composition is applied to the patient's skin once daily. 1.10 Any of the preceding methods, wherein the composition is applied to the patient's skin twice daily. 1.11 Any of the preceding methods, wherein the composition is applied to the patient's skin three times a day. 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 a 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, wherein 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 [Method 2] 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 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 pharma- ceutically 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 at a concentration of about 0.001% by weight to about 10% by weight based on the total weight of the composition. 2.7 Any of the preceding methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1% to about 5% by weight based on the total weight of the composition. 2.8 Any of the preceding methods further comprising a skin absorption enhancer. 2.9 Any of the preceding methods further comprising a skin absorption enhancer including one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 2.10 Any of the preceding methods, wherein the composition is applied to the patient's skin once daily. 2.11 Any of the preceding methods, wherein the composition is applied to the patient's skin twice daily. 2.12 Any of the preceding methods, wherein the composition is applied to the patient's skin three times a day. 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 a 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, wherein the subject is a human. 2.20 Any of the preceding methods, wherein 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 from administration. 3.3 Method 3 or 3.1, wherein the severity of itch is reduced over a 12 hour period from administration. 3.4 Method 3 or 3.1, wherein the severity of itch is reduced over an 18 hour period from administration. 3.5 Method 3 or 3.1, wherein the severity of itch is reduced over a 24 hour period from 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 pharma- ceutically acceptable salt thereof. 3.7 Any of the preceding methods, wherein the composition is in the form of a cream, gel, spray, or ointment. 3.8 Any of the preceding methods, wherein the MgrprX2 antagonist is present in a concentration of about 0.001% to about 10% by weight based on the total weight of the composition. 3.9 Any of the preceding methods, wherein the MgrprX2 antagonist is present in a concentration of about 0.1% to about 5% by weight based on the total weight of the composition. 3.10 Any of the preceding methods further comprising a skin absorption enhancer. 3.11 The prior method wherein the skin absorption enhancer comprises one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes. 3.12 Any of the preceding methods, wherein the composition is applied to the patient's skin once daily. 3.13 Any of the preceding methods, wherein the composition is applied to the patient's skin twice daily. 3.14 Any of the preceding methods, wherein the composition is applied to the patient's skin three times daily. 3.15 Any of the preceding methods, wherein the composition is administered to a patient suffering from an inflammatory disorder. 3.16 Any of the preceding methods, wherein the inflammatory disorder is a skin disorder. 3.17 Any of the preceding methods, wherein the skin is human skin. 3.18 Any of methods 1.12-1.14, wherein the inflammatory disorder activates or is the result of activation of MrgprX2. 3.19 The preceding methods, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by a 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, wherein the subject is a human. 3.22 Any of the preceding methods, wherein 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 be present on the skin of any part of the body, but is more common on the hands, feet, upper chest, and crooks of the elbows or knees. Additional symptoms of atopic dermatitis can include small raised bumps or thickened, scaly skin.

[0048] "Psoriasis" is a chronic skin condition associated with an excessive immune response. Psoriasis can be present on the skin of any part of the body. Symptoms of psoriasis include localized inflammation, skin flaking, and thick white or red discolored areas of 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 urticaria" (hives) is a common skin rash that can be triggered by many things, including certain foods, medicines, and stress. Symptoms can include itchy, raised, red or skin-colored swellings on the skin surface. Considering the role of mast cells in chronic idiopathic urticaria, MrgprX2 shares a key function in mast cell activation. Antibacterial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and several FDA-approved peptide agonist drugs activate human MrgprX2. Unique properties of MrgprX2 that distinguish them from other GPCRs include their presence at both plasma membrane and intracellular sites, as well as their selective expression in MCs. Furthermore, small molecule inhibitors of MrgprX2 may be beneficial for the treatment of MC-dependent allergic and inflammatory disorders, such as chronic urticaria, which are currently treated by targeting the IgE axis of mast cell activity. However, diverse MC activities are dependent on ligand binding to MrgprX2 (Subramanian H et al., 2016, The Journal of Allergy and Clinical Immunology, 138(3), 700-710; https: / / doi.org / 10.1016 / j.jaci.2016.04.051), suggesting that targeting MRGPRX2 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 has become hypersensitive. Mast cell activation via MRGPRB2 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 has a central role in non-histaminergic mast cell activation and in a variety of 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 share 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 Medicine of Sciences,865,141-146.https: / / doi.org / 10.1111 / j.1749-6632.1998.tb11172.x) have 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,BDet 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 affect mast cell activity and vasodilation, these findings together suggest MrgprX2 as a newly emerged 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, hallmark phenomena of asthma. In healthy conditions, only low amounts of transcripts are present, but in severe asthma, characterized by a phenotypic switch of MCTCs from MCTs, levels of MrgprX2 transcripts increase. 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 would 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] "Mammals" 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 wildlife.

[0055] "Therapeutically effective amount" refers to the amount of the compound of the present invention that is sufficient when administered to a mammal, preferably a human, to achieve the treatment of the desired 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 purpose of the present invention, a "therapeutically effective amount" is the amount of the compound of the present invention that is sufficient to inhibit inflammation of the skin.

[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 the occurrence of a disease or condition 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 the 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 thus 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 (eg, 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 skin penetration enhancers, preservatives, viscosity enhancers, pH adjusters, film formers, etc. Non-limiting examples of suitable excipients include water, PEG 200, PEG 400, 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 enhancing agent and an emulsifier.

[0062] The skin (particularly the stratum corneum) provides a physical barrier against the harmful effects of the external environment. In so doing, the skin also interferes with the absorption or transdermal delivery of topical therapeutic drugs. Thus, suitable dermatologically acceptable excipients can include one or more penetration enhancers (or permeation enhancers), which are substances that promote the diffusion of therapeutic drugs (e.g., MrgprX2 antagonists described herein) through the skin barrier. They typically act to reduce the barrier or resistance of the skin, allowing for improved penetration of therapeutic drugs. Specifically, substances that will 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 a direct effect, or any substance that will affect proteins, causing an 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 1-16 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-methylform ... 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 transesterified 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 Ingredients include: 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 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 pentanediones; lanolin derivatives such as lanolin alcohol, PEG16 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] Topical compositions described herein typically contain one or more carriers, preferably having a vapor pressure of 23.8 mm Hg or greater at 25° C. Preferred concentration ranges of a single carrier or total combination of carriers may 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 composition 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 less than water (about 23.8 mm Hg) at 25°C. The carrier typically has a vapor pressure equal to or greater than that of the hydrophilic cosolvent in order 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 in the molecular weight range of 200 to 20,000. Preferably, the solvent will be part of the class of glycol ethers. 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 number 001893} or ethyoxydiglycol. Another preferred co-solvent is 1,3-dimethyl-2-imidazolidinone (DMI).

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

[0067] In certain embodiments, the pharmaceutical composition includes a viscosity enhancer or emulsifier. A gelling agent is used to increase the viscosity of the final composition. An emulsifier is a substance that stabilizes an emulsion. A viscosity enhancer may also act as an emulsifier. Typically, the concentration and combination of the viscosity enhancer will depend on the physical stability of the finished product. The preferred concentration range of the viscosity enhancer 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 polymers, 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 composition of the present invention to minimize bacterial and / or fungal over the shelf life. A preferred concentration range of the preservative in the dermatological composition of the present invention may be from about 0.001% to about 0.01%, more preferably from about 0.01% to about 0.5% by weight of the dermatological composition. Non-limiting examples for use herein include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben. More specifically, the preservative may be a combination of methylparaben and propylparaben.

[0070] The topical compositions described herein may optionally include one or more chelating agents. As used herein, the term "chelating agent" or "chelator" refers to a skin benefit agent capable of removing metal ions from a system by forming a complex such that the metal ions cannot readily participate in or catalyze chemical reactions. Chelants for use herein are preferably formulated at a concentration ranging from about 0.001% to about 10%, more preferably from about 0.05% to about 5.0% by weight of the dermatological composition. Non-limiting examples for use herein include EDTA, disodium edeate, dipotassium edeate, 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 compatible cosmetically acceptable adjuvants that are commonly used, 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 composition 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 dimethylsulfoxide (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) may 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 in the manufacture, packaging, shipping, and / or storage of a dermatologically acceptable composition. The compound of the present disclosure may be present in a solution, partially in a solution with undissolved portions, or in a suspension that is not completely dissolved. The compound of the present disclosure may be present in the dermatological composition of the present invention in a concentration range of about 0.001% to about 80% by weight, about 0.001% to about 50% by weight, about 0.001% to about 25% by weight, 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 itch such as cholestatic or uremic itch, chronic itch caused by systemic disease, or adverse drug responses, topical compositions containing the compounds of the present disclosure are preferably administered directly to the affected area of ​​the skin (e.g., itchy skin) of the human in need of treatment. During use of such compositions (e.g., dermatological compositions containing the compounds of the present disclosure), and when the dermatologically acceptable excipient is placed on the skin of the human 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 composition of the present invention.

[0077] 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 if desired.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.A dermatologically acceptable adhesive can be used to attach the patch to skin for a long period of time.

[0078] Oral route In some embodiments, the pharmaceutical composition herein is provided for oral administration.Therefore, a solid, semi-solid or liquid dosage form for oral administration comprising the compound described herein is provided according to the present disclosure.Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, pellets, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.In addition to the active ingredient, the pharmaceutical composition may contain one or more pharma-ceutically 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 provide 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, extract of Irish moss, Panwar gum, ghatti gum, mucilage of psyllium husk shell, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, methyl paraben, polyalkylene oxide, povidone, polyvinylpyrrolidone (PVP), crospovidone, Veegum, larch arabicol, glyceryl stearate ... Natural and synthetic gums such as arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, 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; clays; align, and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of skill 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 and certified water-soluble FD&C dyes, and water-insoluble FD&C dyes suspended on alumina hydrate, and lake colors, and mixtures thereof. Lake colors are combinations of water-soluble dyes by adsorption 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, syrups, 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 that are 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 that may be beneficial in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets that are 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 may 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 can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two compartments, one over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, globular shells, such as gelatin shells, that are plasticized by adding glycerin, sorbitol, or similar polyols. Soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid 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 can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, which can be oil-in-water or water-in-oil, in which one liquid is dispersed throughout another in the form of small globules. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl)acetals of lower alkyl aldehydes, e.g., acetaldehyde diethyl acetal, and water-miscible solvents with one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, e.g., sucrose, and can also contain preservatives. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, for example water, to be conveniently measured 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 weight 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 metasulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0090] The pharmaceutical compositions provided herein for oral administration can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can 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 are reconstituted into liquid dosage forms.The pharma-ceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents.The pharma-ceutically 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.Thus, in some preferred embodiments, the active ingredient (i.e., calcium channel blocker, or L-arginine, or combination of calcium channel blocker and L-arginine, or their pharma- ceutically acceptable salts, hydrates, solvates, and prodrugs) is administered in a pharmaceutical composition that is preferably an immediate release oral dosage form, with but not necessarily including enteric coating.In some preferred embodiments, the active ingredient is administered in a pharmaceutical composition that is preferably an extended release oral dosage form, with but not necessarily including enteric coating.In further preferred embodiments, the active ingredient is administered in a pharmaceutical composition that contains both an immediate release dose and an extended or pulse release dose of calcium channel blocker, with but not necessarily including enteric coating. Such dual release dosage forms achieve the release of an initial dose of active ingredient followed by a time-delayed 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 that contains one or more polymer matrix materials that promote sustained, delayed or pulsatile release profile.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®, such as Carbopol® 71G NF, Carbopol® 971P NF and Carbopol® 974P NF polymers.

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

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

[0097] Dosage The compositions provided herein contain one or more of the compounds provided herein in a therapeutically effective amount, 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 such carriers known to those skilled in the art to be suitable for a particular mode of administration, preferably topically, orally or via injection.In addition, the compounds 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 a therapeutically useful effect 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 the dosage for humans can be extrapolated therefrom.The human dosage is then typically fine-tuned and titrated to response in clinical trials.

[0099] The concentration of 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 dosing schedule and the dosage, 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 (MgrprX2 antagonist as 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 time intervals.It is understood that the exact dosage and duration of treatment can be determined empirically using known test protocols, or by inference from in vivo or in vitro test data, or subsequent clinical trials, depending on the disease being treated.It should be noted that concentration and dosage values ​​can also vary depending on the severity of the condition being alleviated.It is further understood that for any particular subject, specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0102] Dosage forms or compositions can be prepared that contain active ingredients in the range of 0.005% to 100%, with the remainder consisting of vehicles or carriers. 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 a day. 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 a day, for example, two or three times a day, 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 0.001% to 20% by weight of the composition, for example 0.001% to 10% by weight of the composition, for example 0.001% to 8% by weight, for example 0.001% to 5% by weight, for example 0.001% to 4% by weight, for example 0.001% to 3% by weight, for example 0.001% to 2% by weight, for example 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 article provided herein contains packaging material. Packaging material for use in packaging products is 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 material 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 the various treatments for any disease or disorder described herein.

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

[0111] Example 1 - Preparation of compounds according to the present disclosure Compound E001 TIFF0007645256000005.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 uL, 3.69 mmol) were mixed in DMSO (7.5 mL), purged with nitrogen and stirred at 50° C. for 4 h in a sealed vial. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, 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 h. 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 as a pale yellow oil (39 mg). 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. TIFF0007645256000006.tif37166TIFF0007645256000007.tif221166TIFF0007645256000008.tif225166TIFF0007645256000009.tif216166TIFF0007 645256000010.tif216166TIFF0007645256000011.tif225166TIFF0007645256000012.tif225166TIFF0007645256000013.tif225166TIFF00076452560 00014.tif212166TIFF0007645256000015.tif220166TIFF0007645256000016.tif221166TIFF0007645256000017.tif220166TIFF0007645256000018.tif225166TIFF0007645256000019.tif220166TIFF0007645256000020.tif212166TIFF0007645256000021.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 TIFF0007645256000022.tif17128(1R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]-2,2-dimethyl-cyclopropanecarboxamide

[0117] Synthesized from compound E029 using chiral separation under the following conditions: Chiralpak AD-H column (20 x 250 mm, 5 μm), methanol mobile phase (9 mL / min) was used to give a colorless oil as the second eluting component. Absolute stereochemistry was confirmed by comparison with compound E043. 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 TIFF0007645256000023.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 mixed 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 was continued to stir for 3 h. The reaction mixture was diluted with water (50 mL). The mixture was extracted with EtOAc (3 x 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 SiO2 column, 0-80% EtOAc in heptane) to give 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 / H2O (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 h, followed by MeOH (1 mL) and 1 M NaOH (1 mL) and the reaction mixture was stirred at room temperature for 2 h. 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 red-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 balloon of hydrogen and stirred at room temperature for 16 h. A further portion of 10% palladium on carbon (4.3 mg, 0.0406 mmol) was added and the mixture was placed under a balloon of hydrogen and stirred at room temperature for 5 h. The reaction mixture was filtered through Celite and the Celite was washed with further 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 fitted with a 10% Pd / C cartridge at a reaction temperature of 80° C. at a flow rate of 1 ml / min. The hydrogen generated was fed to the flow at 80 bar. The crude mixture was then passed two more times through an H-cube 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) then 2M 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 TIFF0007645256000024.tif27128N-[5-(2-hydroxy-2-methyl-propoxy)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0124] Synthesized using a similar method as used for compound E079 starting from 2-methyl-2-(phenylmethoxy)-1-propanol. 1H NMR (500MHz, chloroform-d) δ 8.11 (d, J=9.0Hz, 1H), 7.95 (d, J=2.9Hz, 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 TIFF0007645256000025.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 x 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 charcoal (50 mg, 0.470 mmol) was added and stirred under 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. 1H 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 h. The reaction mixture was washed with saturated NaHCO3 (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 h before being 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 TIFF0007645256000026.tif22128N-[5-(2-hydroxyethoxy)pyridin-2-yl]-2,2,3,3-tetramethylcyclopropane-1-carboxamide

[0130] Synthesized using a similar method as used for compound E078, except starting from benzyloxyethanol and using sodium hydride as the base and DMF as the solvent in step 1. 1H 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 similar method 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. TIFF0007645256000027.tif167166TIFF0007645256000028.tif221166*Compounds E089 and E090 were isolated as products from the same reaction.

[0132] Compound E093 TIFF0007645256000029.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 DMF-anhydrous (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 (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 25 g, eluted with 20–100% EtOAc in heptane) to give 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 uL, 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 h, 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 h. The reaction mixture was diluted with brine (10 mL), 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 TIFF0007645256000030.tif20128N-(5-anilino-2-pyridyl)-2-methyl-propanamide

[0136] Step 1 To a stirred solution of isobutyric anhydride (359 uL, 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 uL, 2.89 mmol) was added followed by N,N-dimethylpyridin-4-amine (18 mg, 0.145 mmol) in a sealable pressure tube and stirred at 80 °C for 2 h. 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) was added toluene (3 mL). Aniline (29 mg, 0.314 mMol) was then added and the mixture was degassed under nitrogen for 10 min at room temperature. 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 h before being cooled to room temperature. The reaction mixture was filtered through Celite with EtOAc (30 mL). It was then washed with saturated NaHCO3 (30 mL), followed by brine (30 mL), dried over sodium sulfate, filtered and evaporated to dryness. Purification by preparative HPLC (Method F) afforded 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 TIFF0007645256000031.tif22128N-(5-indolin-1-yl-2-pyridyl)-2-methyl-propanamide

[0139] Synthesized using a similar method 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 TIFF0007645256000032.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 Pd2(dba)3 (45 mg, 0.0493 mmol) in DME (5 mL) was added cesium carbonate (482 mg, 1.48 mmol) and degassed at room temperature under nitrogen for 10 min. To this was added N-methylaniline (0.13 mL, 1.18 mmol) and (R)-BINAP (61 mg, 0.0985 mmol) and the reaction vessel was sealed and heated to 100° C. with stirring for 4 h, 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 uL, 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 uL, 0.602 mmol) followed by N5-methyl-N5-phenyl-pyridine-2,5-diamine (80 mg, 0.402 mmol) in a sealable pressure tube and stirred 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 give 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. TIFF0007645256000033.tif207166

[0145] Compound E102 TIFF0007645256000034.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 / grey 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 min. 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 MgSO4, and concentrated under reduced pressure to give 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 2M ethanamine in THF (4.0 mL, 8.03 mmol) 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 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 not observed.)

[0149] Step 4 A solution of pyridine (40 uL, 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 uL, 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 a similar method to that used for compound E102, using either commercially available amines or amino alcohols synthesized according to compound E102, step 3. TIFF0007645256000035.tif216166TIFF0007645256000036.tif225166TIFF0007645256 000037.tif220166TIFF0007645256000038.tif225166TIFF0007645256000039.tif22016 6TIFF0007645256000040.tif220166TIFF0007645256000041.tif207166TIFF0007645256 000042.tif225166TIFF0007645256000043.tif225166TIFF0007645256000044.tif73166

[0151] Compound E139 TIFF0007645256000045.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 N2 was added (2R)-2-(trifluoromethyl)oxirane (200 mg, 1.78 mmol) followed by THF-anhydrous (8 mL) and the stirred solution was cooled to 100°C in an Et2O / 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 min. Iodomethane (0.17 mL, 2.68 mmol) was then added and the reaction was stirred at this temperature for 2 h, warmed to about 0°C in an ice bath to which was added 2 M methanamine (3.6 mL, 7.14 mmol) and the reaction was allowed to warm to room temperature and 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 as an orange viscous gum (1.10 g). 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 uL, 0.233 mmol) in anhydrous THF (1 mL) and the reaction was stirred at room temperature for 3 hours. 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 uL, 0.317 mmol) in anhydrous THF (1.5 mL) were added and the reaction was stirred at room temperature for 45 minutes. 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 TIFF0007645256000046.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 (500MHz, DMSO-d6) δ 9.28(s,1H), 8.14(d,J=2.8Hz,1H), 7.86(d,J=9.0Hz,1H), 7.59(dd,J=9.1,3.0Hz,1H), 6.98(tt,J=9.3,2.3Hz,1H), 6.78-6.68(m,2H), 3.72(d,J=13.9Hz,1H), 3.46(d,J=14.4Hz,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 TIFF0007645256000047.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. 1H 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 [MH]-, (ESI-), RT=3.30 (Method A).

[0158] Compound E142 TIFF0007645256000048.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 DMF-anhydrous (3.5 mL) and the reaction mixture was cooled to 0° C. before sodium hydride (60%, 106 mg, 2.64 mmol) was added in small portions. The reaction was then stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with water (10 mL) forming a pale yellow precipitate which 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 h. 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 h. 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 h. 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 TIFF0007645256000049.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 h. 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 uL, 0.360 mmol) followed by 2-methylpropanoyl chloride (32 uL, 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 and the residue was dissolved in MeOH (1 mL) and 1M NaOH (1 mL) was added and the reaction mixture was stirred at room temperature for 0.5 h. 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 MgSO4, filtered, concentrated under reduced pressure and purified by flash column chromatography (10 g SiO2 column, 0-60% EtOAc in heptane) to give the title compound as a white solid (39 mg). 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 TIFF0007645256000050.tif22128N-[4-(3,5-difluorophenoxy)-2-pyridyl]cyclopropanecarboxamide

[0166] Synthesized using a method similar to that used for compound E143. 1H NMR (500MHz, DMSO-d6) δ 10.92 (s, 1H), 8.25 (d, J = 5.7Hz, 1H), 7.71 (d, J = 2.3Hz, 1H), 7.20 (tt, J = 9.4, 2.3Hz, 1H), 7.12-6.97 (m, 2H), 6.77 (dd, J = 5.7, 2.4Hz, 1H), 1.98 (tt, J = 6.2, 6.2Hz, 1H), 0.78 (d, J = 6.2Hz, 4H). LCMS: m / z 291.1 [M+H]+, (ESI+), RT = 2.83 (Method A).

[0167] Compound E145 TIFF0007645256000051.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 was added N-ethyl-N-isopropyl-propan-2-amine (1.4 mL, 7.78 mmol), 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) gave a white solid. This 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 TIFF0007645256000052.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 was added a solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (497 mg, 3.10 mmol) in DCM (1 mL) and stirred for 2 h. The reaction mixture was washed with saturated NaHCO3 (2 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in MeOH (5 mL) and 1N NaOH solution (3 mL) and stirred at room temperature for 1 h, after which the solvent was evaporated in vacuum and the residue was washed with brine (15 mL), extracted with EtOAc (3 x 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. 1H 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 min. 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 TIFF0007645256000053.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 uL, 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 h, 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 h. 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. 1H 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 DMF-anhydrous (3 mL) was added sodium hydride (60% dispersion in oil) (24 mg, 0.603 mmol). After gas evolution was stopped, 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 x 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 TIFF0007645256000054.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 1,4-dioxane-anhydrous (8 mL) and the reaction mixture was degassed with N2 for 5 min. 4-Iodopyridin-2-amine (350 mg, 1.59 mmol) was added and the reaction was stirred for 10 min, after which 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 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (15 mL), filtered through a pad of Celite and further washed with EtOAc (30 mL). It was then washed with water (15 mL), extracted with EtOAc (2 x 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. 1H 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) was added 4-[(6-fluoro-3-pyridyl)oxy]pyridin-2-amine (87%, 33 mg, 0.138 mmol) and the mixture was stirred at room temperature for 2 h. Tetramethylcyclopropane-1-carbonyl chloride (10 mg, 0.2 equiv.) and DIPEA (12 uL, 0.2 equiv.) were further added and stirred at room temperature for 45 min. 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 TIFF0007645256000055.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] Dipotassium carbonate (100 mg, 0.724 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (140 uL, 0.972 mmol) were further 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 h and then left 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 h. 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 h then 2 M sodium hydroxide (1.0 mL, 2.00 mmol) was added and the reaction was stirred at 60° C. for 3 h. The methanol was removed in vacuo and the mixture was extracted with EtOAc (4×5 mL). The reaction was dried over MgSO4, concentrated and purified by preparative HPLC (Method G) to give the title compound (47 mg, 77% yield) as an off-white solid. 1H 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 TIFF0007645256000056.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 h. 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 MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 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 a further 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 2M 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 the amino alcohol synthesized according to intermediate I02 or compound E139, step 1, the following compounds were synthesized using a method similar to that used for compound E150. TIFF0007645256000057.tif82166TIFF0007645256000058.tif220166TIFF0007645256000059.tif216166TIFF0007645256000060.tif73166

[0188] Compound E162 TIFF0007645256000061.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 h. 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 NH3 / MeOH (5 CV) to give 4-[(5-fluoro-3-pyridyl)oxy]pyridin-2-amine (180 mg, 85% purity, 85% yield) as a brown oil. 1H 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 a solution of 4-[(5-fluoro-3-pyridyl)oxy]pyridin-2-amine (85%, 60 mg, 0.249 mmol) and pyridine (20 uL, 0.249 mmol) in anhydrous DCM (2 mL) dropwise over 10 min. The reaction was stirred at -78°C for 5 min. Then (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 uL, 0.373 mmol) in anhydrous DCM (2 mL) were added and the reaction was stirred at -78°C for 5 min and then in an ice bath for 1 h. 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 TIFF0007645256000062.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 for the synthesis of compound E162. 1H 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 TIFF0007645256000063.tif251282-Methyl-N-(5-phenyl-2-pyridyl)propanamide

[0194] Step 1 To a stirred solution of isobutyric anhydride (719 uL, 4.34 mmol) and 5-bromopyridin-2-amine (500 mg, 2.89 mmol) in THF (15.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1009 uL, 5.78 mmol) followed by N,N-dimethylpyridin-4-amine (35 mg, 0.289 mmol) and 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 1,4-dioxane-anhydrous (2 mL) and 2M Na2CO3 (0.29 mL, 0.576 mmol) and the reaction mixture was degassed with N2 for 5 min. Pd(dppf)Cl2 (11 mg, 0.0144 mmol) was then added and the reaction was heated to 110° C. for 2 h. 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. TIFF0007645256000064.tif177170TIFF0007645256000065.tif169170

[0197] Compound E177 TIFF0007645256000066.tif23128N-(5-Cyclopentyl-2-pyridyl)-2-methyl-propanamide

[0198] To a solution of N-[5-(cyclopenten-1-yl)-2-pyridyl]-2-methyl-propanamide (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% CH2O2) in MeCN (+0.1% CH2O2) (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 TIFF0007645256000067.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 1,4-dioxane-anhydrous (55 mL) and 2M Na2CO3 (6.0 mL, 12.0 mmol) and the reaction mixture was degassed with N2 for 5 min. To the reaction was added Pd(dppf)Cl2 (212 mg, 0.289 mmol) and the reaction was heated to 110° C. for 2.5 h. It was then cooled to room temperature and concentrated under reduced pressure to 20 mL, 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 7N NH3 / MeOH). It 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 acetonitrile-anhydrous (3 mL) was stirred at room temperature for 1 h. 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 h and then at 80° C. for 2 h. The reaction was re-treated 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 Na2SO4, 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. 1H NMR (500 MHz, DMSO-d6) 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. TIFF0007645256000068.tif78170TIFF0007645256000069.tif234170*Compound E186 was isolated as a by-product from the synthesis of E187.

[0203] Compound E189 TIFF0007645256000070.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 1,4-dioxane-anhydrous (2.15 mL) and 2M Na2CO3 (0.47 mL, 0.949 mmol) was added to the reaction mixture and degassed with nitrogen for 5 min. Palladium-triphenylphosphane (1:4) (26 mg, 0.0227 mmol) was then added, degassed for another 5 min and stirred at 110 °C for 1.5 h. 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 2M 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 THF-anhydrous (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 SCX cartridge (2 g) eluting first with MeOH (3 CV) and then with 2M 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. 1H NMR (400 MHz, DMSO-d6) 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 TIFF0007645256000071.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 TIFF0007645256000072.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 uL, 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 uL, 0.733 mmol) were added and the mixture was stirred at room temperature for another 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 0-100% 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 similar method to that used for compound E191 using aminopyridines either synthesized according to the method for intermediate I03 or from commercial sources. TIFF0007645256000073.tif217170

[0211] Compound E197 TIFF0007645256000074.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 min, after which 2-(tributylstannanyl)-1,3-oxazole (0.79 mL, 2.58 mmol) was added and the reaction was degassed before being sealed and stirred at 90° C. for 18 h. 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 min. 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 before the aqueous solution was extracted again with EtOAc (20 mL). The organics were combined, washed with brine (15 mL), dried over MgSO4, 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. 1H NMR, (400 MHz, DMSO-d6) 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 give 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 uL, 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 uL, 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, (500MHz, chloroform-d) δ 8.89 (d, J=1.8Hz, 1H), 8.29 (dd, J=8.9, 2.3Hz, 1H), 8.15 (d, J=8.8Hz, 1H), 7.73 (d, J=0.7Hz, 1H), 7.24 (d, J=0.7Hz, 1H), 4.27-4.18 (m, 1H), 3.77 (dd, J=15.2, 8.8Hz, 1H), 3.63-3.53 (m, 2H), 3.48 (dq, J=14.6, 7.0Hz, 1H), 1.32 (t, J=7.2Hz, 3H). No OH or NH observed. LCMS: m / z 345.1 [M+H]+, (ESI+), RT=2.47 (Method A).

[0215] Compound E198 TIFF0007645256000075.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 TIFF0007645256000076.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 uL, 0.114 mmol). The reaction mixture was again purged with nitrogen, then the tube was sealed and heated to 110° C. for 15 h. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite, washing with MeOH (20 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (25 g SiO2 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 min. The solvent was then removed under a steady stream of nitrogen, MeOH (2 mL) and 1 M NaOH (2 mL) were added and the reaction mixture was stirred at room temperature for 1 h. 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 TIFF0007645256000077.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 TIFF0007645256000078.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 uL, 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 another 0.5 h. The solvent was then removed under a steady stream of nitrogen, MeOH (4 mL) and 1 M NaOH (4 mL) were added and the reaction mixture was stirred at 45° C. for 4 h and at room temperature for 16 h. Methanol was removed under reduced pressure, the precipitate was filtered, washed with water (10 mL), and purified by flash column chromatography (10 g SiO2 column, 0-60% EtOAc in heptane) to give the title compound as an off-white solid (125 mg). 1H NMR (500 MHz, DMSO-d6) 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. TIFF0007645256000079.tif61170TIFF0007645256000080.tif217170TIFF0007645256000081.tif230170

[0225] Compound E217 TIFF0007645256000082.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 N2 for 5 min. 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 h. 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 MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 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-Phenoxypyrazine-2-amine (50 mg, 0.267 mmol) was dissolved in DCM (2 mL) and N-ethyl-N-isopropyl-propan-2-amine (70 uL, 0.401 mmol) was added followed by 2-methylpropanoyl chloride (31 uL, 0.294 mmol). The reaction was stirred at room temperature for 15 minutes. Further N-ethyl-N-isopropyl-propan-2-amine (70 uL, 0.401 mmol) and 2-methylpropanoyl chloride (31 uL, 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 1M 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). 1H NMR (250 MHz, DMSO-d6) 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. TIFF0007645256000083.tif138170TIFF0007645256000084.tif155170

[0229] compound 226 TIFF0007645256000085.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 1,4-dioxane-anhydrous (10 mL) and 2M Na2CO3 (1.8 mL, 3.60 mmol) and the reaction mixture was degassed with N2 for 5 min. To the reaction was added Pd(dppf)Cl2 (63 mg, 0.0862 mmol) and the reaction was heated to 110 °C for 2.5 h. 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 x 20 mL). The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 0-100% EtOAc in heptane) to give 5-(2,5-difluorophenyl)pyrazin-2-amine (Intermediate I06) as a yellow solid (295 mg). 1H NMR (400 MHz, DMSO-d6) 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 as an off-white solid (39 mg). 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. TIFF0007645256000086.tif159170

[0233] Compounds E231 and E232 TIFF0007645256000087.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 give a single unknown enantiomer. Method: Cellulose-4 column, 21.2 x 250 mm, 5 μm, 90:10 heptane:ethanol, flow rate of 18 mL / min.

[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 TIFF0007645256000088.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 uL, 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 MgSO4, 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. 1H 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 TIFF0007645256000089.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 similar method as Intermediate I05, 50 mg, 0.224 mmol) and pyridine (20 uL, 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 uL, 0.291 mmol) and N-ethyl-N-isopropyl-propan-2-amine (59 uL, 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. 1H 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 similar method as in step 1, the following compounds were synthesized using a similar method as used for compound E234. TIFF0007645256000090.tif190170TIFF0007645256000091.tif221170TIFF0007645256000092.tif204170 TIFF0007645256000093.tif212170TIFF0007645256000094.tif217170TIFF0007645256000095.tif243170

[0243] Compound E265 TIFF0007645256000096.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 1,4-dioxane-anhydrous (4.7 mL) and the reaction mixture was degassed with N2 at room temperature for 5 min. Then, 0.5 M bromo-[(3,5-difluorophenyl)methyl]zinc (14 mL, 6.79 mmol) was added slowly and the reaction was stirred at 60 °C for 2 h. The reaction mixture was then cooled to room temperature and diluted with EtOAc (25 mL), aqueous NaHCO3 (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 MgSO4, 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 give 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 4M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol) and stirred at room temperature for 3 h. Further 4M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol) was added and the mixture was stirred at room temperature for 7 h. It was then concentrated in vacuo and passed through an SCX-2 column (5 g) (flushed with MeOH (2 CV), then 7N 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 as 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. TIFF0007645256000097.tif124170

[0248] Compound E269 TIFF0007645256000098.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), no OH was observed.

[0250] Step 2 2-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid (50 mg, 0.172 mmol) was dissolved in DMF-anhydrous (1.5 mL) and N-ethyl-N-isopropyl-propan-2-amine (90 uL, 0.515 mmol) was added followed by HATU (98 mg, 0.257 mmol). After stirring for 10 min, 2,2,2-trifluoroethanamine (20 uL, 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 x 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 as a white solid (48 mg). 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 TIFF0007645256000099.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 similar method as 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 TIFF0007645256000100.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 similar method as 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 min and then at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure. To the mixture was 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 min and then at 60° C. for 30 min. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method G) to give 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 TIFF0007645256000101.tif331282,2,3,3-Tetramethyl-N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-pyridyl]cyclopropanecarboxamide

[0257] Synthesized using a similar method as 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 TIFF0007645256000102.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 (2×30 mL). The combined organics were dried (MgSO4), 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. 1H NMR, (500 MHz, DMSO-d6) 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 give the title compound (6.1 mg, 15% yield) as a white solid. 1H 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 TIFF0007645256000103.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 similar method as 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 give 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 (400MHz, chloroform-d) δ 8.72 (d, J = 1.4Hz, 1H), 8.17-8.12 (m, 2H), 8.10 (dd, J = 8.7, 2.2Hz, 1H), 7.76 (d, J = 12.2Hz, 1H), 5.58 (d, J = 12.3Hz, 1H), 3.27 (d, J = 6.9Hz, 3H), 2.21 (d, J = 9.2Hz, 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 give 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 TIFF0007645256000104.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 similar method as 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. A further 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 colourless 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 ethynediide (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 had 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 washed with chloroform (2×10 ml). The aqueous solution was then separated and the organics 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 TIFF0007645256000105.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 in small portions 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 h, 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 THF-anhydrous (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 after stirring for 10 min, 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)-hydroxy-methyl]-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 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 Using a similar method to compound E164 (step 1), starting from 5-[(3-fluorophenyl)methyl]pyridin-2-amine (50 mg, 0.242 mmol), the title compound (49 mg, 74% yield) was obtained 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 TIFF0007645256000106.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 h. 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 diamide (22 mg, 0.225 mmol) were stirred in 1,4-dioxane-anhydrous (0.9 mL) for 16 h at 95° C. 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 TIFF0007645256000107.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 (400MHz, 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. TIFF0007645256000108.tif231170

[0278] Compound E284 TIFF0007645256000109.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 DCM-anhydrous (38 mL) was stirred under air for 23 h. Further copper(II) diacetate (145 mg, 0.2 equiv.) and DCM-anhydrous (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 (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. 1H 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 min, 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 h. Then, cooled 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 TIFF0007645256000110.tif181281-[5-(3,4-difluorophenoxy)-2-pyridyl]-3,3-dimethyl-pyrrolidin-2-one

[0282] Synthesized using a similar method as used for compound E284. 1H NMR (400MHz, chloroform-d) δ 8.46 (d, J = 9.1Hz, 1H), 8.13 (d, J = 2.9Hz, 1H), 7.37 (dd, J = 9.1, 3.0Hz, 1H), 7.12 (q, J = 9.0Hz, 1H), 6.82 (ddd, J = 11.1, 6.6, 2.9Hz, 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 TIFF0007645256000111.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 sulfurisocyanatidoyl chloride (58 uL, 0.662 mmol). 2-Chloroethanol (44 uL, 0.662 mmol) was then added via syringe over 1 min, maintaining the internal temperature below 2° C. The reaction mixture was stirred for 1 h before adding N-ethyl-N-isopropyl-propan-2-amine (347 uL, 1.98 mmol). 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 min, then stirred at 0° C. for a further 16 h and allowed to come 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 warmed 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 solution (10 mL), followed by saturated aqueous sodium bicarbonate solution (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, 2.9Hz,1H), 3.67(dd,J=15.2,9.9Hz,1H), 3.58(dd,J=15.2,2.8Hz,1H), 3.40(dq,J=14.4,7.2Hz,1H), 3.28(dq,J=14.3,7.1Hz,1H), 1.18(t,J=7.1Hz,3H), NH and OH were not observed. LCMS: m / z 442.2[M+H]+,(ESI+),RT=3.48(Method A).

[0286] Compound E287 TIFF0007645256000112.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 for 18 h in a sealed vial. Additional cesium carbonate (616 mg, 1.89 mmol) was added to the reaction mixture and stirred at room temperature for an additional 24 h. The reaction mixture was filtered and the crude product was purified using preparative HPLC (Method F) to give 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 mixed 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 give 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 h, 2 mL / min, recirculation mode, 10% Pd / C cartridge). Upon completion, the material was dried in vacuum 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 h in a sealed vial. Upon completion, the solvent was removed in vacuum and the crude material was purified using preparative HPLC (Method E) to give 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 TIFF0007645256000113.tif22128N-[6-[(5-fluoro-3-pyridyl)oxy]pyridazin-3-yl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0291] Synthesized using a similar method as used for compound E217 starting from 6-bromopyridazin-3-amine. 1H NMR (500MHz, chloroform-d) δ 8.67(s,1H), 8.60(d,J=9.5Hz,1H), 8.40(d,J=14.0Hz,2H), 7.42(dt,J=9.2,2.3Hz,1H), 7.28(d,J=9.5Hz,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 TIFF0007645256000114.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 MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 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 TIFF0007645256000115.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. 1H NMR (500MHz, DMSO-d6) δ 9.58(s,1H), 8.39(d,J=0.9Hz,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=7.0Hz,3H). LCMS: m / z 389.1[M+H]+,(ESI+),RT=3.19(Method A).

[0297] Compound E291 TIFF0007645256000116.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. 1H NMR (400MHz, DMSO-d6) δ 9.55(s,1H), 8.42(d,J=0.9Hz,1H), 7.53-7.44(m,1H), 7.33(s,1H), 7.20-7.09(m,2H), 7.06(dd,J=8.1,1.6Hz,1H), 4.34-4.20(m,1H), 3.62-3.41(m,5H), 1.09(t,J=7.0Hz,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 5-100% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 5.3 min, then 100% B in 0.5 min. A second gradient of 100-5% B was then applied in 0.02 min and held for 1.18 min with an injection volume of 1 μL at a flow rate of 0.6 mL / min. UV spectra were recorded using a Waters Acquity PDA detector spectral range: 200-400 nm at 215 nm, and ELS data were collected and reported using a Water Acquity ELS detector (when fitted). Mass spectra were obtained using a Waters SQD (MSQ1) or 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 × 100 mm, 1.7 μm column; temperature: 40 °C) and a gradient of 5-100% (A = 2 mM sodium bicarbonate, buffered to pH 10, B = ACN) in 5.3 min, then 100% B in 0.5 min. A second gradient of 100-5% 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 spectral range: 200-400 nm at 215 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0301] Method C Analytical HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm × 50 mm, 5 μm; temperature: 40 °C) and a gradient of 5 to 100% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) for 1.2 min, then 100% B for 0.1 min. A second gradient of 100 to 5% B was then applied for 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 spectral range: 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 × 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) for 0.75 min, then 100% B for 0.1 min. A second gradient of 100 to 5% B was then applied for 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 on a Waters Acquity PDA spectral range 200-400 nm at 215 nm. Mass spectra were obtained 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 of 10 to 95% B (A = 0.1% formic acid in HO, B = 0.1% formic acid in ACN) in 14.44 min, then 2.11 min at 95% B. 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.

[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, then 2.11 min at 95% B. 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: Standard acidic 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, then 2.10 min at 95% B. A second gradient of 95 to 30% 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.

[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, then 2.10 min at 95% B. A second gradient of 95 to 30% B was then applied in 0.21 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded using a Gilson detector at 215 nm.

[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 power cycle of medicinal science. These compounds were characterized for their antagonist activity in recombinant hMrgpMRGPRX2 expressing cells and their potency was confirmed in the human mast cell line LAD-2, 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, the identified compounds are tested for their orthologous activity using recombinant cell lines expressing mouse MrgprB2, mouse MrgprA1, gerbil MrgpMRGPRX2 ortholog, Chinese hamster MrgpMRGPRX2 ortholog, and cynomolgus monkey MrgpMRGPRX2 ortholog, respectively.

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

[0310] (Table 15) TIFF0007645256000117.tif184139TIFF0007645256000118.tif206139TIFF0007645256000119.tif223139TIFF0007645256000120.tif190139TIFF0007645256000121.tif192139TIFF0007645256000122.tif202139TIFF0007645256000123.tif219139TIFF0007645256000124.tif209139TIFF0007645256000125.tif195139TIFF0007645256000126.tif217139TIFF0007645256000127.tif211139TIFF0007645256000128.tif189139TIFF0007645256000129.tif167139TIFF0007645256000130.tif207139TIFF0007645256000131.tif210139TIFF0007645256000132.tif193139TIFF0007645256000133.tif198139TIFF0007645256000134.tif218139TIFF0007645256000135.tif189139TIFF0007645256000136.tif203139TIFF0007645256000137.tif207139TIFF0007645256000138.tif210139TIFF0007645256000139.tif213139TIFF0007645256000140.tif213139TIFF0007645256000141.tif188139TIFF0007645256000142.tif205139TIFF0007645256000143.tif200139TIFF0007645256000144.tif203139TIFF0007645256000145.tif221139TIFF0007645256000146.tif214139TIFF0007645256000147.tif214139TIFF0007645256000148.tif192139TIFF0007645256000149.tif194139TIFF0007645256000150.tif192139TIFF0007645256000151.tif189139TIFF0007645256000152.tif208139TIFF0007645256000153.tif199139TIFF0007645256000154.tif222139TIFF0007645256000155.tif187139TIFF0007645256000156.tif205139TIFF0007645256000157.tif177139TIFF0007645256000158.tif220139TIFF0007645256000159.tif194139TIFF0007645256000160.tif225139TIFF0007645256000161.tif187139TIFF0007645256000162.tif220139TIFF0007645256000163.tif225139TIFF0007645256000164.tif168139TIFF0007645256000165.tif194139TIFF0007645256000166.tif213139TIFF0007645256000167.tif190139TIFF0007645256000168.tif191139TIFF0007645256000169.tif193139TIFF0007645256000170.tif190139TIFF0007645256000171.tif198139TIFF0007645256000172.tif192139TIFF0007645256000173.tif170139TIFF0007645256000174.tif209139TIFF0007645256000175.tif195139TIFF0007645256000176.tif193139TIFF0007645256000177.tif182139.

Claims

1. A compound having the following formula I: During the ceremony, Q, and Z is -C(=O); R １ is H or C １－３ is alkyl, G １ is N, G ２ , G ３ , G ４ and G ５ But -C-L １ -M １ and 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), When L 1 is a bond, M 1 is H; When L 1 is O, —C(═O), —C(═O)—NH—, —CH 2 — or —O—(CH 2 ) w —, M １ is C ６－１０ aryl, wherein said C ６－１０ Aryl is 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 is C2-6 alkyl, where C2-6 alkyl 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 N.R. ５０２ R ５０３ And C ６－１０ aryl; R ５０２ and R ５０３ are independently H or C １－６ is alkyl, A compound, or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof.

2. L １ The compound of claim 1 , wherein is O.

3. L １ But -CH ２ The compound according to claim 1, wherein

4. L １ The compound of claim 1 , wherein is a bond.

5. L １ The compound of claim 1, wherein is -C(=O).

6. L １ The compound of claim 1, wherein is -C(=O)-NH-.

7. R １ The compound according to any one of claims 1 to 6, wherein is H.

8. Said M １ The substituents are independently halogen, CN, -OH, -C(=O)-NH ２ , C.F. ３ , and -OCH ３ The compound according to any one of claims 1 to 7, selected from:

9. M １ The compound according to any one of claims 1 to 8, wherein is optionally substituted phenyl.

10. 10. The compound of claim 9, wherein the phenyl is substituted at the 4-position.

11. 10. The compound of claim 9, wherein the phenyl is substituted at the 3 and 4 positions.

12. 10. The compound of claim 9, wherein the phenyl is substituted at the 3 and 5 positions.

13. The following:

2. The compound of claim 1 , or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof, selected from:

14. A composition comprising a dermatologically or orally acceptable excipient and a compound according to any one of claims 1 to 13.

15. 14. A composition for treating an inflammatory disorder in a subject, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 and a dermatologically or orally acceptable excipient.

16. 16. The composition of claim 15, in the form of a cream, gel, spray, ointment, or oral unit dosage form.

17. The composition of claim 15, wherein the compound is present in a concentration of from 0.001% to 10% by weight, based on the total weight of the composition.

18. The composition of claim 15, wherein the compound is present in a concentration of 0.1% to 5% by weight, based on the total weight of the composition.

19. The composition according to any one of claims 14 to 18, which is for oral administration.

20. The composition of claim 15 further comprising a skin absorption enhancer.

21. 16. The composition of claim 15, further comprising a skin absorption enhancer comprising one or more of mannitol, sulfoxides, azones, pyrrolidones, alcohols and alkanols, glycols, surfactants, and terpenes.

22. The composition of any one of claims 15 to 18 and 20 to 21, which is applied to the skin of a subject once daily.

23. The composition of any one of claims 15 to 18 and 20 to 21, which is applied to the skin of a subject twice daily.

24. The composition of any one of claims 15 to 18 and 20 to 21, which is applied to the skin of a subject three times a day.

25. The composition of any one of claims 15 to 24, wherein the subject is suffering from an inflammatory disorder.

26. The composition according to any one of claims 15 to 25, wherein the inflammatory disorder is a skin disorder.

27. The composition according to any one of claims 22 to 24 and 26, wherein the skin is human skin.

28. A composition according to any one of claims 15 to 27, wherein the inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2.

29. 29. The composition of any one of claims 15 to 28, 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.

30. The composition according to any one of claims 15 to 29, wherein the inflammatory disorder is atopic dermatitis.

31. The composition according to any one of claims 15 to 30, wherein the subject is a human.

32. The composition of claim 30, wherein the atopic dermatitis is Asian atopic dermatitis or European atopic dermatitis.

33. The composition described in claim 29, wherein the inflammatory disorder is chronic urticaria.

34. The composition of claim 29, wherein the systemic itch is cholestatic or uremic itch.

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