MrgprX2 antagonists and their uses

Abstract

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

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority and the benefit of U.S. Provisional Application Serial No. 62 / 931,174, filed on November 5, 2019, U.S. Provisional Application Serial No. 62 / 931,627, filed on November 6, 2019, and U.S. Provisional Application Serial No. 63 / 046,476, filed on June 30, 2020, the content of each of which is hereby incorporated by reference in its entirety. Background of the Invention

[0003] Atopic dermatitis (AD) is the most common inflammatory skin disease. In the United States, the overall prevalence in adults is 6%; globally, the overall prevalence in adults is 1 - 3%, and in children is 15 - 20%. 17.8 million Americans have AD. The disease usually starts in childhood, and skin manifestations are visible in 60% of patients at 1 year of age. Clinical manifestations include erythematous papules and plaques, exudation, crusting, hypopigmentation, and lichenification. However, the hallmark symptom of AD is severe chronic pruritus that lasts for more than 6 weeks. Despite the high prevalence of chronic pruritus in AD patients, there is no effective first - line treatment with good safety. Pruritus has a significant impact on the quality of life of these patients, including sleep disturbances, which ultimately lead to poor work or school performance. The health - related quality of life of children is negatively correlated with the severity of the disease. Sleep is affected by persistent nocturnal pruritus.

[0004] Oral antihistamines provide moderate symptom relief due to their sedative effects without directly altering pruritus. Topical calcineurin inhibitors (TCIs) and topical corticosteroids (TCSs) may help reduce pruritus. However, their side effects (TCSs: skin atrophy, hypopigmentation, and telangiectasia; TCIs: black box warning regarding skin cancer malignancies) make them less preferred treatment options for long - term use, especially for young children. Therefore, there is a high need among patients and their families to find new treatment options for pruritus. In addition, the relief of chronic pruritus disrupts the itch - scratch cycle, thus having secondary beneficial effects such as improving the skin barrier and may lead to improvement of skin lesions and erythema.

[0005] Finding a cure and effective treatment for chronic pruritus in AD has been a major challenge. Histamine is not the main pruritogen in AD, so antihistamines act on AD patients only through their sedative effects, especially on nocturnal pruritus. Proteases released from immune cells and skin cells in AD patients and acting on GPCRs have been investigated as the main pruritogenic factors in AD. Cathepsin S has been described in the literature as a highly pro-inflammatory protease that triggers pruritus. Overexpression of cathepsin S leads to an AD phenotype in mice with severe chronic pruritus. Recently, a group reported that cathepsin S causes pruritus via MrgprX2. However, knowledge of the key pruritogenic mediators in AD is limited, although some mediators have been identified and hypothesized to play a role.

[0006] Another pruritogenic neuropeptide is substance P, which is released from neurons and non-neuronal dermal cells and is a pro-inflammatory and vasoactive neuropeptide that also acts as a pruritogen. Therefore, targeting its cognate receptor NK1 is considered an ideal treatment method and has been investigated using aprepitant. However, despite preclinical data in mice, the NK1R antagonist aprepitant has failed to significantly block pruritus in humans.

[0007] MrgprX2 is a promising target because it has promiscuous ligand-binding properties with various pruritogenic mediators. A variety of pruritogenic mediators known or suspected to be related to the pathogenesis of AD seem to bind to the MrgprX receptor rather than the cognate receptor.

[0008] The need for effective treatment of AD and its symptoms has not been met. The present invention addresses this and other important objectives. Summary of the Invention

[0009] Compositions comprising MrgprX2 antagonists, and methods of using MrgprX2 antagonists to treat inflammatory conditions such as AD are described herein.

[0010] Thus, in a first aspect, the present disclosure provides a compound as an MrgprX2 antagonist.

[0011] In a second aspect, the present disclosure provides a composition comprising an MrgprX2 antagonist and a pharmaceutically acceptable excipient.

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

[0013] In a fourth aspect, the present disclosure provides a method for reducing inflammation in mammalian skin, the method comprising administering to a subject in need thereof a therapeutically effective amount of a topical or oral composition to the mammalian skin, the 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.

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

[0015] Provided herein are topical or oral compositions for treating inflammatory conditions, such as skin disorders characterized by inflammation. In particular, the pharmaceutical composition comprises a compound that is an antagonist of the Mas-related G protein-coupled receptor MrgprX2.

[0016] MrgprX2 Antagonists for the Compositions and Methods of the Present Disclosure

[0017] In several embodiments, the present disclosure provides a compound [Compound 1], which is an MrgprX2 antagonist having Formula I:

[0018]

[0019] Wherein:

[0020] Q is

[0021]

[0022] Z is -C(=O)-(CR 20 R 21 ) n or -S(=O) 2 -;

[0023] R 1 is H or C 1-3 alkyl;

[0024] n is 0 or 1;

[0025] Each R 20 and R 21 is independently H or C 1-3 alkyl;

[0026] G 1 、G 2 、G 3, G 4 and G 5 each independently is N or -C-L 1 -M 1 provided that at least one of G 1 , G 2 , G 3 , G 4 and G 5 is N;

[0027] Each L 1 independently is a bond, O, -C(=O), -C(=O)-NH-, -CH 2 -, -O-(CH 2 ), where w is 1, 2 or 3, or -N(R w ); or any two L 90 -M groups on adjacent carbon atoms may together form a group of the formula -O-(CH 1 ), where v is 1 or 2; 2 v

[0028]

[0029] Each R 90 independently is H or C 1-3 alkyl;

[0029] Each M 1 independently is 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 is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of: halogen, cyano, -OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and -C(=O)-N(R 91 )(R 92 );

[0030] Each R 91 and R 92 independently is selected from the group consisting of: H and C 1-3 alkyl;

[0031] Each R 50 and R 51 are independently selected from the group consisting of: H, C 1-3 alkyl, and C 6-10 aryl;

[0032] A is -L 2 -M 2 ;

[0033] L 2 is selected from a bond and -(CR 60 R 61 ) k -;

[0034] R 60 and R 61 are each independently H or C 1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from -OH and halogen;

[0035] k is 1, 2 or 3;

[0036] M 2 is 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; wherein 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 each optionally substituted with 1, 2, 3 or 4 independently selected R 200 groups;

[0037] Each R 200 is independently selected from 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;

[0038] R 70 and R 71 are each independently H or C1-3 Alkyl;

[0039] Each R 81 and R 82 is independently selected from H; C 1-6 alkyl and C 3-6 cycloalkyl; wherein said C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from -OH and halogen;

[0040] R 500 and R 501 are independently absent or are C 1-6 alkyl;

[0041] R 502 and R 503 are independently H or C 1-6 alkyl;

[0042] or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof.

[0043] The present disclosure further provides the following compounds:

[0044] 1.1 Compound 1, wherein G 1 is N;

[0045] 1.2 Compound 1 or 1.1, wherein G 2 is N;

[0046] 1.3 Compound 1 or 1.1, wherein G 1 and G 4 are N;

[0047] 1.4 Compound 1 or 1.1, wherein G 1 and G 2 are N;

[0048] 1.5 Compound 1 or 1.1, wherein G 1 and G 5 are N;

[0049] 1.6 Any one of the foregoing compounds, wherein G 3 is -C-L 1 -M 1 ;

[0050] 1.7 Any one of the foregoing compounds, wherein G 4 is -C-L 1 -M 1 ;

[0051] 1.8 Any one of the foregoing compounds, wherein G 2 is -C-L1 -M 1 ;

[0052] 1.9 Any one of the foregoing compounds, wherein L 1 is O;

[0053] 1.10 Any one of the foregoing compounds, wherein L 1 is -CH 2 -;

[0054] 1.11 Any one of the foregoing compounds, wherein L 1 is a bond;

[0055] 1.12 Any one of the foregoing compounds, wherein L 1 is -C(=O);

[0056] 1.13 Any one of the foregoing compounds, wherein L 1 is -C(=O)-NH-;

[0057] 1.14 Any one of the foregoing compounds, wherein L 1 is -N(R 90 );

[0058] 1.15 Any one of the foregoing compounds, wherein R 1 is H;

[0059] 1.16 Any one of the foregoing compounds, wherein n is 0;

[0060] 1.17 Any one of the foregoing compounds, wherein n is 1;

[0061] 1.18 Any one of the foregoing compounds, wherein M 1 is selected from C 6 aryl; C with 1 or 2 ring heteroatoms independently selected from N and O 6 heteroaryl; C with 1 or 2 ring heteroatoms independently selected from N and O 5 or C 6 heterocycloalkyl; and 5-10 membered heterocycloalkyl with 1-3 ring heteroatoms independently selected from N, O and S; each of the foregoing is optionally substituted;

[0062] 1.19 Any one of the foregoing compounds, wherein M 1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran or dihydroindole, each of which is optionally substituted;

[0063] 1.20 Compound 1.19, wherein the substituents of M 1 are independently selected from halogen; CN; -OH; -C(=O)-NH 2 ; CF 3; and -OCH 3 ;

[0064] 1.21 Any one of the foregoing compounds, wherein M 1 is an optionally substituted phenyl;

[0065] 1.22 Compound 1.21, wherein the phenyl is substituted at the 4-position;

[0066] 1.23 Compound 1.21, wherein the phenyl is substituted at the 3- and 4-positions;

[0067] 1.24 Compound 1.21, wherein the phenyl is substituted at the 3- and 5-positions;

[0068] 1.25 Any one of the foregoing compounds, wherein M 1 is an optionally substituted pyridyl;

[0069] 1.26 Any one of the foregoing compounds, wherein M 1 is an optionally substituted pyridin-4-yl;

[0070] 1.27 Any one of the foregoing compounds, wherein M 1 is an optionally substituted pyridin-3-yl;

[0071] 1.28 Compound 1.26, wherein the pyridyl is substituted at the carbon adjacent to the pyridyl nitrogen (i.e., adjacent);

[0072] 1.29 Compound 1.27, wherein the pyridyl is substituted at the meta-carbon of the pyridyl nitrogen;

[0073] 1.30 Compound 1.27, wherein the pyridyl is substituted at the carbon adjacent to the pyridyl nitrogen (i.e., adjacent);

[0074] 1.31 Compound 1.26, wherein the pyridyl is substituted at the meta-carbon of the pyridyl nitrogen;

[0075] 1.32 Any one of the foregoing compounds, wherein M 1 is an optionally substituted heterocycloalkyl;

[0076] 1.33 Any one of the foregoing compounds, wherein M 1 is an optionally substituted pyrrolidinyl;

[0077] 1.34 Any one of the foregoing compounds, wherein M 1 is an optionally substituted pyrrolidin-1-yl;

[0078] 1.35 Any one of the foregoing compounds, wherein M 1 is an optionally substituted tetrahydropyranyl;

[0079] 1.36 Any one of the foregoing compounds, wherein M 1 is an optionally substituted tetrahydropyran-4-yl;

[0080] 1.37 Any one of the foregoing compounds, wherein M 1 is an optionally substituted cycloalkyl;

[0081] 1.38 Any one of the foregoing compounds, wherein M 1 is an optionally substituted C 1-6 alkyl;

[0082] 1.39 Any one of the foregoing compounds, wherein M 1 is -NR 50 R 51 ;

[0083] 1.40 Any one of the foregoing compounds, wherein L 2 is a bond;

[0084] 1.41 Any one of the foregoing compounds, wherein L 2 is -(CR 60 R 61 ) k -;

[0085] 1.42 Any one of the foregoing compounds, wherein M 2 is an optionally substituted C 1-6 alkyl;

[0086] 1.43 Any one of the foregoing compounds, wherein M 2 is an optionally substituted isopropyl;

[0087] 1.44 Any one of the foregoing compounds, wherein M 2 is an optionally substituted C 3-6 cycloalkyl;

[0088] 1.45 Any one of the foregoing compounds, wherein M 2 is cyclopropyl or cyclobutyl, each optionally substituted with 1 to 4 methyl groups;

[0089] 1.46 Any one of the foregoing compounds, wherein M 2 is cyclopropyl or cyclobutyl, each optionally substituted with 1 or 2 substituents independently selected from methyl, halogen, mono-, di- or trihalomethyl, cyano, hydroxymethyl and hydroxy;

[0090] 1.47 Any one of the foregoing compounds, wherein M 2 is cyclopropyl optionally substituted with 1 to 4 methyl groups, halogen or trihalomethyl;

[0091] 1.48 Any one of the foregoing compounds, wherein M 2 is a heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy;

[0092] 1.49 Any one of the foregoing compounds, wherein M 2 is tetrahydrofuran, pyrrolidine, tetrahydropyran or morpholine, each of which is optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy;

[0093] 1.50 Any one of the foregoing compounds, wherein M 2 is -N(R 81 )(R 82 );

[0094] 1.51 Any one of the foregoing compounds, wherein R 81 and R 82 are independently selected from 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;

[0095] 1.52 Any one of the foregoing compounds, wherein the compound is selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof.

[0096] According to the present disclosure, there is also provided a topical or oral composition [Composition 1], which comprises a MrgprX2 antagonist and a dermatologically or orally acceptable excipient. In some embodiments, the MrgprX2 antagonist is Compound I having the above formula I.

[0097] The present disclosure further provides the composition as follows:

[0098] 1.1 Composition 1, wherein the MrgprX2 antagonist is Compound I having the above formula I;

[0099] 1.2 Composition 1.1, wherein G 1 is N;

[0100] 1.3 Composition 1.1, wherein G 2 is N;

[0101] 1.4 Composition 1.1, wherein G 1 and G 4 are N;

[0102] 1.5 Composition 1.1, wherein G 1 and G 2 are N;

[0103] 1.6 Composition 1.1, wherein G1 and G 5 is N;

[0104] 1.7 Composition 1.1, wherein G 3 is -C-L 1 -M 1 ;

[0105] 1.8 Composition 1.1, wherein G 4 is -C-L 1 -M 1 ;

[0106] 1.9 Composition 1.1, wherein G 2 is -C-L 1 -M 1 ;

[0107] 1.10 Any one of the foregoing compositions, wherein L 1 is O;

[0108] 1.11 Any one of the foregoing compositions, wherein L 1 is -CH 2 -;

[0109] 1.12 Any one of the foregoing compositions, wherein L 1 is a bond;

[0110] 1.13 Any one of the foregoing compositions, wherein L 1 is -C(=O);

[0111] 1.14 Any one of the foregoing compositions, wherein L 1 is -C(=O)-NH-;

[0112] 1.15 Any one of the foregoing compositions, wherein L 1 is -N(R 90 )-;

[0113] 1.16 Any one of the foregoing compositions, wherein R 1 is H;

[0114] 1.17 Any one of the foregoing compositions, wherein n is 0;

[0115] 1.18 Any one of the foregoing compositions, wherein n is 1;

[0116] 1.19 Any one of the foregoing compositions, wherein M 1 is selected from C 6 aryl; C with 1 or 2 ring heteroatoms independently selected from N and O 6 heteroaryl; C with 1 or 2 ring heteroatoms independently selected from N and O 5 or C 6Heterocycloalkyl; and 5- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; each of the foregoing is optionally substituted;

[0117] 1.20 Any one of the foregoing compositions, wherein M 1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or indoline, each of which is optionally substituted;

[0118] 1.21 Composition 1.20, wherein M 1 substituents are independently selected from halogen; CN; -OH; -C(=O)-NH 2 ; CF 3 ; and -OCH 3 ;

[0119] 1.22 Any one of the foregoing compositions, wherein M 1 is optionally substituted phenyl;

[0120] 1.23 Composition 1.22, wherein the phenyl is substituted at the 4-position;

[0121] 1.24 Composition 1.22, wherein the phenyl is substituted at the 3- and 4-positions;

[0122] 1.25 Composition 1.22, wherein the phenyl is substituted at the 3- and 5-positions;

[0123] 1.26 Any one of the foregoing compositions, wherein M 1 is optionally substituted pyridyl;

[0124] 1.27 Any one of the foregoing compositions, wherein M 1 is optionally substituted pyridin-4-yl;

[0125] 1.28 Any one of the foregoing compositions, wherein M 1 is optionally substituted pyridin-3-yl;

[0126] 1.29 Composition 1.27, wherein the pyridyl is substituted at the carbon adjacent (i.e., ortho) to the pyridyl nitrogen; 1.30 Composition 1.27, wherein the pyridyl is substituted at the meta-carbon to the pyridyl nitrogen;

[0127] 1.31 Composition 1.28, wherein the pyridyl is substituted at the carbon adjacent (i.e., ortho) to the pyridyl nitrogen;

[0128] 1.32 Composition 1.28, wherein the pyridyl is substituted at the meta-carbon to the pyridyl nitrogen;

[0129] 1.33 Any one of the foregoing compositions, wherein M1 is an optionally substituted heterocycloalkyl;

[0130] 1.34 Any one of the foregoing compositions, wherein M 1 is an optionally substituted pyrrolidinyl;

[0131] 1.35 Any one of the foregoing compositions, wherein M 1 is an optionally substituted pyrrolidin-1-yl;

[0132] 1.36 Any one of the foregoing compositions, wherein M 1 is an optionally substituted tetrahydropyranyl;

[0133] 1.37 Any one of the foregoing compositions, wherein M 1 is an optionally substituted tetrahydropyran-4-yl;

[0134] 1.38 Any one of the foregoing compositions, wherein M 1 is an optionally substituted cycloalkyl;

[0135] 1.39 Any one of the foregoing compositions, wherein M 1 is an optionally substituted C 1-6 alkyl;

[0136] 1.40 Any one of the foregoing compositions, wherein M 1 is -NR 50 R 51 ;

[0137] 1.41 Any one of the foregoing compositions, wherein L 2 is a bond;

[0138] 1.42 Any one of the foregoing compositions, wherein L 2 is -(CR 60 R 61 ) k -;

[0139] 1.43 Any one of the foregoing compositions, wherein M 2 is an optionally substituted C 1-6 alkyl;

[0140] 1.44 Any one of the foregoing compositions, wherein M 2 is an optionally substituted isopropyl;

[0141] 1.45 Any one of the foregoing compositions, wherein M 2 is an optionally substituted C 3-6 cycloalkyl;

[0142] 1.46 Any one of the foregoing compositions, wherein M 2is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 4 methyl groups;

[0143] 1.47 Any one of the foregoing compositions, wherein M 2 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;

[0144] 1.48 Any one of the foregoing compositions, wherein M 2 is cyclopropyl optionally substituted with 1 to 4 methyl groups, halogen or trihalomethyl;

[0145] 1.49 Any one of the foregoing compositions, wherein M 2 is heteroalkyl optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy;

[0146] 1.50 Any one of the foregoing compositions, wherein M 2 is tetrahydrofuran, pyrrolidine, tetrahydropyran or morpholine, each of which is optionally substituted with 1 or 2 groups independently selected from methyl and hydroxy;

[0147] 1.51 Any one of the foregoing compositions, wherein M 2 is -N(R 81 )(R 82 );

[0148] 1.52 Any one of the foregoing compositions, wherein R 81 and R 82 are independently selected from 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;

[0149] 1.53 Any one of the foregoing compositions, wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof;

[0150] 1.54 Any one of the foregoing compositions, wherein the composition is in the form of a cream, gel, spray or ointment.

[0151] 1.55 Any one of the foregoing compositions, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.%, based on the total weight of the composition.

[0152] 1.56 Any one of the foregoing compositions, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.%, based on the total weight of the composition.

[0153] Any one of the foregoing compositions, which further comprises a skin absorption promoter.

[0154] Any one of the foregoing compositions, which further comprises a skin absorption promoter, and the skin absorption promoter comprises one or more of the following: mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., laurocapram), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohol and alkanol (e.g., ethanol or decanol), diol (e.g., propylene glycol, hexylene glycol, polyethylene glycol, diethylene glycol), surfactant (also commonly found in dosage forms), and terpene.

[0155] Any one of the foregoing compositions, wherein the composition is applied to the skin of a patient once a day.

[0156] Any one of the foregoing compositions, wherein the composition is applied to the skin of a patient twice a day.

[0157] Any one of the foregoing compositions, wherein the composition is applied to the skin of a patient three times a day.

[0158] Any one of the foregoing compositions, wherein the composition is administered to a patient suffering from an inflammatory disorder.

[0159] Any one of the foregoing compositions, wherein the inflammatory disorder is a skin disorder.

[0160] Any one of the foregoing compositions, wherein the skin is human skin.

[0161] Any one of the compositions 1.64-1.66, wherein the inflammatory disorder activates MrgprX2 or is caused by the activation of MrgprX2.

[0162] Any one of the foregoing compositions, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, and adverse drug reactions.

[0163] Any one of the compositions 1.63-1.67, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0164] Any one of the foregoing compositions, wherein the subject is a human.

[0165] Any one of the foregoing compositions, wherein the mammalian skin is human skin.

[0166] Any one of the foregoing compositions, wherein the composition is for oral administration.

[0167] As used herein, a "topical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a bioactive compound to mammalian skin, such as human skin. Such a medium includes all dermatologically acceptable carriers, diluents, or excipients.

[0168] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different non-interchangeable three-dimensional structures. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0169] "Solvate" refers to a form of a compound complexed with solvent molecules.

[0170] "Tautomers" refer to two molecules that are structural isomers that are readily interconvertible.

[0171] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts.

[0172] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base and are not undesirable in a biological or other respect, and are formed with inorganic acids and organic acids, such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. for inorganic acids, and acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-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, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0173] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an 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, etc. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0174] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or, for amino acids, (D)- or (L)-. The present invention is intended to embrace all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC).

[0175] "Dermatologically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent, including those approved by the US Food and Drug Administration for dermatological use in humans or domestic animals or those known to be used or suitable for dermatological compositions.

[0176] "Optional" or "optionally" means that the subsequently described situation or event may or may not occur, and the description includes instances where the event or situation occurs and instances where it does not occur. When a functional group is described as "optionally substituted", and subsequently the substituents on the functional group are also "optionally substituted", etc., for the purposes of the present invention, such iteration is limited to three times.

[0177] The term "alkyl" is intended to denote a straight-chain or branched-chain carbon radical containing the indicated number of carbon atoms. Some embodiments contain from 1 to 5 carbons. Some embodiments contain from 1 to 4 carbons. Some embodiments contain from 1 to 3 carbons. Some embodiments contain from 1 to 2 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH 3 )CH 2 CH 2 CH 3 , 2-methylbutyl [i.e., -CH 2 CH(CH 3 )CH 2 CH 3 , n-hexyl, and the like.

[0178] The term "cycloalkyl" is intended to denote a saturated cyclic radical containing the indicated number of carbon atoms. Some embodiments contain from 3 to 6 carbons. Some embodiments contain from 3 to 5 carbons. Some embodiments contain from 5 to 7 carbons. Some embodiments contain from 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0179] The term "haloalkyl" is intended to denote a radical including an alkyl having the indicated number of carbon atoms, which is substituted by one or more halogens. For example, C 1 -C 6 The haloalkyl can be fully substituted, in which case it can be represented by the formula C n L 2n+1 , where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6. When there is more than one halogen, they can be the same or different and are selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl contains from 1 to 5 carbons. In some embodiments, the haloalkyl contains from 1 to 4 carbons. In some embodiments, the haloalkyl contains from 1 to 3 carbons. In some embodiments, the haloalkyl contains 1 or 2 carbons. Examples of haloalkyl 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 halogen substituents, the "haloalkyl" group contains 1, 2, or 3 halogen atoms.

[0180] The term "hydroxyalkyl" is intended to denote a radical comprising an alkyl group having the indicated number of carbon atoms, which is substituted by one or more hydroxy (i.e., -OH) groups. When used without a prefix indicating the number of hydroxy substituents, the "hydroxyalkyl" group contains 1, 2, or 3 hydroxy groups.

[0181] The term "halogen" is intended to denote a fluorine, chlorine, bromine, or iodine group.

[0182] The term "aryl" is intended to denote a ring system containing 6 to 10 carbon atoms, which may contain a single ring or two fused rings, and in which at least one ring is aromatic. Examples include phenyl, indanyl, and naphthyl.

[0183] The term "heteroaryl" is intended to denote a ring system containing 5 to 14 ring atoms, which may contain a single ring, two fused rings, or three fused rings, and in which at least one ring is aromatic and at least one ring atom is a heteroatom selected from, for example: O, S, and N. Some embodiments contain 5 to 6 ring atoms, such as furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc. Some embodiments contain 8 to 14 ring atoms, such as quinazolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridyl, benzothienyl, benzofuryl, isobenzofuran, 2,3-dihydrobenzofuryl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-isoquinolinyl, 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridinyl, 7,8-dihydro-5H-[1,6]naphthyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxolyl, pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, etc.

[0184] The term "cyano" refers to the -CN group.

[0185] The term "alkoxy" refers to a group of the formula -O-alkyl having the indicated number of carbon atoms.

[0186] As used herein, the term "heteroalkyl" is intended to mean a saturated or partially unsaturated non-aromatic 3-6 membered heterocycle optionally fused to a 3-6 membered saturated, partially unsaturated or aromatic aryl or heteroaryl ring. Examples of non-aromatic 3-6 membered heterocycles include oxirane, aziridine, oxetane, tetrahydrofuran, dihydrofuran, pyrrolidine, piperidine, tetrahydropyran, morpholine, piperazine, hexahydropyrimidine, hexahydropyridazine, etc. The heteroalkyl may contain one or more oxo (i.e., -C=O-) groups within the ring, and the sulfur heteroatom may exist as a sulfone. Examples of such heteroalkyl rings include sulfolane, tetrahydro-2H-thiopyran-1,1-dione, thiomorpholine 1,1-dioxide, 2-pyrrolidone, piperidin-2-one, piperazin-2-one, morpholin-3-one, etc. Examples of heteroalkyl having a fused ring include dihydroindole, such as 1,3-dihydroindole.

[0187] The term "spiroalkyl" is intended to mean a structure of two or more rings, wherein two rings share a common atom, and wherein at least one ring is a cycloalkyl ring containing the indicated number of carbon atoms. Examples include spiropropane and spirobutane.

[0188] Methods of using the compounds of the present invention

[0189] The compounds of the present invention can be used to treat inflammatory disorders, such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, adverse drug reactions. Thus, administering or using a preferred MrgprX2 antagonist as described herein, such as the MrgprX2 antagonist described above, such as a compound of formula I, provides a means for improving the symptoms of and / or treating various inflammatory diseases and disorders.

[0190] For example, in one embodiment, the present disclosure provides a method [Method 1] for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a topical or oral composition comprising a therapeutically effective amount of an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure); and a dermatologically or orally acceptable excipient.

[0191] The present disclosure further provides additional embodiments of Method 1 as follows:

[0192] 1.1 Method 1, wherein the MrgprX2 antagonist is a compound according to formula I above;

[0193] 1.2 Method 1.1, wherein the MrgprX2 antagonist is a compound as described in any one of the above compounds 1.1 - 1.55;

[0194] 1.3 Any one of the foregoing methods, wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof;

[0195] 1.4 Any one of the foregoing methods, wherein the composition is in the form of a cream, gel, spray or ointment.

[0196] 1.5 Any one of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.%, based on the total weight of the composition.

[0197] 1.6 Any one of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.%, based on the total weight of the composition.

[0198] 1.7 Any one of the foregoing methods, which further comprises a skin absorption enhancer.

[0199] 1.8 Any one of the foregoing methods, which further comprises a skin absorption enhancer, and the skin absorption enhancer comprises one or more of the following: mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., laurocapram), pyrrolidone (e.g., 2 - pyrrolidone, 2P), alcohol and alkanol (e.g., ethanol or decanol), diol (e.g., propylene glycol, hexylene glycol, polyethylene glycol, diethylene glycol), surfactant (also commonly found in dosage forms) and terpene.

[0200] 1.9 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient once a day.

[0201] 1.10 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient twice a day.

[0202] 1.11 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient three times a day.

[0203] 1.12 Any one of the foregoing methods, wherein the composition is administered to a patient suffering from an inflammatory disorder.

[0204] 1.13 The foregoing method, wherein the inflammatory disorder is a skin disorder.

[0205] 1.14 The foregoing method, wherein the skin is human skin.

[0206] 1.15 Any one of methods 1.12 - 1.14, wherein the inflammatory disorder activates MrgprX2 or is caused by the activation of MrgprX2.

[0207] 1.16 The foregoing method, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases or adverse drug reactions.

[0208] 1.17 Any one of methods 1.12 - 1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0209] 1.18 Any one of the foregoing methods, wherein the subject is a human.

[0210] 1.19 Any one of the foregoing methods, wherein the mammalian skin is human skin.

[0211] 1.20 Any one of the foregoing methods, wherein the composition is for oral administration.

[0212] In another embodiment, the present disclosure provides a method [Method 2] for reducing inflammation of mammalian skin, the method comprising administering to a subject in need thereof an effective amount of a topical or oral composition to the mammalian skin, the topical or oral composition comprising an MrgprX2 antagonist according to the present disclosure and a dermatologically acceptable excipient.

[0213] The present disclosure further provides additional embodiments of Method 2 as follows:

[0214] 2.1 Method 2, wherein the MrgprX2 antagonist is a compound according to Formula I above;

[0215] 2.2 Method 2 or 2.1, wherein the MrgprX2 antagonist is a compound according to any one of Compounds 1.1 - 1.55 above;

[0216] 2.3 Any one of the foregoing methods, wherein the MrgprX2 antagonist is a compound selected from Table 1 herein, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof;

[0217] 2.4 Any one of the foregoing methods, wherein the inflammation is caused by the activation of MrgprX2;

[0218] 2.5 Any one of the foregoing methods, wherein the composition is in the form of a cream, gel, spray or ointment.

[0219] 2.6 Any one of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.%, based on the total weight of the composition.

[0220] 2.7 Any one of the foregoing methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.%, based on the total weight of the composition.

[0221] 2.8 Any one of the foregoing methods, which further comprises a skin absorption promoter.

[0222] 2.9 Any one of the foregoing methods, which further comprises a skin absorption promoter, and the skin absorption promoter comprises one or more of the following: 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), diols (e.g., propylene glycol, hexylene glycol, polyethylene glycol, diethylene glycol), surfactants (also commonly found in dosage forms), and terpenes.

[0223] 2.10 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient once a day.

[0224] 2.11 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient twice a day.

[0225] 2.12 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient three times a day.

[0226] 2.13 Any one of the foregoing methods, wherein the composition is administered to a patient suffering from an inflammatory disorder.

[0227] 2.14 The foregoing method, wherein the inflammatory disorder is a skin disorder.

[0228] 2.15 The foregoing method, wherein the skin is human skin.

[0229] 2.16 Any one of methods 1.12 - 1.14, wherein the inflammatory disorder activates MrgprX2 or is caused by the activation of MrgprX2.

[0230] 2.17 The foregoing method, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

[0231] 2.18 Any one of methods 1.12 - 1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0232] 2.19 Any one of the foregoing methods, wherein the subject is a human.

[0233] 2.20 Any one of the foregoing methods, wherein the mammalian skin is human skin.

[0234] 2.21 Any one of the foregoing methods, wherein the composition is for oral administration.

[0235] Another embodiment provides a method [Method 3] for reducing the incidence or severity of itching, the method comprising administering to the mammalian skin a therapeutically effective amount of a topical or oral composition according to any one of Composition 1 and 1.1 - 1.73.

[0236] The present disclosure further provides additional embodiments of Method 3 as follows:

[0237] 3.1 Method 3, wherein the severity of itching is reduced within 5 minutes of administration.

[0238] 3.2 Method 3 or 3.1, wherein the severity of itching is reduced within 6 hours after administration.

[0239] 3.3 Method 3 or 3.1, wherein the severity of itching is reduced within 12 hours after administration.

[0240] 3.4 Method 3 or 3.1, wherein the severity of itching is reduced within 18 hours after administration.

[0241] 3.5 Method 3 or 3.1, wherein the severity of itching is reduced within 24 hours after administration.

[0242] 3.6 Any one of the foregoing methods, wherein the MgrprX2 antagonist is a compound selected from Table 1 herein, or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof.

[0243] 3.7 Any one of the foregoing methods, wherein the composition is in the form of a cream, gel, spray or ointment.

[0244] 3.8 Any one of the foregoing methods, wherein the MgrprX2 antagonist is present at a concentration of about 0.001 wt.% to about 10 wt.%, based on the total weight of the composition.

[0245] 3.9 Any one of the foregoing methods, wherein the MgrprX2 antagonist is present at a concentration of about 0.1 wt.% to about 5 wt.%, based on the total weight of the composition.

[0246] 3.10 Any one of the foregoing methods, which further comprises a skin penetration enhancer.

[0247] 3.11 The foregoing method, wherein the skin penetration enhancer comprises one or more of the following: 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), diols (e.g., propylene glycol, hexylene glycol, polyethylene glycol, diethylene glycol), surfactants (also commonly found in dosage forms), and terpenes.

[0248] 3.12 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient once a day.

[0249] 3.13 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient twice a day.

[0250] 3.14 Any one of the foregoing methods, wherein the composition is applied to the skin of a patient three times a day.

[0251] 3.15 Any one of the foregoing methods, wherein the composition is administered to a patient suffering from an inflammatory disorder.

[0252] 3.16 Any one of the foregoing methods, wherein the inflammatory disorder is a skin disorder.

[0253] 3.17 Any one of the foregoing methods, wherein the skin is human skin.

[0254] 3.18 Any one of Methods 1.12 - 1.14, wherein the inflammatory disorder activates MrgprX2 or is caused by the activation of MrgprX2.

[0255] 3.19 The foregoing method, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or adverse drug reactions.

[0256] 3.20 Any one of Methods 1.12 - 1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).

[0257] 3.21 Any one of the foregoing methods, wherein the subject is a human.

[0258] 3.22 Any one of the foregoing methods, wherein the mammalian skin is human skin.

[0259] 3.23 Any of the foregoing methods, wherein the composition is for oral administration.

[0260] "Atopic dermatitis" refers to a skin condition involving chronic inflammation, and the symptoms of atopic dermatitis include redness and itchy rashes. Atopic dermatitis can be present on the skin anywhere on the body, but is common on the hands, feet, upper chest, and the bend of the elbows or knees. Additional symptoms of atopic dermatitis may include small raised bumps or thickened, scaly skin.

[0261] "Psoriasis" is a chronic skin condition associated with an overactive immune response. Psoriasis can be present on the skin anywhere on the body. The symptoms of psoriasis include local inflammation, skin peeling, and thick, white or red patches of skin.

[0262] "Alopecia" is an autoimmune skin disease that causes hair loss on the scalp, face, and sometimes on other parts of the body. For example, in alopecia areata, T cell lymphocytes accumulate around the affected hair follicles, leading to inflammation and subsequent hair loss.

[0263] "Chronic urticaria" (urticaria) is a common rash triggered by a variety of factors, including certain foods, medications, and stress. Symptoms may include itchy, raised, red, or skin-colored welts on the surface of the skin. Given the role of mast cells in chronic idiopathic urticaria, MrgprX2 plays a key role in mast cell activation. Antibacterial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and some FDA-approved peptidergic drugs activate human MrgprX2. Unique features of MrgprX2 that distinguish it from other GPCRs include their presence at plasma membrane and intracellular sites and their selective expression in MCs. In addition, small molecule inhibitors of MrgprX2 may be beneficial for the treatment of MC-dependent allergic and inflammatory disorders, such as chronic urticaria, which is currently treated by targeting the IgE axis of mast cell activity. However, multiple MC activities rely 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 ) indicating that targeting MRGPRX2 may indeed be a treatment option for IgE-independent and drug-resistant chronic urticaria.

[0264] "Anaphylactic shock" is an extreme and often life-threatening allergic reaction to an antigen to which the body has become highly sensitive. Activation of mast cells via MrgprB2 has attracted attention because of its IgE-independent mast cell activation and non-histaminergic pruritus (Meixiong J. et al., 2019, Immunity, 50(5), 1163–1171.e5. https: / / doi.org / 10.1016 / j.immuni.2019.03.013 ). Activation of MrgprB2 by adrenomedullin precursor N-terminal peptide 9-20 (PAMP9-20) induces the release of multiple bioactive mediators from mast cells, which in turn activates pruritus-sensitive neurons, indicating that mast cell-specific MrgprB2 is crucial for mast cell degranulation and associated non-histaminergic pruritus. Mast cell MrgprB2 and MrgrpX2 are activated by SP, compound 48 / 80, and pseudoallergy-inducing drugs such as icatibant (McNeil, B.D. et al., 2015, Nature, 519(7542), 237–241; https: / / doi.org / 10.1038 / nature14022 ), thus placing MrgprX2 at the center stage of non-histaminergic mast cell activation and various allergic and non-allergic diseases as well as pseudoallergy reactions.

[0265] "Rosacea" is a condition that causes facial redness and usually produces small, red, pus-filled bumps. MrgrpX2 has also been identified as a receptor for endogenous host defense peptides, including cathelicidin (LL-37) and β-defensin (Subramanian, H. et al., 2011, The Journal of Biological Chemistry, 286(52), 44739–44749; https: / / doi.org / 10.1074 / jbc.M111.277152 and Subramanian, H. et al., 2013, Journal of Immunology (Baltimore, Md.: 1950), 191(1), 345–352; https: / / doi.org / 10.4049 / jimmunol.1300023 ), thus increasing the likelihood of mast cell MrgprX2 involvement in antibacterial host defense. Pituitary adenylate cyclase-activating peptide (PACAP), a potent mast cell degranulator (Baun, M. et al., 2012, Cephalalgia: An International Journal of Headache, 32(4), 337–345; https: / / doi.org / 10.1177 / 0333102412439354and Seebeck, J. et al., 1998, Annals of the New York Academy of Sciences, 865, 141–146. https: / / doi.org / 10.1111 / j.1749- 6632.1998.tb11172.x ), has been shown to activate MrgprX2 (Tatemoto K. et al., 2006, Biochemical and Biophysical Research Communications, 349(4), 1322–1328; https: / / doi.org / 10.1016 / j.bbrc.2006.08.177 ; and McNeil, B.D. et al., 2015, Nature, 519(7542), 237–241; https: / / doi.org / 10.1038 / nature14022 ). These findings suggest that MrgprX2 may also play a role in innate immunity by regulating host defense responses. Given that MrgprX2 is activated by peptides such as LL-37 and the neuropeptide PACAP, both of which are closely associated with rosacea and act as trigger peptides to affect mast cell activity and vasodilation. These findings together suggest that MrgprX2 is an emerging receptor in the pathophysiology of rosacea.

[0266] "Asthma" refers to a condition in which a person's airways become inflamed, narrowed, and swollen, and produce excessive mucus, resulting in difficulty breathing. Mast cells (MCs) also recede near smooth muscle, T cells, and white blood cells, and are important effector cells for airway hyperresponsiveness and inflammation, which are the phenotypic characteristics of asthma. Even though only small amounts of transcripts are present in the healthy state, the level of MrgprX2 transcripts increases in severe asthma characterized by a phenotypic switch from MCT to MCTC. Compared with MCT, the mast cell MCTC population in severe asthma is expressing MrgprX2 (Fajt M.L. et al., 2013; The Journal of Allergy and Clinical Immunology, 131(6), 1504–1512; https: / / doi.org / 10.1016 / j.jaci.2013.01.035 and Balzar, S. et al., 2011, American Journal of Respiratory and Critical Care Medicine, 183(3), 299–309; https: / / doi.org / 10.1164 / rccm.201002-0295OC)。Given the increased SP levels in the lungs of patients with severe asthma who have activated 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 )。

[0267] "Mammal / mammalian" includes humans, as well as domestic animals such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals such as wild animals, etc.

[0268] "Therapeutically effective amount" refers to the amount of a compound of the present invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment of the disease or condition in a mammal, preferably a human, suffering from the target disease or condition. The amount of the compound of the present invention constituting 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 routinely determined by one of ordinary skill in the art in view of his own knowledge and the present disclosure. Preferably, for the purposes of the present invention, a "therapeutically effective amount" is the amount of the compound of the present invention sufficient to inhibit skin inflammation.

[0269] As used herein, "treating / treatment" encompasses treatment of a target disease or condition in a mammal, preferably a human, and includes:

[0270] (i) preventing the occurrence of the disease or condition in the mammal;

[0271] (ii) inhibiting the disease or condition in the mammal, i.e., preventing its development;

[0272] (iii) alleviating the disease or condition in the mammal, i.e., causing the disease or condition to subside; or

[0273] (iv) alleviating the symptoms of the disease or condition in the mammal, i.e., alleviating the symptoms without resolving the underlying disease or condition.

[0274] As used herein, the terms "disease", "disorder" and "condition" may be used interchangeably or may be different, as the causative agent of a particular disease or condition may not yet be known (and thus the etiology has not been determined), and thus it has not yet been considered a disease but only an undesirable condition or syndrome, where a clinician has identified a more or less specific set of symptoms.

[0275] In this specification, unless otherwise indicated, the term "about" means ±20% of the indicated range, value, or structure.

[0276] In some embodiments, the MrgprX2 antagonist (e.g., the MrgprX2 antagonist according to the present disclosure) is present in a topical or oral composition at a concentration of from about 0.05 wt% to about 5 wt%.

[0277] In certain embodiments, the pharmaceutical compositions described herein further comprise a dermatologically acceptable excipient. The dermatologically acceptable excipient can be one or more solvents that solubilize and / or stabilize the active ingredient (e.g., the MrgprX2 antagonist) contained therein. The dermatologically acceptable excipient can also comprise a skin penetration enhancer, a preservative, a thickening agent, a pH adjuster, a film-forming agent, 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).

[0278] A more detailed description of certain suitable excipients is provided below. As will be appreciated, the components of the pharmaceutical formulations described herein can have multiple functions. For example, a given substance can function both as a thickening agent and as an emulsifying agent.

[0279] The skin (especially the stratum corneum) provides a physical barrier against the harmful effects of the external environment. In doing so, it also interferes with the absorption or transdermal delivery of topical therapeutic agents. Thus, suitable dermatologically acceptable excipients can comprise one or more penetration enhancers (or permeation enhancers), which are substances that promote the diffusion of a therapeutic agent (e.g., the MrgprX2 antagonist described herein) through the skin barrier. They generally act to reduce the skin impedance or resistance to improve the permeability of the therapeutic agent. In particular, substances that disrupt the normal structure of the stratum corneum can disrupt the intercellular lipid organization, thereby reducing its effectiveness as a barrier. These substances can comprise any lipid material that partitions into the stratum corneum lipids to cause a direct effect or any material that affects proteins and causes an indirect perturbation of the lipid structure. In addition, solvents such as ethanol can remove lipids from the stratum corneum, thereby disrupting its lipid organization and its barrier function.

[0280] Examples of penetration enhancers or barrier function disruptors include, but are not limited to, alcohol-based enhancers such as alkanols having 1 to 16 carbons, benzyl alcohol, butylene glycol, diethylene glycol, tetraethylene glycol, glycerides, glycerin / glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based enhancers such as N-butyl-N-dodecylacetamide, crotamiton, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, and urea; amino acids such as L-α-amino acids and water-soluble proteins; azone and azone-like compounds such as azacycloalkanes; essential oils such as almond oil, amyl butyrate, 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, and walnut oil; vitamins and herbs such as aloe, allantoin, black walnut extract, chamomile extract, panthenol, papain, tocopherol, and vitamin A palmitate; waxes such as candelilla wax, carnauba wax, ceresin, beeswax, lanolin wax, jojoba oil, petrolatum; mixtures such as the primary esters of fractionated vegetable oil fatty acids with glycerol or propylene glycol and transesterified medium-chain triglyceride oils; fatty acids and fatty acid esters such as amyl caproate, butyl acetate, caprylic acid, cetyl ester, diethyl sebacate, dioctyl malate, ethyl octyl trans-oleate, ethylene glycol palmitostearate, glyceryl behenate, glucosyl glutamate, isobutyl acetate, laureth-4, lauric acid, malic acid, methyl caprate, mineral oil, myristic acid, oleic acid, palmitic acid, PEG fatty acid ester, polyoxyethylene sorbitan monooleate, polypropylene glycol, propylene glycol, sucrose distearate, salicylic acid, sodium citrate, stearic acid, soaps, and triglycerides of caproic, caprylic, capric, and lauric acids; macrocyclic compounds such as butylated hydroxyanisole, cyclopentadecanolide, cyclodextrin; phospholipid and phosphate promoters such as dialkyl phosphates, cetyl phosphate, lecithin, 2-pyrrolidone derivatives such as alkyl pyrrolidone-5-carboxylates, pyroglutamate esters, N-methylpyrrolidone, biodegradable soft penetration promoters such as dioxane derivatives and dioxolane derivatives; sulfoxide promoters such as dimethyl sulfoxide and decyl methyl sulfoxide; acid promoters such as alginic acid, sorbic acid, and succinic acid; cyclic amines; imidazolinones; imidazoles; ketones such as acetone, polydimethylsiloxane, methyl ethyl ketone, and acetylacetone; lanolin derivatives such as lanolin alcohol, PEG16 lanolin, and acetylated lanolin; oxazolines; oxazolinones; proline esters; pyrroles, urethanes; and surfactants such as nonoxynol, polysorbate, polyoxyenol, polyoxyenyl fatty acid esters, sodium lauryl sulfate, and sorbitan monostearate.

[0281] The topical compositions described herein generally contain one or more carriers, which preferably have a vapor pressure greater than or equal to 23.8 mm Hg at 25°C. The preferred concentration range of a single carrier or the total concentration range of a combination of carriers can be from about 0.1 wt.% to about 10 wt.%, more preferably from about 10 wt.% to about 50 wt.%, and more specifically from about 50 wt.% to about 95 wt.% of the dermatological composition. Non-limiting examples of solvents include water (e.g., deionized water) and lower alcohols, including ethanol, 2-propanol, and n-propanol.

[0282] The dermatological compositions of the present invention can contain one or more hydrophilic co-solvents, which are miscible with water and / or lower chain alcohols and preferably have a vapor pressure less than that of water (∼23.8 mm Hg) at 25°C. The carrier generally has a vapor pressure greater than or equal to that of the hydrophilic co-solvent to concentrate the active ingredient (e.g., the MrgprX2 antagonist of the present disclosure) on the skin. The hydrophilic co-solvent can be a diol, particularly propylene glycol. In particular, propylene glycol can be from polyethylene glycols, particularly polyethylene glycols having a molecular weight range of 200 to 20,000. Preferably, the solvent will be part of a glycol ether. More specifically, the hydrophilic co-solvent of the present invention will be diethylene glycol monoethyl ether (carbitol). As used herein, "diethylene glycol monoethyl ether" ("DGME") or "carbitol" refers to 2-(2-ethoxyethoxy)ethanol {CAS NO 001893} or ethoxydiglycol. Another preferred co-solvent is 1,3-dimethyl-2-imidazolidinone (DMI).

[0283] The topical compositions described herein can also contain one or more "humectants" for providing a wetting effect. Preferably, the humectant remains stable in the composition. Any suitable concentration of a single humectant or a combination of humectants can be employed, provided that the resulting concentration provides the desired wetting effect. Generally, the appropriate amount of the humectant will depend on the one or more specific humectants employed. The preferred concentration range of a single humectant or the total concentration range of a combination of humectants can be from about 0.1 wt.% to about 70 wt.%, more preferably from about 5.0 wt.% to about 30 wt.%, and more specifically from about 10 wt.% to about 25 wt.% of the dermatological composition. Non-limiting examples for use herein include glycerin, polyols, and silicone oils. More preferably, the humectant is glycerin, propylene glycol, and / or cyclomethicone. Specifically, the filler will be glycerin and / or cyclomethicone.

[0284] In certain embodiments, the pharmaceutical composition comprises a thickening agent or an emulsifying agent. A gelling agent is used to increase the viscosity of the final composition. An emulsifying agent is a substance that stabilizes an emulsion. A thickening agent can also be used as an emulsifying agent. Generally, the concentration and combination of the thickening agent will depend on the physical stability of the finished product. The preferred concentration range of the thickening agent can be from about 0.01 wt.% to about 20 wt.%, more preferably from about 0.1 wt.% to about 10 wt.%, and more specifically from about 0.5 wt.% to about 5 wt.% of the dermatological composition. Non-limiting examples of thickening agents for use herein include the classes of cellulose, acrylate polymers, and acrylate crosslinked polymers, such as hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, carbomer 980, carbomer 1342, and carbomer 940, more preferably hydroxypropyl cellulose, Pluronic PF127, carbomer 980, and carbomer 1342, and more specifically hydroxypropyl cellulose( EF, GF, and / or HF), Pluronic PF127, carbomer 980, and / or carbomer 1342( TR-1, TR-2, and / or ETD 2020). Examples of emulsifying agents for use herein include polysorbates, laureth-4, and potassium cetyl sulfate.

[0285] The topical or oral compositions described herein may contain one or more antioxidants, free radical scavengers, and / or stabilizers, with a preferred concentration range of from about 0.001 wt.% to about 0.1 wt.%, more preferably from about 0.1 wt.% to about 5 wt.% of the dermatological composition. Non-limiting examples for use herein include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tocopherol, and propyl gallate. More specifically, the antioxidant can be ascorbyl palmitate, vitamin E acetate, vitamin E-TPGS, vitamin E, or butylated hydroxytoluene.

[0286] The topical or oral compositions described herein may also contain preservatives that exhibit antibacterial and / or antifungal properties. The preservative may be present in the gelled dermatological composition of the present invention to minimize bacteria and / or fungi during its shelf life. The preferred concentration range of the preservative in the dermatological composition of the present invention can be from about 0.001 wt.% to about 0.01 wt.%, more preferably from about 0.01 wt.% to about 0.5 wt.% of the dermatological composition. Non-limiting examples for use herein include diazolidinyl urea, methyl paraben, propyl paraben, EDTA tetrasodium, and ethyl paraben. More specifically, the preservative is a combination of methyl paraben and propyl paraben.

[0287] The topical compositions described herein may optionally contain one or more chelating agents. As used herein, the term "chelating agent" refers to those skin-beneficial agents that can remove metal ions from a system by forming complexes so that the metal ions cannot readily participate in or catalyze chemical reactions. Chelating agents for use herein are preferably formulated at a concentration of from about 0.001 wt.% to about 10 wt.%, more preferably from about 0.05 wt.% to about 5.0 wt.%, of the dermatological composition. Non-limiting examples for use herein include EDTA, disodium edetate, dipotassium edetate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid, and potassium gluconate. Specifically, the chelating agent may be EDTA, disodium edetate, dipotassium edetate, trisodium edetate, or potassium gluconate.

[0288] The topical or oral compositions described herein may contain one or more conventional compatible cosmetically acceptable adjuvants, such as colorants, fragrances, emollients, etc., as well as botanicals, such as aloe vera, chamomile, witch hazel, etc.

[0289] Alternatively, other drug delivery systems may be used for the pharmaceutical compositions of the present invention. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds or prodrugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be employed.

[0290] The topical compositions described herein may 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 matrix, vehicle, or carrier that dries in a cosmetically acceptable manner and does not impart the greasy appearance associated with lotions or ointments when applied to the skin).

[0291] Any suitable amount of an MrgprX2 antagonist (e.g., a compound according to the present disclosure) can be used in such dermatological compositions, provided that the amount effectively reduces local inflammation and / or vascular dysfunction and remains stable in the composition for a long time. Preferably, the stability lasts for a long time, such as up to about 3 years, up to 1 year, or up to about 6 months, which is typical in the manufacture, packaging, transportation, and / or storage of dermatologically acceptable compositions. The compounds of the present disclosure can be dissolved in solution, partially dissolved in solution and partially undissolved, or be a completely undissolved suspension. The compounds of the present disclosure can be present in the dermatological compositions of the present invention in a concentration range of from about 0.001 wt.% to about 80 wt.%, from about 0.001 wt.% to about 50 wt.%, from about 0.001 wt.% to about 25 wt.%, or from about 0.001 wt.% to about 6 wt.%. In one embodiment, the compounds of the present disclosure can be present in a concentration range of from about 0.001 wt.% to about 10 wt.%, from about 0.1 wt.% to about 10 wt.%, or from about 1.0 wt.% to about 5.0 wt.%.

[0292] In the treatment of inflammatory disorders, such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic reactions triggered by small molecules, such as anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic pruritus, such as cholestatic or uremic pruritus, chronic pruritus triggered by systemic diseases, or drug adverse reactions, it is preferred to directly apply a topical composition comprising a compound of the present disclosure to the affected area of the skin of a person in need (e.g., itchy skin). When using such compositions (e.g., when using a dermatological composition comprising a compound of the present disclosure) and placing a dermatologically acceptable excipient on the skin of a person in need, the MrgprX2 antagonist is in continuous contact with the patient's skin, thereby enabling penetration and treatment.

[0293] When topically applying the pharmaceutical composition of the present invention, the skin of the person to be treated can optionally be pretreated (e.g., cleaning the skin with soap and water or cleaning the skin with an alcohol-based cleanser) before applying the dermatological composition of the present invention.

[0294] If desired, the pharmaceutical composition of the present invention can be present in a package or dispensing device, which can contain one or more unit dosage forms containing the active compound. The topical compositions described herein can also be provided in a patch, wherein the topical composition is located on the side of the patch that directly contacts the skin. A dermatologically acceptable adhesive can be used to fix the patch to the skin for a long time.

[0295] Oral administration

[0296] In some embodiments, the pharmaceutical compositions herein are provided for oral administration. Accordingly, solid, semi-solid or liquid dosage forms for oral administration are provided according to the present disclosure, which comprise a compound as described herein. Suitable oral dosage forms include but are not limited to tablets, capsules, pills, lozenges, pellets, granules, powder grains, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, enteric coatings, film costing agents, modified release agents, colorants, dye migration inhibitors, sweeteners and flavoring agents.

[0297] Binders or granulating agents impart adhesiveness to tablets to ensure that the tablets remain 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., STARCH1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Irish moss extract, Panwar gum, Indian gum, psyllium mucilage, ethyl cellulose, carboxymethyl cellulose, methyl cellulose, methyl paraben, polyalkylene oxides, polyvinylpyrrolidone (PVP), crospovidone, Veegum, larch arabinogalactan, tragacanth powder and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include but are not limited to talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose binder, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or filler may be present in the pharmaceutical composition provided herein in an amount of about 50% to about 99% by weight.

[0298] 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. When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart to some compressed tablets the property of allowing disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0299] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethylcellulose; cross-linked polymers, such as cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starch, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and will be readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.5 to about 15% by weight or from about 1 to about 5% by weight of disintegrant.

[0300] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gel, such as 200 (W.R. Grace Co., Baltimore, MD) and (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein can contain from about 0.1 to about 5% by weight of lubricant.

[0301] Suitable glidants include colloidal silica, Cabot Corporation of Boston, Massachusetts and asbestos-free talc. Colorants include any approved and certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on hydrated alumina, as well as lakes and mixtures thereof. Lakes are combinations produced by adsorbing water-soluble dyes onto hydrated oxides of heavy metals, thereby producing insoluble forms of the dyes. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic mixtures of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include gelatin, gum arabic, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate ( 20), polyoxyethylene sorbitan monooleate 80 ( 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Preservatives include glycerol, methyl paraben, and propyl paraben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerol, sorbitol, ethanol, and syrups. Examples of non-aqueous liquids for emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0302] It should be understood that multiple carriers and excipients can perform multiple functions, even in the same formulation.

[0303] The pharmaceutical compositions provided herein can be provided in the form of compressed tablets, developed tablets, chewable lozenges, instant tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with a sugar coating, which may help to mask unpleasant tastes or odors and protect the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multi-compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, compressed-coated tablets, or dry-coated tablets.

[0304] Tablet dosage forms can be prepared from the active ingredient alone in powder, crystalline or granular form or in combination with one or more of the carriers or excipients described herein, which carriers or excipients include binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavoring agents and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0305] The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry filled capsules (DFC), consist of two parts that slide over one another to completely enclose the active ingredient. Soft elastic capsules (SEC) are a soft spherical shell, such as a gelatin shell, which is plasticized by the addition of glycerol, sorbitol or a similar polyol. Soft gelatin shells can contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methylparaben and propylparaben, as well as 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. Capsules can also be coated as known to those skilled in the art to modify or maintain the dissolution of the active ingredient.

[0306] The pharmaceutical compositions provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of small spheres in another liquid, which can be water-in-oil or oil-in-water. Emulsions can contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifying agents and preservatives. Suspensions can contain pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can contain pharmaceutically acceptable acetals, such as bis(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened water-alcohol solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of pharmaceutically acceptable liquid carrier, such as water, to facilitate convenient measurement upon administration.

[0307] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamate.

[0308] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nano-systems. Micellar dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0309] The pharmaceutical compositions provided herein may be provided in the form of non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a source of carbon dioxide.

[0310] Colorants and flavorants may be used in all of the above dosage forms.

[0311] The pharmaceutical compositions provided herein may be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release forms. Thus, in some preferred embodiments, the active ingredient (i.e., a calcium channel blocker or L-arginine, or a combination of a calcium channel blocker and L-arginine, or a pharmaceutically acceptable salt, hydrate, solvate, and prodrug thereof) is administered in a pharmaceutical composition that is an immediate release oral dosage form, preferably but not necessarily including an enteric coating. In some preferred embodiments, the active ingredient is administered in a pharmaceutical composition that is a delayed release oral dosage form, preferably but not necessarily including an enteric coating. In additional preferred embodiments, the active ingredient is administered in a pharmaceutical composition that contains an immediate release dose and a delayed release dose or a pulsatile release dose of a calcium channel blocker, preferably but not necessarily further including an enteric coating. Such dual release dosage forms achieve an initial dose of the active ingredient being released first, followed by another pulsatile release or sustained release dose at a later time. Methods for preparing such dual release dosage forms are well known in the art.

[0312] In some embodiments, the active ingredient is formulated as a controlled release matrix tablet containing one or more polymeric matrix materials that promote sustained release, delayed release, or pulsatile release profiles. Non-limiting examples of such polymeric matrix materials include the cellulose materials and carbomers described above, such as those sold by the Lubrizol Corporation under the name for example 71G NF, 971P NF, and 974P NF polymers.

[0313] Some preferred examples of extended release compositions suitable for the methods and compositions of the present invention include, for example but not limited to, extended release compositions found in nifedipine formulations such as Adalat XL, CR, and XL; and extended release compositions found in diltiazem formulations such as CD, LA, SR, XT, and XR.

[0314] In some embodiments, the present disclosure provides pharmaceutical compositions for oral administration for treating the conditions and disorders described herein.

[0315] Dosage

[0316] The compositions provided herein contain a therapeutically effective amount of one or more compounds and vehicles useful for preventing, treating, or ameliorating one or more symptoms of the diseases or disorders described herein. Vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art that are suitable for a particular mode of administration, preferably topical, oral, or via injection. Additionally, the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients.

[0317] The amount of the active compound contained in the vehicle is sufficient to exert a therapeutically useful effect without undesirable side effects on the patient being treated. The therapeutically effective concentration can be predicted empirically by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then inferring the dose for humans therefrom. Then, the human dose is typically fine-tuned in clinical trials and titrated according to the response.

[0318] The concentration of the active compound in the composition will depend on the rate of absorption, inactivation, and excretion of the active compound, the physicochemical properties of the compound, the dosage regimen and the administered amount, as well as other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of the disease or disorder as described herein.

[0319] In some embodiments, the therapeutically effective dose should be from about 0.0001 mg to about 1000 mg per day. In some embodiments, 0.001 - 50 mg of the active ingredient (such as the MgrprX2 antagonist as described herein) per kilogram of body weight per day is delivered locally, orally, or via injection as described herein. In some embodiments, the MgrprX2 antagonist is administered at a dose of up to 1500 mg / day, for example 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.

[0320] The active ingredient can be administered as a single dose, or it can be divided into multiple smaller doses and administered at intervals. It should be understood that the precise dosage and duration of treatment vary with the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data or subsequent clinical testing. It should be noted that the concentration and dosage values may also vary with the severity of the condition to be alleviated. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering the composition 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 composition.

[0321] Dosage forms or compositions containing the active ingredient in the range of 0.005% to 100% can be prepared, with the remaining amount consisting of a vehicle or carrier. The methods for preparing these compositions are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Company, Easton, Pa., 1975 or later editions.

[0322] Oral dosage

[0323] The oral dosage forms of the invention containing the MrgprX2 antagonists of the present disclosure will generally be administered at the dosages described above.

[0324] In some preferred embodiments, the daily dosage is administered once daily. In some embodiments, the dosage form is a sustained-release composition.

[0325] In some embodiments, the daily dosage is administered as a single dose. In other embodiments, the daily dosage is administered in smaller increments multiple times a day, such as two or three times a day, the combined amount being equal to the above daily value.

[0326] In some preferred embodiments, the daily dosage is administered as a single dose that provides efficacy for up to 12, up to 18, or up to 24 hours.

[0327] Topical dosage

[0328] In some embodiments, a topical formulation containing the compounds of the present disclosure will contain the MrgprX2 antagonist at a concentration of 0.001 wt% to 20 wt% of the composition, such as 0.001 wt% - 10 wt% of the composition, such as 0.001 wt% - 8 wt% of the composition, such as 0.001 wt% - 5 wt% of the composition, such as 0.001 wt% - 4 wt% of the composition, such as 0.001 wt% - 3 wt% of the composition, such as 0.001 wt% - 2 wt% of the composition, such as 0.001 wt% - 1 wt% of the composition.

[0329] The compound or derivative may be packaged as an article containing a packaging material, the compound or its derivative provided herein within the packaging material, and a label, the compound or its derivative being effective to treat, prevent, or ameliorate one or more symptoms of the above diseases or disorders, and the label indicating that the compound or composition or its derivative is for treating, preventing, or ameliorating one or more symptoms of the above diseases or disorders.

[0330] The articles provided herein contain a packaging material. Packaging materials for packaging products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment. A variety of formulations of the compounds and compositions provided herein are contemplated for use as a variety of treatments for any of the diseases or disorders described herein.

[0331] Those skilled in the art can use the following examples to determine the effectiveness of the compounds of the invention in treating humans suffering from skin conditions characterized by inflammation.

[0332] Example

[0333] Example 1 - Preparation of the Compounds According to the Present Disclosure

[0334] Compound E001

[0335]

[0336] 2 - Cyano - N - [5 - (3 - fluorophenoxy) - 2 - pyridyl] - 2 - methyl - propanamide

[0337] Step 1

[0338] 5 - Bromo - 2 - nitro - pyridine (750 mg, 3.69 mmol), cesium carbonate (2.4 g, 7.39 mmol) and 3 - fluorophenol (335 μL, 3.69 mmol) were mixed in DMSO (7.5 mL), purged with nitrogen, and stirred at 50 °C 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 column KP - Sil 50 g; 0 - 50% EtOAc / heptane]. The pooled fractions were 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 (500 MHz, DMSO - d6) δ 8.46 (d, J = 2.8 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 9.0, 2.9 Hz, 1H), 7.54 (td, J = 8.3, 6.8 Hz, 1H), 7.22 (dt, J = 10.0, 2.4 Hz, 1H), 7.17 (tdd, J = 8.6, 2.5, 0.7 Hz, 1H), 7.10 (dd, J = 8.2, 2.2 Hz, 1H)

[0339] Step 2: 5 - (3 - fluorophenoxy)pyridin - 2 - amine

[0340] To a solution of 5-(3-fluorophenoxy)-2-nitropyridine (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 hydrogen balloon 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 (500 MHz, DMSO-d6) δ 7.78 (d, J = 2.9 Hz, 1H), 7.41–7.30 (m, 1H), 7.24 (dd, J = 8.9, 3.0 Hz, 1H), 6.87 (tdd, J = 8.6, 2.2, 0.9 Hz, 1H), 6.77–6.68 (m, 2H), 6.51 (d, J = 8.9 Hz, 1H), 5.93 (s, 2H).

[0341] Step 3

[0342] 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-isopropylpropan-2-amine (0.13 mL, 0.735 mmol) and T3P (50% EtOAc solution) (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 (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.25 (d, J = 2.9 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.63 (dd, J = 9.0, 3.0 Hz, 1H), 7.43 (ddd, J = 8.3, 8.3, 7.0 Hz, 1H), 7.04–6.95 (m, 1H), 6.96–6.92 (m, 1H), 6.89–6.81 (m, 1H), 1.68 (s, 6H).

[0343] LCMS: m / z 300.2 [M+H]+, (ESI+), RT = 3.35 (method A)

[0344] Table 1: The following compounds were synthesized using a method similar to that used for compound E001

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] *E075 is formed as a by-product of the synthesis of E042

[0358] **E076 is formed as a by-product of the synthesis of E063

[0359] Compound E078

[0360]

[0361] (1R)-N-[5-(3,4-difluorophenoxy)-2-pyridinyl]-2,2-dimethyl-cyclopropanecarboxamide

[0362] Chiral separation of the compound E029 was performed under the following conditions: Chiralpak AD-H column (20x250 mm, 5 μm), mobile phase of methanol (9 mL / min), to give a colorless oil as the second eluted fraction. Comparison with compound E043 confirmed the absolute stereochemistry. The product was further purified by column chromatography (10 g Biotage SNAP cartridge, 0-40% ethyl acetate / heptane gradient) 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, 0.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.53 (dd, J = 9.1, 3.0 Hz, 1H), 7.44 (dt, J = 10.5, 9.2 Hz, 1H), 7.23 (ddd, J = 11.8, 6.8, 3.0 Hz, 1H), 6.87 (dtt, J = 8.4, 3.2, 1.8 Hz, 1H), 1.87 (dd, J = 7.9, 5.5 Hz, 1H), 1.14 (d, J = 3.0 Hz, 6H), 0.99 (dd, J = 5.3, 3.9 Hz, 1H), 0.80 (dd, J = 7.9, 3.8 Hz, 1H). LCMS: m / z 319.2 [M+H]+, (ESI+), RT = 3.82 (Method A)

[0363] Compound E079

[0364]

[0365] 2,2,3,3-Tetramethyl-N-[5-(methylamino)-2-pyridinyl]cyclopropanecarboxamide

[0366] Step 1

[0367] 5-Bromo-2-nitropyridine (250 mg, 1.23 mmol), cesium carbonate (803 mg, 2.46 mmol), and N-methyl-1-phenylmethanamine (0.16 mL, 1.23 mmol) were combined in DMSO (6.25 mL), purged with nitrogen, and stirred at 50 °C in an RBF for 3 h. The reaction temperature was raised to 80 °C and the reaction mixture was stirred for an additional 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 in vacuo. The crude product was purified by flash column chromatography (50 g SiO2 column, 0 - 80% EtOAc / heptane) to afford N-benzyl-N-methyl-6-nitropyridin-3-amine (60 mg, 0.230 mmol, 19% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 3.1 Hz, 1H), 7.36 (ddd, J = 7.5, 6.3, 1.2 Hz, 2H), 7.31–7.20 (m, 4H), 4.82 (s, 2H), 3.25 (s, 3H).

[0368] Step 2

[0369] To a solution of N-benzyl-N-methyl-6-nitropyridin-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 x 25 mL). The filtrate was diluted with water (25 mL), the layers were separated, and the aqueous layer was extracted twice with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine, dried (hydrophobic frit), and concentrated in vacuo to afford N5-benzyl-N5-methylpyridine-2,5-diamine (90.0%) (52 mg, 0.219 mmol, 95% yield) as a black oil. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 2.7 Hz, 1H), 7.31 (ddd, J = 9.7, 4.4, 2.4 Hz, 2H), 7.22 (td, J = 5.2, 4.7, 2.2 Hz, 3H), 7.10 (dd, J = 8.9, 3.1 Hz, 1H), 6.39 (dd, J = 8.8, 0.6 Hz, 1H), 5.21 (s, 2H), 4.30 (s, 2H), 2.76 (s, 3H).

[0370] Step 3

[0371] While stirring, 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (42 mg, 0.263 mmol) was added to a solution of N5-benzyl-N5-methylpyridine-2,5-diamine (90%, 52 mg, 0.219 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.077 mL, 0.439 mmol) in anhydrous THF (3 mL) at room temperature over 2 h. Then MeOH (1 mL) and 1 M NaOH (1 mL) were added 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 layer was extracted with additional EtOAc (2 x 15 mL). The combined organic extracts were dried (hydrophobic sieve plate) and concentrated in vacuo to give N-[5-[benzyl(methyl)amino]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92.0%) (75 mg, 0.203 mmol, 93% yield) as a red-brown oil. 1H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 9.1 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 3.1 Hz, 1H), 7.24 (t, J = 7.3 Hz, 2H), 7.16 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 7.1 Hz, 2H), 7.01 (dd, J = 9.1, 3.1 Hz, 1H), 4.41 (s, 2H), 2.92 (s, 3H), 1.23 (s, 6H), 1.12 (s, 6H), 0.93 (s, 1H).

[0372] Step 4

[0373] A stirred solution of N-[5-[benzyl(methyl)amino]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92%, 75 mg, 0.203 mmol) in ethyl acetate (10 mL) was placed under a hydrogen balloon and stirred at room temperature for 16 h. Another portion of 10% palladium on carbon (4.3 mg, 0.0406 mmol) was added and the mixture was placed under a hydrogen balloon and stirred at room temperature for 5 h. The reaction mixture was filtered through Celite, which was washed with additional dioxane (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was dissolved in methanol (5 mL). The solution was passed through an H-Cube flow hydrogenator equipped with a 10% Pd / C cartridge at a flow rate of 1 mL / min and a reaction temperature of 80 °C. The hydrogen gas generated was supplied to the flow at a pressure of 80 bar. The crude mixture was then passed through the H-Cube two more times under the same conditions, but acetic acid (5% (v / v)) was added to the reaction mixture. The mixture was concentrated under reduced pressure and purified by preparative HPLC (method E), followed by passing through an SCX-cartridge (1 g), eluting first with methanol (3 CV) and then with 2 M ammonia / 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), which was a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 8.9, 3.0 Hz, 1H), 5.56 (d, J = 5.2 Hz, 1H), 2.68 (d, J = 5.1 Hz, 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)

[0374] Compound E080

[0375]

[0376] N-[5-(2-hydroxy-2-methyl-propoxy)-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0377] Synthesized using a method similar to that used in compound E079, starting from 2-methyl-2-(phenylmethoxy)-1-propanol. 1H NMR (500 MHz, chloroform-d) δ 8.11 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.9 Hz, 1H), 7.89 (s, 1H), 7.26–7.22 (m, 1H), 3.80 (s, 2H), 2.18 (s, 1H), 1.35 (s, 6H), 1.31 (s, 6H), 1.21 (s, 6H), 1.00 (s, 1H). LCMS: m / z 307.5 [M+H]+, (ESI+), RT = 2.73 (method A)

[0378] Compound E081

[0379]

[0380] 2-Methyl-N-(5-pyrrolidin-1-yl-2-pyridinyl)propanamide

[0381] Step 1

[0382] While stirring, a suspension of 5-bromo-2-nitropyridine (1 g, 4.93 mmol) in pyrrolidine (2.1 mL, 24.6 mmol) was heated to 120 °C in a microwave reactor for 1 hour. 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 column, 10-60% EtOAc / heptane) gave 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).

[0383] Step 2

[0384] At room temperature, 10% palladium on carbon (50 mg, 0.470 mmol) was added to a degassed suspension of 2-nitro-5-pyrrolidin-1-yl-pyridine (486 mg, 2.52 mmol) in ethanol (10 mL), and the mixture was stirred under a hydrogen atmosphere for 4 h. The reaction mixture was filtered through celite (5 g) and evaporated to dryness to afford the brown solid 5-pyrrolidin-1-ylpyridin-2-amine (466 mg, 2.31 mmol, 92% yield). 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).

[0385] Step 3

[0386] At room temperature, a solution of 2-methylpropanoyl chloride (0.060 mL, 0.573 mmol) in DCM (1 mL) was added to a stirred solution of 5-pyrrolidin-1-ylpyridin-2-amine (58 mg, 0.288 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.573 mmol) in DCM (5 mL), and the mixture was 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), stirred at room temperature for 1 h, and then evaporated in vacuo. Purification by preparative HPLC (method H) followed by lyophilization gave the title product as a white solid (31 mg, 0.132 mmol, 46% yield). 1H NMR (250 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.28–3.15 (m, 4H), 2.77–2.58 (m, 1H), 2.01–1.88 (m, 4H), 1.06 (d, J = 6.8 Hz, 6H). LCMS: m / z 234.1 [M+H]+, (ESI+), RT = 1.49 (method A) Compound E082

[0387]

[0388] N-[5-(2-Hydroxyethoxy)pyridin-2-yl]-2,2,3,3-tetramethylcyclopropane-1-carboxamide

[0389] Synthesized using a method similar to that used for compound E078, starting from benzyloxyethanol, except that sodium hydride was used as the base and DMF was used 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)

[0390] Table 2: The following compounds were synthesized using a method similar to that used for compound E001, except that sodium hydride was used as the base and DMF was used as the solvent in step 1.

[0391]

[0392]

[0393]

[0394] * Compounds E089 and E090 were separated as products from the same reaction

[0395] Compound E093

[0396]

[0397] 2,2,3,3-Tetramethyl-N-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]cyclopropanecarboxamide

[0398] Step 1

[0399] To a stirred mixture of 6-aminopyridin-3-ol (150 mg, 1.36 mmol) and cesium carbonate (0.67 g, 2.04 mmol) in anhydrous DMF (3.6 mL) was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.22 mL, 1.50 mmol). After stirring for 6 h at room temperature, the mixture was concentrated to dryness under reduced pressure. To the residue was added EtOAc (20 ml) and water (20 ml). The organic layer was separated and the aqueous layer was extracted with additional EtOAc (2 x 20 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 25 g, eluting with 20 - 100% EtOAc / heptane) to afford 5-(2,2,2-trifluoroethoxy)pyridin-2-amine (60 mg, 22% yield) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ 7.74 (d, J = 3.0 Hz, 1H), 7.22 (dd, J = 8.9, 3.1 Hz, 1H), 6.43 (d, J = 8.9 Hz, 1H), 5.65 (s, 2H), 4.62 (q, J = 9.0 Hz, 2H)

[0400] Step 2

[0401] While stirring, 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (60 mg, 0.371 mmol) was added to a solution of 5-(2,2,2-trifluoroethoxy)pyridin-2-amine (60 mg, 0.309 mmol) and N-ethyl-N-isopropylpropan-2-amine (108 uL, 0.618 mmol) in anhydrous THF (2.5 mL) at room temperature over 16 h, then 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) and extracted with EtOAc (3 x 10 mL), and the combined organic extracts were concentrated in vacuo. The crude product was first purified by flash column chromatography (SiO2, 50 g, 0 - 30% EtOAc / heptane) and then by preparative HPLC (method G) to afford 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)

[0402] Compound E094

[0403]

[0404] N-(5-Anilino-2-pyridinyl)-2-methyl-propanamide

[0405] Step 1

[0406] To a stirred solution of isobutyric anhydride (359 μL, 2.17 mmol) and 5-bromopyridin-2-amine (250 mg, 1.45 mmol) in THF (15.453 mL) was added N-ethyl-N-isopropyl-propan-2-amine (505 μL, 2.89 mmol), then N,N-dimethylpyridin-4-amine (18 mg, 0.145 mmol), and the mixture was stirred at 80 °C in a sealable pressure tube for 2 h. The reaction mixture was then evaporated to dryness. Purification by flash chromatography (50 g KP-Sil Biotage SNAP column, 10 - 100% EtOAc / heptane) afforded N-(5-bromo-2-pyridinyl)-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).

[0407] Step 2

[0408] To a mixture of N-(5-bromo-2-pyridinyl)-2-methyl-propanamide (70 mg, 0.285 mMol) and sodium tert-butoxide (41 mg, 0.428 mMol) was added toluene (3 mL). Then aniline (29 mg, 0.314 mMol) was added, and the mixture was degassed under nitrogen at room temperature for 10 minutes. Then Pd2(dba)3 (26 mg, 0.0283 mMol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (40.8 mg, 0.0855 mMol) were added to the mixture, and the reaction vessel was sealed and heated to 100 °C with stirring for 4 hours, then cooled to room temperature. The reaction mixture was filtered through diatomaceous earth with EtOAc (30 mL). Then it was washed with saturated NaHCO3 (30 mL), then with brine (30 mL), dried over sodium sulfate, filtered and evaporated to dryness. Purification by preparative HPLC (method F) gave the title compound as a white solid (3.6 mg, 5%). 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.51 (dd, J = 8.9, 2.9 Hz, 1H), 7.25–7.19 (m, 2H), 6.99 (dd, J = 8.6, 1.0 Hz, 2H), 6.81 (tt, J = 7.4, 1.1 Hz, 1H), 2.71 (hept, J = 6.8 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H). LCMS: m / z 256.2 [M+H]+, (ESI+), RT = 2.30 (method A)

[0409] Compound E095

[0410]

[0411] N-(5-indolin-1-yl-2-pyridinyl)-2-methyl-propanamide

[0412] Synthesized using a method similar to that used for compound E094. 1H NMR (250 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 9.2, 3.0 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.10–6.94 (m, 2H), 6.77–6.68 (m, 1H), 3.93 (t, J = 8.6 Hz, 2H), 3.10 (t, J = 8.6 Hz, 2H), 2.77 (m, J = 1.9 Hz, 1H), 1.09 (d, J = 6.8 Hz, 6H). LCMS: m / z 282.2 [M+H]+, (ESI+), RT = 3.02 (Method A)

[0413] Compound E096

[0414]

[0415] 2-Methyl-N-[5-(N-methylanilino)-2-pyridyl]propanamide

[0416] Step 1

[0417] To a solution of 5-bromo-2-nitropyridine (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 the mixture was degassed under nitrogen at room temperature for 10 minutes. To this was added N-methylaniline (0.13 mL, 1.18 mmol) and (R)-BINAP (61 mg, 0.0985 mmol), and the reaction vessel was sealed and heated to 100 °C with stirring for 4 hours, then cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc, then the aqueous layer was extracted with EtOAc, the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give N-methyl-6-nitro-N-phenylpyridin-3-amine as a dark yellow solid (187.7 mg, 83.1%). 1H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.55–7.50 (m, 2H), 7.38–7.34 (m, 3H), 7.21 (dd, J = 9.2, 3.0 Hz, 1H), 3.43 (s, 3H).

[0418] Step 2

[0419] To a solution of N-methyl-6-nitro-N-phenylpyridin-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 hydrogen balloon 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-phenylpyridine-2,5-diamine as a colorless oil (138 mg, 85%). 1H NMR (500 MHz, DMSO-d6) δ 7.76 (dd, J = 2.7, 0.6 Hz, 1H), 7.22 (dd, J = 8.7, 2.7 Hz, 1H), 7.15–7.10 (m, 2H), 6.68–6.60 (m, 3H), 6.49 (dd, J = 8.7, 0.7 Hz, 1H), 5.88 (s, 2H), 3.13 (s, 3H).

[0420] Step 3

[0421] To a stirred solution of N-ethyl-N-isopropylpropan-2-amine (140 μL, 0.803 mmol) and N,N-dimethylpyridin-4-amine (4.9 mg, 0.0402 mmol) in anhydrous THF (2.5 mL) was added isobutyric anhydride (100 μL, 0.602 mmol), then N5-methyl-N5-phenylpyridine-2,5-diamine (80 mg, 0.402 mmol), and the mixture was stirred in a sealable pressure tube at 80 °C for 48 h. The reaction mixture was then evaporated to dryness and purified by column chromatography (Biotage SNAP cartridge KP-Sil 10 g; 0–100% EtOAc / heptane) to give the title compound (57.3 mg, 53%) as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.09–8.01 (m, 2H), 7.49 (dd, J = 8.9, 2.9 Hz, 1H), 7.30–7.20 (m, 2H), 6.97–6.84 (m, 3H), 3.25 (s, 3H), 2.73 (hept, J = 6.8 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H). LCMS: m / z 270.2 [M+H]+, (ESI+), RT = 2.59 (Method A)

[0422] Table 3: The following compounds were synthesized using a method similar to that used for compound E096.

[0423]

[0424]

[0425] Compound E102

[0426]

[0427] 3-[5-(3,4-Difluorophenoxy)-2-pyridinyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0428] Step 1

[0429] Mix 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) in DMSO (25 mL), purge with nitrogen, and stir at 50 °C in an RBF for 2 h. Cool the reaction mixture, dilute with water (75 mL) to form a beige / grey precipitate. Filter it, wash with water, and purify by FCC (Biotage SNAP KP-Sil 25 g, 0-50% EtOAc / heptane) to give 5-(3,4-difluorophenoxy)-2-nitro-pyridine (2.09 g, 81% yield), which is an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.44 (dd, J = 8.9, 2.8 Hz, 1H), 7.32–7.21 (m, 1H), 7.00 (ddd, J = 9.9, 6.5, 2.9 Hz, 1H), 6.88 (dq, J = 8.6, 3.1 Hz, 1H).

[0430] Step 2

[0431] To a solution of 5-(3,4-difluorophenoxy)-2-nitropyridine (2 g, 8 mmol) in EtOH (50 mL) and H2O (10 mL) was added ammonium chloride (4.43 g, 82.9 mmol). The reaction mixture was heated to 50 °C and iron (4.63 g, 82.9 mmol) was added. The reaction was then stirred at 70 °C for 25 minutes. The reaction mixture was then cooled, filtered through a pad of diatomaceous earth, 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 x 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), which was a brown oil. 1H NMR (500 MHz, chloroform-d) δ 7.89 (d, J = 2.8 Hz, 1H), 7.18 (dd, J = 8.8, 2.9 Hz, 1H), 7.11–7.03 (m, 1H), 6.75 (ddd, J = 11.5, 6.6, 3.0 Hz, 1H), 6.64 (dtt, J = 8.3, 3.2, 1.8 Hz, 1H), 6.55–6.50 (m, 1H), 4.43 (s, 2H).

[0432] Step 3

[0433] To a solution of 2M ethylamine 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, which was a dark yellow solid (Intermediate I02, 530 mg, 94%, 75% purity). It 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 were not observed).

[0434] Step 4

[0435] To a stirred solution of (4-nitrophenyl)carbonyl chloride (100 mg, 0.495 mmol) in anhydrous THF (3 mL) was added a solution of pyridine (40 μL, 0.495 mmol) and 5-(3,4-difluorophenoxy)pyridin-2-amine (100 mg, 0.450 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 4.5 h. A solution of (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (92 mg, 0.585 mmol) and N-ethyl-N-isopropyl-propan-2-amine (118 μL, 0.675 mmol) in anhydrous THF (3 mL) was added to the reaction mixture and stirred overnight at room temperature. The product was purified first by silica gel flash column chromatography (0-40% EtOAc / heptane) and then by preparative HPLC (method G) to give the title compound (77 mg, 0.189 mmol, 42% yield) as a transparent glass. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.83 (d, J = 9.1 Hz, 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, 2.6 Hz, 1H), 3.50–3.38 (m, 3H), 1.11 (t, J = 7.0 Hz, 3H). LCMS: m / z 406.2 [M+H]+, (ESI+), RT = 3.61 (method B)

[0436] Table 4: The following compounds were synthesized using a method similar to that used for compound E102, using commercially available amines or amino alcohols, and were synthesized according to step 3 of compound E102

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] Compound E139

[0447]

[0448] 3-[5-(3,4-difluorophenoxy)-2-pyridinyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0449] Step 1

[0450] Under N2, (2R)-2-(trifluoromethyl)oxirane (200 mg, 1.78 mmol) was added to a three-necked RBF, then anhydrous THF (8 mL) was added, and the stirred solution was cooled to -100 °C using an Et2O / dry ice bath. Then 1.6 M butyllithium (1.2 mL, 1.96 mmol) was added dropwise, and the mixture was stirred at this temperature for 10 minutes. Then iodomethane (0.17 mL, 2.68 mmol) was added and the reaction mixture was stirred at this temperature for 2 hours, warmed to ~0 °C using an ice bath, 2 M methylamine (3.6 mL, 7.14 mmol) was added thereto, and the reaction mixture was warmed to room temperature and stirred overnight and left over the weekend. Then the solvent was removed under reduced pressure to obtain (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).

[0451] Step 2

[0452] To a solution of 4-nitrophenyl chloroformate (47 mg, 0.233 mmol) in anhydrous THF (1.5 mL) was added a solution of 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 mixture was stirred at room temperature for 3 h. Next, a solution of (2R)-1,1,1-trifluoro-2-methyl-3-(methylamino)propan-2-ol (25% pure, 133 mg, 0.212 mmol) and N-ethyl-N-isopropylpropan-2-amine (55 uL, 0.317 mmol) in anhydrous THF (1.5 mL) was added, and the reaction mixture was stirred at room temperature for 45 min. Then it was concentrated under reduced pressure and purified by preparative HPLC (Method G) to give the title compound (25 mg, 29% yield), which is 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)

[0453] Compound E140

[0454]

[0455] 3-[5-(3,5-Difluorophenoxy)-2-pyridinyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]urea

[0456] Synthesized using a method similar to that used for Compound E139. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 9.1, 3.0 Hz, 1H), 6.98 (tt, J = 9.3, 2.3 Hz, 1H), 6.78–6.68 (m, 2H), 3.72 (d, J = 13.9 Hz, 1H), 3.46 (d, J = 14.4 Hz, 1H), 3.06 (s, 3H), 1.30 (s, 3H). LCMS: m / z 406.3 [M+H]+, (ESI+), RT = 3.64 (Method B)

[0457] Compound E141

[0458]

[0459] 3-[5-(2,4-Difluorophenoxy)-2-pyridinyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0460] 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 [M-H]-, (ESI-), RT = 3.30 (Method A)

[0461] Compound E142

[0462]

[0463] 1-Ethyl-3-(5-pyrazol-1-yl-2-pyridinyl)-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0464] Step 1

[0465] Mix 5-fluoro-2-nitropyridine (250 mg, 1.76 mmol) and 1H-pyrazole (126 mg, 1.85 mmol) in anhydrous DMF (3.5 mL), cool the reaction mixture to 0 °C, and then add sodium hydride (60%, 106 mg, 2.64 mmol) portionwise. Then stir the reactants at room temperature for 2 hours. After completion, dilute the reaction mixture with water (10 mL) to form a pale yellow precipitate. Filter it, wash with water (50 ml) and dry to obtain 2-nitro-5-pyrazol-1-yl-pyridine (235 mg, 1.17 mmol, 67% yield), which is a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.23–9.16 (m, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 8.9, 2.6 Hz, 1H), 8.51–8.45 (m, 1H), 7.97 (d, J = 1.6 Hz, 1H), 6.73 (dd, J = 2.6, 1.7 Hz, 1H).

[0466] Step 2

[0467] 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 hydrogen balloon and stirred at room temperature for 4 h. The reaction mixture was filtered through celite, which was then washed with additional dioxane (50 mL). The filtrate was concentrated under reduced pressure to afford 5-pyrazol-1-yl-pyridin-2-amine (188 mg, 90% yield) as a sandy brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.8, 2.8 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 6.49–6.43 (m, 1H), 6.10 (s, 2H).

[0468] Step 3

[0469] To a solution of (4-nitrophenyl) chloroformate (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 mixture was stirred at room temperature for 1 h. Then a solution of (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 μL, 0.445 mmol) in anhydrous THF (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. It was then concentrated under reduced pressure and purified by preparative HPLC (Method G) to give the title compound (47 mg, 0.133 mmol, 45% yield), which was a pale yellow solid. 1H NMR (400 MHz, chloroform-d) δ 8.58 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.99–7.91 (m, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.76–7.71 (m, 1H), 6.50 (t, J = 1.9 Hz, 1H), 5.74 (s, 1H), 4.26–4.14 (m, 1H), 3.80 (dd, J = 15.2, 8.7 Hz, 1H), 3.59–3.47 (m, 2H), 3.41 (dq, J = 14.8, 7.3 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H). LCMS: m / z 344.3 [M+H]+, (ESI+), RT = 2.48 (Method A).

[0470] Compound E143

[0471]

[0472] N-[4-(3,5-difluorophenoxy)-2-pyridinyl]-2-methyl-propanamide

[0473] Step 1

[0474] At room temperature, N-ethyl-N-isopropyl-propan-2-amine (0.82 mL, 4.67 mmol) was added 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). The reaction mixture was stirred at 160 °C for 18 h. Then it was 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 x 20 mL). The combined organic extracts 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 (400 MHz, DMSO-d6) δ 7.86 (d, J = 5.8 Hz, 1H), 7.13 (tt, J = 9.4, 2.3 Hz, 1H), 7.03–6.85 (m, 2H), 6.20 (dd, J = 5.8, 2.3 Hz, 1H), 6.02 (s, 2H), 5.95 (d, J = 2.2 Hz, 1H).

[0475] Step 2

[0476] 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), then 2-methylpropanoyl chloride (32 uL, 0.306 mmol) was added and the reaction was stirred at room temperature for 0.5 h. Then the solvent was removed under a steady stream of nitrogen and the residue was dissolved in MeOH (1 mL), 1M NaOH (1 mL) was added and the reaction mixture was stirred at room temperature for 0.5 h. The MeOH was removed under a steady stream of nitrogen and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash column chromatography (10 g SiO2 column, 0-60% EtOAc / heptane) to give the title compound as a white solid (39 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.21 (tt, J = 9.4, 2.3 Hz, 1H), 7.12–7.00 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 2.72 (hept, J = 6.8 Hz, 1H), 1.05 (d, J = 6.8 Hz, 6H). LCMS: m / z 292.8 [M+H]+, (ESI+), RT = 3.02 (method A).

[0477] Compound E144

[0478]

[0479] N-[4-(3,5-Difluorophenoxy)-2-pyridinyl]cyclopropanecarboxamide

[0480] Synthesized using a method similar to that used for Compound E143. 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.20 (tt, J = 9.4, 2.3 Hz, 1H), 7.12–6.97 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 1.98 (tt, J = 6.2, 6.2 Hz, 1H), 0.78 (d, J = 6.2 Hz, 4H). LCMS: m / z 291.1 [M+H]+, (ESI+), RT = 2.83 (Method A).

[0481] Compound E145

[0482]

[0483] 2-Methyl-N-(4-phenoxy-2-pyridinyl)propanamide

[0484] Step 1

[0485] At room temperature, to a solution of 4-chloropyridin-2-amine (500 mg, 3.89 mmol) in THF (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.4 mL, 7.78 mmol), then 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-Sil Biotage SNAP column, 5-40% EtOAc / heptane) gave a white solid. It was dissolved in DCM (30 mL) and washed with 1N 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-methylpropanamide (546 mg, 69% yield), which was 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).

[0486] Step 2

[0487] At room temperature, to a solution of N-(4-chloro-2-pyridyl)-2-methylpropanamide (100 mg, 0.498 mmol) and phenol (47 mg, 0.498 mmol) in DMSO (1 mL) 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), then concentration and lyophilization gave the title compound as an off-white solid (56 mg, 0.218 mmol, 44% yield). 1H NMR (250 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.18 (d, J = 5.7 Hz, 1H), 7.68 (d, J = 2.3 Hz, 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, 2.4 Hz, 1H), 2.77–2.60 (m, 1H), 1.03 (d, J = 6.8 Hz, 6H). LCMS: m / z 257.1 [M+H]+, (ESI+), RT = 2.33 (Method A)

[0488] Compound E146

[0489]

[0490] 2,2,3,3 - Tetramethyl - N-(4 - pyrrolidin - 1 - yl - 2 - pyridyl)cyclopropanecarboxamide

[0491] Step 1

[0492] At room temperature, a solution of 2,2,3,3 - tetramethylcyclopropanecarbonyl chloride (497 mg, 3.10 mmol) in DCM (1 mL) was added to a stirred solution of 4 - chloropyridin - 2 - amine (200 mg, 1.56 mmol) and N - ethyl - N - isopropylpropan - 2 - amine (0.54 mL, 3.09 mmol) in DCM (3 mL), and the mixture was 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), stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. 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%) gave N-(4 - chloro - 2 - pyridyl)-2,2,3,3 - tetramethylcyclopropanecarboxamide (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).

[0493] Step 2

[0494] At 225 °C, a mixture of N-(4-chloro-2-pyridinyl)-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 for 30 minutes. The mixture was washed with ethyl acetate (20 mL) and extracted with water (2 x 30 mL). The combined organics were dried using a hydrophobic filter and evaporated under reduced pressure. The crude reaction mixture was purified by preparative HPLC (Method E) to afford the title compound (28 mg, 37% yield), which was a white solid. 1H NMR (500 MHz, chloroform-d) δ 8.68 (s, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 6.18 (dd, J = 6.8, 2.5 Hz, 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).

[0495] Compound E147

[0496]

[0497] N-[4-[(5-Fluoro-3-pyridinyl)oxy]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0498] Step 1

[0499] While stirring, 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (506 mg, 3.15 mmol) was added to a solution of 4-fluoropyridin-2-amine (300 mg, 2.62 mmol) and N-ethyl-N-isopropylpropan-2-amine (916 μL, 5.25 mmol) in anhydrous THF (15 mL) at room temperature for 16 h, then 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), extracted with EtOAc (3 x 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 gel cartridge, 0-20% EtOAc / heptane) to give N-(4-fluoro-2-pyridinyl)-2,2,3,3-tetramethylcyclopropanecarboxamide (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).

[0500] Step 2

[0501] Sodium hydride (60% oil dispersion) (24 mg, 0.603 mmol) was added to a stirred solution of 5-fluoropyridin-3-ol (48 mg, 0.422 mmol) in anhydrous DMF (3 mL). After the evolution of gas ceased, N-(4-fluoro-2-pyridinyl)-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 column, 0 - 35% EtOAc / heptane), followed by lyophilization, afforded the title product as a colorless solid (37 mg, 27% yield). 1H NMR (500 MHz, chloroform-d) δ 8.36 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.16 (dt, J = 9.1, 2.4 Hz, 1H), 6.58 (dd, J = 5.7, 2.3 Hz, 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)

[0502] Compound E148

[0503]

[0504] N-[4-[(6-Fluoro-3-pyridinyl)oxy]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0505] Step 1

[0506] 6-Fluoropyridin-3-ol (270 mg, 2.39 mmol) and N,N-dimethylglycine hydrochloride (1:1) (178 mg, 1.27 mmol) were suspended in anhydrous 1,4-dioxane (8 mL), and the reaction mixture was degassed with N2 for 5 minutes. 4-Iodopyridin-2-amine (350 mg, 1.59 mmol) was added, and the reactants were stirred for 10 minutes, then copper(I) iodide (121 mg, 0.636 mmol) and cesium carbonate (1296 mg, 3.98 mmol) were added, and the mixture was heated to 90 °C in a microwave reactor for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc (15 mL), filtered through a Celite pad and further washed with EtOAc (30 mL). Then it was washed with water (15 mL) and extracted with EtOAc (2 x 20 mL), dried, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Biotage Sfar Duo 50 g cartridge, 0-10% MeOH / EtOAc) to give 4-[(6-fluoro-3-pyridinyl)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).

[0507] Step 2

[0508] To a solution of tetramethylcyclopropane-1-carbonyl chloride (22 mg, 0.138 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.024 mL, 0.138 mmol) in anhydrous THF (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. Additional tetramethylcyclopropane-1-carbonyl chloride (10 mg, 0.2 equiv) and DIPEA (12 uL, 0.2 equiv) were added, and the mixture was 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 x 25 mL). The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Biotage Sfar Duo 25 g cartridge, eluent: 0 - 100% EtOAc / heptane) to afford the title compound (27 mg, 56% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 8.12 (d, J = 5.7 Hz, 1H), 8.04 (dd, J = 2.8, 1.4 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.54 (ddd, J = 9.1, 6.4, 3.0 Hz, 1H), 6.99 (dd, J = 8.8, 3.5 Hz, 1H), 6.51 (dd, J = 5.7, 2.4 Hz, 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).

[0509] Compound E149

[0510]

[0511] 2,2,3,3-Tetramethyl-N-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]cyclopropanecarboxamide

[0512] Step 1

[0513] To a stirred suspension of 2-aminopyridin-4-ol (500 mg, 4.54 mmol) in MeCN (10 mL) was added 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). The reaction mixture was stirred at 40 °C overnight. Water (5 mL) was added and the mixture was concentrated to remove MeCN. The residue was triturated with water (5 mL) to give a gum. The crude material was suspended in DMF (3 mL), potassium carbonate (500 mg, 3.62 mmol) was added, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (390 μL, 2.71 mmol) was added and the reaction mixture was stirred at 80 °C for 2 h.

[0514] Additional potassium carbonate (100 mg, 0.724 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (140 μL, 0.972 mmol) were added and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled and added dropwise to stirred water (30 mL). The mixture was extracted with EtOAc (3 x 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 / 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).

[0515] Step 2

[0516] tert-Butyl N-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]carbamate (70%, 160 mg, 0.383 mmol) was stirred in a 4 M solution of hydrogen chloride in dioxane (1.0 mL, 4.00 mmol) for 2 h and then left overnight. The reaction mixture 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).

[0517] Step 3

[0518] To a stirred solution of 4-(2,2,2-trifluoroethoxy)pyridin-2-amine (38 mg, 0.192 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.074 mL, 0.422 mmol) in THF (1 mL) was added dropwise a solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (62 mg, 0.384 mmol) in THF (1 mL), and the reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was concentrated in vacuo, then diluted with MeOH (2 mL), and 1 M sodium hydroxide (1.0 mL, 1.00 mmol) was added. The reaction mixture 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 mixture was stirred at 60 °C for 3 h. Methanol was removed in vacuo, and the mixture was extracted with EtOAc (4 x 5 mL). The organic layer 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).

[0519] Compound E150

[0520]

[0521] 3-[4-(3,4-Difluorophenoxy)-2-pyridinyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0522] Step 1

[0523] At room temperature, N-ethyl-N-isopropyl-propan-2-amine (0.76 mL, 4.37 mmol) was added 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). The reaction mixture was stirred at 180 °C for 8 h. Then it was 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 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 / heptane) to give 4-(3,4-difluorophenoxy)pyridin-2-amine (260 mg, 86% purity, 46% yield) as a beige solid. 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 5.8 Hz, 1H), 7.53 (ddd, J = 10.5, 9.2, 9.2 Hz, 1H), 7.39 (ddd, J = 11.5, 6.9, 2.9 Hz, 1H), 7.02 (dddd, J = 8.8, 3.6, 3.5, 1.8 Hz, 1H), 6.14 (dd, J = 5.8, 2.3 Hz, 1H), 5.97 (s, 2H), 5.85 (d, J = 2.3 Hz, 1H).

[0524] Step 2

[0525] 4-(3,4-Difluorophenoxy)pyridin-2-amine (86%, 40 mg, 0.155 mmol) was dissolved in anhydrous DCM (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 anhydrous DCM (1 mL) was added, and the mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with water, passed through a hydrophobic frit and concentrated. The product was purified by preparative HPLC (Method E), followed by an SCX cartridge (2 g), eluting first with MeOH (3 CV) and then with 2 M ammonia / MeOH (3 CV). The ammonia fractions were combined and concentrated to give the title compound (8.6 mg, 0.0212 mmol, 14% yield), which was a pale grey solid. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.13 (d, J = 5.7 Hz, 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, 2.4 Hz, 1H), 4.29–4.20 (m, 1H), 3.57–3.50 (m, 1H), 3.45–3.38 (m, 3H), 1.07 (t, J = 7.0 Hz, 3H). LCMS: m / z 406.3 [M+H]+, (ESI+), RT = 3.57 (Method B). Table 5: The following compounds were synthesized using a method similar to that used in Compound E150, using the or amino alcohol, which was synthesized according to Intermediate I02 or Step 1 of Compound E139

[0526]

[0527]

[0528]

[0529]

[0530] Compound E162

[0531]

[0532] 1-Ethyl-3-[4-[(5-fluoropyridin-3-yl)oxy]-2-pyridinyl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0533] Step 1

[0534] At room temperature, N-ethyl-N-isopropyl-propan-2-amine (0.31 mL, 1.75 mmol) was added 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). The reaction mixture was stirred at 180 °C for 5 h. Then it was 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 x 20 mL). The combined organic extracts were dried (hydrophobic sieve plate), concentrated under reduced pressure and purified by passing through a SCX-2 cartridge 5 g, washed with MeOH (5 CV), eluted with 7N NH3 / MeOH (5 CV) to give 4-[(5-fluoropyridin-3-yl)oxy]pyridin-2-amine (180 mg, 85% purity, 85% yield), which was 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).

[0535] Step 2

[0536] To a solution of bis(trichloromethyl) carbonate (30 mg, 0.0994 mmol) in anhydrous DCM (2 mL) cooled in a dry ice - acetone bath was added dropwise 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) over 10 minutes. The reaction mixture was stirred at - 78 °C for 5 minutes. Then a solution of (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) was added, and the reaction mixture was stirred at - 78 °C for 5 minutes and then in an ice bath for 1 hour. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (Method G) to give the title compound (7.9 mg, 7.9% yield), which was a yellow solid. 1H NMR (500 MHz, chloroform - d) δ 8.43 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 8.09 (d, J = 5.9 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.24 (dt, J = 8.9, 2.3 Hz, 1H), 6.63 (dd, J = 5.9, 2.3 Hz, 1H), 4.23–4.12 (m, 1H), 3.88–3.77 (m, 1H), 3.60–3.38 (m, 3H), 1.30 (t, J = 7.2 Hz, 3H). LCMS: m / z 389.1 [M + H]+, (ESI+), RT = 2.08 (Method A).

[0537] Compound E163

[0538]

[0539] 3 - [4-(3,5 - difluorophenoxy)-2 - pyridyl]-1 - ethyl - 1 - [(2R)-3,3,3 - trifluoro - 2 - hydroxy - propyl]urea

[0540] Synthesized using a method similar to that for synthesizing 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).

[0541] Compound E164

[0542]

[0543] 2-Methyl-N-(5-phenylpyridin-2-yl)propanamide

[0544] Step 1

[0545] To a stirred solution of isobutyric anhydride (719 μL, 4.34 mmol) and 5-bromopyridin-2-amine (500 mg, 2.89 mmol) in THF (15.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (1009 μL, 5.78 mmol), then N,N-dimethylpyridin-4-amine (35 mg, 0.289 mmol), and the mixture was stirred at 80 °C in a sealable pressure tube for 2 h. The reaction mixture was then evaporated to dryness. Purification by flash chromatography (Biotage 50 g KP-Sil SNAP column, 10–100% EtOAc / heptane) gave N-(5-bromopyridin-2-yl)-2-methylpropanamide (502 mg, 71% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.98 (dd, J = 8.9, 2.5 Hz, 1H), 2.74 (hept, J = 6.8 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H).

[0546] Step 2

[0547] N-(5-Bromo-2-pyridinyl)-2-methyl-propanamide (70 mg, 0.288 mmol) and phenylboronic acid (39 mg, 0.317 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) and 2 M Na2CO3 (0.29 mL, 0.576 mmol), and the reaction mixture was degassed with N2 for 5 minutes. Then Pd(dppf)Cl2 (11 mg, 0.0144 mmol) was added, and the reaction was heated to 110 °C for 2 hours. It was then washed with water and 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 (250 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.63 (dd, J = 2.5, 0.8 Hz, 1H), 8.19 (dd, J = 8.7, 0.8 Hz, 1H), 8.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.75–7.66 (m, 2H), 7.54–7.43 (m, 2H), 7.42–7.34 (m, 1H), 2.76 (h, J = 6.8 Hz, 1H), 1.10 (d, J = 6.8 Hz, 6H). LCMS: m / z 241.2 [M+H]+, (ESI+), RT = 2.93 (Method A).

[0548] Table 6: The following compounds were synthesized using a method similar to that used for Compound E164

[0549]

[0550]

[0551] Compound E177

[0552]

[0553] N-(5-Cyclopentyl-2-pyridinyl)-2-methyl-propanamide

[0554] To a solution of N-[5-(cyclopent-1-yl)-2-pyridinyl]-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 hydrogen balloon and stirred at room temperature for 2 h. It was then filtered through celite, washed with EtOAc and concentrated under reduced pressure and purified by flash chromatography (Biotage Isolera, C18 12 g Ultra SNAP column), eluting with a solution of water (+0.1% CH2O2) in MeCN (+0.1% CH2O2) (10 to 100%) to give the title compound as a light brown solid (10.7 mg, 24.3%). 1H NMR (500 MHz, chloroform-d) δ 8.24 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 8.6, 2.4 Hz, 1H), 3.00–2.92 (m, 1H), 2.56 (hept, J = 6.9 Hz, 1H), 2.11–2.04 (m, 2H), 1.86–1.65 (m, 4H), 1.61–1.50 (m, 2H), 1.26 (d, J = 6.9 Hz, 6H). LCMS: m / z 233.2 [M+H]+, (ESI+), RT = 2.43 (Method A).

[0555] Compound E178

[0556]

[0557] 2-Cyano-N-[5-(3,5-difluorophenyl)-2-pyridinyl]-2-methyl-propanamide

[0558] Step 1

[0559] 5-Bromopyridin-2-amine (1.00 g, 5.78 mmol) and (3,5-difluorophenyl)boronic acid (913 mg, 5.78 mmol) were dissolved in anhydrous 1,4-dioxane (55 mL) and 2 M Na2CO3 (6.0 mL, 12.0 mmol), and the reaction mixture was degassed with N2 for 5 minutes. Pd(dppf)Cl2 (212 mg, 0.289 mmol) was added to the reactants, and the reactants were heated to 110 °C for 2.5 h. Then it was cooled to room temperature, concentrated under reduced pressure to 20 mL, and the reactants were washed with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by passing through an SCX-2 cartridge (washed with MeOH, 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%), which was 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).

[0560] Step 2

[0561] A solution of 2-cyano-2-methylpropanoic acid (42 mg, 0.373 mmol), HATU (142 mg, 0.373 mmol) and DIPEA (0.18 mL, 1.02 mmol) in anhydrous acetonitrile (3 mL) was stirred at room temperature for 1 h. 5-(3,5-Difluorophenyl)pyridin-2-amine (70 mg, 0.339 mmol) was added to the solution and the reaction mixture was stirred at 70 °C for 4 h and then at 80 °C for 2 h. The reaction mixture 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).

[0562] Table 7: The following compounds were synthesized using a method similar to that used for compound E178

[0563]

[0564]

[0565] * Compound E186 was isolated as a by-product from the synthesis of E187

[0566] Compound E189

[0567]

[0568] 2,2,3,3-Tetramethyl-N-[5-(2-methyl-1,2,3-triazol-4-yl)-2-pyridinyl]cyclopropanecarboxamide

[0569] Step 1

[0570] 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-1,2,3-triazole (81 mg, 0.500 mmol) were dissolved in anhydrous 1,4-dioxane (2.15 mL), and 2 M Na2CO3 (0.47 mL, 0.949 mmol) was added to the reaction mixture and degassed with nitrogen for 5 minutes. Then palladium-triphenylphosphine (1:4) (26 mg, 0.0227 mmol) was added, degassed for another 5 minutes 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 through an SCX column (2 g), eluting first with MeOH (3 CV) and then with 2 M ammonia / MeOH (3 CV). The ammonia fraction was concentrated to give 5-(2-methyl-1,2,3-triazol-4-yl)pyridin-2-amine (60.0%) (EV-PGN001-228-002) (45 mg, 60% purity, 34% yield), which was a green solid. LCMS: m / z 175.8 [M+H]+, (ESI+), RT = 0.25 (Method D).

[0571] Step 2

[0572] To a solution of 5-(2-methyl-1,2,3-triazol-4-yl)pyridin-2-amine (60%, 45 mg, 0.154 mmol) in anhydrous THF (1.2889 mL) was added tetramethylcyclopropane-1-carbonyl chloride (27 mg, 0.170 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.054 mL, 0.308 mmol). The reaction mixture was stirred at room temperature for 4.5 h. Water (2 mL) was added to the reaction mixture and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica (0 - 40% EtOAc / heptane), followed by purification through an SCX column (2 g), eluting first with MeOH (3 CV) and then with 2 M ammonia / MeOH (3 CV). The crude product was then further purified by flash column chromatography on silica (0 - 100% EtOAc / heptane) to give the title compound (4.5 mg, 8.8% yield), which was 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).

[0573] Compound E190

[0574]

[0575] 2,2,3,3 - Tetramethyl - N - [5 - (1 - methyl - 1H - 1,2,3 - triazol - 4 - yl)pyridin - 2 - yl]cyclopropanecarboxamide

[0576] 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).

[0577] Compound E191

[0578]

[0579] 3 - [5 - (3,5 - Difluorophenyl)pyridin - 2 - yl]-1 - [(2S)-2 - hydroxypropyl]-1 - methyl - urea

[0580] To a solution of (4 - nitrophenyl) chloroformate (54 mg, 0.268 mmol) in THF (1 mL) was added 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), 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 - isopropylpropan - 2 - amine (128 uL, 0.733 mmol) were added, and the mixture was stirred at room temperature for an additional 1 h. The mixture was concentrated in vacuo and the residue was purified first by preparative HPLC (Method F) and then by FCC (10 g Biotage SNAP column, gradient 0 - 100% EtOAc / heptane) to give the title compound (17 mg, 22% yield), which was a white solid.

[0581] Table 8: The following compounds were synthesized using a method similar to that used for Compound E191, using aminopyridines, which were synthesized according to the method of Intermediate I03 or obtained from commercial sources.

[0582]

[0583]

[0584] Compound E197

[0585]

[0586] 1-Ethyl-3-(5-oxazol-2-yl-2-pyridinyl)-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0587] Step 1

[0588] 5-Bromo-2-nitropyridine (300 mg, 1.48 mmol) and palladium-triphenylphosphine (1:4) (200 mg, 0.173 mmol) were stirred in anhydrous toluene (4 mL) and degassed with nitrogen for 5 minutes, then 2-(tributylstannyl)-1,3-oxazole (0.79 mL, 2.58 mmol) was added, and the reaction mixture was degassed, then sealed and stirred at 90 °C for 18 hours. The reaction mixture was cooled to room temperature and treated with an aqueous KF solution (~8 M) (5 mL) and MeOH (5 mL), and stirred vigorously for 30 minutes. Then the mixture was filtered through a Celite pad and washed with EtOAc (20 mL). The filtrate was washed with water (15 mL), the layers were separated, and the aqueous layer was extracted again with EtOAc (20 mL). The organic layers were combined, washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified using normal-phase Biotage (Sfar Duo, 100 g, eluent: EtOAc / heptane, 0-100%) to give 2-(6-nitro-3-pyridinyl)oxazole (139 mg, 92% purity, 45% yield), which was 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).

[0589] Step 2

[0590] 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 flushed with nitrogen three times. 10% Palladium on carbon (14 mg, 0.133 mmol) was added, and the reaction mixture was placed under a hydrogen balloon and stirred at room temperature. After completion, the reaction mixture was filtered through a pad of Celite, and the 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), which was a pale yellow solid. 1H NMR, (400 MHz, DMSO-d6) δ 8.51 (dd, J = 2.4, 0.6 Hz, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.88 (dd, J = 8.7, 2.4 Hz, 1H), 7.25 (d, J = 0.8 Hz, 1H), 6.55–6.53 (m, 2H), 6.52 (d, J = 0.7 Hz, 1H).

[0591] Step 3

[0592] To a solution of 4-nitrophenyl chloroformate (72 mg, 0.357 mmol) in anhydrous THF (1.5 mL) was added a solution of 5-oxazol-2-ylpyridin-2-amine (95%, 55 mg, 0.324 mmol) and pyridine (29 μL, 0.357 mmol) in anhydrous THF (1 mL), and the reactants were stirred at room temperature for 3 h. Next, a solution of (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 51 mg, 0.324 mmol) and N-ethyl-N-isopropyl-propan-2-amine (85 μL, 0.486 mmol) in anhydrous THF (1 mL) was added, and the reactants were stirred at room temperature for 45 min. Then it was concentrated under reduced pressure and purified by preparative HPLC (Method H) to give the title compound (32 mg, 28% yield), which was a white solid. 1H NMR, (500 MHz, chloroform-d) δ 8.89 (d, J = 1.8 Hz, 1H), 8.29 (dd, J = 8.9, 2.3 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.24 (d, J = 0.7 Hz, 1H), 4.27–4.18 (m, 1H), 3.77 (dd, J = 15.2, 8.8 Hz, 1H), 3.63 - 3.53 (m, 2H), 3.48 (dq, J = 14.6, 7.0 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H). OH and NH were not observed. LCMS: m / z 345.1 [M+H]+, (ESI+), RT = 2.47 (Method A)

[0593] Compound E198

[0594]

[0595] 2,2,3,3 - Tetramethyl - N-(5 - oxazol - 2 - yl - 2 - pyridyl)cyclopropanecarboxamide

[0596] Synthesized from Intermediate I04 using a method similar to that used in Step 2 of Compound E093. 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)

[0597] Compound E199

[0598]

[0599] 2,2,3,3 - Tetramethyl - N-(5 - pyrazol - 1 - yl - 2 - pyridyl)cyclopropanecarboxamide

[0600] Step 1

[0601] Add 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) to a sealed tube. After purging it with nitrogen, add anhydrous 2 - propanol (5 mL) to it, and then add ethylene - 1,2 - diol (6.3 uL, 0.114 mmol). Purge the reaction mixture with nitrogen again, then seal the tube and heat it to 110 °C for 15 hours. Then cool the reaction mixture to room temperature, filter it through a pad of diatomaceous earth, and wash it with MeOH (20 mL). Concentrate the filtrate under reduced pressure and purify it by flash column chromatography (25 g SiO2 column, 0 - 15% MeOH / DCM) to obtain the title compound as a beige solid (145 mg, 50% purity).

[0602] Step 2

[0603] While stirring, 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (211 mg, 1.31 mmol) was added to a solution of 5-pyrazol-1-ylpyridin-2-amine (140 mg, 0.874 mmol) and N-ethyl-N-isopropylpropan-2-amine (305 μL, 1.75 mmol) in anhydrous THF (2 mL) at room temperature over 30 minutes. The solvent was then removed under a steady stream of nitrogen, and MeOH (2 mL) and 1 M NaOH (2 mL) were added, and the reaction mixture was stirred at room temperature for 1 hour. The MeOH was then removed under a steady stream of nitrogen, resulting in the formation of a beige precipitate. It 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 (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.81–8.73 (m, 1H), 8.48 (dd, J = 2.5, 0.5 Hz, 1H), 8.22–8.07 (m, 2H), 7.76 (dd, J = 1.8, 0.5 Hz, 1H), 6.56 (dd, J = 2.5, 1.8 Hz, 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).

[0604] Compound E200

[0605]

[0606] N-(5-Iodo-2-pyridinyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0607] The title compound was isolated as a byproduct of 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).

[0608] Compound E201

[0609]

[0610] N-[5-(Dimethylamino)-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0611] To a solution of N5,N5-dimethylpyridine-2,5-diamine (100 mg, 0.729 mmol) and N-ethyl-N-isopropylpropan-2-amine (255 μL, 1.46 mmol) in anhydrous THF (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. Additional 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (39 mg, 0.243 mmol) was added, and the mixture was stirred for an additional 0.5 h. The solvent was then removed under a steady stream of nitrogen, and MeOH (4 mL) and 1 M NaOH (4 mL) were added, 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 / 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)

[0612] Table 9: The following compounds were synthesized using a method similar to that used for Compound E201

[0613]

[0614]

[0615]

[0616] Compound E217

[0617]

[0618] 2-Methyl-N-(5-phenoxypyrazin-2-yl)propanamide

[0619] Step 1

[0620] 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 minutes. N,N-Dimethylglycine hydrochloride (1:1) (24 mg, 0.172 mmol) was added, then copper(I) iodide (33 mg, 0.172 mmol) was added 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 / heptane) to give 5-phenoxypyrazin-2-amine (Intermediate I05) as a pale yellow oil which solidified on 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).

[0621] Step 2

[0622] 5-Phenoxypyrazin-2-amine (50 mg, 0.267 mmol) was dissolved in DCM (2 mL), and N-ethyl-N-isopropyl-propan-2-amine (70 μL, 0.401 mmol) was added, followed by 2-methylpropanoyl chloride (31 μL, 0.294 mmol). The reaction mixture was stirred at room temperature for 15 minutes. Additional N-ethyl-N-isopropyl-propan-2-amine (70 μL, 0.401 mmol) and 2-methylpropanoyl chloride (31 μL, 0.294 mmol) were added, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was washed with saturated aqueous NaHCO3, passed through a TELOS phase separator and concentrated under reduced pressure. The residue was dissolved in MeOH (1 mL) and 1 M aqueous NaOH (1 mL) and stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative HPLC (Method E) to give the title compound as a white solid (57 mg). 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).

[0623] Table 10: The following compounds were synthesized using a method similar to that used for Compound E217

[0624]

[0625]

[0626] Compound 226

[0627]

[0628] N-[5-(2,5-Difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide

[0629] Step 1

[0630] 5-Bromopyrazin-2-amine (300 mg, 1.72 mmol) and (2,5-difluorophenyl)boronic acid (275 mg, 1.74 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL) and 2 M Na2CO3 (1.8 mL, 3.60 mmol), and the reaction mixture was degassed with N2 for 5 minutes. Pd(dppf)Cl2 (63 mg, 0.0862 mmol) was added to the reactants, and the reactants were heated to 110 °C for 2.5 hours. Then it was 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 layer 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 / 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).

[0631] Step 2

[0632] 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-isopropylpropan-2-amine (0.19 mL, 1.09 mmol) and T3P (50% EtOAc solution) (0.32 mL, 0.543 mmol), and the reaction mixture was stirred for 10 minutes. 5-(2,5-Difluorophenyl)pyrazin-2-amine (75 mg, 0.362 mmol) was added thereto, and the reaction mixture 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 / heptane) to give the title compound as an off-white solid (39 mg). 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.45 (d, J = 1.5 Hz, 1H), 8.92–8.67 (m, 1H), 7.73 (ddd, J = 9.3, 6.0, 3.3 Hz, 1H), 7.44 (ddd, J = 10.5, 9.2, 4.5 Hz, 1H), 7.40–7.30 (m, 1H), 1.94 (dd, J = 7.8, 5.5 Hz, 1H), 1.17 (s, 3H), 1.16 (s, 3H), 1.05 (dd, J = 5.3, 4.0 Hz, 1H), 0.89 (dd, J = 7.8, 3.9 Hz, 1H). LCMS: m / z 304.2 [M+H]+, (ESI+), RT = 3.81 (Method A)

[0633] Table 11: The following compounds were synthesized using a method similar to the method used in compound E226

[0634]

[0635]

[0636] Compounds E231 and E232

[0637]

[0638] Unknown single enantiomer of N-[5-(3,5-difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide

[0639] Chiral separation of N-[5-(3,5-difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide (Compound E228) to give an unknown single enantiomer. Method: cellulose-4 column, 21.2 x 250 mm, 5 μm, 90:10 heptane:ethanol, flow rate 18 mL / min.

[0640] Compound E231 (first elution):

[0641] 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.40 (d, J = 1.4 Hz, 1H), 9.08 (d, J = 1.4 Hz, 1H), 7.90–7.76 (m, 2H), 7.32 (tt, J = 9.1, 2.2 Hz, 1H), 1.94 (dd, J = 7.8, 5.5 Hz, 1H), 1.17 (s, 3H), 1.17 (s, 3H), 1.05 (dd, J = 5.3, 4.1 Hz, 1H), 0.89 (dd, J = 7.8, 3.9 Hz, 1H). LCMS: m / z 304.2 [M+H]+, (ESI+), RT = 3.93 (Method A).

[0642] Compound E232 (second elution):

[0643] 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.40 (d, J = 1.5 Hz, 1H), 9.08 (d, J = 1.5 Hz, 1H), 7.90–7.76 (m, 2H), 7.32 (tt, J = 9.2, 2.3 Hz, 1H), 1.94 (dd, J = 7.8, 5.5 Hz, 1H), 1.17 (s, 3H), 1.17 (s, 3H), 1.08–1.03 (m, 1H), 0.89 (dd, J = 7.8, 3.9 Hz, 1H). LCMS: m / z 304.2 [M+H]+, (ESI+), RT = 3.93 (Method A).

[0644] Compound E233

[0645]

[0646] 2,2,3,3-Tetramethyl-N-(5-pyrrolidin-1-ylpyrazin-2-yl)cyclopropanecarboxamide

[0647] Step 1

[0648] 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 mixture was concentrated in vacuo and purified by FCC (Biotage SNAP KP-Sil 10 g, 50 - 100% EtOAc / heptane) to afford 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).

[0649] Step 2

[0650] To a stirred solution of 5-pyrrolidin-1-ylpyrazin-2-amine (50 mg, 0.304 mmol) and N-ethyl-N-isopropylpropan-2-amine (120 μL, 0.670 mmol) in THF (1 mL) was added dropwise a solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (54 mg, 0.335 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature for approximately 20 h. Additional N-ethyl-N-isopropylpropan-2-amine (58 μL, 0.335 mmol) and a solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (20 mg, 0.125 mmol) in THF (0.5 mL) were added, and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (5 mL) and extracted into EtOAc (3 x 5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method G) to afford 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).

[0651] Compound E234

[0652]

[0653] 3-[5-(3,5-Difluorophenoxy)pyrazin-2-yl]-1-isopropyl-1-methylurea

[0654] To a solution of (4-nitrophenyl) chloroformate (50 mg, 0.246 mmol) in anhydrous THF (2 mL) was added a solution of 5-(3,5-difluorophenoxy)pyrazin-2-amine (prepared using a method similar to Intermediate I05, 50 mg, 0.224 mmol) and pyridine (20 μL, 0.246 mmol) in anhydrous THF (2 mL), and the reaction mixture was stirred at room temperature for 1.5 h. Next, a solution of N-methylpropan-2-amine (30 μL, 0.291 mmol) and N-ethyl-N-isopropylpropan-2-amine (59 μL, 0.336 mmol) in anhydrous THF (2 mL) was added, and the reaction mixture was stirred at room temperature for 2.5 h. Then it was concentrated under reduced pressure and purified first by preparative HPLC (Method E) and then by flash column chromatography (SNAP KP-Sil, 10 g, 0 - 55% EtOAc / 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)

[0655] Table 12: The following compounds were synthesized using a method similar to that used for Compound E234, using precursors prepared using methods similar to those for Intermediates I02, I05, I06 and Step 1 of Compound E139.

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662] Compound E265

[0663]

[0664] 3-[5-[(3,5-Difluorophenyl)methyl]pyrazin-2-yl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0665] Step 1

[0666] tert-Butyl N-(5-bromopyrazin-2-yl)carbamate (500 mg, 1.70 mmol) and dichloro(1,3-bis(diphenylphosphino)propane)nickel (92 mg, 0.170 mmol) were suspended in anhydrous 1,4-dioxane (4.7 mL), and the reaction mixture was degassed with N2 at room temperature for 5 minutes. Then 0.5 M bromo-[(3,5-difluorophenyl)methyl]zinc (14 mL, 6.79 mmol) was added dropwise, 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 organic layers were washed with brine (15 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by normal-phase flash column chromatography (Sfar Duo, 100 g, eluent: EtOAc / 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).

[0667] Step 2

[0668] To tert-butyl N-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]carbamate (424 mg, 1.28 mmol) was added a solution of 4 M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol), and the mixture was stirred at room temperature for 3 h. A further solution of 4 M 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) (rinsed first with MeOH (2 CV) and then with 7 N NH3 / MeOH (2.5 CV)) to give 5-[(3,5-difluorophenyl)methyl]pyrazin-2-amine (264 mg, 88% yield), which was a brown solid. 1H NMR, (500 MHz, DMSO-d6) δ 7.84 (dd, J = 33.4, 1.4 Hz, 2H), 7.03 (tt, J = 9.4, 2.4 Hz, 1H), 6.98–6.90 (m, 2H), 6.27 (s, 2H), 3.90 (s, 2H).

[0669] Step 3

[0670] The urea was formed using a method similar to that used in compound E191 to give the title compound (36 mg, 34% yield), which was a white solid. 1H NMR, (500 MHz, chloroform-d) δ 9.26 (d, J = 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.47 (s, 1H), 6.81–6.74 (m, 2H), 6.67 (tt, J = 9.0, 2.3 Hz, 1H), 4.82 (s, 1H), 4.20 (s, 1H), 4.08 (s, 2H), 3.81 (dd, J = 15.3, 8.7 Hz, 1H), 3.56–3.46 (m, 2H), 3.40 (dq, J = 14.7, 7.2 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H). LCMS: m / z 405.2 [M+H]+, (ESI+), RT = 3.42 (Method A).

[0671] Table 13: The following compounds were synthesized using a method similar to that used in compound E265.

[0672]

[0673] Compound E269

[0674]

[0675] 2-[(2,2,3,3-Tetramethylcyclopropanecarbonyl)amino]-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide

[0676] Step 1

[0677] Starting from methyl 2-aminopyridine-4-carboxylate (200 mg, 1.31 mmol), using a method similar to that of compound E199 (Step 2), 2-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid (260 mg, 90% purity, 68% yield) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.61–8.51 (m, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.45 (dd, J = 5.1, 1.3 Hz, 1H), 1.57 (s, 1H), 1.24 (s, 6H), 1.17 (s, 6H), OH not observed.

[0678] Step 2

[0679] Dissolve 2-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid (50 mg, 0.172 mmol) in anhydrous DMF (1.5 mL), add N-ethyl-N-isopropylpropan-2-amine (90 uL, 0.515 mmol), and then add HATU (98 mg, 0.257 mmol). After stirring for 10 minutes, add 2,2,2-trifluoroethylamine (20 uL, 0.257 mmol), and stir the reaction mixture overnight at room temperature. Then it was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL), 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 (500 MHz, 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, 1.6 Hz, 1H), 4.08 (td, J = 9.6, 5.6 Hz, 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).

[0680] Compound E270

[0681]

[0682] 2,2,3,3-Tetramethyl-N-[5-(pyrrolidin-1-ylmethyl)-2-pyridinyl]cyclopropanecarboxamide

[0683] To a stirred solution of N-(5-formyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (Step 2), 100 mg, 0.406 mmol) in DCE (2 mL) was added pyrrolidine (41 μL, 0.487 mmol), followed by acetic acid (2.3 μL, 0.0406 mmol). After 4 h, sodium triacetoxyborohydride (172 mg, 0.812 mmol) was added. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (25 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (hydrophobic filter cartridge) and concentrated to dryness under reduced pressure. The crude material was purified first by flash chromatography (Biotage 11 g SNAP-KPNH cartridge, 0 - 25% EtOAc / heptane) and then by additional chromatography (C18 silica gel, 12 g SNAP Ultra cartridge, eluent: acetonitrile solution of 0.1% formic acid - aqueous solution of 0.1% formic acid, 15 - 30%). The crude product was then washed with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). Final purification by flash chromatography (Biotage 11 g SNAP-KPNH cartridge, 0 - 20% EtOAc / heptane) gave the title product as a colorless solid (15 mg, 12% yield). 1H NMR (500 MHz, chloroform-d) δ 8.17 (d, J = 1.9 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.64 (dd, J = 8.5, 2.2 Hz, 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).

[0684] Compound E271

[0685]

[0686] 2,2,3,3-Tetramethyl-N-[5-(1,2,4-oxadiazol-3-yl)-2-pyridyl]cyclopropanecarboxamide

[0687] Step 1

[0688] To a solution of N-(5-cyano-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (Step 2), 247 mg, 0.934 mmol) in ethanol (5.8974 mL) was added hydroxylamine (50%, 0.50 mL, 0.934 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. DCM (10 ml) and water (10 ml) were added to the mixture. The colorless precipitate was separated by filtration to give N-[5-(N-hydroxyformamidinyl)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (176 mg, 67% yield), which was a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.64 (s, 1H), 8.55 (dd, J = 2.3, 0.7 Hz, 1H), 8.08–8.01 (m, 1H), 7.96 (dd, J = 8.8, 2.4 Hz, 1H), 5.87 (s, 2H), 1.56 (s, 1H), 1.24 (s, 6H), 1.17 (s, 6H).

[0689] Step 2

[0690] To a stirred solution of N-[5-(N-hydroxyformamidinyl)-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 reactants were stirred at room temperature for 5 minutes and then at 60 °C for 30 minutes. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method G) to give the title compound (39 mg, 75% yield), which was a colorless solid. 1H NMR (400 MHz, 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).

[0691] Compound E272

[0692]

[0693] 2,2,3,3-Tetramethyl-N-[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-pyridyl]cyclopropanecarboxamide

[0694] Synthesized using a method similar to that used for compound E271. 1H NMR (400 MHz, chloroform-d) δ 8.97–8.92 (m, 1H), 8.36–8.29 (m, 2H), 8.15 (s, 1H), 2.68 (s, 3H), 1.36 (s, 6H), 1.26 (s, 6H), 1.07 (s, 1H). LCMS: m / z 301.2 [M+H]+, (ESI+), RT = 3.78 (method B).

[0695] Compound E273

[0696]

[0697] 2,2,3,3-Tetramethyl-N-(5-oxazol-5-yl-pyridin-2-yl)cyclopropanecarboxamide

[0698] Step 1

[0699] To a mixture of 1-(isocyanomethylsulfonyl)-4-methyl-benzene (320 mg, 1.64 mmol) and potassium 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 kept at reflux for 2.5 h, then cooled, concentrated under reduced pressure and partitioned between MTBE (35 ml) and water (25 mL). After separating the layers, the aqueous layer was extracted twice with EtOAc (2 x 30 mL). The combined organics were dried (MgSO4), filtered and concentrated to give 5-oxazol-5-ylpyridin-2-amine (199 mg, 35% purity), which was a yellow oil and 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).

[0700] Step 2

[0701] Starting from 5-oxazol-5-ylpyridin-2-amine (65 mg, 35% pure), using a method similar to that of Compound E199 (Step 2), the title compound (6.1 mg, 15% yield) was obtained 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).

[0702] Compound E274

[0703]

[0704] N-(5-Isoxazol-5-yl-2-pyridinyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0705] Step 1

[0706] N-(5-Acetyl-2-pyridinyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to that of 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, the excess volatiles were removed under reduced pressure to give N-[5-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (109 mg, 85% pure) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.72 (d, J = 1.4 Hz, 1H), 8.17–8.12 (m, 2H), 8.10 (dd, J = 8.7, 2.2 Hz, 1H), 7.76 (d, J = 12.2 Hz, 1H), 5.58 (d, J = 12.3 Hz, 1H), 3.27 (d, J = 6.9 Hz, 3H), 2.21 (d, J = 9.2 Hz, 3H), 1.26 (s, 6H), 1.15 (s, 6H), 0.98 (s, 1H).

[0707] Step 2

[0708] Dissolve N-[5-[(E)-3-(dimethylamino)prop-2-enoyl]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (85%, 109 mg, 0.294 mmol) and hydroxylamine hydrochloride (1:1) (24 mg, 0.352 mmol) in ethanol (2 mL), and heat the reactants to 80 °C with stirring for 1 h. Thereafter, cool the reaction mixture to room temperature and remove the solvent under reduced pressure. The crude product was purified by preparative HPLC (method G) to give the title compound (14 mg, 16% yield), which is a pale yellow solid. 1H NMR (500 MHz, chloroform-d) δ 8.72 (d, J = 1.8 Hz, 1H), 8.35–8.31 (m, 2H), 8.10 (s, 1H), 8.06 (dd, J = 8.8, 2.3 Hz, 1H), 6.54 (d, J = 1.9 Hz, 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).

[0709] Compound E275

[0710]

[0711] N-(5-Isoxazol-3-yl-2-pyridinyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0712] Step 1

[0713] N-(5-Formyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using a method similar to E199 (Step 2), 90 mg, 0.345 mmol) and hydroxylamine hydrochloride (1:1) (36 mg, 0.518 mmol) were dissolved in water (9 mL) and methanol (4 mL). Sodium carbonate (66 mg, 0.621 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 h. Another portion of hydroxylamine hydrochloride (1:1) (36 mg, 0.518 mmol) and sodium carbonate (66 mg, 0.621 mmol) were added together with THF (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Water (20 ml) and EtOAc (20 ml) were added to the residue. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc (2 x 20 ml). The combined organics were dried (hydrophobic sieve plate) and concentrated under reduced pressure to give N-[5-[oxomethyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92 mg, 0.316 mmol, 92% yield) as a colorless solid. 1H NMR (500 MHz, chloroform-d) δ 8.31 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.85 (dd, J = 8.7, 2.2 Hz, 1H), 7.75 (s, 1H), 1.25 (s, 6H), 1.14 (s, 6H), 0.96 (s, 1H).

[0714] Step 2

[0715] N-[5-[(hydroxyimino)methyl]-2-pyridinyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92 mg, 0.351 mmol), calcium acetylide (70%, 225 mg, 2.46 mmol) and 1-chloropyrrolidine-2,5-dione (59 mg, 0.439 mmol) were dissolved in benzene (1 mL) and DCM (1 mL). The resulting solution was stirred until the oxime dissolved. Then water (1.1475 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solid was washed with chloroform (2 x 10 ml). The aqueous layer was then separated and the organic matter was dried (hydrophobic sieve plate). The organic matter was concentrated under reduced pressure and purified by preparative HPLC (method H) to give the title compound (8.4 mg, 7.5% yield), which was a pale grey solid. 1H NMR (400 MHz, chloroform-d) δ 8.75–8.70 (m, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.12 (dd, J = 8.7, 2.3 Hz, 1H), 8.07 (s, 1H), 6.68 (d, J = 1.7 Hz, 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).

[0716] Compound E276

[0717]

[0718] N-[5-[(3-fluorophenyl)methyl]-2-pyridinyl]-2-methyl-propanamide

[0719] Step 1

[0720] At 0 °C, Boc anhydride (2.78 g, 12.7 mmol) was added portionwise 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), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness. Purification by flash chromatography (Biotage Isolera, 100 g KP-Sil SNAP column, 2-20% EtOAc / heptane) gave tert-butyl N-(5-bromo-2-pyridinyl)-N-tert-butoxycarbonylcarbamate (1.98 g, 90% purity, 83% yield) as a white solid. To a solution of tert-butyl N-(5-bromo-2-pyridinyl)-N-tert-butoxycarbonylcarbamate (90%, 1.00 g, 2.41 mmol) in methanol (10 mL) was added 1 M sodium hydroxide (2.5 mL, 2.53 mmol), and the mixture was stirred at 50 °C for 2 h and then cooled to room temperature. It was then concentrated in vacuo, neutralized with 1 N HCl solution, extracted with DCM (2 x 50 mL), dried over sodium sulfate, filtered and evaporated to dryness to give tert-butyl N-(5-bromo-2-pyridinyl)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).

[0721] Step 2

[0722] At nitrogen and 0 °C, a suspension of potassium hydride (30%, 0.42 mL, 4.57 mmol) in THF (5 mL) was added to a stirred solution of tert-butyl N-(5-bromo-2-pyridyl)carbamate (630 mg, 2.28 mmol) in anhydrous THF (10 mL). After 10 minutes, the reaction mixture was cooled to -78 °C. 3-Fluorobenzaldehyde (0.29 mL, 2.74 mmol) was added and stirred for 10 minutes, then a portion of 1.6 M butyllithium (2.9 mL, 4.57 mmol) was added. The reaction mixture was stirred for 1 hour, then allowed to warm to room temperature and quenched slowly with saturated NH4Cl solution (3 mL). The reaction mixture was diluted with EtOAc (30 mL), washed first with water (30 mL) and then with 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 column, 10 - 80% EtOAc / heptane) to give tert-butyl N-[5-[(3-fluorophenyl)-hydroxy-methyl]-2-pyridyl]carbamate (396 mg, 52% yield), which was a pale grey 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).

[0723] Step 3

[0724] To a solution of tert-butyl N-[5-[(3-fluorophenyl)-hydroxy-methyl]-2-pyridinyl]carbamate (396 mg, 1.19 mmol) in DCE (10 mL) was added 2,2,2-trifluoroacetic acid (3.0 mL, 40.4 mmol), then triethylsilane (3.0 mL, 18.8 mmol), and the mixture was stirred at 50 °C overnight. The reaction mixture was then cooled to room temperature and evaporated to dryness. Purification by flash chromatography (Biotage C18 30 g KP-Ultra SNAP cartridge, eluting with 10 - 100% water (+0.1% NH4OH) / MeCN (+0.1% NH4OH)) gave 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).

[0725] Step 4

[0726] Starting from 5-[(3-fluorophenyl)methyl]pyridin-2-amine (50 mg, 0.242 mmol), using a method similar to that for compound E164 (Step 1), the title compound (49 mg, 74% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.62 (dd, J = 8.5, 2.4 Hz, 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 = 6.8 Hz, 6H). LCMS: m / z 273.1 [M+H]+, (ESI+), RT = 2.85 (Method A).

[0727] Compound E277

[0728]

[0729] (2R)-N-[5-(3,4-difluorophenoxy)-2-pyridinyl]-1-sulfamoyl-pyrrolidine-2-carboxamide

[0730] Step 1

[0731] To tert-butyl (2R)-2-[[5-(3,4-difluorophenoxy)-2-pyridinyl]carbamoyl]pyrrolidine-1-carboxylate (synthesized by a method similar to E001 (Step 3), 90% pure, 446 mg, 0.957 mmol) was added a solution of 4 M hydrogen chloride in dioxane (2.9 mL, 11.5 mmol), and the mixture was stirred at room temperature for 1 h. Then it was concentrated in vacuo and purified by passing through an SCX-2 cartridge, washed with MeOH, and eluted with 7N NH3 / MeOH to give (2R)-N-[5-(3,4-difluorophenoxy)-2-pyridinyl]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, 2.6 Hz, 2H), 7.59 (dd, J = 9.1, 2.9 Hz, 1H), 7.45 (dt, J = 10.4, 9.2 Hz, 1H), 7.24 (ddd, J = 11.8, 6.8, 3.0 Hz, 1H), 6.88 (dtt, J = 8.5, 3.2, 1.8 Hz, 1H), 3.77 (dd, J = 9.1, 5.4 Hz, 1H), 3.18 (s, 1H), 2.95 (dt, J = 10.2, 6.7 Hz, 1H), 2.84 (dt, J = 10.2, 6.4 Hz, 1H), 2.07 (ddt, J = 12.5, 8.9, 7.3 Hz, 1H), 1.86–1.74 (m, 1H), 1.65 (p, J = 6.5 Hz, 2H).

[0732] Step 2

[0733] At 95 °C, (2R)-N-[5-(3,4-difluorophenoxy)-2-pyridinyl]pyrrolidine-2-carboxamide (90%, 47 mg, 0.132 mmol) and bis(2,2,2-trifluoroethyl)amine (22 mg, 0.225 mmol) were stirred in anhydrous 1,4-dioxane (0.9 mL) for 16 h. 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), which was a grayish white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.20–8.16 (m, 1H), 8.13 (d, J = 9.3 Hz, 1H), 7.60 (dd, J = 9.0, 3.0 Hz, 1H), 7.46 (dt, J = 10.4, 9.2 Hz, 1H), 7.26 (ddd, J = 11.8, 6.8, 3.0 Hz, 1H), 7.05 (s, 2H), 6.93–6.85 (m, 1H), 4.28 (dd, J = 8.7, 4.4 Hz, 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).

[0734] Compound E278

[0735]

[0736] (2R)-N-[5-(3,4-difluorophenoxy)-2-pyridinyl]-1-methyl-pyrrolidine-2-carboxamide

[0737] Synthesized from Intermediate I01 using a method similar to that used in Compound E001 (Step 3) to obtain the title compound, which is an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.17 (s, 1H), 8.17–8.14 (m, 1H), 7.60 (dd, J = 8.9, 3.0 Hz, 1H), 7.46 (dt, J = 10.5, 9.2 Hz, 1H), 7.25 (ddd, J = 11.8, 6.8, 3.0 Hz, 1H), 6.88 (ddq, J = 8.4, 3.4, 1.8 Hz, 1H), 3.18–3.10 (m, 1H), 3.03 (dd, J = 9.8, 5.1 Hz, 1H), 2.42–2.35 (m, 4H), 2.20 (ddd, J = 17.0, 11.6, 7.8 Hz, 1H), 1.85–1.70 (m, 3H). LCMS: m / z 334.2 [M+H]+, (ESI+), RT = 3.89 (Method B) /

[0738] Table 14: The following compounds were synthesized using a method similar to that used in Compound E277.

[0739]

[0740]

[0741] Compound E284

[0742]

[0743] 1-[5-(3,4-Difluorophenoxy)-2-pyridinyl]-4,4-dimethyl-pyrrolidin-2-one

[0744] Step 1

[0745] 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 A mixture of the molecular sieve in anhydrous DCM (38 mL) was stirred under air for 23 h. Additional copper(II) diacetate (145 mg, 0.2 equiv) and anhydrous DCM (10 mL) were added and the mixture was stirred for 17 h. The suspension was diluted with dichloromethane, filtered twice through celite, washed with water (40 mL) and saturated aqueous Rochelle salt (50 mL). The organic layer was 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 / heptane) to afford 2-chloro-5-(3,4-difluorophenoxy)pyridine (426 mg, 45% yield) as a pale 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).

[0746] Step 2

[0747] At room temperature, a solution of potassium carbonate (90 mg, 0.649 mmol) and 2-chloro-5-(3,4-difluorophenoxy)pyridine (80 mg, 0.324 mmol) in anhydrous toluene (2.5 mL) was degassed under nitrogen for 15 minutes, then 4,4-dimethylpyrrolidin-2-one (37 mg, 0.324 mmol) and XPhos Pd G3 (14 mg, 0.0162 mmol) were added. The reaction vessel was sealed and heated to 90 °C with stirring for 16 hours. Then it was cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL), then the aqueous layer was extracted with EtOAc (3 x 20 mL), the combined organic extracts were dried over a hydrophobic filter and evaporated to dryness. The crude compound was purified by flash column chromatography (Biotage Sfar Duo 10 g, first 0 - 80% DCM / heptane, then 0 - 40% MeOH / EtOAc) to give the title compound (20 mg, 19% yield), which was an orange solid. 1H NMR, (400 MHz, chloroform-d) δ 8.43 (d, J = 9.1 Hz, 1H), 8.11 (d, J = 2.9 Hz, 1H), 7.37 (dd, J = 9.1, 2.9 Hz, 1H), 7.12 (q, J = 9.1 Hz, 1H), 6.82 (ddd, J = 11.1, 6.6, 3.0 Hz, 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)

[0748] Compound E285

[0749]

[0750] 1-[5-(3,4-Difluorophenoxy)-2-pyridyl]-3,3-dimethyl-pyrrolidin-2-one

[0751] Synthesized using a method similar to that used for Compound E284. 1H NMR (400 MHz, chloroform-d) δ 8.46 (d, J = 9.1 Hz, 1H), 8.13 (d, J = 2.9 Hz, 1H), 7.37 (dd, J = 9.1, 3.0 Hz, 1H), 7.12 (q, J = 9.0 Hz, 1H), 6.82 (ddd, J = 11.1, 6.6, 2.9 Hz, 1H), 6.74–6.66 (m, 1H), 4.03–3.97 (m, 2H), 2.03–1.96 (m, 2H), 1.27 (s, 6H). LCMS: m / z 319.2 [M+H]+, (ESI+), RT = 3.93 (Method A).

[0752] Compound E286

[0753]

[0754] 5-(3,4-Difluorophenoxy)-2-[[ethyl-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]sulfamoyl]amino]pyridine

[0755] Step 1

[0756] Chlorosulfonyl isocyanate (58 μL, 0.662 mmol) was added to a cold DCM (3 mL) solution. Then 2-chloroethanol (44 μL, 0.662 mmol) was added via syringe within 1 minute to keep the internal temperature below 2 °C. After stirring the reaction mixture for 1 hour, N-ethyl-N-isopropyl-propan-2-amine (347 μL, 1.98 mmol) was added. A solution of 5-(3,4-difluorophenoxy)pyridin-2-amine (Intermediate I01, 150 mg, 0.662 mmol) in DCM (3 mL) was added dropwise within 5 minutes, and then the mixture was stirred at 0 °C to room temperature for another 16 hours overnight. The reaction was quenched by adding 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), which is a white solid. 1H NMR, (500 MHz, chloroform-d) δ 7.84 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 9.4, 2.9 Hz, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.17 (q, J = 9.0 Hz, 1H), 6.88 (ddd, J = 10.7, 6.5, 3.0 Hz, 1H), 6.77–6.70 (m, 1H), 4.40 (dd, J = 8.7, 7.0 Hz, 2H), 4.16 (dd, J = 8.7, 7.1 Hz, 2H).

[0757] Step 2

[0758] N-[5-(3,4-Difluorophenoxy)-2-pyridinyl]-2-oxo-oxazolidine-3-sulfonamide (40 mg, 0.102 mmol), (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (80%, 26 mg, 0.133 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.18 mL, 1.02 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated to 130 °C using microwave irradiation for 1 h. After cooling to room temperature, it was diluted with EtOAc (10 mL) and washed first with saturated aqueous ammonium chloride (10 mL) and then with saturated aqueous sodium bicarbonate (2 x 10 mL). The organic layer was separated and concentrated in vacuo. The crude product was purified by FCC (Biotage SNAP KP-Sil 10 g, 0-100% EtOAc / heptane) to give the title compound (4.0 mg, 8.4% yield) as a light brown glass. 1H NMR, (500 MHz, chloroform-d) δ 8.07 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 8.8, 2.9 Hz, 1H), 7.16 (q, J = 9.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.85 (ddd, J = 10.8, 6.5, 2.9 Hz, 1H), 6.75–6.71 (m, 1H), 4.31 (dqd, J = 9.6, 6.8, 2.9 Hz, 1H), 3.67 (dd, J = 15.2, 9.9 Hz, 1H), 3.58 (dd, J = 15.2, 2.8 Hz, 1H), 3.40 (dq, J = 14.4, 7.2 Hz, 1H), 3.28 (dq, J = 14.3, 7.1 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), NH and OH not observed. LCMS: m / z 442.2 [M+H]+, (ESI+), RT = 3.48 (Method A)

[0759] Compound E287

[0760]

[0761] N-[5-(3-Fluorophenoxy)-3-hydroxy-2-pyridinyl]-2-methyl-propanamide

[0762] Step 1

[0763] 5-Chloro-2-nitropyridin-3-ol (300.0 mg, 1.72 mmol), cesium carbonate (616.02 mg, 1.89 mmol) and benzyl chloride (239.33 mg, 1.89 mmol) were mixed in DMF (4.5 mL), purged with nitrogen, and stirred at room temperature in a sealed vial for 18 h. Additional cesium carbonate (616 mg, 1.89 mmol) was added to the reaction mixture and stirring was continued at room temperature for 24 h. The reaction mixture was filtered and the crude product was purified by preparative HPLC (method F) to give 3-benzyloxy-5-chloro-2-nitropyridine (330 mg, 73% yield) as an off-white solid.

[0764] Step 2

[0765] 3-Benzyloxy-5-chloro-2-nitropyridine (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 at 50 °C in a sealed vial for 18 h. After completion, the reaction mixture was filtered and the crude product was purified by preparative HPLC (method F) to give 3-benzyloxy-5-(3-fluorophenoxy)-2-nitropyridine (225 mg, 53% yield) as a yellow solid.

[0766] Step 3

[0767] 3-Benzyloxy-5-(3-fluorophenoxy)-2-nitropyridine (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; recycle mode, 10% Pd / C cartridge). After completion, the material was dried under vacuum, mixed with a solution of N-ethyl-N-isopropyl-propan-2-amine (0.11 mL, 0.658 mmol) and isobutyric anhydride (52 mg, 0.329 mmol) in THF (4 mL), and stirred in a sealed vial at 80 °C for 18 h. After completion, the solvent was removed under vacuum and the crude material was purified by preparative HPLC (method E) to afford the title compound (44 mg, 46% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.53 (s, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.44 (td, J = 8.3, 6.9 Hz, 1H), 7.06–6.94 (m, 3H), 6.89 (dd, J = 8.2, 2.2 Hz, 1H), 2.86 (sept, J = 6.8 Hz, 1H), 1.13 (d, J = 6.8 Hz, 6H). LCMS: m / z 291.2 [M+H]+, (ESI+), RT = 3.33 (method A).

[0768] Compound E288

[0769]

[0770] N-[6-[(5-Fluoro-3-pyridinyl)oxy]pyridazin-3-yl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0771] Synthesized using a method similar to that used for Compound E217, starting from 6-bromopyridazin-3-amine. 1H NMR (500 MHz, chloroform-d) δ 8.67 (s, 1H), 8.60 (d, J = 9.5 Hz, 1H), 8.40 (d, J = 14.0 Hz, 2H), 7.42 (dt, J = 9.2, 2.3 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 1.35 (s, 6H), 1.22 (s, 6H), 1.18 (s, 1H). LCMS: m / z 331.5 [M+H]+, (ESI+), RT = 3.44 (method A).

[0772] Compound E289

[0773]

[0774] 3-[6-(3,4-Difluorophenoxy)pyrimidin-4-yl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0775] Step 1

[0776] 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, then at 80 °C for 14 h, and at 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 x 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 / heptane) to give 6-(3,4-difluorophenoxy)pyrimidin-4-amine (180 mg, 70% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 0.8 Hz, 1H), 7.48 (ddd, J = 10.6, 9.2, 9.2 Hz, 1H), 7.39 (ddd, J = 11.6, 6.9, 2.8 Hz, 1H), 7.03 (dddd, J = 9.0, 3.7, 2.9, 1.8 Hz, 1H), 6.90 (s, 2H), 5.80 (d, J = 0.9 Hz, 1H).

[0777] Step 2

[0778] Starting from 6-(3,4-difluorophenoxy)pyrimidin-4-amine (70%, 85 mg, 0.267 mmol), using a method similar to that of compound E191, the title compound (48 mg, 44% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.43 (d, J = 0.8 Hz, 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 = 7.0 Hz, 3H). LCMS: m / z 407.2 [M+H]+, (ESI+), RT = 3.31 (method A).

[0779] Compound E290

[0780]

[0781] 1-Ethyl-3-[6-(2-fluorophenoxy)pyrimidin-4-yl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0782] Synthesized using a method similar to the method used for compound E289. 1H NMR (500 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.39 (d, J = 0.9 Hz, 1H), 7.46–7.30 (m, 4H), 7.30–7.23 (m, 1H), 7.13 (s, 1H), 4.39–4.20 (m, 1H), 3.65–3.54 (m, 1H), 3.54–3.37 (m, 3H), 1.10 (t, J = 7.0 Hz, 3H). LCMS: m / z 389.1 [M+H]+, (ESI+), RT = 3.19 (Method A).

[0783] Compound E291

[0784]

[0785] 1-Ethyl-3-[6-(3-fluorophenoxy)pyrimidin-4-yl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0786] Synthesized using a method similar to the method used for compound E289. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.42 (d, J = 0.9 Hz, 1H), 7.53–7.44 (m, 1H), 7.33 (s, 1H), 7.20–7.09 (m, 2H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 4.34–4.20 (m, 1H), 3.62–3.41 (m, 5H), 1.09 (t, J = 7.0 Hz, 3H). LCMS: m / z 389.2 [M+H]+, (ESI+), RT = 3.33 (Method A).

[0787] HPLC method

[0788] Analytical LCMS

[0789] Method A

[0790] Analytical uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μM; temperature: 40 °C) with a gradient of 5 - 100% B (A = H2O solution of 0.1% formic acid; B = ACN solution of 0.1% formic acid) for 5.3 minutes, then 100% B for 0.5 minutes. Then a second gradient of 100 - 5% B was applied in 0.02 minutes and continued for 1.18 minutes with an injection volume of 1 μL and a flow rate of 0.6 mL / min. The UV spectrum was recorded at 215 nm using a Waters Acquity PDA detector with a spectral range of 200 - 400 nm. ELS data was collected and reported using a Waters Acquity ELS detector (if equipped). Mass spectra were obtained using a Waters SQD (MSQ1) or a Waters Acquity QDA (MSQ2). Data was integrated and reported using Waters MassLynx and OpenLynx software.

[0791] Method B

[0792] On a Waters Acquity uPLC system using Waters BEH™ C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40 °C) for analytical uPLC-MS with a gradient of 5 - 100% (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) for 5.3 minutes, then 100% B for 0.5 minutes. Then a second gradient of 100 - 5% B was applied in 0.02 minutes and continued for 1.18 minutes with an injection volume of 1 μL and a flow rate of 0.6 mL / min. The UV spectrum was recorded at 215 nm using a Waters Acquity photodiode array detector. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data was integrated and reported using Waters MassLynx and OpenLynx software.

[0793] Method C

[0794] Analytical HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40 °C) with a gradient of 5 - 100% B (A = H2O solution of 0.1% formic acid; B = ACN solution of 0.1% formic acid) for 1.2 minutes, then 100% B for 0.1 minute. Then a second gradient of 100 - 5% B was applied within 0.01 minute with an injection volume of 3 μL and a flow rate of 1.2 mL / min. The UV spectrum was recorded at 215 nm using an SPD-M20A photodiode array detector with a spectral range of 200 - 400 nm. The mass spectrum was obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0795] Method D

[0796] On a Waters Acquity uPLC system using Waters BEH™ C18 column (2.1 mm x 30 mm, 1.7 μm; temperature 40 °C) for analytical uHPLC-MS with a gradient of 5 - 100% B gradient (A: 2 mM ammonium bicarbonate, buffered to pH 10, B: ACN) for 0.75 minutes, then 100% B for 0.1 minute. Then a second gradient of 100 - 5% B was applied within 0.05 minute and continued for 0.1 minute with an injection volume of 1 μL and a flow rate of 1 mL / min. The UV spectrum was recorded at 215 nm using a Waters Acquity PDA with a spectral range of 200 - 400 nm. The mass spectrum was obtained using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0797] Preparative HPLC method

[0798] The purification method is as follows:

[0799] Method E: Acidic early method

[0800] Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) with a gradient of 10 - 95% B (A = H2O solution of 0.1% formic acid; B = ACN solution of 0.1% formic acid) for 14.44 minutes, then 95% B for 2.11 minutes. Then a second gradient of 95 - 10% B was applied within 0.2 minute with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0801] Method F: Alkaline Early Method

[0802] Purification was carried out on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) with a gradient of 10 - 95% B (A = H2O solution of 0.2% ammonium hydroxide; B = ACN solution of 0.2% ammonium hydroxide) for 14.44 minutes, then 95% B for 2.11 minutes. Then a second gradient of 95 - 10% B was applied in 0.2 minutes, with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0803] Method G: Acidic Standard Method

[0804] Purification was carried out on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) with a gradient of 30 - 95% B (A = aqueous solution of 0.1% formic acid; B = ACN solution of 0.1% formic acid) for 11.00 minutes, then 95% B for 2.10 minutes. Then a second gradient of 95 - 30% B was applied in 0.2 minutes, with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0805] Method H: Alkaline Standard Method

[0806] Purification was carried out on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) with a gradient of 30 - 95% B (A = aqueous solution of 0.2% ammonium hydroxide; B = ACN solution of 0.2% ammonium hydroxide) for 11.00 minutes, then 95% B for 2.10 minutes. Then a second gradient of 95 - 30% B was applied in 0.21 minutes, with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0807] Example 2 - Screening of Compounds

[0808] Potent and selective hMrgpMRGPRX2 compounds have been generated from compounds identified during high-throughput screening (HTS) campaigns and subsequently subjected to structure-activity based medicinal chemistry work cycles. These compounds were characterized for their antagonist activity in recombinant hMrgpMRGPRX2-expressing cells and 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 of intracellular calcium mobilization using the FLIPRTM technology. In these FLIPR assays, we tested the ortholog activity of the identified compounds using recombinant cell systems expressing mouse MrgprB2, mouse MrgprA1, gerbil MrgpMRGPRX2 ortholog, Chinese hamster MrgpMRGPRX2 ortholog, and cynomolgus monkey MrgpMRGPRX2 ortholog, respectively.

[0809] The results are summarized in Table 15 below.

[0810] Table 15

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

Claims

1. A compound of the following formula I or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein: Q is Z is -C(=O)-; R 1 is H or C 1-3 alkyl; G 1 、G 2 、G 3 、G 4 and G 5 each independently is N or -CH or -C-O-M 1 provided that one of G 1 、G 2 、G 3 、G 4 and G 5 is N, or one of G 3 and G 5 is N, or one of G 1 and G 4 is N, or one of G 2 and G 5 is N, and one of G 2 、G 3 、and G 4 is -C-O-M 1 ; Each M 1 is independently C 6 aryl or a 5-6 membered heteroaryl having 1-2 ring N heteroatoms; wherein said C 6 aryl and each of the 5-6 membered heteroaryls is optionally substituted with 1, 2 or 3 substituents independently selected from halogen; A is -L 2 -M 2 ; L 2 is a key; M 2 is -N(R 81 )(R 82 ); and Each R 81 and R 82 is C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from -OH and halogen.

2. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein G 1 is N.

3. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein G 2 is N.

4. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein G 1 and G 4 is N.

5. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein G 3 is -C-O-M 1 .

6. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein G 4 is -C-O-M 1 .

7. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein G 2 is -C-O-M 1 .

8. A compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 1 is H.

9. The compound according to any one of claims 1-7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein M 1 is selected from C 6 aryl; and C 6 heteroaryl having 1 or 2 ring heteroatoms independently selected from N 10. The compound according to claim 8, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein M 1 is selected from C 6 aryl; and C 6 heteroaryl having 1 or 2 ring heteroatoms independently selected from N.

11. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 10, wherein M 1 is phenyl, pyridyl or pyridazine.

12. The compound according to claim 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein M 1 is phenyl.

13. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 12, wherein the phenyl group is substituted at the 4-position.

14. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 12, wherein the phenyl group is substituted at the 3- and 4-positions.

15. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 12, wherein the phenyl group is substituted at the 3- and 5-positions.

16. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 11, wherein M 1 is pyridyl.

17. The compound according to claim 16, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein M 1 is pyridin-4-yl.

18. The compound according to claim 16, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein M 1 is pyridin-3-yl.

19. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 16, wherein the pyridyl group is substituted at the carbon adjacent to the pyridyl nitrogen.

20. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 16, wherein the pyridyl group is substituted at the meta-carbon of the pyridyl nitrogen.

21. A compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 10, and 12-20, wherein R 81 and R 82 are independently selected from C 1-3 alkyl; each of which is optionally substituted with 1 or 2 substituents independently selected from -OH and halogen.

22. A compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof selected from the following:

23. A composition comprising a dermatologically or orally acceptable excipient and a compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-22.

24. Use of a compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-22 in the preparation of a pharmaceutical composition for the treatment of an inflammatory disorder, comprising administering the pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of a compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-22 and a dermatologically or orally acceptable excipient, wherein the inflammatory disorder is a skin disorder.

25. The use according to claim 24, wherein the pharmaceutical composition is in the form of a cream, gel, spray, ointment or oral unit dosage form.

26. The use according to claim 24, wherein the compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is present at a concentration of 0.001 wt.% to 10 wt.% based on the total weight of the pharmaceutical composition.

27. The use according to claim 24, wherein the compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is present at a concentration of 0.1 wt.% to 5 wt.% based on the total weight of the pharmaceutical composition.

28. The use according to claim 24, wherein the pharmaceutical composition further comprises a skin penetration enhancer.

29. The use according to claim 24, wherein the pharmaceutical composition further comprises a skin penetration enhancer, which comprises one or more of the following: mannitol, sulfoxide, pyrrolidone, alcohol, surfactant and terpene.

30. The use according to claim 24, wherein the pharmaceutical composition further comprises a skin penetration enhancer, which comprises one or more of the following: azone and diol.

31. The use according to claim 24, wherein the pharmaceutical composition further comprises a skin penetration enhancer, which comprises alkanol.

32. The use according to claim 29, wherein the sulfoxide is dimethyl sulfoxide DMSO, and / or the pyrrolidone is 2-pyrrolidone 2P, and / or the alcohol is ethanol or decanol.

33. The use according to claim 30, wherein the azone is laurocapram, and / or the diol is propylene glycol, hexylene glycol, polyethylene glycol or diethylene glycol.

34. The use according to any one of claims 24-33, wherein the pharmaceutical composition is applied to the skin of a patient once a day.

35. The use according to any one of claims 24-33, wherein the pharmaceutical composition is applied to the skin of a patient twice a day.

36. The use according to any one of claims 24-33, wherein the pharmaceutical composition is applied to the skin of a patient three times a day.

37. The use according to any one of claims 24-33, wherein the skin is human skin.

38. The use according to claim 34, wherein the skin is human skin.

39. The use according to claim 35, wherein the skin is human skin.

40. The use according to claim 36, wherein the skin is human skin.

41. The use according to any one of claims 24-33 and 38-40, wherein the inflammatory disorder activates MrgprX2 or is caused by the activation of MrgprX2.

42. The use according to claim 37, wherein the inflammatory disorder activates MrgprX2 or is caused by the activation of MrgprX2.

43. The use according to any one of claims 24-33, 38-40 and 42, wherein the inflammatory disorder is atopic dermatitis, chronic urticaria, pseudoallergic reaction triggered by small molecules, or systemic pruritus.

44. The use according to claim 43, wherein the pseudoallergic reaction triggered by small molecules is an anaphylactoid drug reaction, or rosacea.

45. The use according to claim 43, wherein the systemic pruritus is cholestatic or uremic pruritus, or chronic pruritus triggered by a systemic disease.

46. The use according to claim 43, wherein the inflammatory disorder is atopic dermatitis.

47. The use according to claim 46, wherein the atopic dermatitis is Asian atopic dermatitis or European atopic dermatitis.

48. The use according to any one of claims 24-33, 38-40, 42 and 44-47, wherein the subject is a human.

49. The use according to any one of claims 24-33, 38-40, 42 and 44-47, wherein the pharmaceutical composition is for oral administration.

50. The use according to claim 48, wherein the pharmaceutical composition is for oral administration.

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