Mrgprx2 antagonists and uses thereof

Abstract

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

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 62 / 931,174, filed on November 5, 2019; U.S. Provisional Application No. 62 / 931,627, filed on November 6, 2019; and U.S. Provisional Application No. 63 / 046,476, filed on June 30, 2020, the contents of each of which are hereby incorporated by reference in their entirety.

Background Art

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

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

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

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

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

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

Summary of the Invention

[0008] Summary Compositions comprising MrgprX2 antagonists and methods for using MrgprX2 antagonists for the treatment of inflammatory conditions such as AD are described herein.

[0009] Thus, in a first aspect, the disclosure provides a compound that is an MrgprX2 antagonist.

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

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

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

[0013] In a fifth aspect, the present disclosure provides a method for reducing the occurrence or severity of itching in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a topical or oral composition comprising an MrgprX2 antagonist (e.g., an MrgprX2 antagonist according to the present disclosure) to the skin of a mammal. [The present invention 1001] A compound having the following formula I, TIFF2025090638000001.tif33128wherein, Q is, TIFF2025090638000002.tif38128and Z is -C(=O)-(CR 20 R 21 ) n or -S(=O)2-, R1 is H or C 1-3 alkyl, n is 0 or 1, each R 20 and R 21 is independently H or C 1-3 alkyl, G1, G2, G3, G4, and G5 are each independently N or -C-L1-M1, provided that at least one of G1, G2, G3, G4, and G5 is N, each L1 is independently a bond, O, -C(=O), -C(=O)-NH-, -CH2- -O-(CH2) w -(where w is 1, 2, or 3), or -N(R 90 )-, or any two L1-M groups on adjacent carbon atoms may together form a group of the formula -O-(CH2) v -O-(where v is 1 or 2), each R 90 is independently H or C 1-3 alkyl, each M1 is independently H, -OH, halogen, cyano, C 6-10 aryl; 5- to 10-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S; C 1-6 alkyl; C 3-6 cycloalkyl: -NR 50 R 51 ; 4- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, where each of said C 6-10 aryl, 5- to 10-membered heteroaryl, C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 10-membered heterocycloalkyl is each independently substituted with 1, 2, or 3 substituents 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 ), each R 91 and R 92 is independently selected from the group consisting of H and C 1-3 alkyl, each R 50 and R 51 is independently H, C 1-3 alkyl, and C6-10 selected from the group consisting of aryl, A is -L2-M2, L2 is a bond and -(CR 60 R 61 ) k - selected from, R 60 and R 61 are each independently H, or C optionally substituted with 1, 2, or 3 substituents independently selected from -OH and halogen 1-3 alkyl, k is 1, 2, or 3, M2 is C 1-6 alkyl; C 3-6 cycloalkyl; C 5-10 spiroalkyl; 4- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; -N(R 81 )(R 82 ); and C 6-10 aryl, where each C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 spiroalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl may each be optionally substituted with 1, 2, 3, or 4 independently selected R 200 groups, each R 200 is independently C 1-6 alkyl; C 1-6 hydroxyalkyl; C 3-6 cycloalkyl; 5- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; C 1-6 mono-, di-, or trihaloalkyl; halogen; cyano; -OH; C 1-6 alkoxy; S(=O)2NR 502 R 503 and C 6-10 aryl selected from, each R 81 and R 82 are each independently H, C 1-6Alkyl and C 3-6 selected from cycloalkyl, where said C 1-6 alkyl and C 3-6 cycloalkyl may be substituted with 1, 2, 3, or 4 substituents independently selected from -OH and halogen, R 500 and R 501 are independently absent or are C 1-6 alkyl, R 502 and R 503 are independently H or C 1-6 alkyl, a compound, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof. [Invention 1002] A compound of Invention 1001, wherein G1 is N. [Invention 1003] A compound of Invention 1001, wherein G2 is N. [Invention 1004] A compound of Invention 1001, wherein G1 and G4 are N. [Invention 1005] A compound of Invention 1001, wherein G1 and G2 are N. [Invention 1006] A compound of Invention 1001, wherein G1 and G5 are N. [Invention 1007] A compound of Invention 1001, wherein G3 is -C-L1-M1. [Invention 1008] A compound of Invention 1001, wherein G4 is -C-L1-M1. [Invention 1009] A compound of Invention 1001, wherein G2 is -C-L1-M1. [Invention 1010] A compound of any one of Inventions 1001 to 1009, wherein L1 is O. [Invention 1011] A compound of any one of Inventions 1001 to 1009, wherein L1 is -CH2-. [Invention 1012] Any compound of the present invention 1001-1009, wherein L1 is a bond. [Present Invention 1013] Any compound of the present invention 1001-1009, wherein L1 is -C(=O). [Present Invention 1014] Any compound of the present invention 1001-1009, wherein L1 is -C(=O)-NH-. [Present Invention 1015] Any compound of the present invention 1001-1009, wherein L1 is -N(R 90 )-. [Present Invention 1016] Any compound of the prior present invention, wherein R1 is H. [Present Invention 1017] Any compound of the prior present invention 1001, wherein n is 0. [Present Invention 1018] Any compound of the present invention 1001-1015, wherein n is 1. [Present Invention 1019] Any compound of the prior present invention, wherein M1 is selected from C6 aryl; C6 heteroaryl having 1 or 2 ring heteroatoms independently selected from N and O; C5 or C6 heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N and O; and 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, and each of the foregoing may be substituted. [Present Invention 1020] Any compound of the prior present invention, wherein M1 is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or dihydroindiol, and each of them may be substituted. [Present Invention 1021] Any compound of the prior present invention, wherein the substituents of M1 are independently selected from halogen, CN, -OH, -C(=O)-NH2, CF3, and -OCH3. [Present Invention 1022] Any compound of the prior present invention, wherein M1 is optionally substituted phenyl. [Invention 1023] Any compound of Inventions 1001 - 1021, wherein the phenyl is substituted at the 4-position. [Invention 1024] Any compound of Inventions 1001 - 1021, wherein the phenyl is substituted at the 3- and 4-positions. [Invention 1025] Any compound of Inventions 1001 - 1021, wherein the phenyl is substituted at the 3- and 5-positions. [Invention 1026] Any compound of the prior Inventions, wherein M1 is optionally substituted pyridyl. [Invention 1027] Any compound of the prior Inventions, wherein M1 is optionally substituted pyridin-4-yl. [Invention 1028] Any compound of the prior Inventions, wherein M1 is optionally substituted pyridin-3-yl. [Invention 1029] Any compound of the prior Inventions, wherein the pyridyl is substituted at the carbon ortho (i.e., adjacent) to the nitrogen of the pyridyl. [Invention 1030] Any compound of the prior Inventions, wherein the pyridyl is substituted at the carbon meta to the nitrogen of the pyridyl. [Invention 1031] Any compound of Inventions 1001 - 1029, wherein the pyridyl is substituted at the carbon meta to the nitrogen of the pyridyl. [Invention 1032] Any compound of the prior Inventions, wherein M1 is optionally substituted heterocycloalkyl. [Invention 1033] Any compound of the prior Inventions, wherein M1 is optionally substituted pyrrolidinyl. [Invention 1034] Any compound of Inventions 1001 - 1018, wherein M1 is optionally substituted pyrrolidin-1-yl. [The present invention 1035] Any compound of the present invention 1001 - 1018, wherein M1 is optionally substituted tetrahydropyranyl. [The present invention 1036] Any compound of the present invention 1001 - 1018, wherein M1 is optionally substituted tetrahydropyran - 4 - yl. [The present invention 1037] Any compound of the present invention 1001 - 1018, wherein M1 is optionally substituted cycloalkyl. [The present invention 1038] Any compound of the present invention 1001 - 1018, wherein M1 is optionally substituted C 1-6 alkyl. [The present invention 1039] Any compound of the present invention 1001 - 1018, wherein M1 is - NR 50 R 51 . [The present invention 1040] Any compound of the previous present invention, wherein L2 is a bond. [The present invention 1041] Any compound of the present invention 1001 - 1039, wherein L2 is - (CR 60 R 61 ) k -. [The present invention 1042] Any compound of the previous present invention, wherein M2 is optionally substituted C 1-6 alkyl. [The present invention 1043] Any compound of the previous present invention, wherein M2 is optionally substituted isopropyl. [The present invention 1044] Any compound of the present invention 1001 - 1041, wherein M2 is optionally substituted C 3-6 cycloalkyl. [The present invention 1045] Any compound of the present invention 1001 - 1041, wherein M2 is cyclopropyl or cyclobutyl, each of which may be substituted with 1 - 4 methyl groups. [The present invention 1046] A compound according to any one of the present inventions 1001 to 1041, wherein M2 is cyclopropyl or cyclobutyl, each of which may be substituted with one or two substituents independently selected from methyl, halogen, mono-, di- or trihalomethyl, cyano, hydroxymethyl, and hydroxy. [The present invention 1047] A compound according to any one of the present inventions 1001 to 1041, wherein M2 is cyclopropyl which may be substituted with 1 to 4 methyl groups, halogen or trihalomethyl. [The present invention 1048] A compound according to any one of the present inventions 1001 to 1041, wherein M2 is heterocycloalkyl which may be substituted with one or two groups independently selected from methyl and hydroxy. [The present invention 1049] A compound according to any one of the present inventions 1001 to 1041, wherein M2 is tetrahydrofuran, pyrrolidine, tetrahydropyran, or morpholine, each of which may be substituted with one or two groups independently selected from methyl and hydroxy. [The present invention 1050] M2 is -N(R 81 )(R 82 ), a compound according to any one of the preceding present inventions. [The present invention 1051] R 81 and R 82 are independently selected from C 1-3 alkyl and C 3-4 cycloalkyl, each of which may be substituted with one or two substituents independently selected from -OH and halogen, a compound according to any one of the preceding present inventions. [The present invention 1052] A compound according to any one of the preceding present inventions, selected from the compounds in Table 1 herein, or stereoisomers, solvates, tautomers, or pharmaceutically acceptable salts thereof. [The present invention 1053] A composition comprising a dermatologically or orally acceptable excipient and a compound according to any one of the preceding present inventions. [The present invention 1054] A method for treating an inflammatory disorder, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of the compound of the present invention 1001 and a dermatologically or orally acceptable excipient. [The present invention 1055] The method of the present invention 1054, wherein the composition is in the form of a cream, gel, spray, ointment, or oral unit dosage form. [The present invention 1056] The method of the present invention 1054, 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. [The present invention 1057] The method of the present invention 1054, 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. [The present invention 1058] The method of the present invention 1054, wherein the composition further comprises a skin absorption enhancer. [The present invention 1059] The method of the present invention 1054, wherein the composition further comprises a skin absorption enhancer comprising one or more of mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., laurocapram), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohol and alkanol (e.g., ethanol or decanol), glycol (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactant (which is also common in dosage forms), and terpene. [The present invention 1060] The method according to any one of the present inventions 1054 to 1059, wherein the composition is applied to the skin of the patient once a day. [The present invention 1061] The method according to any one of the present inventions 1054 to 1059, wherein the composition is applied to the skin of the patient twice a day. [The present invention 1062] The method according to any one of the present inventions 1054 to 1059, wherein the composition is applied to the skin of the patient three times a day. [Invention 1063] Any of the methods of the present invention 1054-1062, wherein the composition is administered to a patient suffering from an inflammatory disorder. [Invention 1064] Any of the methods of the present invention 1054-1063, wherein the inflammatory disorder is a skin disorder. [Invention 1065] Any of the methods of the present invention 1054-1064, wherein the skin is human skin. [Invention 1066] Any of the methods of the present invention 1063-1065, wherein the inflammatory disorder activates MrgprX2 or is a result of the activation of MrgprX2. [Invention 1067] Any of the methods of the present invention 1063-1066, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, such as anaphylaxis-like drug responses, anaphylactic shock, alcohol flushing, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, or drug adverse responses. [Invention 1068] Any of the methods of the present invention 1063-1067, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). [Invention 1069] Any of the methods of the present invention 1054-1068, wherein the subject is human. [Invention 1070] Any of the methods of the present invention 1054-1068, wherein the mammalian skin is human skin. [Invention 1071] Any of the methods of the prior invention, wherein the composition is for oral administration. [Mode for Carrying Out the Invention]

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

[0015] MrgprX2 antagonists for use in the compositions and methods of the present disclosure In some embodiments, the present disclosure provides a compound [Compound 1] that is an MrgprX2 antagonist having the formula I, TIFF2025090638000003.tif38128wherein, Q is, TIFF2025090638000004.tif38128and, Z is -C(=O)-(CR 20 R 21 ) n or -S(=O)2-, R1 is H or C 1-3 alkyl, n is 0 or 1, each R 20 and R 21 is independently H or C 1-3 alkyl, G1, G2, G3, G4 and G5 are each independently N or -C-L1-M1, provided that at least one of G1, G2, G3, G4 and G5 is N, each L1 is independently a bond, O, -C(=O), -C(=O)-NH-, -CH2--O-(CH2) w -(where w is 1, 2 or 3), or -N(R 90 )-, or any two L1-M groups on adjacent carbon atoms may together form a group of the formula -O-(CH2) v -O-(where v is 1 or 2), each R 90 is independently H or C 1-3 alkyl, each M1 is independently H, -OH, halogen, cyano, C 6-10Aryl; 5- to 10-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S; C 1-6 Alkyl; C 3-6 Cycloalkyl; -NR 50 R 51 ; 4- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein each C 6-10 Aryl, 5- to 10-membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and 4- to 10-membered heterocycloalkyl may each be independently substituted with 1, 2, or 3 substituents 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 ), and each R 91 and R 92 is independently selected from the group consisting of H and C 1-3 Alkyl, and each R 50 and R 51 is independently selected from the group consisting of H, C 1-3 Alkyl, and C 6-10 Aryl, and A is -L2-M2, L2 is selected from a bond and -(CR 60 R 61 ) k -, R 60 and R 61 are each independently H, or C 1-3 Alkyl which may be optionally substituted with 1, 2, or 3 substituents independently selected from -OH and halogen, k is 1, 2, or 3, M2 is C 1-6 Alkyl; C 3-6 Cycloalkyl; C 6-10Spiroalkyl; 4- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; -N(R 81 )(R 82 ); and C 6-10 aryl, wherein each C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 spiroalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl may each be substituted with 1, 2, 3, or 4 independently selected R 200 groups, each R 200 is independently C 1-6 alkyl; C 1-6 hydroxyalkyl; C 3-6 cycloalkyl; 5- to 10-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S; C 1-6 mono-, di-, or trihaloalkyl; halogen; cyano; -OH; C 1-6 alkoxy; S(=O)2NR 502 R 503 and C 6-10 aryl, selected from R 70 and R 71 are each independently H or C 1-3 alkyl, each R 81 and R 82 are each independently H, C 1-6 alkyl and C 3-6 cycloalkyl, where C 1-6 alkyl and C 3-6 cycloalkyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from -OH and halogen, R 500 and R 501 are each independently absent or C 1-6 alkyl, R 502 and R 503 are each independently H or C1-6 which is alkyl, There is provided a compound [Compound 1], or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof.

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

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

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

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

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

[0021] "Solvates" refer to the form of a compound complexed by solvent molecules.

[0022] "Tautomers" refer to two molecules that are structural isomers and can easily interconvert.

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

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

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

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

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

[0028] "Optionally" or "may be" means that the event or circumstance described thereafter may or may not occur, and that the description includes both the case where the event or circumstance occurs and the case where it does not occur. When a functional group is described as "optionally substituted" and, by extension, the substituents on the functional group are also "optionally substituted," etc., for the purposes of the present invention, such reiterations are limited to up to three times.

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

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

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

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

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

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

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

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

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

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

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

[0040] Methods of using the compounds of the present invention The compounds of the present invention are useful for the treatment of inflammatory disorders such as atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudo-allergic responses caused by small molecules such as anaphylactoid drug responses, anaphylactic shock, alcohol flushing, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, and drug adverse responses. Accordingly, administration or use of a preferred MrgprX2 antagonist described herein, such as the MrgprX2 antagonists described above, such as a compound of formula I, provides a means for ameliorating and / or providing treatment for the symptoms of various inflammatory diseases and disorders.

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

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

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

[0044] The present disclosure further provides further embodiments of Method 2 as follows: 2.1 Method 2, wherein the MrgprX2 antagonist is a compound according to Formula I above; 2.2 Method 2 or 2.1, wherein the MrgprX2 antagonist is a compound according to any of Compounds 1.1 to 1.55 above; 2.3 Any of the prior methods, wherein the MrgprX2 antagonist is a compound selected from the compounds in Table 1 herein, or a stereoisomer, solvate, tautomer, or pharmaceutically acceptable salt thereof; 2.4 Any of the prior methods, wherein the inflammation is a result of activation of MrgprX2; 2.5 Any of the prior methods, wherein the composition is in the form of a cream, gel, spray, or ointment. 2.6 Any of the prior methods, wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt% to about 10 wt% based on the total weight of the composition. 2.7 Any of the prior 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. 2.8 Any of the prior methods, further comprising a skin absorption enhancer. Any of the prior methods further comprising a skin absorption enhancer comprising one or more of mannitol, sulfoxide (e.g., dimethyl sulfoxide, DMSO), azone (e.g., laurocapram), pyrrolidone (e.g., 2-pyrrolidone, 2P), alcohol and alkanol (e.g., ethanol or decanol), glycol (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactant (which is also common in dosage forms), and one of the terpenes. Any of the prior methods, wherein the composition is applied to the skin of a patient once a day. Any of the prior methods, wherein the composition is applied to the skin of a patient twice a day. Any of the prior methods, wherein the composition is applied to the skin of a patient three times a day. Any of the prior methods, wherein the composition is administered to a patient suffering from an inflammatory disorder. The prior method, wherein the inflammatory disorder is a skin disorder. The prior method, wherein the skin is human skin. Any of Methods 1.12 - 1.14, wherein the inflammatory disorder activates MrgprX2 or is a result of the activation of MrgprX2. The prior method, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g., anaphylactoid drug responses, anaphylactic shock, alcohol flush, asthma, systemic pruritus such as cholestatic or uremic pruritus, chronic pruritus caused by systemic diseases, or drug adverse responses. Any of Methods 1.12 - 1.16, wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis). Any of the prior methods, wherein the subject is human. Any of the prior methods, wherein the mammalian skin is human skin. Any of the prior methods, wherein the composition is for oral administration.

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

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

[0047] "Atopic dermatitis" refers to a skin condition with chronic inflammation. Symptoms of atopic dermatitis include rashes with redness and itching. Atopic dermatitis can be present on the skin of any part of the body, but is common on the hands, feet, upper chest, and the flexures of the elbows or knees. Additional symptoms of atopic dermatitis can include small raised bumps or thickened scaly skin.

[0048] "Psoriasis" is a chronic skin condition associated with an overactive immune response. Psoriasis can be present on the skin of any part of the body. Symptoms of psoriasis include local inflammation, skin peeling, and white or red thickened discolored areas of the skin.

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

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

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

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

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

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

[0055] "Therapeutically effective amount" refers to the amount of a compound of the present invention that is sufficient to achieve treatment of a disease or condition in a mammal, preferably a human, when administered to the mammal, preferably a human, having the disease or condition. The amount of the compound of the present invention corresponding to a "therapeutically effective amount" will vary depending on the compound, the disease or condition and its severity, the mode of administration, and the age of the mammal being treated, but can be determined in the usual manner considering the person skilled in the art's own knowledge and the present disclosure. Preferably, for the purposes of the present invention, a "therapeutically effective amount" is the amount of the compound of the present invention that is sufficient to inhibit skin inflammation.

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

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

[0058] In this specification, unless otherwise indicated, the term "about" means ±20% of the indicated range, value, or structure.

[0059] 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 about 0.05 wt% to about 5 wt%.

[0060] In certain embodiments, the pharmaceutical compositions described herein further comprise a dermatologically acceptable excipient. The dermatologically acceptable excipient can be one or more solvents that solubilize and / or stabilize the active ingredient (e.g., the MrgprX2 antagonist) contained in the composition. The dermatologically acceptable excipient can also include a skin penetration enhancer, a preservative, a viscosity enhancer, a pH adjuster, a film-forming agent, and the like. Non-limiting examples of suitable excipients include water, PEG200, PEG400, ethanol, glycerol, Transcutol P (diethylene glycol monoethyl ether), propylene glycol, 1,3-dimethyl-2-imidazolidinone (DMI), sodium metabisulfite, butylated hydroxytoluene (BHT), benzyl alcohol, sodium benzoate, isopropyl myristate, diisopropyl adipate, Crodamol OHS (ethylhexyl hydroxystearate), mineral oil, Betadex, TWEEN20, Brij S20 (polyoxyethylene (20) stearyl ether).

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

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

[0063] Examples of penetration enhancers or barrier function disruptors include, but are not limited to, alcohol-based promoters such as alkanols having 1 to 16 carbons, benzyl alcohol, butylene glycol, diethylene glycol, glycol flow, glyceride, glycerin, glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based agents such as N-butyl-N-dodecylacetamide, chlorothen, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, and urea; amino acids such as L-α-amino acids and water-soluble proteins; azones and azone-like compounds such as azacycloalkanes, essential oils such as almond oil, amyl butyrate, almond oil, avocado oil, camphor, castor oil, 1-carboxylic, coconut oil, corn oil, cottonseed oil, eugenol, menthol, anise oil, clove oil, orange oil, peanut oil, peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil (squalene), soybean oil, sunflower oil, walnut oil; vitamins and herbs such as aloe, allantoin, black cumin extract, chamomile extract, panthenol, papain, tocopherol, vitamin A palmitate; waxes such as candelilla wax, carnauba wax, ceresine wax, beeswax, lanolin wax, jojoba oil, petrolatum; mixtures such as mixtures of fractionated vegetable oil fatty acids with glycerin or propylene glycol and transesterified medium-chain triglyceride oils; fatty acids and fatty acid esters such as amyl caproate, butyl acetate, caprylic acid, cetyl ester, diethyl sebacate, dioctyl malate, ethyl caprylate elaidate, ethylene glycol palmitostearate, glyceryl behenate, glucose glutamate, isobutyl acetate, laureth-4, lauric acid, malic acid, methyl caprylate, mineral oil, myristic acid, oleic acid, palmitic acid, PEG fatty acid ester, polyoxyethylene sorbitan monooleate, polypropylene glycol, propylene glycol, sucrose distearate, salicylic acid, sodium citrate, stearic acid, soap, and caproic acid-, caprylic acid-, capric acid-, and lauric acid-triglycerides;Macrocycles, e.g., butylated hydroxyanisole, cyclopentadecanolide, cyclodextrin; phospholipids and phosphate enhancers, e.g., dialkyl phosphates, ditetradecyl phosphate, lecithin, 2-pyrrolidone derivatives, e.g., alkyl pyrrolidone-5-carboxylate ester, pyroglutamic acid ester, N-methylpyrrolidone, biodegradable soft penetration enhancers, e.g., dioxane derivatives and dioxolane derivatives; sulfoxide enhancers, e.g., dimethyl sulfoxide and decyl methyl sulfoxide; acid enhancers, e.g., alginic acid, sorbic acid, and succinic acid; cyclic amines; imidazolinone; imidazole; ketones, e.g., acetone, dimethicone, methyl ethyl ketone, and pentanedione; lanolin derivatives, e.g., lanolin alcohol, PEG16 lanolin, and acetylated lanolin; oxazoline; oxazolidinone; proline ester; pyrrole, urethane; and surfactants, e.g., nonoxynol, polysorbate, polyoxyethylene alcohol, polyoxyethylene fatty acid ester, sodium lauryl sulfate, and sorbitan monostearate are included.;

[0064] The topical compositions described herein typically preferably contain one or more carriers having a vapor pressure of 23.8 mm Hg or more at 25°C. The total preferred concentration range of a single carrier or combination of carriers can be from about 0.1 wt% to about 10 wt%, 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.;

[0065] The dermatological composition of the present invention may contain one or more hydrophilic co-solvents that are miscible with water and / or lower alcohols and preferably have a vapor pressure of less than water (about 23.8 mm Hg) at 25°C. The carrier typically has a vapor pressure higher than that of the hydrophilic co-solvent in order to concentrate the active ingredient (e.g., the MrgprX2 antagonist of the present disclosure) on the skin. The hydrophilic co-solvent can be a glycol, specifically propylene glycol. Specifically, propylene glycol can be from the class of polyethylene glycols having a molecular weight in the range of 200 to 20,000. Preferably, the solvent will be part of the class of glycol ethers. More specifically, the hydrophilic co-solvent of the present invention will be diethylene glycol monoethyl ether (transcutol). As used herein, "diethylene glycol monoethyl ether" ("DGME") or "transcutol" refers to 2-(2-ethoxyethoxy)ethanol {CAS number 001893} or ethyoxydiglycol. Another preferred co-solvent is 1,3-dimethyl-2-imidazolidinone (DMI).

[0066] The topical compositions described herein may also contain one or more "humectants" used to provide a wetting effect. Preferably, the humectant remains stable in the composition. Any suitable concentration of a single humectant or combination of humectants can be used, provided that the resulting concentration provides the desired wetting effect. Typically, the suitable amount of humectant will depend on the particular humectant or humectants used. The total preferred concentration range of a single humectant or combination of humectants can be from about 0.1 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, polyhydric alcohols, and silicone oils. More preferably, the humectant is glycerin, propylene glycol, and / or cyclomethicone. Specifically, the filler will be glycerin and / or cyclomethicone.

[0067] In certain embodiments, the pharmaceutical composition includes a viscosity enhancer or an emulsifier. A gelling agent is used to increase the viscosity of the final composition. An emulsifier is a substance that stabilizes an emulsion. A viscosity enhancer can also act as an emulsifier. Typically, the concentration and combination of the viscosity enhancer will depend on the physical stability of the finished product. The preferred concentration range of the viscosity enhancer can be from about 0.01 wt% to about 20 wt% of the dermatological composition, more preferably from about 0.1 wt% to about 10 wt%, and more specifically from about 0.5 wt% to about 5 wt%. Non-limiting examples of viscosity enhancers used herein include hydroxypropylcellulose, hydroxymethylcellulose, pluronic PF127 polymer, carbomer 980, carbomer 1342, and carbomer 940, more preferably hydroxypropylcellulose, pluronic PF127, carbomer 980, and carbomer 1342, and more specifically cellulose, acrylate polymers, and classes of acrylate cross-polymers such as hydroxypropylcellulose (Klucel® EF, GF and / or HF), pluronic PF127, carbomer 980, and / or carbomer 1342 (Pemulen® TR-1, TR-2 and / or Carbopol® ETD2020). Examples of emulsifiers for use herein include polysorbate, laureth-4, and potassium cetyl sulfate.

[0068] The topical or oral compositions described herein may contain one or more antioxidants, radical scavengers, and / or stabilizers, and the preferred concentrations range from about 0.001 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, tocopherolsolan, and propyl gallate. More specifically, the antioxidant can be ascorbyl palmitate, vitamin E acetate, vitamin E-TPGS, vitamin E, or butylated hydroxytoluene.

[0069] The topical or oral compositions described herein may also contain a preservative exhibiting 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 over the 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, methylparaben, propylparaben, EDTA tetrasodium, and ethylparaben. More specifically, the preservative will be a combination of methylparaben and propylparaben.

[0070] The topical compositions described herein may optionally include one or more chelating agents. As used herein, the terms "chelating agent" or "chelator" refer to a skin-beneficial agent capable of removing metal ions from a system by forming a complex such that the metal ions cannot readily participate in or catalyze chemical reactions. Chelating agents for use herein are preferably formulated at a concentration in the range 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 can be EDTA, disodium edetate, dipotassium edate, trisodium edetate, or potassium gluconate.

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

[0072] Alternatively, other pharmaceutical 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 used.

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

[0074] Any suitable amount of MrgprX2 antagonist (e.g., a compound according to the present disclosure) can be used in such a dermatological composition, provided that the amount effectively reduces local inflammation and / or vascular dysfunction and maintains stability in the composition over a long period of time. Preferably, the stability is typical in the manufacture, packaging, shipping, and / or storage of dermatologically acceptable compositions over a long period of time, e.g., up to about 3 years, up to about 1 year, or up to about 6 months. The compounds of the present disclosure can be present in solution, partially in a solution having undissolved portions, or completely in a suspension that is not completely dissolved. The compounds of the present disclosure can be present in the dermatological composition of the present invention in a concentration range of about 0.001 wt% to about 80 wt%, about 0.001 wt% to about 50 wt%, about 0.001 wt% to about 25 wt%, or about 0.001 wt% to about 6 wt%. In one embodiment, the compounds of the present disclosure can be present in a concentration range of about 0.001 wt% to about 10 wt%, about 0.1 wt% to about 10 wt%, or about 1.0 wt% to about 5.0 wt% of the dermatological composition.

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

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

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

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

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

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

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

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

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

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

[0085] The pharmaceutical compositions provided herein can be provided as compressed tablets, powder tablets, chewable troches, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets that are coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating that can be useful for covering unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings generally impart the same characteristics as sugar coatings. Multiple compressed tablets are compressed tablets produced by two or more compression cycles, including layered tablets and pre-coated or dry-coated tablets.

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

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

[0088] The pharmaceutical compositions provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system that can be oil-in-water or water-in-oil, in which one liquid is dispersed in small spherical form throughout another liquid. Emulsions can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifying agent, and a preservative. Suspensions can contain a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcohol solutions can include pharmaceutically acceptable acetals such as di(lower alkyl) acetals of lower alkyl aldehydes, e.g., acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups such as propylene glycol and ethanol. An elixir is a clear, sweetened, aqueous alcoholic solution. A syrup is a concentrated aqueous solution of sugar, e.g., sucrose, and can also contain a preservative. In liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a pharmaceutically acceptable liquid carrier, e.g., water, in an amount sufficient to be conveniently metered for administration.

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

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

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

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

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

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

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

[0096] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration for use in the treatment of the conditions and disorders described herein.

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

[0098] The active compound is contained in the vehicle in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the patient being treated. The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then the dosage for humans can be estimated therefrom. The human dosage is then typically fine-tuned and titrated against the response in clinical trials.

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

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

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

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

[0103] Oral dosage The oral dosage forms of the invention containing the MrgprX2 antagonist of the present disclosure will typically be administered at the dosages described above.

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

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

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

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

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

[0109] The manufactured articles provided herein contain a packaging material. Packaging materials for use in packaging the 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 intended mode of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated, as well as the various treatments for any of the diseases or disorders described herein.

[0110] The following examples can be used by those skilled in the art to determine the efficacy of the compounds of the invention in the treatment of humans having a cutaneous chemical condition characterized by inflammation.

Examples

[0111] Example 1 - Preparation of the Compounds According to the Present Disclosure Compound E001 TIFF2025090638000005.tif231282 - Cyano - N - [5 - (3 - fluorophenoxy) - 2 - pyridyl] - 2 - methyl - propanamide

[0112] Step 1 5 - Bromo - 2 - nitro - pyridine (750 mg, 3.69 mmol), cesium carbonate (2.4 g, 7.39 mmol) and 3 - fluorophenol (335 μL, 3.69 mmol) were mixed in DMSO (7.5 mL), purged with nitrogen, and stirred at 50 °C for 4 hours in a sealed vial. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by column chromatography [Biotage SNAP cartridge KP - Sil 50 g; 0 - 50% EtOAc in heptane]. The combined 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)

[0113] Step 2: 5 - (3 - fluorophenoxy)pyridin - 2 - amine 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 afford 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).

[0114] Step 3 To a solution of 5-(3-fluorophenoxy)pyridin-2-amine (50 mg, 0.245 mmol) and 2-cyano-2-methylpropanoic acid (28 mg, 0.245 mmol) in ethyl acetate (2 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.735 mmol) and T3P (50% in EtOAc) (0.22 mL, 0.367 mmol), and the reaction was stirred at 70 °C for 6 h. It was then cooled to room temperature, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (method F) to afford 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). LCMS: m / z 300.2 [M+H]+, (ESI+), RT = 3.35 (method A)

[0115] (Table 1) The following compounds were synthesized using a method similar to that used for compound E001. TIFF2025090638000006.tif37166TIFF2025090638000007.tif221166TIFF2025090638000008.tif225166TIFF2025090638000009.tif216166TIFF2025090638000010.tif216166TIFF2025090638000011.tif225166TIFF2025090638000012.tif225166TIFF2025090638000013.tif225166TIFF2025090638000014.tif212166TIFF2025090638000015.tif220166TIFF2025090638000016.tif221166TIFF2025090638000017.tif220166TIFF2025090638000018.tif225166TIFF2025090638000019.tif220166TIFF2025090638000020.tif212166TIFF2025090638000021.tif153166*E075 was formed as a by-product in the synthesis of E042. **E076 was formed as a by-product in the synthesis of E063.

[0116] Compound E078 TIFF2025090638000022.tif17128(1R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]-2,2-dimethyl-cyclopropanecarboxamide

[0117] It was synthesized from Compound E029 using chiral separation under the following conditions. Using a Chiralpak AD-H column (20×250 mm, 5 μm) and a methanol mobile phase (9 mL / min), a colorless oil was obtained as the second eluted component. The absolute stereochemistry was confirmed by comparison with Compound E043. The product was further purified by column chromatography (10 g Biotage snap cartridge, gradient of 0 - 40% ethyl acetate in heptane) to obtain 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)

[0118] Compound E079 TIFF2025090638000023.tif241282,2,3,3-Tetramethyl-N-[5-(methylamino)-2-pyridyl]cyclopropanecarboxamide

[0119] Step 1 5-Bromo-2-nitro-pyridine (250 mg, 1.23 mmol), cesium carbonate (803 mg, 2.46 mmol), and N-methyl-1-phenyl-methanamine (0.16 mL, 1.23 mmol) were mixed in DMSO (6.25 mL), purged with nitrogen, and stirred in an RBF at 50 °C for 3 h. The reaction temperature was raised to 80 °C and the reaction was continued to stir for 3 h. The reaction mixture was diluted with water (50 mL). The mixture was extracted with EtOAc (3 × 25 ml). The combined organics were dried (hydrophobic frit) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (50 g of SiO2 column, 0 - 80% EtOAc in heptane) to give N-benzyl-N-methyl-6-nitro-pyridin-3-amine (60 mg, 0.230 mmol, 19% yield) as a yellow oil. 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).

[0120] Step 2 To a solution of N-benzyl-N-methyl-6-nitro-pyridin-3-amine (60 mg, 0.230 mmol) in 3:1 EtOH / H2O (4 mL) was added iron (128 mg, 2.30 mmol) and ammonium chloride (123 mg, 2.30 mmol). The reaction mixture was heated at 70 °C for 2 h. The reaction mixture was then cooled, filtered through a Celite pad, and washed with EtOAc (2 × 25 mL). The filtrate was diluted with water (25 mL), the layers were separated, and the aqueous layer was extracted twice with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine, dried (hydrophobic frit), and concentrated under reduced pressure to give N5-benzyl-N5-methyl-pyridine-2,5-diamine (90.0%) (52 mg, 0.219 mmol, 95% yield) as a black oil. 1H NMR (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).

[0121] Step 3 A solution of N5-benzyl-N5-methyl-pyridine-2,5-diamine (90%, 52 mg, 0.219 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.077 mL, 0.439 mmol) in anhydrous THF (3 mL) was stirred at room temperature for 2 h, and then 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (42 mg, 0.263 mmol) was added. Subsequently, 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 solution was further extracted with EtOAc (2×15 mL). The combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo to give N-[5-[benzyl(methyl)amino]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92.0%) (75 mg, 0.203 mmol, 93% yield) as a reddish brown oil. 1H NMR (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).

[0122] Step 4 A stirred solution of N-[5-[benzyl(methyl)amino]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92%, 75 mg, 0.203 mmol) in ethyl acetate (10 mL) was placed under a hydrogen balloon and stirred at room temperature for 16 h. A further portion of 10% palladium on carbon (4.3 mg, 0.0406 mmol) was added, the mixture was placed under a hydrogen balloon and stirred at room temperature for 5 h. The reaction mixture was filtered through Celite and the Celite was further washed with dioxane (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was dissolved in methanol (5 mL). The solution was passed through an H-Cube flow hydride equipped with a 10% Pd / C cartridge at a flow rate of 1 mL / min at a reaction temperature of 80 °C. The generated hydrogen was supplied to the flow at 80 bar. The crude mixture was then passed through the H-Cube two more times under the same conditions but with acetic acid (5% (v / v)) added to the reaction mixture. The mixture was concentrated under reduced pressure and purified by preparative HPLC (method E), followed by an SCX cartridge (1 g) eluting with methanol (3 CV), then 2 M ammonia in methanol (3 CV). The ammonia-containing fractions were combined and concentrated to give the title compound (5.4 mg, 0.0214 mmol, 11% yield) as a pale 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)

[0123] Compound E080 TIFF2025090638000024.tif27128N-[5-(2-Hydroxy-2-methyl-propoxy)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

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

[0125] Compound E081 TIFF2025090638000025.tif241282-Methyl-N-(5-pyrrolidin-1-yl-2-pyridyl)propanamide

[0126] Step 1 A suspension of 5-bromo-2-nitro-pyridine (1 g, 4.93 mmol) in pyrrolidine (2.1 mL, 24.6 mmol) was heated to 120 °C for 1 hour in a microwave reactor with stirring. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. Purification by flash chromatography (50 g Biotage KP-Sil cartridge, 10 - 60% EtOAc in heptane) 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).

[0127] Step 2 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 hours. The reaction mixture was filtered through Celite (5 g), evaporated to dryness, and 5-pyrrolidin-1-ylpyridin-2-amine (466 mg, 2.31 mmol, 92% yield), a brown solid, was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.35 (d, J = 2.9 Hz, 1H), 6.84 (dd, J = 8.8, 3.0 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.01 (s, 2H), 3.14 - 3.04 (m, 4H), 1.96 - 1.84 (m, 4H).

[0128] Step 3 To a stirred solution of 5-pyrrolidin-1-ylpyridin-2-amine (58 mg, 0.288 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.10 mL, 0.573 mmol) in DCM (5 mL), a solution of 2-methylpropanoyl chloride (0.060 mL, 0.573 mmol) in DCM (1 mL) was added at room temperature, and the mixture was stirred for 2 hours. 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 hour, 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)

[0129] Compound E082 TIFF2025090638000026.tif22128N-[5-(2-Hydroxyethoxy)pyridin-2-yl]-2,2,3,3-tetramethylcyclopropane-1-carboxamide

[0130] Starting from benzyloxyethanol, it was synthesized using a method similar to that used in Compound E078, 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)

[0131] (Table 2) The following compounds were synthesized using a method similar to that used in Compound E001, except that sodium hydride was used as the base and DMF was used as the solvent in Step 1. TIFF2025090638000027.tif167166TIFF2025090638000028.tif221166* Compounds E089 and E090 were isolated as products from the same reaction.

[0132] Compound E093 TIFF2025090638000029.tif271282,2,3,3-Tetramethyl-N-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]cyclopropanecarboxamide

[0133] Step 1 To a stirred mixture of 6-aminopyridin-3-ol (150 mg, 1.36 mmol) and cesium carbonate (0.67 g, 2.04 mmol) in DMF-anhydrous (3.6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.22 mL, 1.50 mmol) dropwise. After stirring 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 further extracted with EtOAc (2×20 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 in heptane) to give 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)

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

[0135] Compound E094 TIFF2025090638000030.tif20128N-(5-anilino-2-pyridyl)-2-methyl-propanamide

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

[0137] Step 2 To a mixture of N-(5-bromo-2-pyridyl)-2-methyl-propanamide (70 mg, 0.285 mmol) and sodium tert-butoxide (41 mg, 0.428 mmol) was added toluene (3 mL). Then aniline (29 mg, 0.314 mmol) was added and the mixture was degassed at room temperature for 10 minutes under nitrogen. 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, the reaction vessel was sealed and heated to 100 °C with stirring for 4 hours and then cooled to room temperature. The reaction mixture was filtered through Celite with EtOAc (30 mL). Then it was washed with saturated NaHCO3 (30 mL), followed by brine (30 mL), dried over sodium sulfate, filtered and evaporated to dryness. Purification by preparative HPLC (method F) 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)

[0138] Compound E095 TIFF2025090638000031.tif22128N-(5-indolin-1-yl-2-pyridyl)-2-methyl-propanamide

[0139] It was 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)

[0140] Compound E096 TIFF2025090638000032.tif 241282-Methyl-N-[5-(N-methylanilino)-2-pyridyl]propanamide

[0141] Step 1 To a solution of 5-bromo-2-nitro-pyridine (200 mg, 0.985 mmol) and Pd2(dba)3 (45 mg, 0.0493 mmol) in DME (5 mL), cesium carbonate (482 mg, 1.48 mmol) was added and the mixture was degassed at room temperature for 10 minutes under nitrogen. To this, N-methylaniline (0.13 mL, 1.18 mmol) and (R)-BINAP (61 mg, 0.0985 mmol) were added, the reaction vessel was sealed, and the mixture was heated to 100 °C with stirring for 4 hours and 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 organic extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methyl-6-nitro-N-phenyl-pyridine-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).

[0142] Step 2 To a solution of N-methyl-6-nitro-N-phenyl-pyridine-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. Then it was filtered through celite, washed with EtOAc, and concentrated under reduced pressure to afford N5-methyl-N5-phenyl-pyridine-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).

[0143] Step 3 To a stirred solution of N-ethyl-N-isopropyl-propan-2-amine (140 μL, 0.803 mmol) and N,N-dimethylpyridine-4-amine (4.9 mg, 0.0402 mmol) in anhydrous THF (2.5 mL) was added isobutyric anhydride (100 μL, 0.602 mmol), followed by N5-methyl-N5-phenyl-pyridine-2,5-diamine (80 mg, 0.402 mmol), and the mixture was stirred at 80 °C for 48 h in a sealable pressure tube. Then the reaction mixture was evaporated to dryness and purified by column chromatography (Biotage SNAP cartridge KP-Sil 10 g, 0 - 100% EtOAc in heptane) to afford the title compound (57.3 mg, 53%) as a light brown solid. 1H NMR (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)

[0144] (Table 3) The following compounds were synthesized using a method similar to that used for compound E096. TIFF2025090638000033.tif207166

[0145] Compound E102 TIFF2025090638000034.tif211283-[5-(3,4-difluorophenoxy)-2-pyridyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0146] Step 1 5-Bromo-2-nitro-pyridine (2.00 g, 9.85 mmol), cesium carbonate (6.42 g, 19.7 mmol), and 3,4-difluorophenol (1.28 g, 9.85 mmol) were mixed in DMSO (25 mL), purged with nitrogen, and stirred at 50 °C for 2 hours in an RBF. The reaction mixture was cooled, diluted with water (75 mL), and a beige / grey precipitate was formed. This was filtered, washed with water, and purified by FCC (Biotage SNAP KP-Sil 25 g, 0 - 50% EtOAc in heptane) to give 5-(3,4-difluorophenoxy)-2-nitro-pyridine (2.09 g, 81% yield) as an off-white solid. 1H NMR (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).

[0147] Step 2 A solution of 5-(3,4-difluorophenoxy)-2-nitro-pyridine (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 and filtered through a pad of celite and washed with EtOH (50 mL) and EtOAc (150 mL). The filtrate was diluted with water (100 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (75 mL), dried over MgSO4, and concentrated under reduced pressure to give 5-(3,4-difluorophenoxy)pyridin-2-amine (Intermediate I01, 1.87 g, quantitative yield) as a brown oil. 1H NMR (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).

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

[0149] Step 4 A solution of pyridine (40 μL, 0.495 mmol) and 5-(3,4-difluorophenoxy)pyridin-2-amine (100 mg, 0.450 mmol) in anhydrous THF (3 mL) was added to a stirred solution of (4-nitrophenyl) carbonochloridate (100 mg, 0.495 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 at room temperature overnight. The product was purified by silica flash column chromatography (0 - 40% EtOAc in heptane), followed by preparative HPLC (method G) to afford the title compound (77 mg, 0.189 mmol, 42% yield) as a clear glassy solid. 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)

[0150] (Table 4) Using either a commercially available amine or Compound E102 or an amino alcohol synthesized according to Step 3, the following compounds were synthesized using a method similar to that used with Compound E102. TIFF2025090638000035.tif216166TIFF2025090638000036.tif225166TIFF2025090638000037.tif220166TIFF2025090638000038.tif225166TIFF2025090638000039.tif220166TIFF2025090638000040.tif220166TIFF2025090638000041.tif207166TIFF2025090638000042.tif225166TIFF2025090638000043.tif225166TIFF2025090638000044.tif73166

[0151] Compound E139 TIFF2025090638000045.tif181283-[5-(3,4-Difluorophenoxy)-2-pyridyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0152] Step 1 Under N2, (2R)-2-(trifluoromethyl)oxirane (200 mg, 1.78 mmol) was added to a three-necked RBF, followed by anhydrous THF (8 mL), and the stirred solution was cooled to 100 °C in 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 about 0 °C in an ice bath, to which 2 M methanamine (3.6 mL, 7.14 mmol) was added, and the reaction mixture was warmed to room temperature and stirred overnight and left standing 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).

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

[0154] Compound E140 TIFF2025090638000046.tif191283-[5-(3,5-difluorophenoxy)-2-pyridyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

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

[0156] Compound E141 TIFF2025090638000047.tif241283 - [5-(2,4-Difluorophenoxy)-2-pyridyl]-1-methyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl]urea

[0157] It was 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)

[0158] Compound E142 TIFF2025090638000048.tif271281 - Ethyl-3-(5-pyrazol-1-yl-2-pyridyl)-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0159] Step 1 5-Fluoro-2-nitropyridine (250 mg, 1.76 mmol) and 1H-pyrazole (126 mg, 1.85 mmol) were mixed in anhydrous DMF (3.5 mL). After cooling the reaction mixture to 0 °C, sodium hydride (60%, 106 mg, 2.64 mmol) was added portionwise. The reaction was then stirred at room temperature for 2 h. After completion, the reaction mixture was diluted with water (10 mL) to form a pale yellow precipitate. This was filtered, washed with water (50 mL) and dried to give 2-nitro-5-pyrazol-1-yl-pyridine (235 mg, 1.17 mmol, 67% yield) as a pale yellow solid. 1H NMR (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).

[0160] Step 2 To a stirred solution of 2-nitro-5-pyrazol-1-yl-pyridine (235 mg, 1.24 mmol) in 1,4-dioxane (10 mL) and methanol (5 mL), 10% Pd / C (53 mg, 0.25 mmol) was added. The reaction mixture was placed under a hydrogen balloon and stirred at room temperature for 4 h. The reaction mixture was filtered through Celite, and the Celite was further washed with dioxane (50 mL). The filtrate was concentrated under reduced pressure to give 5-pyrazol-1-ylpyridin-2-amine (188 mg, 90% yield) as a sandy brown solid. 1H NMR (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).

[0161] Step 3 A solution of (4-nitrophenyl)carbonochloridate (66 mg, 0.326 mmol) in anhydrous THF (2 mL) was added to 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, (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) were added, and the reaction mixture was stirred at room temperature for 1 h. Then, it was concentrated under reduced pressure and purified by preparative HPLC (Method G) to obtain the title compound (47 mg, 0.133 mmol, 45% yield) as 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).

[0162] Compound E143 TIFF2025090638000049.tif23128N-[4-(3,5-difluorophenoxy)-2-pyridyl]-2-methyl-propanamide

[0163] Step 1 A solution of 4-chloropyridin-2-amine (300 mg, 2.33 mmol) and 3,5-difluorophenol (395 mg, 3.03 mmol) in NMP (5 mL) was added with N-ethyl-N-isopropyl-propan-2-amine (0.82 mL, 4.67 mmol) at room temperature. The reaction mixture was stirred at 160 °C for 18 h. It was then cooled to room temperature and diluted with EtOAc (30 mL) and water / brine (1:1, 30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over MgSO4, filtered, concentrated under reduced pressure and purified by preparative HPLC (method F) to give 4-(3,5-difluorophenoxy)pyridin-2-amine as a light brown solid (85 mg). 1H NMR (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).

[0164] Step 2 To a solution of 4-(3,5-difluorophenoxy)pyridin-2-amine (40 mg, 0.180 mmol) in DCM (1 mL) was added N-ethyl-N-isopropyl-propan-2-amine (63 μL, 0.360 mmol), followed by 2-methylpropanoyl chloride (32 μL, 0.306 mmol), and the reaction was stirred at room temperature for 0.5 h. The solvent was then removed under a steady stream of nitrogen, and the residue was dissolved in MeOH (1 mL), 1 M NaOH (1 mL) was added, and the reaction mixture was stirred at room temperature for 0.5 h. The MeOH was removed under a steady stream of nitrogen, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (10 g SiO2 column, 0 - 60% EtOAc in heptane) to give the title compound as a white solid (39 mg). 1H NMR (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).

[0165] Compound E144 TIFF2025090638000050.tif22128N-[4-(3,5-Difluorophenoxy)-2-pyridyl]cyclopropanecarboxamide

[0166] It was 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).

[0167] Compound E145 TIFF2025090638000051.tif 181282-Methyl-N-(4-phenoxy-2-pyridyl)propanamide

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

[0169] Step 2 To a solution of N-(4-chloro-2-pyridyl)-2-methyl-propanamide (100 mg, 0.498 mmol) and phenol (47 mg, 0.498 mmol) in DMSO (1 mL) at room temperature was added potassium tert-butoxide (67 mg, 0.598 mmol). The reaction mixture was stirred at 160 °C for 3 hours and cooled to room temperature. The mixture was diluted with EtOAc (20 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. Purification by preparative HPLC (method F), followed by concentration and lyophilization 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)

[0170] Compound E146 TIFF2025090638000052.tif221282,2,3,3-Tetramethyl-N-(4-pyrrolidin-1-yl-2-pyridyl)cyclopropanecarboxamide

[0171] Step 1 A stirred solution of 4-chloropyridin-2-amine (200 mg, 1.56 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.54 mL, 3.09 mmol) in DCM (3 mL) at room temperature was added a solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (497 mg, 3.10 mmol) in DCM (1 mL), and 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, and the residue was washed with brine (15 mL), extracted with EtOAc (3×15 mL), and concentrated under reduced pressure. Purification by flash column chromatography (Biotage SNAP KP-Sil 50 g, heptane:ethyl acetate, 0 - 20%) gave N-(4-chloro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (150 mg, 35% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.29 (d, J = 1.8 Hz, 1H), 8.15 - 8.09 (m, 2H), 6.99 (dd, J = 5.4, 1.9 Hz, 1H), 1.32 (s, 6H), 1.22 (s, 6H), 1.02 (s, 1H).

[0172] Step 2 A mixture of N-(4-chloro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (70 mg, 0.260 mmol) and pyrrolidine (0.11 mL, 1.30 mmol) in NMP (2 mL) was heated under microwave irradiation at 225 °C for 30 min. The mixture was washed with ethyl acetate (20 mL), extracted with water (2×30 mL), and the combined organics were dried using a hydrophobic filter and evaporated under reduced pressure. The crude reaction mixture was concentrated and purified by preparative HPLC (Method E) to give the title compound (28 mg, 37% yield) as an off-white solid. 1H NMR (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).

[0173] Compound E147 TIFF2025090638000053.tif22128N-[4-[(5-Fluoro-3-pyridyl)oxy]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

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

[0175] Step 2 To a stirred solution of 5-fluoropyridin-3-ol (48 mg, 0.422 mmol) in DMF-anhydrous (3 mL) was added sodium hydride (60% dispersion in oil) (24 mg, 0.603 mmol). After cessation of gas evolution, N-(4-fluoro-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (100 mg, 0.402 mmol) was added and the reaction mixture was heated to 100 °C. The reaction mixture was then heated to 120 °C for 16 h. The reaction mixture was washed with water (30 mL) and extracted with diethyl ether (2 × 20 mL). The combined organic layers were dried (hydrophobic filter) and concentrated to dryness under reduced pressure. After purification (10 g Biotage SNAP KP-Sil cartridge, 0 - 35% EtOAc in heptane), lyophilization gave 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)

[0176] Compound E148 TIFF2025090638000054.tif22128N-[4-[(6-fluoro-3-pyridyl)oxy]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0177] Step 1 6-Fluoropyridin-3-ol (270 mg, 2.39 mmol) and N,N-dimethylglycine hydrochloride (1:1) (178 mg, 1.27 mmol) were suspended in anhydrous 1,4-dioxane (8 mL), and the reaction mixture was degassed with N2 for 5 minutes. 4-Iodopyridin-2-amine (350 mg, 1.59 mmol) was added, and the reaction was 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 pad of celite, and further washed with EtOAc (30 mL). It was then washed with water (15 mL), extracted with EtOAc (2 × 20 mL), dried, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (Biotage Sfar Duo 50 g cartridge, 0 - 10% MeOH in EtOAc) to give 4-[(6-fluoro-3-pyridyl)oxy]pyridin-2-amine (33 mg, purity 87%, yield 8.7%) as an off-white solid. 1H NMR, (500 MHz, chloroform-d) δ 8.05 (dd, J = 2.8, 1.4 Hz, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7.53 (ddd, J = 9.3, 6.4, 3.0 Hz, 1H), 6.99 (dd, J = 8.7, 3.4 Hz, 1H), 6.26 (dd, J = 5.9, 2.2 Hz, 1H), 5.95 (d, J = 2.1 Hz, 1H), 4.49 (s, 2H).

[0178] Step 2 A solution of tetramethylcyclopropane-1-carbonyl chloride (22 mg, 0.138 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.024 mL, 0.138 mmol) in anhydrous THF (1.5 mL) was added to 4-[(6-fluoro-3-pyridyl)oxy]pyridin-2-amine (87%, 33 mg, 0.138 mmol), and the mixture was stirred at room temperature for 2 h. Tetramethylcyclopropane-1-carbonyl chloride (10 mg, 0.2 equiv) and DIPEA (12 uL, 0.2 equiv) were further added, and the mixture was stirred at room temperature for 45 min. The reaction mixture was then concentrated to dryness under reduced pressure, the residue was washed with water (30 mL), and extracted with EtOAc (2×25 mL). The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified using column chromatography (Biotage Sfar Duo 25 g cartridge, eluent: 0 - 100% EtOAc in heptane) to afford the title compound (27 mg, 56% yield) as a white solid. 1H NMR (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).

[0179] Compound E149 TIFF2025090638000055.tif211282,2,3,3-Tetramethyl-N-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]cyclopropanecarboxamide

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

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

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

[0183] Step 3 2,2,3,3-Tetramethylcyclopropanecarbonyl chloride (62 mg, 0.384 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-(2,2,2-trifluoroethoxy)pyridin-2-amine (38 mg, 0.192 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.074 mL, 0.422 mmol) in THF (1 mL) and the reaction was stirred at room temperature for 3.5 h. The reaction was concentrated in vacuo and then diluted with MeOH (2 mL) and 1 M sodium hydroxide (1.0 mL, 1.00 mmol) was added. The reaction was stirred at room temperature for a total of 72 h and then 2 M sodium hydroxide (1.0 mL, 2.00 mmol) was added and the reaction was stirred at 60 °C for 3 h. Methanol was removed in vacuo and the mixture was extracted with EtOAc (4 × 5 mL). The reaction was dried over MgSO4, concentrated and purified by preparative HPLC (Method G) to give the title compound (47 mg, 77% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 5.8 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 5.8, 2.5 Hz, 1H), 4.42 (q, J = 8.0 Hz, 2H), 1.32 (s, 6H), 1.22 (s, 6H), 1.02 (s, 1H). LCMS: m / z 317.5 [M+H]+, (ESI+), RT = 2.97 (Method A).

[0184] Compound E150 TIFF2025090638000056.tif201283 - [4-(3,4-difluorophenoxy)-2-pyridyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0185] Step 1 To a solution of 4-fluoropyridine-2-amine (250 mg, 2.19 mmol) and 3,4-difluorophenol (370 mg, 2.84 mmol) in NMP (3 mL) at room temperature was added N-ethyl-N-isopropyl-2-amine (0.76 mL, 4.37 mmol). The reaction mixture was stirred at 180 °C for 8 hours. It was then cooled to room temperature and diluted with EtOAc (30 mL) and water / brine (1:1, 30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 0 - 100% EtOAc in heptane) to give 4-(3,4-difluorophenoxy)pyridine-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).

[0186] Step 2 4-(3,4-Difluorophenoxy)pyridin-2-amine (86%, 40 mg, 0.155 mmol) was dissolved in DCM-anhydrous (1 mL), and CDI (33 mg, 0.201 mmol) was added. The reaction mixture was stirred at room temperature for 22 h. A solution of (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 32 mg, 0.201 mmol) in DCM-anhydrous (1 mL) was added, and the mixture was stirred at room temperature for a further 1 h. The reaction mixture was diluted with water, passed through a hydrophobic frit, and concentrated. The product was purified by preparative HPLC (Method E), followed by an SCX cartridge (2 g) eluting first with MeOH (3 CV) and then with 2 M ammonia in MeOH (3 CV). The ammonia fractions were combined and concentrated to give the title compound as an off-white solid (8.6 mg, 0.0212 mmol, 14% yield). 1H NMR (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)

[0187] (Table 5) Using the amino alcohol synthesized according to Intermediate I02 or Compound E139, Step 1, the following compounds were synthesized using a method similar to that used for Compound E150. TIFF2025090638000057.tif82166TIFF2025090638000058.tif220166TIFF2025090638000059.tif216166TIFF2025090638000060.tif73166

[0188] Compound E162 TIFF2025090638000061.tif 201281 - ethyl - 3 - [4 - [(5 - fluoro - 3 - pyridyl)oxy]-2 - pyridyl]-1 - [(2R)-3,3,3 - trifluoro - 2 - hydroxy - propyl]urea

[0189] Step 1 To a solution of 4 - fluoropyridin - 2 - amine (100 mg, 0.874 mmol) and 5 - fluoropyridine - 3 - ol (129 mg, 1.14 mmol) in NMP (2 mL) at room temperature, N - ethyl - N - isopropyl - propane - 2 - amine (0.31 mL, 1.75 mmol) was added. 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 (2×20 mL). The combined organic extracts were dried (hydrophobic frit), concentrated under reduced pressure, washed with MeOH (5 CV), and purified on a 5 g SCX - 2 cartridge eluting with 7N NH3 / MeOH (5 CV) to give 4 - [(5 - fluoro - 3 - pyridyl)oxy]pyridin - 2 - amine (180 mg, 85% purity, 85% yield) as a brown oil. 1H NMR (500 MHz, chloroform - d) δ 8.39 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.20 (dt, J = 9.1, 2.4 Hz, 1H), 6.34 (dd, J = 5.9, 2.2 Hz, 1H), 6.06 (d, J = 2.1 Hz, 1H), 4.57 (s, 2H).

[0190] Step 2 A solution of bis(trichloromethyl) carbonate (30 mg, 0.0994 mmol) in anhydrous DCM (2 mL) was added dropwise over 10 minutes to a solution of 4-[(5-fluoro-3-pyridyl)oxy]pyridin-2-amine (85%, 60 mg, 0.249 mmol) and pyridine (20 μL, 0.249 mmol) in anhydrous DCM (2 mL). The reaction mixture was stirred at -78 °C for 5 minutes. Then, (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 51 mg, 0.323 mmol) and N-ethyl-N-isopropyl-propan-2-amine (65 μL, 0.373 mmol) in anhydrous DCM (2 mL) were 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) as 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).

[0191] Compound E163 TIFF2025090638000062.tif261283 - [4-(3,5-difluorophenoxy)-2-pyridyl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

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

[0193] Compound E164 TIFF2025090638000063.tif 251282-Methyl-N-(5-phenyl-2-pyridyl)propanamide

[0194] Step 1 To a stirred solution of isobutyric anhydride (719 μL, 4.34 mmol) and 5-bromopyridin-2-amine (500 mg, 2.89 mmol) in THF (15.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1009 μL, 5.78 mmol), followed by N,N-dimethylpyridin-4-amine (35 mg, 0.289 mmol), and the mixture was stirred at 80 °C for 2 h in a sealable pressure tube. The reaction mixture was then evaporated to dryness. Purification by flash chromatography (Biotage 50 g KP-Sil SNAP cartridge, 10 - 100% EtOAc in heptane) gave N-(5-bromo-2-pyridyl)-2-methyl-propanamide (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).

[0195] Step 2 N-(5-Bromo-2-pyridyl)-2-methyl-propanamide (70 mg, 0.288 mmol) and phenylboronic acid (39 mg, 0.317 mmol) were dissolved in 1,4-dioxane-anhydrous (2 mL) and 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 at 110 °C for 2 hours. Then, it was washed with water, extracted with ethyl acetate, cooled to room temperature, concentrated under reduced pressure, and purified by preparative HPLC (Method F) to obtain 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).

[0196] (Table 6) Using a method similar to that used in Example E164, the following compounds were synthesized. TIFF2025090638000064.tif177170TIFF2025090638000065.tif169170

[0197] Compound E177 TIFF2025090638000066.tif23128N-(5-Cyclopentyl-2-pyridyl)-2-methyl-propanamide

[0198] A solution of N-[5-(cyclopenten-1-yl)-2-pyridyl]-2-methyl-propanamide (synthesized using the same method as that used for Compound E164, 43 mg, 0.188 mmol) in ethanol (5 mL) was added with 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 hours. Then, it was filtered through celite, washed with EtOAc, concentrated under reduced pressure, and purified by flash chromatography (Biotage Isolera, C18 12 g Ultra SNAP cartridge) eluting with a solution of water (+0.1% CH2O2) in MeCN (+0.1% CH2O2) (10 - 100%) to obtain 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).

[0199] Compound E178 TIFF2025090638000067.tif351282-Cyano-N-[5-(3,5-difluorophenyl)-2-pyridyl]-2-methyl-propanamide

[0200] Step 1 5-Bromopyridin-2-amine (1.00 g, 5.78 mmol) and (3,5-difluorophenyl)boronic acid (913 mg, 5.78 mmol) were dissolved in anhydrous 1,4-dioxane (55 mL) and 2 M 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 reaction, and the reaction was heated to 110 °C for 2.5 hours. It was then cooled to room temperature, concentrated to 20 mL under reduced pressure, the reaction was washed with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by SCX-2 cartridge (washed with MeOH and eluted with 7N NH3 / MeOH). This was concentrated under reduced pressure to give 5-(3,5-difluorophenyl)pyridin-2-amine (Intermediate I03, 947 mg, 74%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ 8.37 - 8.28 (m, 1H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.12 - 7.02 (m, 1H), 6.51 (dd, J = 8.7, 0.7 Hz, 1H), 6.23 (s, 2H).

[0201] Step 2 A solution of 2-cyano-2-methylpropanoic acid (42 mg, 0.373 mmol), HATU (142 mg, 0.373 mmol), and DIPEA (0.18 mL, 1.02 mmol) in acetonitrile - anhydrous (3 mL) was stirred at room temperature for 1 hour. 5-(3,5-Difluorophenyl)pyridin-2-amine (70 mg, 0.339 mmol) was added to the solution, and the reaction was stirred at 70 °C for 4 hours and then at 80 °C for 2 hours. The reaction was re-treated with HATU (142 mg, 0.373 mmol) and 2-cyano-2-methylpropanoic acid (42 mg, 0.373 mmol) and stirred at 80 °C overnight. It was then washed with water, extracted with EtOAc (30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method E) to obtain the title compound (12.6 mg, 12%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.82 (dd, J = 2.6, 0.7 Hz, 1H), 8.25 (dd, J = 8.7, 2.6 Hz, 1H), 8.09 (dd, J = 8.7, 0.7 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.30 - 7.23 (m, 1H), 1.70 (s, 6H). LCMS: m / z 302.2 [M+H]+, (ESI+), RT = 3.45 (Method A).

[0202] (Table 7) Using a method similar to that used in Example E178, the following compounds were synthesized. TIFF2025090638000068.tif78170TIFF2025090638000069.tif234170* Compound E186 was isolated as a by-product from the synthesis of E187.

[0203] Compound E189 TIFF2025090638000070.tif281282,2,3,3-Tetramethyl-N-[5-(2-methyl-1,2,3-triazol-4-yl)-2-pyridyl]cyclopropanecarboxamide

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

[0205] Step 2 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 with 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 the mixture was extracted with EtOAc (3 × 2 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica flash column chromatography (0 - 40% EtOAc in heptane), followed by purification with an SCX cartridge (2 g) eluting first with MeOH (3 CV) and then with 2 M ammonia in MeOH (3 CV). The crude product was then further purified by silica flash column chromatography (0 - 100% EtOAc in heptane) to afford the title compound (4.5 mg, 8.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.74 (t, J = 1.6 Hz, 1H), 8.53 (s, 1H), 8.14 (d, J = 1.6 Hz, 2H), 4.10 (s, 3H), 1.57 (s, 1H), 1.26 (s, 6H), 1.18 (s, 6H). LCMS: m / z 300.2 [M + H]+, (ESI+), RT = 3.10 (Method B)

[0206] Compound E190 TIFF2025090638000071.tif281282,2,3,3-Tetramethyl-N-[5-(1-methyl-1,2,3-triazol-4-yl)-2-pyridyl]cyclopropanecarboxamide

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

[0208] Compound E191 TIFF2025090638000072.tif311283 - [5-(3,5-Difluorophenyl)-2-pyridyl]-1-[(2S)-2-hydroxypropyl]-1-methyl-urea

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

[0210] (Table 8) The following compounds were synthesized using a method similar to that used for Compound E191, either according to the method of Intermediate I03 or using aminopyridine from a commercial source. TIFF2025090638000073.tif217170

[0211] Compound E197 TIFF2025090638000074.tif261281-Ethyl-3-(5-oxazol-2-yl-2-pyridyl)-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0212] Step 1 5-Bromo-2-nitropyridine (300 mg, 1.48 mmol) and palladium-triphenylphosphane (1:4) (200 mg, 0.173 mmol) were stirred in anhydrous toluene (4 mL), degassed with nitrogen for 5 minutes, then 2-(tributylstannanyl)-1,3-oxazole (0.79 mL, 2.58 mmol) was added. After degassing the reaction mixture, it was sealed and stirred at 90 °C for 18 hours. The reaction mixture was cooled to room temperature, treated with aqueous KF solution (about 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 in heptane, 0 - 100%) to obtain 2-(6-nitro-3-pyridyl)oxazole (139 mg, purity 92%, yield 45%) as a pale yellow solid. 1H NMR, (400 MHz, DMSO-d6) δ 9.22 (dd, J = 2.2, 0.6 Hz, 1H), 8.73 (dd, J = 8.5, 2.2 Hz, 1H), 8.47 (dd, J = 7.7, 0.7 Hz, 2H), 7.59 (d, J = 0.7 Hz, 1H).

[0213] Step 2 A stirred solution of 2-(6-nitro-3-pyridyl)oxazole (92%, 139 mg, 0.667 mmol) in EtOAc (10 mL) and 1,4-dioxane (3 mL) was evacuated and backfilled 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. When complete, the reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate (25 mL). The filtrate was concentrated to dryness under reduced pressure to afford 5-oxazol-2-ylpyridin-2-amine (Intermediate I04, 110 mg, 95% purity, 97% yield) as a pale yellow solid. 1H NMR, (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).

[0214] Step 3 A solution of 4-nitrophenyl carbonochloridate (72 mg, 0.357 mmol) in anhydrous THF (1.5 mL) was added to a solution of 5-oxazol-2-ylpyridin-2-amine (95%, 55 mg, 0.324 mmol) and pyridine (29 μL, 0.357 mmol) in anhydrous THF (1 mL), and the reaction mixture was stirred at room temperature for 3 minutes. Next, (2R)-3-(ethylamino)-1,1,1-trifluoro-propan-2-ol (Intermediate I02, 51 mg, 0.324 mmol) and N-ethyl-N-isopropyl-propan-2-amine (85 μL, 0.486 mmol) in anhydrous THF (1 mL) were added, and the reaction mixture was stirred at room temperature for 45 minutes. Then, it was concentrated under reduced pressure and purified using preparative HPLC (Method H) to obtain the title compound (32 mg, yield 28%) as a white solid. 1H NMR, (500 MHz, chloroform-d) δ 8.89 (d, J = 1.8 Hz, 1H), 8.29 (dd, J = 8.9, 2.3 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.24 (d, J = 0.7 Hz, 1H), 4.27 - 4.18 (m, 1H), 3.77 (dd, J = 15.2, 8.8 Hz, 1H), 3.63 - 3.53 (m, 2H), 3.48 (dq, J = 14.6, 7.0 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H). OH and NH were not observed. LCMS: m / z 345.1 [M+H]+, (ESI+), RT = 2.47 (Method A)

[0215] Compound E198 TIFF2025090638000075.tif271282,2,3,3-Tetramethyl-N-(5-oxazol-2-yl-2-pyridyl)cyclopropanecarboxamide

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

[0217] Compound E199 TIFF2025090638000076.tif271282, 2,3,3-Tetramethyl-N-(5-pyrazol-1-yl-2-pyridyl)cyclopropanecarboxamide

[0218] Step 1 5-Iodopyridin-2-amine (250 mg, 1.14 mmol), copper(I) iodide (22 mg, 0.114 mmol), tripotassium phosphate (734 mg, 3.41 mmol), and 1H-pyrazole (85 mg, 1.25 mmol) were added to a sealed tube. After purging with nitrogen, anhydrous 2-propanol (5 mL) was added, followed by ethan-1,2-diol (6.3 μL, 0.114 mmol). The reaction mixture was purged with nitrogen again, then the tube was sealed and heated to 110 °C for 15 h. The reaction mixture was then cooled to room temperature, filtered through a pad of celite, and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (25 g SiO2 column, 0 - 15% MeOH in DCM) to afford the title compound as an off-white solid (145 mg, 50% purity).

[0219] Step 2 A solution of 5-pyrazol-1-ylpyridin-2-amine (140 mg, 0.874 mmol) and N-ethyl-N-isopropyl-propan-2-amine (305 μL, 1.75 mmol) in anhydrous THF (2 mL) was added with 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (211 mg, 1.31 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, the solvent was removed under a steady stream of nitrogen, MeOH (2 mL) and 1 M NaOH (2 mL) were added, and the reaction mixture was stirred at room temperature for 1 hour. Subsequently, MeOH was removed under a steady stream of nitrogen to form a beige precipitate. This was filtered, washed with water, and the solid was purified by preparative HPLC (method F) to obtain 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)

[0220] Compound E200 TIFF2025090638000077.tif22128N-(5-Iodo-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

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

[0222] Compound E201 TIFF2025090638000078.tif27128N-[5-(Dimethylamino)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0223] To a solution of N5,N5-dimethylpyridine-2,5-diamine (100 mg, 0.729 mmol) and N-ethyl-N-isopropyl-propan-2-amine (255 uL, 1.46 mmol) in 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. Further, 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (39 mg, 0.243 mmol) was added, and the mixture was stirred for an additional 0.5 h. Then, the solvent was removed under a steady stream of nitrogen, MeOH (4 mL) and 1 M NaOH (4 mL) were added, and the reaction mixture was stirred at 45 °C for 4 h and at room temperature for 16 h. Methanol was removed under reduced pressure, the precipitate was filtered, washed with water (10 mL), and purified by flash column chromatography (10 g SiO2 column, 0 - 60% EtOAc in heptane) to afford the title compound as an off-white solid (125 mg). 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.14 (dd, J = 9.1, 3.2 Hz, 1H), 2.86 (s, 6H), 1.46 (s, 1H), 1.22 (s, 6H), 1.15 (s, 6H). LCMS: m / z 262.3 [M+H]+, (ESI+), RT = 2.10 (Method A)

[0224] (Table 9) Using a method similar to that used in Example E201, the following compounds were synthesized. TIFF2025090638000079.tif61170TIFF2025090638000080.tif217170TIFF2025090638000081.tif230170

[0225] Compound E217 TIFF2025090638000082.tif 181282-Methyl-N-(5-phenoxypyrazin-2-yl)propanamide

[0226] Step 1 5-Bromopyrazin-2-amine (300 mg, 1.72 mmol), phenol (178 mg, 1.90 mmol), and cesium carbonate (1.12 g, 3.45 mmol) were suspended in anhydrous 1,4-dioxane (4 mL), and the reaction mixture was degassed with N2 for 5 minutes. N,N-Dimethylglycine hydrochloride (1:1) (24 mg, 0.172 mmol) was added, followed by copper(I) iodide (33 mg, 0.172 mmol), and the reaction was heated to 115 °C in a sealed tube for 2.5 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc and water, and filtered. Next, the organic phase was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 0–70% EtOAc in heptane) to give 5-phenoxypyrazin-2-amine (Intermediate I05) as a pale yellow oil that solidified upon standing (205 mg). 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 1.4 Hz, 1H), 7.41–7.28 (m, 2H), 7.14–7.05 (m, 1H), 7.00–6.93 (m, 2H), 6.22 (s, 2H).

[0227] Step 2 5-Phenoxypyrazin-2-amine (50 mg, 0.267 mmol) was dissolved in DCM (2 mL), 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. Further, N-ethyl-N-isopropyl-propan-2-amine (70 μL, 0.401 mmol) and 2-methylpropanoyl chloride (31 μL, 0.294 mmol) were added, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was washed with saturated NaHCO3, passed through a TELOS phase separator, and concentrated under reduced pressure. The residue was dissolved in MeOH (1 mL) and 1 M aqueous NaOH (1 mL), and stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative HPLC (Method E) to give the title compound as a white solid (57 mg). 1H NMR (250 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.89 (d, J = 1.4 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 7.50 - 7.34 (m, 2H), 7.29 - 7.08 (m, 3H), 2.74 (h, J = 6.9 Hz, 1H), 1.10 (d, J = 6.8 Hz, 6H). LCMS: m / z 258.3 [M+H]+, (ESI+), RT = 2.99 (Method A).

[0228] (Table 10) Using a method similar to that used in Example E217, the following compounds were synthesized. TIFF2025090638000083.tif138170TIFF2025090638000084.tif155170

[0229] Compound 226 TIFF2025090638000085.tif30128N-[5-(2,5-Difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide

[0230] Step 1 5-Bromopyrazine-2-amine (300 mg, 1.72 mmol) and (2,5-difluorophenyl)boronic acid (275 mg, 1.74 mmol) were dissolved in 1,4-dioxane-anhydrous (10 mL) and 2 M Na2CO3 (1.8 mL, 3.60 mmol), and the reaction mixture was degassed with N2 for 5 minutes. Pd(dppf)Cl2 (63 mg, 0.0862 mmol) was added to the reaction, and the reaction was heated to 110 °C for 2.5 hours. It was then cooled to room temperature, diluted with water (20 mL) and EtOAc (20 mL), and filtered through celite. The layers in the filtrate were separated, and the aqueous solution was extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 0-100% EtOAc in heptane) to give 5-(2,5-difluorophenyl)pyrazine-2-amine (Intermediate I06) as a yellow solid (295 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 2.3, 1.6 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.62 (ddd, J = 9.6, 6.1, 3.3 Hz, 1H), 7.33 (ddd, J = 10.8, 9.1, 4.6 Hz, 1H), 7.26-7.08 (m, 1H), 6.78 (s, 2H).

[0231] Step 2 To a stirred solution of 2,2-dimethylcyclopropanecarboxylic acid (43 mg, 0.380 mmol) in ethyl acetate (2.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.19 mL, 1.09 mmol) and T3P (50% in EtOAc) (0.32 mL, 0.543 mmol), and the reaction was stirred for 10 minutes. To this was added 5-(2,5-difluorophenyl)pyrazin-2-amine (75 mg, 0.362 mmol), and the reaction was stirred at 80 °C for 20 hours. It was then cooled to room temperature, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (10 g SiO2 column, 0 - 50% EtOAc in heptane) to give the title compound as an off-white solid (39 mg). 1H NMR (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)

[0232] (Table 11) Using a method similar to that used in Example E226, the following compounds were synthesized. TIFF2025090638000086.tif159170

[0233] Compounds E231 and E232 TIFF2025090638000087.tif31128The unknown single enantiomer of N-[5-(3,5-difluorophenyl)pyrazin-2-yl]-2,2-dimethyl-cyclopropanecarboxamide

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

[0235] Compound E231 (first elution): 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).

[0236] Compound E232 (second elution): 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).

[0237] Compound E233 TIFF2025090638000088.tif271282,2,3,3-tetramethyl-N-(5-pyrrolidin-1-ylpyrazin-2-yl)cyclopropanecarboxamide

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

[0239] Step 2 2,2,3,3-Tetramethylcyclopropanecarbonyl chloride (54 mg, 0.335 mmol) in THF (1 mL) was added dropwise to a stirred solution of 5-pyrrolidin-1-ylpyrazine-2-amine (50 mg, 0.304 mmol) and N-ethyl-N-isopropyl-propan-2-amine (120 μL, 0.670 mmol) in THF (1 mL). The reaction was stirred at room temperature for approximately 20 h. Further, N-ethyl-N-isopropyl-propan-2-amine (58 μL, 0.335 mmol) and 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (20 mg, 0.125 mmol) in THF (0.5 mL) were added and the reaction was stirred for 1 h. The reaction was diluted with water (5 mL) and extracted into EtOAc (3 × 5 mL), the organics were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (method G) to give the title compound (22 mg, 25% yield) as a yellowish-brown solid. 1H NMR (500 MHz, chloroform-d) δ 8.91 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 3.51 - 3.45 (m, 4H), 2.09 - 2.00 (m, 4H), 1.33 (s, 6H), 1.23 (s, 6H), 1.04 (s, 1H). LCMS: m / z 289.2 [M+H]+, (ESI+), RT = 3.45 (method A).

[0240] Compound E234 TIFF2025090638000089.tif181283 - [5-(3,5-Difluorophenoxy)pyrazin-2-yl]-1-isopropyl-1-methyl-urea

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

[0242] (Table 12) Using the precursors synthesized using the same method as in Step 1 for Intermediates I02, I05, I06 and Compound E139, the following compounds were synthesized using the same method as that used for Compound E234. TIFF2025090638000090.tif190170TIFF2025090638000091.tif221170TIFF2025090638000092.tif204170TIFF2025090638000093.tif212170TIFF2025090638000094.tif217170TIFF2025090638000095.tif243170

[0243] Compound E265 TIFF2025090638000096.tif201283-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]-1-ethyl-1-[(2R)-3,3,3-trifluoro-2-hydroxy-propyl]urea

[0244] Step 1 tert-Butyl N-(5-bromopyrazin-2-yl)carbamate (500 mg, 1.70 mmol) and dichloro(1,3-bis(diphenylphosphino)propane)nickel (92 mg, 0.170 mmol) were suspended in anhydrous 1,4-dioxane (4.7 mL), and the reaction mixture was degassed with N2 at room temperature for 5 minutes. Then, 0.5 M bromo-[(3,5-difluorophenyl)methyl]zinc (14 mL, 6.79 mmol) was added slowly, and the reaction was stirred at 60 °C for 2 hours. The reaction mixture was then cooled to room temperature and diluted with EtOAc (25 mL), aqueous NaHCO3 (25 mL), and brine (15 mL). The aqueous layer was separated and extracted with EtOAc (25 mL). The combined organics were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated. The crude material was then purified by normal-phase flash column chromatography (Sfar Duo, 100 g, eluent: EtOAc in heptane, 0 - 60%) to give tert-butyl N-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]carbamate (424 mg, 75% yield) as a white solid. 1H NMR, (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.94 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H), 7.11 - 6.94 (m, 3H), 4.09 (s, 2H), 1.47 (s, 9H).

[0245] Step 2 tert-Butyl N-[5-[(3,5-difluorophenyl)methyl]pyrazin-2-yl]carbamate (424 mg, 1.28 mmol) was treated with 4 M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol) and stirred at room temperature for 3 h. Further, 4 M hydrogen chloride in dioxane (3.5 mL, 14.1 mmol) was added and the mixture was stirred at room temperature for 7 h. It was then concentrated in vacuo and passed through an SCX-2 column (5 g) (flashed with MeOH (2 CV), then 7 N NH3 in MeOH (2.5 CV)) to afford 5-[(3,5-difluorophenyl)methyl]pyrazin-2-amine (264 mg, 88% yield) as 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).

[0246] Step 3 Urea was formed using a method similar to that used for Compound E191 to afford the title compound (36 mg, 34% yield) as 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).

[0247] (Table 13) The following compounds were synthesized using a method similar to that used for Compound E265. TIFF2025090638000097.tif124170

[0248] Compound E269 TIFF2025090638000098.tif211282-[(2,2,3,3-Tetramethylcyclopropanecarbonyl)amino]-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide

[0249] Step 1 Starting from 2-aminopyridine-4-carboxylate methyl (200 mg, 1.31 mmol), 2-[(2,2,3,3-tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid was obtained (260 mg, purity 90%, yield 68%) using the same method as in Compound E199 (Step 2). 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 was not observed.

[0250] Step 2 2-[(2,2,3,3-Tetramethylcyclopropanecarbonyl)amino]pyridine-4-carboxylic acid (50 mg, 0.172 mmol) was dissolved in DMF-anhydrous (1.5 mL), N-ethyl-N-isopropyl-propan-2-amine (90 uL, 0.515 mmol) was added, followed by HATU (98 mg, 0.257 mmol). After stirring for 10 minutes, 2,2,2-trifluoroethanamine (20 uL, 0.257 mmol) was added and the reaction was stirred at room temperature overnight. Then it was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 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).

[0251] Compound E270 TIFF2025090638000099.tif211282,2,3,3-Tetramethyl-N-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]cyclopropanecarboxamide

[0252] To a stirred solution of N-(5-formyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using the same method as E199 (step 2), 100 mg, 0.406 mmol) in DCE (2 mL), pyrrolidine (41 μL, 0.487 mmol) was added, 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 hydrogen carbonate (25 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (hydrophobic filter), and concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (Biotage 11g SNAP-KPNH cartridge, 0 - 25% EtOAc in heptane), followed by further chromatography (C18 silica gel, 12g SNAP Ultra cartridge, eluent: 0.1% formic acid in acetonitrile - 0.1% formic acid in water, 15 - 30%). The crude product was then washed with saturated aqueous sodium hydrogen carbonate (20 mL) and extracted with ethyl acetate (2 × 20 mL). Final purification by flash chromatography (Biotage 11g SNAP-KPNH cartridge, 0 - 20% EtOAc in heptane) gave the title product as a colorless solid (15 mg, yield 12%). 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).

[0253] Compound E271 TIFF2025090638000100.tif271282,2,3,3-tetramethyl-N-[5-(1,2,4-oxadiazol-3-yl)-2-pyridyl]cyclopropanecarboxamide

[0254] Step 1 To a solution of N-(5-cyano-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using the same method as E199 in Step 2, 247 mg, 0.934 mmol) in ethanol (5.8974 mL), hydroxylamine (50%, 0.50 mL, 0.934 mmol) was added. 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 isolated by filtration to give N-[5-(N-hydroxycarbamoylamido)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (176 mg, yield 67%) as 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).

[0255] Step 2 To a stirred solution of N-[5-(N-hydroxycarbamoylamido)-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (100%, 50 mg, 0.181 mmol) in trimethoxymethane (3.0 mL, 0.181 mmol), a catalytic amount of 2,2,2-trifluoroacetic acid (0.0013 mL) was added. The reaction was stirred at room temperature for 5 minutes and then at 60 °C for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method G) to give the title compound (39 mg, yield 75%) as 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).

[0256] Compound E272 TIFF2025090638000101.tif331282,2,3,3 - Tetramethyl - N - [5 - (5 - methyl - 1,2,4 - oxadiazol - 3 - yl) - 2 - pyridyl] cyclopropanecarboxamide

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

[0258] Compound E273 TIFF2025090638000102.tif281282,2,3,3 - Tetramethyl - N - (5 - oxazol - 5 - yl - 2 - pyridyl) cyclopropanecarboxamide

[0259] Step 1 To a mixture of 1 - (isocyanomethylsulfonyl) - 4 - methyl - benzene (320 mg, 1.64 mmol) and potassium carbonate (226 mg, 1.64 mmol) in methanol (4.5 mL), 6 - aminopyridine - 3 - carbaldehyde (200 mg, 1.64 mmol) was added. After refluxing the reaction mixture for 2.5 h, it was cooled and concentrated under reduced pressure and partitioned between MTBE (35 ml) and water (25 ml). After separation of the layers, the aqueous layer was extracted twice with EtOAc (2 × 30 mL). The combined organics were dried (MgSO4), filtered, and concentrated to give 5 - oxazol - 5 - yl pyridin - 2 - amine (199 mg, purity 35%) as a yellow oil and used directly in the next step without further purification. 1H NMR, (500 MHz, DMSO - d6) δ 8.31 (s, 1H), 8.30 - 8.27 (m, 1H), 7.46 - 7.44 (m, 1H), 7.40 (s, 1H), 6.52 (dd, J = 8.7, 0.7 Hz, 1H), 6.31 (s, 2H).

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

[0261] Compound E274 TIFF2025090638000103.tif27128N-(5-Isooxazol-5-yl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

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

[0263] Step 2 N-[5-[(E)-3-(Dimethylamino)prop-2-enoyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (85%, 109 mg, 0.294 mmol) and hydroxylamine hydrochloride (1:1) (24 mg, 0.352 mmol) were dissolved in ethanol (2 mL), and the reaction was heated to 80 °C for 1 h with stirring. After this time, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Method G) to afford the title compound (14 mg, yield 16%) as 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).

[0264] Compound E275 TIFF2025090638000104.tif28128N-(5-Isooxazol-3-yl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide

[0265] Step 1 N-(5-Formyl-2-pyridyl)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (synthesized using the same method as E199 (Step 2), 90 mg, 0.345 mmol) and hydroxylamine hydrochloride (1:1) (36 mg, 0.518 mmol) were dissolved in water (9 mL) and methanol (4 mL). Sodium carbonate (66 mg, 0.621 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 hours. Further portions 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 solution was further extracted with EtOAc (2×20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated under reduced pressure to give N-[5-[hydroxyiminomethyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92 mg, 0.316 mmol, 92% yield) as a colorless solid. 1H NMR (500 MHz, chloroform-d) δ 8.31 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.85 (dd, J = 8.7, 2.2 Hz, 1H), 7.75 (s, 1H), 1.25 (s, 6H), 1.14 (s, 6H), 0.96 (s, 1H).

[0266] Step 2 N-[5-[Hydroxyiminomethyl]-2-pyridyl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide (92 mg, 0.351 mmol), calcium ethyne-dide (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 was stirred at room temperature overnight. The reaction mixture was filtered and the solid was washed with chloroform (2 x 10 ml). The aqueous solution was then separated and the organics were dried (hydrophobic frit). The organics were concentrated under reduced pressure and purified by preparative HPLC (method H) to give the title compound (8.4 mg, 7.5% yield) as an off-white solid. 1H NMR (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).

[0267] Compound E276 TIFF2025090638000105.tif18128N-[5-[(3-Fluorophenyl)methyl]-2-pyridyl]-2-methyl-propanamide

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

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

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

[0271] Step 4 Starting from 5-[(3-fluorophenyl)methyl]pyridin-2-amine (50 mg, 0.242 mmol), using a similar method to 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).

[0272] Compound E277 TIFF2025090638000106.tif19128(2R)-N-[5-(3,4-Difluorophenoxy)-2-pyridyl]-1-sulfamoyl-pyrrolidine-2-carboxamide

[0273] Step 1 To tert-butyl (2R)-2-[[5-(3,4-difluorophenoxy)-2-pyridyl]carbamoyl]pyrrolidine-1-carboxylate (synthesized using the same method as in E001 (Step 3), 90% purity, 446 mg, 0.957 mmol), 4 M hydrogen chloride in dioxane (2.9 mL, 11.5 mmol) was added and stirred at room temperature for 1 hour. Then, this was concentrated in vacuo, washed with MeOH, and purified by an SCX-2 cartridge eluting with 7N NH3 / MeOH to give (2R)-N-[5-(3,4-difluorophenoxy)-2-pyridyl]pyrrolidine-2-carboxamide (285 mg, 90% purity, 84% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.16 (dd, J = 6.0, 2.6 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).

[0274] Step 2 (2R)-N-[5-(3,4-Difluorophenoxy)-2-pyridyl]pyrrolidine-2-carboxamide (90%, 47 mg, 0.132 mmol) and diamide sulfate (22 mg, 0.225 mmol) were stirred in anhydrous 1,4-dioxane (0.9 mL) at 95 °C 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) as an off-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)

[0275] Compound E278 TIFF2025090638000107.tif19128(2R)-N-[5-(3,4-Difluorophenoxy)-2-pyridyl]-1-methyl-pyrrolidine-2-carboxamide

[0276] Using a method similar to that used for Compound E001 (Step 3), it was synthesized from Intermediate I01 to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.17 (s, 1H), 8.17 - 8.14 (m, 1H), 7.60 (dd, J = 8.9, 3.0 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)

[0277] (Table 14) Using a method similar to that used for Compound E277, the following compound was synthesized. TIFF2025090638000108.tif231170

[0278] Compound E284 TIFF2025090638000109.tif241281-[5-(3,4-difluorophenoxy)-2-pyridyl]-4,4-dimethyl-pyrrolidin-2-one

[0279] Step 1 A mixture of 6-chloropyridin-3-ol (500 mg, 3.86 mmol), (3,4-difluorophenyl)boronic acid (0.91 g, 5.79 mmol), copper(II) diacetate (729 mg, 4.01 mmol), triethylamine (2.7 mL, 19.3 mmol), and powdered activated 4 Å molecular sieves in DCM-anhydrous (38 mL) was stirred under air for 23 h. Further, copper(II) diacetate (145 mg, 0.2 equiv) and DCM-anhydrous (10 mL) were added and the mixture was stirred for 17 h. The suspension was diluted with dichloromethane, filtered twice through celite, washed with water (40 mL) and saturated aqueous Rochelle salt solution (50 mL). The organic matter 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 in heptane) to afford 2-chloro-5-(3,4-difluorophenoxy)pyridine (426 mg, 45% yield) as a light brown oil. 1H NMR, (500 MHz, chloroform-d) δ 8.15 (dd, J = 2.9, 0.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.22 - 7.12 (m, 1H), 6.88 (ddd, J = 10.8, 6.5, 2.9 Hz, 1H), 6.75 (dtd, J = 9.0, 3.2, 1.9 Hz, 1H).

[0280] Step 2 A solution of potassium carbonate (90 mg, 0.649 mmol) and 2-chloro-5-(3,4-difluorophenoxy)pyridine (80 mg, 0.324 mmol) in toluene anhydrous (2.5 mL) was degassed at room temperature 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 for 16 hours with stirring. Then it was cooled to room temperature, the reaction mixture was diluted with water (15 mL), extracted with EtOAc (20 mL), then the aqueous layer was extracted with EtOAc (3 × 20 mL), the organic extracts were combined, dried over a hydrophobic filter, and evaporated to dryness. The crude compound was purified using flash column chromatography (Biotage Sfar Duo 10 g, 0 - 80% DCM in heptane, followed by 0 - 40% MeOH in EtOAc) to give the title compound (20 mg, 19% yield) as 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)

[0281] Compound E285 TIFF2025090638000110.tif181281 - [5-(3,4-difluorophenoxy)-2-pyridyl]-3,3-dimethyl-pyrrolidin-2-one

[0282] It was 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).

[0283] Compound E286 TIFF2025090638000111.tif201285-(3,4-difluorophenoxy)-2-[[ethyl-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]sulfamoyl]amino]pyridine

[0284] Step 1 To a solution of ice-cold DCM (3 mL), sulfuryl isocyanatidyl chloride (58 μL, 0.662 mmol) was added. Then, 2-chloroethanol (44 μL, 0.662 mmol) was added via syringe over 1 minute while maintaining an 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 over 5 minutes, and then stirred at 0 °C for an additional 16 hours and brought to room temperature 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) as 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).

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

[0286] Compound E287 TIFF2025090638000112.tif18128N-[5-(3-Fluorophenoxy)-3-hydroxy-2-pyridyl]-2-methyl-propanamide

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

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

[0289] Step 3 3-Benzyloxy-5-(3-fluorophenoxy)-2-nitro-pyridine (112.0 mg, 0.33 mmol) was dissolved in methanol (20 mL) and hydrogenated using an H-cube (room temperature, 3 h, 2 mL / min, recirculation mode, 10% Pd / C cartridge). When complete, the material was dried in vacuo and mixed with N-ethyl-N-isopropyl-propan-2-amine (0.11 mL, 0.658 mmol) and isobutyl anhydride (52 mg, 0.329 mmol) in THF (4 mL) and stirred in a sealed vial at 80 °C for 18 h. Upon completion, the solvent was removed in vacuo and the crude material was purified using preparative HPLC (method E) to afford the title compound (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).

[0290] Compound E288 TIFF2025090638000113.tif22128N-[6-[(5-Fluoro-3-pyridyl)oxy]pyridazin-3-yl]-2,2,3,3-tetramethyl-cyclopropanecarboxamide

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

[0292] Compound E289 TIFF2025090638000114.tif201283 - [6 - [(3,4 - difluorophenoxy)pyrimidin - 4 - yl] - 1 - ethyl - 1 - [(2R) - 3,3,3 - trifluoro - 2 - hydroxy - propyl]urea

[0293] Step 1 6 - Chloropyrimidin - 4 - amine (250 mg, 1.93 mmol), cesium carbonate (1.26 g, 3.86 mmol), and 3,4 - difluorophenol (251 mg, 1.93 mmol) were mixed in DMSO (5 mL), purged with nitrogen, and stirred in a sealed tube at 50 °C for 3 h, then at 80 °C for 14 h, and then 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 × 30 mL). The combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (25 g SiO2 column, 25 - 100% EtOAc in heptane) to give 6 - (3,4 - difluorophenoxy)pyrimidin - 4 - amine (180 mg, 70% purity) as an off - white solid. 1H NMR (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).

[0294] Step 2 Starting from 6-(3,4-difluorophenoxy)pyrimidin-4-amine (70%, 85 mg, 0.267 mmol), using the same method as for 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).

[0295] Compound E290 TIFF2025090638000115.tif 201281-Ethyl-3-[6-(2-fluorophenoxy)pyrimidin-4-yl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0296] Synthesized using the same method as that 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).

[0297] Compound E291 TIFF2025090638000116.tif 201281-Ethyl-3-[6-(3-fluorophenoxy)pyrimidin-4-yl]-1-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]urea

[0298] It was synthesized using a method similar to that 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).

[0299] HPLC method Analytical LCMS Method A Analytical uHPLC-MS was performed using a Waters Acquity uPLC system with a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40 °C) and a gradient of 5 - 100% B (A = 0.1% formic acid in H2O, B = 0.1% formic acid in ACN) for 5.3 minutes, then 100% B for 0.5 minute. Then, a second gradient of 100 - 5% B was applied for 0.02 minute and held for 1.18 minutes with a flow rate of 0.6 mL / min and an injection volume of 1 μL. The Waters Acquity PDA detector spectral range: 200 - 400 nm was used at 215 nm to record the UV spectrum, and the Waters Acquity ELS detector (when applicable) was used to collect and report the ELS data. A mass spectrum was obtained using a Waters SQD (MSQ1) or Waters Acquity QDA (MSQ2). The data was integrated and reported using Waters MassLynx and OpenLynx software.

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

[0301] Method C Analysis was performed using a Kinetex Core shell C18 column (2.1 mm × 50 mm, 5 μm; temperature: 40 °C) and a Shimadzu LCMS system with a gradient of 5 to 100% B (A = 0.1% formic acid in H2O, B = 0.1% formic acid in ACN) for 1.2 minutes, followed by 100% B for 0.1 minutes. Then, a second gradient of 100 to 5% B was applied for 0.01 minutes at an injection volume of 3 μL and a flow rate of 1.2 mL / min. The UV spectrum was recorded using an SPD-M20A photodiode array detector with a spectral range of 200 - 400 nm at 215 nm. The mass spectrum was obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0302] Method D Analysis uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH C18 column (2.1 mm × 30 mm, 1.7 μm column; temperature: 40 °C) and a gradient of 5–100% B (A: 2 mM ammonium bicarbonate, buffered to pH 10, B: ACN) for 0.75 min, then 100% B for 0.1 min. Then, a second gradient of 100–5% B was applied for 0.05 min and held for 0.1 min at an injection volume of 1 μL and a flow rate of 1 mL / min. The UV spectrum was recorded at 215 nm in the Waters Acquity PDA spectral range of 200–400 nm. A Waters Quattro Premier XE was used to obtain the mass spectrum. Waters MassLynx and OpenLynx software were used to integrate and report the data.

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

[0304] Method E: Acidic initial method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μm; temperature: room temperature) and a gradient of 10–95% B (A = 0.1% formic acid in H2O, B = 0.1% formic acid in ACN) for 14.44 min, then 95% B for 2.11 min. Then, a second gradient of 95–10% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.2 min. A Gilson detector was used at 215 nm to record the UV spectrum.

[0305] Method F: Basic initial method Purification was carried out on a Gilson LC system using a Waters X-Bridge C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature), and a gradient of 10 - 95% B (A = 0.2% ammonium hydroxide in H2O, B = 0.2% ammonium hydroxide in ACN) for 14.44 minutes, followed by 95% B for 2.11 minutes. Then, a second gradient of 95 - 10% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.2 minutes. The Gilson detector was used at 215 nm to record the UV spectrum.

[0306] Method G: Standard acidic method Purification was carried out on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature), and a gradient of 30 - 95% B (A = 0.1% formic acid in water, B = 0.1% formic acid in ACN) for 11.00 minutes, followed by 95% B for 2.10 minutes. Then, a second gradient of 95 - 30% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.2 minutes. The Gilson detector was used at 215 nm to record the UV spectrum.

[0307] Method H: Standard basic method Purification was carried out on a Gilson LC system using a Waters X-Bridge C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature), and a gradient of 30 - 95% B (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in ACN) for 11.00 minutes, followed by 95% B for 2.10 minutes. Then, a second gradient of 95 - 30% B, an injection volume of 1500 μL, and a flow rate of 40 mL / min were applied for 0.21 minutes. The Gilson detector was used at 215 nm to record the UV spectrum.

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

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

[0310] (Table 15) TIFF2025090638000117.tif184139TIFF2025090638000118.tif206139TIFF2025090638000119.tif223139TIFF2025090638000120.tif190139TIFF2025090638000121.tif192139TIFF2025090638000122.tif202139TIFF2025090638000123.tif219139TIFF2025090638000124.tif209139TIFF2025090638000125.tif195139TIFF2025090638000126.tif217139TIFF2025090638000127.tif211139TIFF2025090638000128.tif189139TIFF2025090638000129.tif167139TIFF2025090638000130.tif207139TIFF2025090638000131.tif210139TIFF2025090638000132.tif193139TIFF2025090638000133.tif198139TIFF2025090638000134.tif218139TIFF2025090638000135.tif189139TIFF2025090638000136.tif203139TIFF2025090638000137.tif207139TIFF2025090638000138.tif210139TIFF2025090638000139.tif213139TIFF2025090638000140.tif213139TIFF2025090638000141.tif188139TIFF2025090638000142.tif205139TIFF2025090638000143.tif200139TIFF2025090638000144.tif203139TIFF2025090638000145.tif221139TIFF2025090638000146.tif214139TIFF2025090638000147.tif214139TIFF2025090638000148.tif192139TIFF2025090638000149.tif194139TIFF2025090638000150.tif192139TIFF2025090638000151.tif189139TIFF2025090638000152.tif208139TIFF2025090638000153.tif199139TIFF2025090638000154.tif222139TIFF2025090638000155.tif187139TIFF2025090638000156.tif205139TIFF2025090638000157.tif177139TIFF2025090638000158.tif220139TIFF2025090638000159.tif194139TIFF2025090638000160.tif225139TIFF2025090638000161.tif187139TIFF2025090638000162.tif220139TIFF2025090638000163.tif225139TIFF2025090638000164.tif168139TIFF2025090638000165.tif194139TIFF2025090638000166.tif213139TIFF2025090638000167.tif190139TIFF2025090638000168.tif191139TIFF2025090638000169.tif193139TIFF2025090638000170.tif190139TIFF2025090638000171.tif198139TIFF2025090638000172.tif192139TIFF2025090638000173.tif170139TIFF2025090638000174.tif209139TIFF2025090638000175.tif195139TIFF2025090638000176.tif193139TIFF2025090638000177.tif182139.

Claims

1. A compound having the following formula I: During the ceremony, Q, and Z is -C(=O)-(CR ２０ R ２１ ) ｎ Or -S(=O) ２ - and R １ is H or C １－３ is alkyl, n is 0 or 1; Each R ２０ and R ２１ are independently H or C １－３ is alkyl, G １ , G ２ , G ３ , G ４ and G ５ are each independently N or -CL １ -M １ where G １ , G ２ , G ３ , G ４ and G ５ at least one of is N; Each L １ are independently a bond, O, —C(═O), —C(═O)—NH—, or —CH ２ - -O-(CH ２ ) ｗ - (wherein w is 1, 2 or 3), or -N(R ９０ )-, or any two L on adjacent carbon atoms １ The -M groups taken together represent a compound of the formula -O-(CH ２ ) ｖ -O- (where v is 1 or 2) group, Each R ９０ are independently H or C １－３ is alkyl, Each M １ are independently H, —OH, halogen, cyano, C ６－１０ aryl; 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S; C １－６ Alkyl; C ３－６ Cycloalkyl: -NR ５０ R ５１ 4-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S, wherein each C ６－１０ Aryl, 5-10 membered heteroaryl, C １－６ Alkyl, C ３－６ Cycloalkyl and 4- to 10-membered heterocycloalkyl are each independently selected from halogen, cyano, —OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and -C(=O)-N(R ９１ ) (R ９２ and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: Each R ９１ and R ９２ independently, H and C １－３ is selected from the group consisting of alkyl, Each R ５０ and R ５１ However, independently, H, C １－３ Alkyl, and C ６－１０ aryl; A is -L ２ -M ２ and L ２ is a bond and -(CR ６０ R ６１ ) ｋ - selected from R ６０ and R ６１ each of which is optionally substituted with H, or 1, 2, or 3 substituents independently selected from —OH and halogen; １－３ is alkyl, k is 1, 2, or 3; M ２ But, C １－６ Alkyl; C ３－６ Cycloalkyl; C ５－１０ spiroalkyl; 4-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; -N(R ８１ ) (R ８２ ); and C ６－１０ aryl, where each C １－６ Alkyl, C ３－６ Cycloalkyl, C ６－１０ spiroalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, and C ６－１０ Each aryl is selected from 1, 2, 3, or 4 independently selected R ２００ may be substituted with a group, Each R ２００ But independently, C １－６ Alkyl; C １－６ Hydroxyalkyl; C ３－６ Cycloalkyl; 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; C １－６ Mono-, di-, or trihaloalkyl; halogen; cyano; -OH; C １－６ Alkoxy; S(=O) ２ N.R. ５０２ R ５０３ And C ６－１０ aryl; Each R ８１ and R ８２ However, independently, H, C １－６ Alkyl and C ３－６ cycloalkyl, wherein said C １－６ Alkyl and C ３－６ The cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from -OH and halogen; R ５００ and R ５０１ is independently absent or C １－６ is alkyl, R ５０２ and R ５０３ are independently H or C １－６ is alkyl, A compound, or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

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

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

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

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

15. L １ But -N(R ９０ 10. The compound according to claim 1, wherein

16. R １ A compound according to any one of the preceding claims, wherein is H.

17. 2. The compound of any preceding claim 1, wherein n is 0.

18. The compound according to any one of claims 1 to 15, wherein n is 1.

19. M １ But, C ６ Aryl; C having 1 or 2 ring heteroatoms independently selected from N and O ６ Heteroaryl; C having 1 or 2 ring heteroatoms independently selected from N and O ５ Or C ６ 4. The compound of any one of the preceding claims, selected from: heterocycloalkyl; and 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, each of the foregoing being optionally substituted.

20. M １ 4. A compound according to any one of the preceding claims, wherein is phenyl, pyridyl, pyrrolidine, pyridazine, tetrahydrofuran, tetrahydropyran, or dihydroynediol, each of which is optionally substituted.

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

22. M １ 4. A compound according to any one of the preceding claims, wherein is optionally substituted phenyl.

23. The compound of any one of claims 1 to 21, wherein the phenyl is substituted at the 4-position.

24. The compound of any one of claims 1 to 21, wherein the phenyl is substituted at the 3 and 4 positions.

25. The compound of any one of claims 1 to 21, wherein the phenyl is substituted at the 3 and 5 positions.

26. M １ 4. A compound according to any one of the preceding claims, wherein is optionally substituted pyridyl.

27. M １ A compound according to any one of the preceding claims, wherein is optionally substituted pyridyl-4-yl.

28. M １ A compound according to any one of the preceding claims, wherein is optionally substituted pyridyl-3-yl.

29. 2. A compound according to any one of the preceding claims, wherein the pyridyl is substituted at the carbon that is ortho (i.e. adjacent) to the nitrogen of the pyridyl.

30. 2. A compound according to any one of the preceding claims, wherein the pyridyl is substituted at the carbon that is meta to the nitrogen of the pyridyl.

31. 30. The compound of any one of claims 1 to 29, wherein the pyridyl is substituted at the carbon that is meta to the nitrogen of the pyridyl.

32. M １ 4. A compound according to any one of the preceding claims, wherein is optionally substituted heterocycloalkyl.

33. M １ 4. A compound according to any one of the preceding claims, wherein is optionally substituted pyrrolidinyl.

34. M １ The compound according to any one of claims 1 to 18, wherein is optionally substituted pyrrolidin-1-yl.

35. M １ The compound according to any one of claims 1 to 18, wherein is optionally substituted tetrahydropyranyl.

36. M １ The compound according to any one of claims 1 to 18, wherein is optionally substituted tetrahydropyran-4-yl.

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

38. M １ is optionally substituted C １－６ The compound according to any one of claims 1 to 18, which is alkyl.

39. M １ But -NR ５０ R ５１ The compound according to any one of claims 1 to 18,

40. L ２ A compound according to any one of the preceding claims, wherein is a bond.

41. L ２ But - (CR ６０ R ６１ ) ｋ The compound according to any one of claims 1 to 39, wherein

42. M ２ is optionally substituted C １－６ 2. A compound according to any one of the preceding claims, which is alkyl.

43. M ２ 4. A compound according to any one of the preceding claims, wherein is optionally substituted isopropyl.

44. M ２ is optionally substituted C ３－６ The compound of any one of claims 1 to 41, which is cycloalkyl.

45. M ２ The compound of any one of claims 1 to 41, wherein is cyclopropyl or cyclobutyl, each of which is optionally substituted with one to four methyl groups.

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

47. M ２ A compound according to any one of claims 1 to 41, wherein is cyclopropyl optionally substituted with one to four methyl groups, halogen or trihalomethyl.

48. M ２ The compound of any one of claims 1 to 41, wherein is heterocycloalkyl optionally substituted with one or two groups independently selected from methyl and hydroxy.

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

50. M ２ But -N(R ８１ ) (R ８２ ) a compound according to any one of the preceding claims.

51. R ８１ and R ８２ But independently, C １－３ Alkyl and C ３－４ cycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from -OH and halogen.

52. 10. A compound according to any one of the preceding claims selected from the compounds of Table 1 herein, or a stereoisomer, solvate, tautomer, or pharma- ceutically acceptable salt thereof.

53. A composition comprising a dermatologically or orally acceptable excipient and a compound according to any one of the preceding claims.

54. A method for treating an inflammatory disorder, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of claim 1 and a dermatologically or orally acceptable excipient.

55. 55. The method of claim 54, wherein the composition is in the form of a cream, gel, spray, ointment, or oral unit dosage form.

56. 55. The method of claim 54, wherein the MrgprX2 antagonist is present at a concentration of about 0.001% to about 10% by weight, based on the total weight of the composition.

57. 55. The method of claim 54, wherein the MrgprX2 antagonist is present at a concentration of about 0.1% to about 5% by weight, based on the total weight of the composition.

58. 55. The method of claim 54, wherein the composition further comprises a skin absorption enhancer.

59. 55. The method of claim 54, wherein the composition further comprises a skin absorption enhancer comprising one or more of mannitol, sulfoxides (e.g., dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms), and terpenes.

60. 60. The method of any one of claims 54 to 59, wherein the composition is applied to the patient's skin once daily.

61. 60. The method of any one of claims 54 to 59, wherein the composition is applied to the patient's skin twice daily.

62. 60. The method of any one of claims 54 to 59, wherein the composition is applied to the patient's skin three times a day.

63. 63. The method of any one of claims 54 to 62, wherein the composition is administered to a patient suffering from an inflammatory disorder.

64. 64. The method of any one of claims 54 to 63, wherein the inflammatory disorder is a skin disorder.

65. The method according to any one of claims 54 to 64, wherein the skin is human skin.

66. 66. The method of any one of claims 63 to 65, wherein the inflammatory disorder activates MrgprX2 or is a result of activation of MrgprX2.

67. 67. The method of any one of claims 63 to 66, wherein the inflammatory disorder is atopic dermatitis (e.g. Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudoallergic responses caused by small molecules, e.g. anaphylactoid drug responses, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch caused by a systemic disease, or adverse drug response.

68. 68. The method of any one of claims 63 to 67, wherein the inflammatory disorder is atopic dermatitis (e.g. Asian atopic dermatitis, European atopic dermatitis).

69. The method of any one of claims 54 to 68, wherein the subject is a human.

70. 69. The method according to any one of claims 54 to 68, wherein the mammalian skin is human skin.

71. 10. The method of any one of the preceding claims, wherein the composition is for oral administration.

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