Mrgprx2 modulators for use in treating mrgprx2 dependent conditions in subjects with low ige

Abstract

The invention relates to methods of treating Mas-related G-protein coupled receptor X2 (MRGPRX2) dependent conditions in subjects with low blood serum IgE levels.

Description

1MRGPRX2 MODULATORS FOR USE IN TREATING MRGPRX2 DEPENDENT CONDITIONS IN SUBJECTS WITH LOW IGEBACKGROUNDTechnical Field

[0001] The invention generally relates to methods of treating Mas-related G-protein coupled receptor X2 (MRGPRX2) dependent conditions in subjects with low blood serum IgE levels.Description of the Related Art

[0002] Mas-related G-protein receptors (MRGPRs) are a group of orphan receptors with limited expression in very specialized tissues. Very little is known about the function of most of these receptors. In humans, there are eight members in the MRGPR family of receptors. Of these, MRGPRX2 is a receptor that is predominantly expressed on mast cells.

[0003] MRGPRX2 mediates disorders including pseudo-allergic drug reactions, chronic itch (e.g., pruritus), inflammation and autoimmune disorders, pain disorders, skin disorders, wound healing, visceral inflammatory diseases, and lung inflammation / COPD. Mast cells are innate immune cells that primarily reside at sites exposed to the external environment, such as the skin, oral / gastrointestinal mucosa and respiratory tract. Mast cells express numerous receptors that respond to both internal and external environmental stimuli. Upon activation, classically by allergens via immunoglobulin E (IgE), mast cells release pre-formed mediators from granules (e.g., histamine, proteases, and heparin) and newly synthesized mediators (e.g., thromboxane, prostaglandin D2, leukotriene C4, multiple inflammatory cytokines and chemokines such as tumor necrosis factor alpha, eosinophil chemotactic factor, and platelet-activating factor) that elicit allergic and inflammatory responses. Histamine dilates post-capillary venules, activates the endothelium, and increases blood vessel permeability. This causes local edema, warmth, redness, and other inflammatory mediators produce chemotaxis of other inflammatory cells to the site of release resulting in more chronic inflammatory conditions. Histamine also contributes to neuronal sensitization that leads to pain or itch.

[0004] MRGPRX2 mediates IgE independent activation of mast cells. MRGPRX2 is a receptor activated by (or sensitive to activation by) various ligands, including basic secretagogues (small cationic molecules), neuropeptides, inflammatory peptides and antimicrobial peptides and2 certain drugs (e.g., cationic peptidergic drugs), , and thus are important for non-IgE mediated pseudo-allergic reactions, inflammation, pain, and itch conditions. Mast cells may also contribute to the progression of autoimmune disorders by promoting chronic inflammation in the local tissue microenvironment. Thus, modulating MRGPRX2 allows for treatment of, for example, autoimmune diseases, pseudo-allergic drug reactions, pain, itch, and inflammatory disorders such as inflammatory bowel disease, urticaria, atopic dermatitis, interstitial cystitis, sinusitis, asthma, rosacea, and endometriosis.

[0005] While significant advances have been made relating to modulating MRGPRX2 for treatment of a variety of conditions and diseases, particularly in the context small molecule modulators of MRGPRX2, there remains a need for further advances and improvements in this field.BRIEF SUMMARY

[0006] In one embodiment is provided a method of treating an MRGPRX2 dependent condition in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of a small molecule MRGPRX2 modulator when the patient has been found to have a blood serum IgE level at or below an IgE reference level.

[0007] In one embodiment, the IgE reference level is about 150 U / mL. In another embodiment, the IgE reference level is about 100 U / mL. In another embodiment, the IgE reference level is about 100 U / mL. In another embodiment, the IgE reference level is about 40 U / mLBRIEF DESCRIPTION OF THE DRAWINGS

[0008] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0009] Figure 1 shows the MRGPRX2 IC50 inhibition curve for compound l-X-30 in a mast cell P-hexosaminidase release assay, with Corti statin- 14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P-hexosaminidase release is shown to be inhibited by compound l-X-30 modulation of MRGPRX2. The average IC50 of compound l-X-30 against MRGPRX2 was calculated to be 4.2± 0.9 nM.

[0010] Figure 1 also shows the IgE ICso inhibition curve for compound l-X-30 in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing3 biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release. Figure 1 shows that compound l-X-30 does not inhibit IgE degranulation at a concentration less than at least 30 pM.

[0011] Figure 2 shows the MRGPRX2 ICso inhibition curve for compound l-X-32 in a mast cell P-hexosaminidase release assay, with Corti statin- 14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P-hexosaminidase release is shown to be inhibited by compound l-X-32 modulation of MRGPRX2. The average ICso of compound l-X-32 against MRGPRX2 was calculated to be 3.2± 1.3 nM.

[0012] Figure 2 also shows the IgE ICso inhibition curve for compound l-X-32 in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release. Figure 2 shows that compound l-X-32 does not inhibit IgE degranulation at a concentration less than at least about 30 pM.

[0013] Figure 3 shows the MRGPRX2 ICso inhibition curve for compound 5-10-1B in a mast cell P-hexosaminidase release assay, with Corti statin- 14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P-hexosaminidase release is shown to be inhibited by compound 5-10-1B modulation of MRGPRX2. The average ICso of compound 5-10-1B against MRGPRX2 was calculated to be 3.3± 1.3 nM.

[0014] Figure 3 also shows the IgE ICso inhibition curve for compound 5-10-1B in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release. Figure 3 shows that compound 5-10-1B does not inhibit IgE degranulation at a concentration less than at least 30 pM.

[0015] Figure 4 shows the MRGPRX2 ICso inhibition curve for compound 8-211 in a mast cell P-hexosaminidase release assay, with Corti statin- 14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P- hexosaminidase release is shown to be inhibited by compound 8-211 modulation of MRGPRX2 The average ICso of compound 8-211 against MRGPRX2 was calculated to be 183 ± 80 nM.

[0016] Figure 4 also shows the IgE ICso inhibition curve for compound 8-211 in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release.4Figure 4 shows that compound 8-211 does not inhibit IgE degranulation at a concentration less than at least 30 pM.

[0017] Figure 5 shows the MRGPRX2 ICso inhibition curve for compound 8-224 in a mast cell P-hexoaminidase release assay, with Cortistatin-14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P- hexosaminidase release is shown to be inhibited by compound 8-224 modulation of MRGPRX2 The average ICso of compound 8-224 against MRGPRX2 was calculated to be 145 ± 22 nM.

[0018] Figure 5 also shows the IgE ICso inhibition curve for compound 8-224 in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release. Figure 5 shows that compound 8-224 does not inhibit IgE degranulation at a concentration less than at least 30 pM.

[0019] Figure 6 shows the MRGPRX2 ICso inhibition curve for compound 10-129 in a mast cell P-hexosaminidase release assay, with Cortistatin-14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P-hexosaminidase release is shown to be inhibited by compound 10-129 modulation of MRGPRX2. The ICso of compound 10-129 against MRGPRX2 was calculated to be 3.8 ± 0.8 nM.

[0020] Figure 6 also shows the IgE ICso inhibition curve for compound 10-129 in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release Figure 6 shows that compound 10-129 does not inhibit IgE degranulation at a concentration less than at least 30 pM.

[0021] Figure 7 shows the MRGPRX2 ICso inhibition curve for compound 14-37 in a mast cell P-hexosaminidase release assay, with Cortistatin-14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P- hexosaminidase release is shown to be inhibited by compound 14-37 modulation of MRGPRX2 The ICso of compound 14-37 against MRGPRX2 was calculated to be 520 nM.

[0022] Figure 7 also shows the IgE ICso inhibition curve for compound 14-37in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release. Figure 7 shows that compound 14-37 does not inhibit IgE degranulation at a concentration less than at least 30 pM.5

[0023] Figure 8 shows the MRGPRX2 ICso inhibition curve for compound 15-16 in a mast cell P-hexosaminidase release assay, with Corti statin- 14 as the degranulation inducing agonist of MRGPRX2. Percent degranulation of the mast cells is measured by P-hexosaminidase release. P- hexosaminidase release is shown to be inhibited by compound 15-16 modulation of MRGPRX2 The average ICso of compound 15-16 against MRGPRX2 was calculated to be 2 ± 0.8 nM.

[0024] Figure 8 also shows the IgE ICso inhibition curve for compound 15-16 in a mast cell P-hexosaminidase release assay, with streptavidin stimulating the degranulation inducing biotinylated-IgE. Percent degranulation of the mast cells is measured by P-hexosaminidase release. Figure 8 shows that compound 15-16 does not inhibit IgE degranulation at a concentration less than at least 30 LIM.

[0025] Figure 9 shows the study design for a Phase IB open-label study in approximately30 participants with chronic inducible urticaria (CIndU) to evaluate the safety, tolerability, and pharmacodynamics (PD) of 150 mg Compound l-X-30 administered orally (PO), once daily (QD) over 4 weeks.

[0026] Figure 10 shows the critical friction threshold (CFT) over time for patients with symptomatic dermograhism (SDerm) following treatment with Compound l-X-30.

[0027] Figure 11 shows the critical temperature threshold (CTT) over time for patients with cold urticaria (ColdU) following treatment with Compound l-X-30.

[0028] Figure 12 shows critical friction threshold (CFT) over time by subgroup with baseline total IgE <100 kU / L and with baseline total IgE >100 kU / L.

[0029] Figure 13 shows individual CFT responses (rather than the mean shown in Figure 12) and for two essential timepoints: before (baseline) and after treatment (week 4).

[0030] Figure 14 shows critical temperature threshold (CTT) over time by subgroup with baseline total IgE <100 kU / L and with baseline total IgE >100 kU / L.

[0031] Figure 15 shows individual CTT responses (rather than the mean shown in Figure 14) and for two essential timepoints: before (baseline) and after treatment (week 4).DETAILED DESCRIPTION

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and is not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the6 specification, the singular forms "a, I"I I "Ian" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means I "Iand / or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0033] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.

[0034] Reference in the specification to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.

[0035] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0036] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about lOOpL" means "about lOOpL" and also "lOOpL." In some embodiments, about means within 5% of the value. Hence, "about 100 pL" means 95-105 pL. In some embodiments, about means within 4% of the value. In some embodiments, about means within 3% of the value. In some embodiments, about means within2% of the value. In some embodiments, about means within 1% of the value. Generally, the term "about" includes an amount that would be expected to be within experimental error.Method of Treatment

[0037] In one embodiment, a method is provided for treating an MRGPRX2 dependent condition in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a small molecule MRGPRX2 modulator when the patient has been selected based on the presence of a blood serum IgE level at or below an IgE reference level.7

[0038] In one embodiment is provided a method of treating an MRGPRX2 dependent condition in a patient comprising: obtaining a sample from the patient; determining the level of IgE in the sample collected from the patient; comparing the IgE level in the sample collected from the patient to an IgE reference level; and administering to the patient a therapeutically effective dose of an MRGPRX2 modulator if the IgE level in the sample collected from the patient is less than the IgE reference level.

[0039] “MRGPR” refers to one or more of the Mas-related G protein coupled receptors, which are a group of orphan receptors with limited expression in very specialized tissues (e.g., in mast cells and dorsal root ganglia) and barrier tissues. There are eight related receptors in this class expressed in humans.

[0040] “MRGPRX2,” also referred to as “MRGX2,” or “MGRG3,” refers to a member of the MRGPR family that is expressed on mast cells and capable of mediating IgE independent activation (e.g., mast cell degranulation) in response to ligand binding. An exemplary human MRGPRX2 amino acid sequence is set forth in Uniprot Q96LB1.

[0041] As used herein, a small molecule MRGPRX2 “modulator” is a compound that interacts with MRGPRX2 in a manner such that it functions as an inverse agonist to the receptor, as a competitive antagonist to the receptor, or both. Thus “modulating” MRGPRX2 means that the small molecule interacts with MRGPRX2 in a manner such that it functions as an inverse agonist to the receptor, as a competitive antagonist to the receptor, or both.

[0042] In one embodiment, the small molecule that functions MRGPRX2 modulator does not also function as an IgE inhibitor. That is, the small molecule MRGPRX2 modulator does not inhibit the function of IgE. In one embodiment, the small molecule MRGPRX2 modulator does not inhibit the function of IgE at biologically relevant concentrations.

[0043] Unlike IgE inhibitors, which may prevent allergic reactions by blocking the interaction between IgE antibodies and their receptors, small molecule MRGPRX2 modulators work by preventing the activation of mast cells in an IgE independent fashion. In one embodiment, the small molecule MRGPRX2 modulator is not-active against IgE according to one of the following ICso values as measured against IgE in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is not active against IgE has an ICso against IgE greater than about 30 pM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is not active against IgE has an ICso against IgE greater than about 25 pM as measured in the assay described herein. In one embodiment, the small molecule8MRGPRX2 modulator that is not active against IgE has an IC50 against IgE greater than about 20 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is not active against IgE has an IC50 against IgE greater than about 15 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is not active against IgE has an IC50 against IgE greater than about 10 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is not active against IgE has an IC50 against IgE greater than about 5 gM as measured in the assay described herein.

[0044] In one embodiment, the small molecule MRGPRX2 modulator is active against MRGPRX2 according to one of the following IC50 values as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 5 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 4 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 3 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 2 gM as measured in the assay described herein. In one embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 1 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 0.9 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 0.8 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 0.7 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 0.6 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an IC50 against MRGPRX2 less than about 0.5 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 0.4 gM as measured in the assay described herein. In another embodiment, the small9 molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 0.3 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 0.2 pM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 0.1 gM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 90 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 80 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 70 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 60 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 50 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 40 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 30 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 20 nM as measured in the assay described herein. In another embodiment, the small molecule MRGPRX2 modulator that is active against MRGPRX2 has an ICso against MRGPRX2 less than about 10 nM as measured in the assay described herein.

[0045] As used herein, a “ “ssmmaallll mmoolleeccuullee”” i iss a chemical compound that can be manufactured by chemical synthesis, and typically comprises 20 to 100 atoms and have a molecular mass of less than 1000 g / mol or 1 kilodalton [kDa],

[0046] As mentioned above, the invention relates to methods of treating MRGPRX2 (dependent conditions in subjects with low serum IgE levels. It has been found that subjects having a lower level of blood serum IgE respond more favorably to administration of small molecule MRGPRX2 modulators, while patients with higher levels of blood serum IgE respond less10 favorably. This inflection point between low and high levels of blood serum IgE is referred to herein as the “reference level.”

[0047] The level of blood serum IgE measured as referred to herein means the total level of IgE antibodies in the blood, as measured in the blood serum and often referred to as total IgE. The level of blood serum IgE, or total IgE, can be measured by various known methodologies, including a radioimmunosorbent test (RIST), an enzyme-linked immunosorbent assay (ELISA), a fluorescence immunoassay (FIA), a chemiluminescent immunoassay (CLIA), an immunoturbidimetric, or a fluoroenzyme immunoassay (FEIA) such as ImmunoCAP™ Total IgE. In contrast, the IgE reference level described herein does not refer to levels identified in a Specific IgE Test, which is a test that measures specific IgE levels in response to specific allergens. In one embodiment, the Total IgE test is an FDA approved test for measuring total IgE. In one embodiment, the Total IgE test is ImmunoCAP™ Total IgE.

[0048] In one embodiment, the IgE reference level is about 150 U / mL (antibody units per milliliter of blood serum) as measured by any of the above methodologies.

[0049] In another embodiment, the reference level is about 100 U / mL as measured by any of the above methodologies.

[0050] In another embodiment, the reference level is about 50 U / mL as measured by any of the above methodologies

[0051] In another embodiment, the IgE reference level is about 20 U / mL, 21 U / mL, 22 U / mL, 23 U / mL, 24 U / mL, 25 U / mL, 26 U / mL, 27 U / mL, 28 U / mL, 29 U / mL, 30 U / mL, 31 U / mL,32 U / mL, 33 U / mL, 34 U / mL, 35 U / mL, 36 U / mL, 37 U / mL, 38 U / mL, 39 U / mL, 40 U / mL, 41U / mL, 42 U / mL, 43 U / mL, 44 U / mL, 45 U / mL, 46 U / mL, 47 U / mL, 48 U / mL, 49 U / mL, or 50U / mL. In another embodiment, the IgE reference level is about 51 U / mL, 52 U / mL, 53 U / mL, 54U / mL, 55 U / mL, 56 U / mL, 57 U / mL, 58 U / mL, 59 U / mL, 60 U / mL, 61 U / mL, 62 U / mL, 63 U / mL,64 U / mL, 65 U / mL, 66 U / mL, 67 U / mL, 68 U / mL, 69 U / mL, 70 U / mL, 71 U / mL, 72 U / mL, 73U / mL, 74 U / mL, 75 U / mL, 76 U / mL, 77 U / mL, 78 U / mL, 79 U / mL, 80 U / mL, 81 U / mL, 82 U / mL,83 U / mL, 84 U / mL, 85 U / mL, 86 U / mL, 87 U / mL, 88 U / mL, 89 U / mL, 90 U / mL, 91 U / mL, 92U / mL, 93 U / mL, 94 U / mL, 95 U / mL, 96 U / mL, 97 U / mL, 98 U / mL, 99 U / mL, or 100 U / mL.

[0052] In another embodiment, the IgE reference level is about 101 U / mL, 102 U / mL, 103U / mL, 104 U / mL, 105 U / mL, 106 U / mL, 107 U / mL, 108 U / mL, 109 U / mL, 110 U / mL, 111 U / mL,112 U / mL, 113 U / mL, 114 U / mL, 115 U / mL, 116 U / mL, 117 U / mL, 118 U / mL, 119 U / mL, 120U / mL, 121 U / mL, 122 U / mL, 123 U / mL, 124 U / mL, 125 U / mL, 126 U / mL, 127 U / mL, 128 U / mL,129 U / mL, 130 U / mL, 131 U / mL, 132 U / mL, 133 U / mL, 134 U / mL, 135 U / mL, 136 U / mL, 13711U / mL, 138 U / mL, 139 U / mL, 140 U / mL, 141 U / mL, 142 U / mL, 143 U / mL, 144 U / mL, 145 U / mL,146 U / mL, 147 U / mL, 148 U / mL, 149 U / mL, or 150 U / mL.

[0053] In one embodiment a small molecule MRGPRX2 modulator is administered to a subject having a total IgE level at or below the reference level for the purpose of treating an MRGPRX2 dependent condition. In one embodiment, the subject having a total IgE level at or below the reference level has been found to have a total IgE level at or below the reference level as measured by any of the above methodologies. In one embodiment, the methodology to measure the IgE level is an FDA-approved test.

[0054] In the context of identifying a specific level of total IgE in a patient, several phrases can be used synonymously with “when the patient has been selected based on the presence of’. For example, “when the patient has been found to have” is one such phrase. “When the patient has been screened for” is another such phrase. Other alternatives could include “when the patient has been detected with”, indicating that the test has pinpointed a particular level of total IgE. “When the patient has been established to have” is another phrase that conveys a similar meaning, suggesting that the test results have led to a specific finding. “When the patient has shown the presence of’ is yet another phrase that can be used, implying that the test results reveal a particular quantity of total IgE. Additionally, "when the patient has been chosen due to the measurement of' indicates that the act of measuring and finding the IgE levels to be at or below the reference has been a decisive factor in the selection of the patient. Another such phrase that conveys the same idea is, “when the presence of an IgE level at or below a reference level has been confirmed in the patient prior to administering the small molecule MRGPRX2 modulator”. These phrases all convey the idea that a medical test by, but not limited to, one of the methodologies as listed above has quantified a particular level of total IgE in the subject’s blood sample at or below a reference level, leading to the selection of the patient for treatment with a small molecule MRGPRX2 modulator.

[0055] As used herein, the term "administering" or "administration" refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.

[0056] As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for12 example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed. The terms cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development: and / or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0057] As used herein, the term “subject” refers to a human. A subject to be treated according to the methods described herein may be one who has been diagnosed with a MRGPRX2 dependent condition , such as a pseudo-allergic reaction, an itch associated condition, a pain associated condition, a cancer associated condition, an inflammatory or autoimmune disorder. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. The term “patient” may be used interchangeably with the term “subject.” A subject may refer to an adult or pediatric subject.

[0058] The Federal Food, Drug, and Cosmetic Act defines “pediatric” as a subject aged 21 or younger at the time of their diagnosis or treatment. Pediatric subpopulations are further characterized as: (i) neonates - from birth through the first 28 days of life; (ii) infants - from 29 days to less than 2 years; (iii) children - 2 years to less than 12 years; and (iv) adolescents - aged 12 through 21. Despite the definition, depending on the susceptible patient population and clinical trial evaluation, an approved regulatory label may include phrasing that specifically modifies the range of a pediatric population, such as, for example, pediatric patients up to 22 years of age.

[0059] As used herein, the term "effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being13 treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.

[0060] As used herein, the term "therapeutically effective amount" or “"pharmaceutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of a compound of the present invention in combination with other active ingredients effective to act as a modulator of MRGPRX2 or effective to treat or prevent a disease or disorder associated with MRGPRX2.

[0061] As used herein, the phrase “MRGPRX2 dependent condition” means a condition where the activation, over sensitization, or desensitization of MRGPRX2 by a natural or synthetic ligand initiates, mediates, sustains, or augments a pathological condition. For example, it is known that some cationic peptidergic drugs cause pseudo-allergic reactions in patients where MRGPRX2 is sensitive to (or activated by) secretagogues, cationic peptidergic drugs, including Icatibant, Leuprolide, or Ganirelix, neutral and anionic peptidergic drugs (e g., Exenatide, Glucagon, Liraglutide, Enfuvirtide, Colistimethate), non-steroidal agonist (atracurium mivacurium), nonsteroidal antagonist drugs, neuropeptides, and antimicrobial peptides. Moreover, overexpression of MRGPRX2 and / or overactivity MRGPRX2 may also render mast cells more susceptible to activation by endogenous ligands, by exogenous ligands, and / or by drug mediated agonism (provocation). Without being limited by theory, it is to be understood that by modulating MRGPRX2, pseudo-allergic reactions, itch, pain, inflammatory or autoimmune disorders can be eased.

[0062] In some embodiments, the MRGPRX2 dependent condition is a condition that is caused by IgE independent activation of MRGPRX2 IgE independent activation of MRGPRX2 is capable of inducing mast cell degranulation. For example, IgE independent mast cell activation is associated with some cases of chronic urticaria and other mast cell mediated conditions, which are not responsive to current anti-IgE or antihistamine therapies. Thus, the compounds of the present disclosure may be used for treating an MRGPRX2 dependent condition caused by IgE independent activation of MRGPRX2 and that would benefit from modulating MRGPRX2.

[0063] In some embodiments, the MRGPRX2 dependent condition is an itch associated condition, a pain associated condition, a cancer associated condition, a pseudo-allergic reaction, or an autoimmune or inflammatory disorder in humans or other mammals.14

[0064] As used herein the phrase “pseudo-allergic reaction” refers to an IgE-independent allergic reaction, characterized by histamine release, inflammation, airway contraction, or any combination thereof. A pseudo-allergic reaction may be an anaphylactic reaction. A pseudo- allergic reaction may be caused by a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. Thus, in one embodiment, the method of present invention is provided to treat a pseudo-allergic reaction, such as pseudo-allergic reactions caused by secretagogues, cationic peptidergic drugs, anionic peptidergic drugs, neutral peptidergic drugs, non-steroidal antagonist drugs, neuropeptides, and antimicrobial peptides. In one embodiment, the pseudo-allergic reaction is caused by MCD peptide, Substance P, VIP, PACAP, dynorphin, somatostatin, Compound 48 / 80, Corti statin- 14, Mastoparan, Melettin, Cathelicidin Peptides, Ciprofloxacin, Vancomycin, Leuprolide, Goserelin, Histrelin, Triptorelin, Cetrorelix, Ganirelix, Degarelix, Octreotide, Lanreotide, Pasireotide, Sermorelin, Tesamorelin, Icatibant, Glatiramer Acetate, Teriparatide, Pramlintide, Bleomycin, Exenatide, Glucagon, Liraglutide, Enfuvirtide, Colistimethate, Succinylcholine, Tubocurarine, Atracurium, Mivacurium, or Rocuronium.

[0065] As used herein, the phrase “itch associated condition” means pruritus (including acute and chronic pruritus) associated with any condition. The itch sensation can originate, e.g., from the peripheral nervous system (e.g., dermal or neuropathic itch) or from the central nervous system (e.g., neuropathic, neurogenic or psychogenic itch). Thus, in one embodiment, the method of present invention is provided to treat an itch associated condition, such as acne, allergic blepharitis, anaphylaxis, anaphylactoid drug reactions, anaphylactic shock, anemia, atopic dermatitis, bullous pemphigoid, bum healing, candidiasis, chicken pox, cholestatic pruritis, chronic itch, chronic urticaria, chronic prurigo / pmrigo nodularis, contact dermatitis, cutaneous amyloidosis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, end-stage renal failure, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, food allergy, folliculitis, fungal skin infection, hemodialysis, hemorrhoids, herpes, HIV infection, Hodgkin’s disease, hyperthyroidism, iodinated contrast dye allergy, iron deficiency anemia, kidney disease, leukemia, porphyria, lymphoma, mast cell activation syndrome, malignancy, mastocytosis, multiple myeloma, neurodermatitis, ocular itch, onchocerciasis, Paget’s disease, pediculosis, polycythemia rubra vera, pmrigo nodularis, lichen planus, lichen sclerosis, pmritus ani, pseudo-allergic reactions, pseudorabies, psoriasis, chronic pmrigo / pmrigo nodularis, rectal prolapse, rosacea, sarcoidosis granulomas, scabies, schistosomiasis, scleroderma, severe stress, Stasia dermatitis, swimmer's itch, thyroid disease, tinea cmris, uremic pmritus, urticaria, or wound15 healing. In another embodiment, the itch associated condition is chronic itch, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chicken pox, endstage renal failure, hemodialysis, chronic urticaria, chronic spontaneous urticaria, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, food allergy, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iodinated contrast dye allergy, iron deficiency anemia, kidney disease, leukemia, porphyrias, lymphoma, malignancy, mastocystosis, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia rubra vera, prurigo nodularis, lichen planus, lichen sclerosis, pruritus ani, pseudorabies, psoriasis, chronic prurigo / prurigo nodularis, rectal prolapse, sarcoidosis granulomas, scabies, schistosomiasis, scleroderma, severe stress, stasia dermatitis, swimmer's itch, thyroid disease, tinea cruris, rosacea, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, ocular itch, or urticaria. In another embodiment, the itch associated condition is chronic urticaria, chronic spontaneous urticaria, urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, chronic prurigo / prurigo nodularis, contact dermatitis, or eczema.

[0066] As used herein, the phrase “pain associated condition” means any pain due to a medical condition. Thus, in one embodiment, the method of present invention is provided to treat a pain associated condition, such as acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet’s Disease (Syndrome), bladder pain, burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn’s disease, degenerative disc disease, dental pain, Dercum’s disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers- Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headaches, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatosis and dermatomyositis, knee injury, leg pain, loin pain-haematuria syndrome, lupus, Lyme disease, medullary sponge kidney (MSK), meralgia paresthetica, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget’s disease, Parsonage Turner16 syndrome, pelvic pain, periodontitis pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, post herniorrhaphy pain syndrome, post mastectomy, postoperative pain, pain syndrome, post stroke pain, post thoracotomy pain syndrome, postherpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud’s Disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann’s Kyphosis disease, sciatica, scoliosis, shingles (herpes zoster), Sjogren’s syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinal cerebellum ataxia (SCA Ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov cysts, transverse myelitis, trigeminal neuralgia, ulcerative colitis, vascular pain, or vulvodynia.

[0067] As used herein, the term “autoimmune disorder”, or “inflammatory disorder” means a disease or disorder arising from and / or directed against an individual’s own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom. Typically, various clinical and laboratory markers of autoimmune diseases may exist including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposits in tissues, clinical benefit from corticosteroid or immunosuppressive treatments, and lymphoid cell aggregates in affected tissues. Thus, in one embodiment, the method of present invention is provided to treat an autoimmune disorder, such as chronic inflammation, mast cell activation syndrome, multiple sclerosis, Steven Johnson’s syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, allergic rhinitis, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, Crohn’s Disease, ulcerative colitis, lupus erythematous, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstmctive pulmonary disease, permanent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, eosinophilic gastroenteritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatoisis, tubulointerstitial nephritis, glomerulonephritis,17 diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, reflux nephropathy, polycystic kidney disease, liver fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic hepatitis B and C virus, liver tumors and cancer, alcoholic liver disease, polycystic liver disease, liver cholangiocarcinoma, neuromyelitis optica spectum disorder, cardiovascular disease, inflammation induced by bacterial or viral infection, inflammation associated with SARS- CoV-2 infection or its variants and coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome, pneumonia, long / long-term / chronic COVID, post-acute sequelae of COVID- 19 (PASC), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS “Brain Fog”), or vasculitis. In one embodiment, the inflammatory or autoimmune condition is asthma, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, or nasal polyposis. In a further embodiment, asthma is moderate to severe persistent asthma.

[0068] As used herein the phrase “cancer associated condition” means any disease arising from the proliferation of malignant cancerous cells. Thus, in one embodiment, the method of present invention is provided to treat a cancer / tumor associated condition, such as adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxiatelangiectasia, Beckwith-Wiedemann syndrome, cholangiocarcinoma, Birt-Hogg-Dube syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), prostrate, basal cell, melanoma, colon, colorectal, bladder, kidney cancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lung cancer (non-small cell, small cell), leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T cell lymphocytic, eosinophilic), liver cancer, Li-Fraumei syndrome, lymphoma (Hodgkin and non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma, multiple endocrine neoplasia, multiple myeloma, MUTYH-associated polyposis, myelodyspastic syndrome, nasal cavity and paranasal sinus cancer, neuroblastoma, neuroendocrine tumors, neurofibromatosis, penile cancer, parathyroid cancer, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary gland tumor, pleupulmonary blastoma, oral and oropharyngeal , thyroid, uterine, pancreatic, Carney complex, brain and spinal cord cancer, cervical cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary, leiomyomastosis and renal cell cancer,18 hereditary pancreatitis, hereditary papillary renal carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS related cancers, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, vulver cancer, Werner syndrome, or xeroderma pigmentosum.

[0069] In another embodiment, a method of treating a subject having an itch associated condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the itch associated condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, chronic prurigo / prurigo nodularis, contact dermatitis, or eczema. In another embodiment, a method of treating a subject having an inflammation or autoimmune associated condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the inflammation or autoimmune associated condition is sinusitis, asthma, rosacea, or endometriosis.

[0070] In another embodiment, a method of treating a subject having a pain associated condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the pain associated condition is chronic pelvic pain syndrome, endometriosis pain, bladder pain syndrome, fibromyalgia, migraine or postoperative pain.Small Molecule MRGPRX2 Modulators

[0071] As mentioned above, a small molecule MRGPRX2 modulator is a compound that interacts with MRGPRX2 in a manner such that it functions as an inverse agonist to the receptor, as a competitive antagonist to the receptor, or both. Such modulation of MRGPRX2 may be partially or fully selective against other MRGPRs, such as MRGPR XI, X3, X4 and / or D. Such small molecules can generally be made by chemical synthesis, comprises 20 to 100 atoms, and have a molecular mass of less than 1000 g / mol or 1 kilodalton [kDa],

[0072] In one embodiment, a compound is provided comprising an MRGPRX2 modulator for treating an MRGPRX2 dependent condition, wherein the MRGPRX2 modulator is19 administered to a patient in need thereof when the patient has been selected based on the presence of a blood serum IgE level at or below an IgE reference level.WO 2022 / 067094, WO 2022 / 087083, and WO 2023 / 192901 | Escient Pharmaceuticals

[0073] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 067094, WO 2022 / 087083, or WO 2023 / 192901, the entirety of which are incorporated herein by reference.

[0074] In more specific embodiments, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (I):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, -(CH=CH)nQ, or~CQ(R)2, where Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CH2C(O)OR, -C(O)OR, -C(O)NHR, -OC(O)R, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, and where R1and / or Q is optionally substituted with one or more Rq; each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, N(R)2, alkylamino, — (CH2)nR', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups together with the atom to which it is attached forms a double bond, carbocycle or heterocycle, wherein R is optionally substituted with one or more of X, haloalkyl, or haloalkoxy; each Rqis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, oxo, -OR, -SR, -O(CH2)nR, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, OC(O)R, X, CX3, CX2H, C(X)H2, -CN, -N(O)2, =NH, N(R)2, N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -B(OR)2, -C(H)Q'R, -O(CH2)nQ', or -(CH2)nQ', where Q' is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR', -C(O)OR', -OC(O)R', X, -CX3, -CX2H, -C(X)H2,20-C(CH3)2X, -C(CH3)2OH, -CN, -N(R')2, -N(R')C(O)R', or -N(R')S(O)2R', and where Rqand / or Q’ is optionally substituted with one or more RY;R2, R3, R4, R5, and R6are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C(X)2R, -C(X)(R)2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; each Rxis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or S(O)2R, or Rxtogether with R1forms a heterocyclic ring; each RYis independently C1-6alkyl, cycloalkyl, oxo, X, -CX3, -OR, or -C(O)OR;W is N or CRW;Z is N or CRZ;Rwis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rzis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each R’ is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each X is independently F, Cl, Br, or I; and each n is independently 0, 1, 2, 3, 4 or 5.

[0075] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (I-A):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, -(CH=CH)nQ, or-CQ(R)2, where Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CH2C(O)OR, -C(O)OR, -C(O)NHR, -OC(O)R, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, and where R1and / or Q is optionally substituted with one or more Rq;21 each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -N(R)2, alkylamino, -(CH2)nR', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups together with the atom to which it is attached forms a double bond, carbocycle or heterocycle, wherein R is optionally substituted with one or more of X, haloalkyl, or haloalkoxy; each Rqis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, oxo, -OR, -SR, -O(CH2)nR, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CCXX33,, -CX2H, -C(X)H2, -C CNN,, -N(O)2, =NH, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -B(0R)2, -C(H)Q'R, -O(CH2)nQ', or -(CH2)nQ', where Q' is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', X, -C CXX33,, -CX2H, -C(X)H2, -C(CH3)2X, -C(CH3)2OH, -CN, -N(R')2, -N(R')C(O)R', or -N(R')S(O)2R', and where Rqand / or Q’ is optionally substituted with one or more RY;R2, R3, R4, R5, and R6are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C(X)2R, -C(X)(R)2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; each Rxis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(0)2R, or -S(O)2R, or Rxtogether with R1forms a heterocyclic ring; each RYis independently C1-6alkyl, cycloalkyl, oxo, X, -CX3, -OR, or -C(O)OR;W is N or CRW;Z is N or CRZ;Rwis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rzis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each R' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each X is independently F, Cl, Br, or I; and each n is independently 0, 1, 2, 3, 4 or 5.

[0076] In one embodiment, the small molecule MRGPRX2 modulator is a compound having a structure shown in Table 1.TABLE 1222829365659

[0077] In one embodiment, the small molecule MRGPRX2 modulator is:or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0078] In one embodiment, the small molecule MRGPRX2 modulator is:or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0079] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (I-B):60or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2where Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CH2C(O)OR, -C(O)OR, -C(O)NHR, -OC(O)R, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, where R1and / or Q is optionally substituted with one or more Rq; each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, alkylamino, -(CH2)nR', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups together with the atom to which it is attached forms a carbocycle; each Rqis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -O(CH2)nR, -OX3, -OX2H, -O(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -C(H)Q'R, or -(CH2)nQ' where Q' is selected from C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', -CX3, -CX2H, -C(X)H2, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(0)2R';R2, R4, and R5are at each occurrence, independently H, C1-6alkyl, C2-6alkenyl,C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, ~C(O)OR, ~OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C(X)2R, -C(X)(R)2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;R3is at each occurrence, independently C1-6alkyl, C2-6alkenyl, H, OH, F, Br, I, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R;R6is at each occurrence, independently H, C1-6alkyl, C2-6alkenyl, X, CF3, -CF2H, -C(F)H2, -C(F)2R, or -C(F)(R)2; each Rxis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, and -S(O)2R;61 each R' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;W is N or CRW;Z is N or CRZ;Rwis C1-6alkyl, C2-6alkenyl, C2-6alkynyl, H, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rzis C1-6alkyl, C2-6alkenyl, H, OH, F, Br, I, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or N(R)S(O)2R; each X is independently F, Cl, Br, and I; and n is independently 0, 1, 2, 3, 4 and 5.

[0080] In one embodiment, the small molecule MRGPRX2 modulator is a compound having a structure shown in Table 2.6265707475769091WO 2022 / 125636 | Escient Pharmaceuticals

[0081] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 125636, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (II):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2, wherein R1is optionally substituted with one or more Rql;Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -CH2C(O)OR, C(O)OR, -C(O)NHR, trihalomethyl, dihalomethyl, -CN, -N(R)z, -N(R)C(O)R, N(R)C(O)OR, or -N(R)S(O)2R, wherein Q is optionally substituted with one or more Rq2;Rqland Rq2are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -O(CH2)nR, haloalkoxy, -C(O)OR, -C(O)R, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(=NH)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -C(H)Q'R, or -CH2)nQ' where Q' is selected from C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', haloalkyl, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(O)2R';D is N or CRd;W is N or CRW;Z is N or CRZ; each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(O)NHR', amino, -(CH2)nR', halo, aryl, cycloalkyl, heteroaryl or heterocyclyl, or two R groups taken together with the atom to which they are attached form a carbocycle or heterocycle;R' is H, C1-6alkyl, haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;92when D is CRd, W is CRW, and Z is CRZ, then R2is H, C1-6alkyl, C2-6alkenyl, cycloalkyl, -OR, -C(O)OR, -OC(O)R, halo, -CF3, -CF2H, -C(F)H2, -C(F)2R, -C(F)(R)2, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; or when at least one of D, W or Z is N, then R2is C1-6alkyl, C2-6alkenyl, cycloalkyl, -OR, -C(O)OR, -OC(O)R, halo, -CF3, -CF2H, -C(F)H2, -C(F)2R, -C(F)(R)2, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; and each R3is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R.

[0082] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (II-A):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0083] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (II-B) :93or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0084] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 3.98WO 2022 / 140520 | Escient Pharmaceuticals

[0085] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 140520, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (III):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2, wherein R1is optionally substituted with one or more Rql;Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -CH2C(O)OR, -C(O)OR, -C(O)NHR, haloalkyl, -CN, -N(R)i, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, wherein Q is optionally substituted with one or more Rq2;Rqland Rq2are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -O(CH2)nR, haloalkoxy, -C(O)OR, -C(O)R, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -C(H)Q'R, or -(CH2)nQ' where Q' is selected from C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', haloalkyl, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(O)2R';A is N or CRa;99each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, alkylamino, -(CH2)nR', halo, aryl, cycloalkyl, heteroaryl or heterocyclyl, or two R groups taken together with the atom to which they are attached form a carbocycle or heterocycle;R' is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rais H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rbis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rcis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl,OR, C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or-S(O)2R;Rdis either absent, or when present, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Reis either absent, or when present, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rsis either absent, or when present, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;100RW is either absent, or when present, H, C1-6alkyl, C 2-6 alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Ryis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rzis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; n is independently 0, 1, 2, 3, 4 and 5;R6is Ci-4 alkyl, phenyl, -C(O)R, - (CH2)nOR, -CN, F, Cl, Br, CF3, CF2H or CFH2, with the proviso that R is not H; each R8is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; andR2, R3, R4, R5and R7are the same or different and either absent or, when present, independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; wherein: adjacent atoms on either the “a” ring or “b” ring may be joined together by single bonds to form a 9 atom carbocyclic or heterocyclic ring structure; or atoms 1 and 2, 3 and 4, 5 and 6 and 8 and 9 on rings “a” ring and “b” ring may be joined together by double bonds to form an aromatic 9 atom carbocyclic or heterocyclic ring structure; or atoms 1 and 2, 3 and 4, 6 and 7 and 8 and 9 on rings “a” ring and “b” ring may be joined together by double bonds to form an aromatic 9 atom carbocyclic or heterocyclic ring structure.

[0086] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (III-A):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0087] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (III-A-1) or Formula (III-A-2):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0088] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (III-B):102( ) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0089] In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (III-B-1) or Formula (III-B-2):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0090] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 4.104105106107108109110111112113114115116117118119120121122123124125126127US Serial No. 63 / 588,638 (PC17US2024 / 50100) | Escient Pharmaceuticals

[0091] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in U.S. Serial No. 63 / 588,638, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (IV):or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:L1is (CR'R")q-, -(CR'R")u-CR'=CR'-(CR'R")v- -(CR'R'')u-C=C-(CR'R'')v-,(CR'R' ')U-O-(CR'R' ')v-, -(CR'R' ')U-NR'-(CR'RF')v- -(CR'R' ')U-C(O)-(CR'R' ')v-;L2is -(CRaRb)w-;128R1is C1-6alkyl, carbocycle or heterocycle, wherein R1is substituted with -(R5)n;R2is halo, C1-6alkyl, carbocycle or heterocycle, wherein R2is substituted with -(R6)P;R3is H or C1-6alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring;R4is, at each occurrence, independently halo, -CN, OR7, -N(R7)2, C1-6alkyl, Cue haloalkyl;R5is, at each occurrence, independently halo, -CN, -OR7, -N(R7)2, -S(O)2-R7, C1-6alkyl, Cue haloalkyl, carbocycle, or heterocycle;R6is, at each occurrence, independently halo, -CN, -OR7, -N(R7)2, -SR7, -C(O)OR7, -N(R8)C(O)R7, -N(R8)C(O)OR7, -C(O)N(R8)2, -S(O)2-R7, -C1-6alkyl-R7, C1-6haloalkyl, carbocycle substituted with -(R7)x, or heterocycle substituted with -(R7)x;R7is, at each occurrence, independently H, -OR8, -N(R8)2, -C(O)OR8, -NHC(O)OR8, -C1-6alkyl-R8, C1-6haloalkyl, carbocycle substituted with -(R8)y, or heterocycle substituted with -(R8)y;R8is, at each occurrence, independently H, -OR, NR2, -C1-6alkyl-R, carbocycle substituted with -(R)z, or heterocycle substituted with -(R)z;R' and R" are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6alkyl, or C1-6alkenyl, or, independently, at each occurrence of R' and R" attached to the same carbon atom, R' and R", together with the carbon to which they are attached, form a cycloalkyl;Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl;R is, at each occurrence, independently H, halo, -CN, -OH, -NH2, or C1-6alkyl; m is 0-5; n is 0-5; p is 0-5 q is 1-3; u is, at each occurrence, independently 0-3; v is, at each occurrence, independently 0-3; w is 0-3; x is 0-3; y is 0-3; and z is 0-3.129

[0092] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 5.130131132133134135137138139140141144145149152153154157

[0093] In one embodiment, the small molecule MRGPRX2 modulator is:or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.WO 2022 / 111473 | Bioardis

[0094] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 111473, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (V) or Formula (V'):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, whereinR1is C1-6alkyl, C4-C12 cycloalkyl, or 3-12 membered heterocyclyl, wherein the C1-6alkyl, C4-C12 cycloalkyl, and 3-12 membered heterocyclyl are each independently optionally substituted by halo, -OH, or C1-6alkoxy;R2is hydrogen, -CN, halo, C1-6alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently optionally substituted by halo, -OH, or Ci -e alkoxy; each R3is independently halo, C1-6alkyl, -CN, or -OH; n is an integer from 0-4;158R5ai s Ci-Cs alkyl, C2-C20 alkenyl, -(C1-6alkylene)-O-(C1-6alkylene)-O-(C1-6alkyl), or Ce-Cio aryl;R5bis C1-6alkyl or -(C1-6alkylene)-O-(C1-6alkyl);R5Ci iss C1-6alkyl, -(C1-6alkylene)-O-(C1-6alkyl), or-(C1-6alkylene)-O-(C1-6alkylene)-O-(C1-6alkyl);R5di IsS Ci -e alkyl, (C1-6alkylene)-O-(C1-6alkyl), or-(C1-6alkylene)-O-(C1-6alkylene)-O-(C1-6alkyl);R5eis C1-6alkyl;R5fI iSs C1-6alkyl, -(C1-6alky lene)-OH, (C1-6alkylene)-O-(C1-6alkyl), or-(C1-6alkylene)-O-(C1-6alkylene)-O-(C1-6alkyl) ;R5gand R5haarree independently C1-6alkyl, -(C1-6alkylene)-O-(C1-6alkyl), -(C1-6alkylene)-O-(C1-6alkylene)-O-(C1-6alkyl), or -O-(C1-6alkyl) , or R5gand R5hare taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C1-6alkyl, -(C1-6alkylene)-O-(C1-6alkyl), or -O-(C1-6alkyl); and R51and R5jare independently C1-6alkyl or -(C1-6alkylene)-O-(C1-6alkyl) , or R51and R5' are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N, O, and S, and wherein the 4- to 10-membered heterocyclyl is optionally substituted by 1-5 groups independently selected from the group consisting of C1-6alkyl, -(C1-6alkylene)-O-(C1-6alkyl), or -Q-(CI-6 alkyl).

[0095] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 6.TABLE 6159160161162163164W02021092240 | Dermira

[0096] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2021 / 092240, the entirety of which is incorporated herein by reference. In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (VI):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:W is absent or isAi is a ring system selected from systems 1-21 :165RA is absent or is selected from H, C1-3alkyl, -C(=O)-NH2, -C(=O)-OH, halogen, phenyl, CN, and benzyl; k, q, m and p are each independently 0 or 1 ;Ra is H or C1-3alkyl;R1is selected from H; C1-6alkyl or C3-6 cycloalkyl, which is optionally substituted with 1,2 or 3 independently selected R50 groups; or a 3-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1, 2 or3 independently selected Rsi groups, and which optionally comprises a -(C=O) group or -S(=O)2- group in the ring; each Rso is independently selected from hydroxy, -NR20N21; -SO2R22; C1-3haloalkyl; halogen; C(=O) R26; CN; C3-6 cycloalkyl which is optionally substituted with 1-3 R25 groups; C1-3hydroxyalkyl; and a 5-10 membered heterocycloalkyl having1661-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1, 2 or 3 independently selected Rsi groups, and which optionally comprises a -(C=O)group in the ring; each R2O and R2I is independently selected from H, C1-6alkyl and -SChNRsoRu; each R22is independently C1-6alkyl; each R25 is independently selected from hydroxy, C1-3haloalkyl and C1-3hydroxyalkyl; each R26 is independently selected from hydroxy, C1-3haloalkyl and C1-6alkoxy; each R2? and R2s is independently selected from H, hydroxy, C1-3haloalkyl and C1-3alkoxy; each R51 is independently selected from C1-6alkyl; -SO2NR30R31; -C(=O)-O-R32; halogen; hydroxy; cyano; C1-3hydroxyalkyl; -C(=O)-NR33R34; -C(=O)-R3s; CN; -SO2R22; C1-3haloalkyl; NR33R34; and C1-3alkoxy; each R30 and R31 is independently selected from H and C1-6alkyl; each R22is independently selected from H and C1-6alkyl; each R33 and R34 is independently selected from H and C1-6alkyl; each R35 is independently C1-6alkyl;R2is H, C1-6alkyl or C3-6 cycloalkyl, each optionally substituted with 1, 2 or 3 groups selected from hydroxy, C1-3haloalkyl, halogen, C1-3alkoxy and CN; or R2is -SO2(C1-6alkyl); or R2and R3 together form a -CH2-CH2- group, such as a ring of formulaLi is O, CH2, CH(CI-3alkyl)-, C(=O)-NH-CH2-, C(OH)(CH3)- CH(OH)--(C=O)-, -N(C1-6alkyl)-, or -NH-;A2is C6-10aryl, C3-7 cycloalkyl, or a 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein each of C6-10aryl, C3-7 cycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 independently selected Rso groups; and each Reo is independently selected from halogen, CN, hydroxy, C1-3alkoxy, C1-3haloalkoxy, C1-3haloalkyl, -C(=O)-O-R35 and C1-3alkyl optionally substituted with 1-3 substituents independently selected from hydroxy, CN and C1-3alkoxy.

[0097] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 7.167170173175WO2021092262 | Dermira

[0098] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2021 / 092262, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (VII):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:Q is176R1is H or C1-3alkyl; n is 0 or 1 ; each R20 and R21 is independently H or C1-3alkyl;G1, G2, G3, G4, and Gs are each independently N or -C-L1-M1, provided that at least one of G1, G2, G3, G4, and Gs is N; each Li is independently a bond, O, -C(=O), -C(=O)-NH-, -CH2-, -O-(CH2)wwhere w is 1, 2 or 3, or -N(Rgo)-; or any two Li~M groups on adjacent carbon atoms can together form a group of formula -O-(CH2)v-O- where v is 1 or 2; each R90 is independently H or C1-3alkyl; each Mi is independently H, -OH, halogen, cyano, C6-10aryl; 5-10 member heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S; C1-6alkyl; C3-6 cycloalkyl, 4-10 member heterocycloalkyl having 1-3 ring heteroatoms independently selectedfrom N, O and S; wherein each of the Ce- 10 aryl; 5-10 member heteroaryl; C1-6alkyl; C3-6 cycloalkyl and 4-10 member heterocycloalkyl is each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, -OH, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, andeach R91and R92 is independently selected from the group consisting of H and C1-3alkyl; each R50and Rsi is independently selected from the group consisting of H, C1-3alkyl, and C6-10aryl;A is -L2-M2;L2 is selected from a bond and -Reo and Rei are each independently H or C1-3alkyl optionally substituted with 1, 2 or 3 substituents independently selected from -OH and halogen; k is 1, 2, or 3;M2is C1-6alkyl; C3-6 cycloalkyl; C6-10spiroalkyl; 4-10 member heterocycloalkyl having 1- 3 ring heteroatoms independently selected from N, O and S; -N(R81)(R82); and C6-10aryl; wherein each C1-6alkyl, C3-6 cycloalkyl, C6-10spiroalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, and C6-10aryl is each optionally substituted with 1, 2, 3 or 4 independently selected R200 groups;177 each is independently selected from C1-6alkyl; C1-6hydroxyalkyl; C3-6 cycloalkyl; 5- 10 member heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S; C1-6mono-, di-, or tri-haloalkyl; halogen; cyano; -OH; C1-6alkoxy; and C6-10aryl;R70 and R71 are each independently H or C1-3alkyl; each is independently selected from H; C1-6alkyl and C3-6 cycloalkyl; whereinthe C1-6alkyl and C3-6 cycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from -OH and halogen;R500 and R501 are independently absent or C1-6alkyl; andR502 and R503 are independently H or C1-6alkyl.

[0099] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 8.178179180181182183184185186187188189190or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.WO2021092264 | Dermira

[0102] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2021 / 092264, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (VIII):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein: G2isq is 0 or 1 ; m is 0 or 1 ; n is 0, 1 or 2; k is 0 or 1 ; provided that k, q and m are not all 0; provided that q is not 0 when m and k are each 1;R1and R2are each independently H, C1-6alkyl; C3-6 cycloalkyl; 5-10 member heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S; wherein each C1-6alkyl, C3-6 cycloalkyl and 5-10 member heterocycloalkyl is optionally substituted with 1 to 3 R20 groups;191 provided that R1and R2are not simultaneously H; each R20 is independently selected from 1) hydroxy, 2) cyano, 3) C1-3alkyl, 4) C1-3alkoxy, 5) C1-3haloalkyl, 6) halogen, 7) C1-3alkyl, 8) C3-6 cycloalkyl optionally substituted with 1-3 substituents selected from hydroxy, cyano, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen, and 9) 5-10 member heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S optionally substituted with 1-3 substituents selected from hydroxy, cyano, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen; or R1and R2together with the nitrogen atom to which they are attached can form a 5 or 6 member saturated, partially unsaturated or aromatic heterocycle having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1, 2 or 3 groups selected from hydroxy, C1-3alkyl, C1-3hydroxyalkyl, C1-3alkoxy, C1-3haloalkyl, cyano and halogen;R3 is H or C1-3alkyl; each R4and Rs is independently H or C1-3alkyl;G1is C6-10aryl; C3-7 cycloalkyl; C1-3haloalkyl; C1-3alkyl and 5-10 member heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S; wherein each of the Ce- 10 aryl, C3-7 cycloalkyl, C1-3haloalkyl and 5-10 member heteroaryl is optionally substituted with 1, 2 or 3 independently selected R30 groups; and each R30 is independently selected from halogen, cyano, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy optionally substituted with halogen, and hydroxy.

[0103] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 9.192193194W02022073904 | GSK

[0104] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 073904, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (IX):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:W is N or CH; each X1is independently N or CR10; each X2is independently N or CR11;Y1is N or CR12;Y2is N or CR12;195 n is 0 or 1 ;R1is hydrogen, halogen, C1-6alkyl, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl , -C1-6alkyl-C3-8cycloalkyl, -C1-6alkyl-aryl, 5- or 6- membered heteroarylC 1-4 alkyl-, C3-8cycloalkyl, C2-6alkenyl, -C2-6alkenyl-C3-8cycloalkyl, -OH, C1-4alkoxy, -O-C1-6alkyl— C3-8cycloalkyl, -O-C1-6alkyl-aryl, -O-C1-6alkyl-5-6 membered heteroaryl, -O-C2-6alkenyl, -O-C3-8cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2C1-6alkyl, -CO2C3-8cycloalkyl, -O2C C1-6alkyl, -O2CC3-8cycloalkyl, -NH2, -NHCI-6 alkyl, -N(C1-6alkyl)(C1-6alkyl), aryl, or 5-6 membered heteroaryl, wherein any said C1-6alkyl, -C1-6alkyl-Cs-8 cycloalkyl, -C1-6alkyl-aryl, C1-4alkoxy, -O-C1-6alkyl-C3-8cycloalkyl, -O-C3-8cycloalkyl, -O-aryl, -0-5-6-membered heteroaryl, -C(O)-aryl, aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R14;R2is hydrogen, halogen, C1-6alkyl, or -OH, wherein any said C1-6alkyl is optionally substituted one, two, or three times by halogen;R3is hydrogen, halogen, C1-6alkyl, or -OH, wherein any said C1-6alkyl is optionally substituted one, two, or three times by halogen;R4is hydrogen, halogen, or C1-6alkyl;R5is hydrogen, halogen, or C1-6alkyl;R6is hydrogen, halogen, C1-6alkyl, C3-8cycloalkyl, C1-4alkoxy, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl),-C1-6alkyl-N-(C1-6alkyl)(C1-6alkyl), -C1-6alkyl-NH(C1-6alkyl)-OH,-C1-6alkyl-NH((C1-6alkyl)-O-C1-6alkyl), ■C1-6alkyl-N-(C1-6alkyl)(C1-6alkyl)-OH, -C1-6alkyl-N-(C1-6alkyl)(C1-6alkyl)-O-C1-6alkyl), -C1-6alkyl-NH-C3-8cycloalkyl, -C1-6alkyl-NH-4- ttoo 6-membered heterocycloalkyl, C1-6alkyl-4- ttoo 6-membered heterocycloalkyl, -C1-6alkyl-NHC(O)-(C1-6alkyl), -C1-6alkyl-SO2-C1-6alkyl, -C1-6alkyl-SO2-NH-C1-6alkyl, -CN, -C(O)NH2, -C(O)NHCI-6alkyl), C(O)NCI-6alkyl) C1-6alkyl), — NH2, -NHCI-6 alkyl, -N(C1-6alkyl)(C1-6alkyl), -SO2(C1-6alkyl),-SO2-NH(C1-6alkyl), or aryl, wherein any said C1-6alkyl, C3-8cycloalkyl, -C1-6alkyl-OH, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-NH-C3-8cycloalkyl,-C1-6alkyl-NH-4- to 6-membered heterocycloalkyl, oorr -C1-6alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen;R7is hydrogen, C1-6alkyl, or -OH;R8is hydrogen, C1-6alkyl, or C1-4alkoxy;196R9is hydrogen, C1-6alkyl, or C1-4alkoxy; each R10is independently hydrogen, halogen, C1-6alkyl, C2-6alkenyl, -C1-6alkyl-NEb, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl), C2-6alkenyl, -O-C1-6alkyl, -NH2, -NH(CI-6alkyl), -N(CI-6 alkyl)(C1-6alkyl), -NCH2, or -CHNH; or R1and any R10taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, C1-6alkyl, -C1-6alkyl-Ca-8 cycloalkyl, haloC1-6alkyl, and C3-8cycloalkyl; each R11is independently hydrogen, halogen, C1-6alkyl, or C2-6alkenyl; or any R10and any R11taken together with the atoms to which they are attached, form a 5-, 6-, or 7 -membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halogen, C1-6alkyl, haloC1-6alkyl, and C3-8cycloalkyl;R12is hydrogen, halogen, or C1-6alkyl, wherein said C1-6alkyl is optionally substituted one, two, or three times by halogen;R13is hydrogen, C1-6alkyl, -C1-6alkyl-SO2-C1-6alkyl, -C1-6alkyl-aryl, or -C1-6alkyl-5- 6-membered heteroaryl, wherein said C1-6alkyl, -C1-6alkyl-SO2-C1-6alkyl, -C1-6alkyl-aryl, or -C1-6alkyl-5-6-membered heteroaryl is optionally substituted one, two, or three times by halogen; and each R14is independently halogen, C1-6alkyl, C3-8cycloalkyl, - ■CCNN,, -C1-6alkyl-OH, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl), OH, C1-4alkoxy, -O-C3-8cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein C1-6alkyl, C3-8cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, or C1-4alkoxy

[0105] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 10.TABLE 10198199200201202203204205206207208209210211

[0106] In another embodiment, the small molecule MRGPRX2 modulator is:or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.WO 2022 / 073905 | GSK

[0107] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 073905, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (X):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:212 each X1is independently N or CR6; each X2is independently N or CR7; Y1is N or CR8;Y2is N or CR8;R1is hydrogen, halogen, C1-6alkyl, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl), -C1-6alkyl-C3-8cycloalkyl, -C1-6alkyl-aryl, 5- or 6- membered heteroarylC 1-4 alkyl-, C3-8cycloalkyl, C2-6alkenyl, -C 2-6 alkenyl-C3-8cycloalkyl, -OH, C1-4alkoxy, -O-C1-6alkyl-C3-8cycloalkyl, -O-C1-6alkyl-aryl, -O-C1-6alkyl-5-6 membered heteroaryl, -O-C2-6alkenyl, -O-C3-8cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO2H, -CO2-C1-6alkyl, -CO2C3-8cycloalkyl, -O2C-C1-6alkyl, -O2CC3-8cycloalkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)(C1-6alkyl), aryl, or 5-6 membered heteroaryl, wherein any said C1-6alkyl, -C1-6alkyl-C3-8cycloalkyl, -C1-6alkyl-aryl, C1-4alkoxy, -O-C1-6alkyl-C3-8cycloalkyl, -O-C3-8cycloalkyl, -O-aryl, -0-5-6-membered heteroaryl, -C(O)-aryl, aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R10;R2is hydrogen, C1-6alkyl, or C1-4alkoxy;R3is hydrogen, C1-6alkyl, or C1-4alkoxy;R4is hydrogen, C1-6alkyl, or -OH;R5is hydrogen, halogen, C1-6alkyl, C3-8cycloalkyl, C1 -4alkoxy, -C1-6alkyl-OH, - C1-6a alkyl-O-C1-6alkyl, - C1-6alkyl-NH2, -C1-6alkyl-NH C1-6alkyl),-C1-6alkyl-N-(C1-6alkyl)(C1-6alkyl), -C1-6alkyl-NHC1-6alkyl)-OH,-C1-6alkyl-NHC1-6alkyl)-O-C1-6alkyl), -C1-6alkyl-N-(C1-6alkyl)(C1-6alkyl)-OH,-C1-6alkyl-N-(C1-6alkyl)( C1-6alkyl)-O-C1-6alkyl), -C1-6alkyl-NH-C3-8cycloalkyl,-C1-6alkyl-NH-4- to 6-membered heterocycloalkyl, -C1-6alkyl-4- ttoo 6-membered heterocycloalkyl, -C1-6alkyl-NHC(O)-(C1-6alkyl), -C1-6alkyl-SO2-C1-6alkyl, -C1-6alkyl-SO2-NH-C1-6alkyl, -CN, -C(O)NH2, -C(O)NHC1-6alkyl), -C(O)NC1-6alkyl) C1-6alkyl), -NH2, -NHC1-6alkyl, -N(C1-6alkyl)(C1-6alkyl), -SO2(C1-6alkyl),— SO2— NH((C1-6alkyl), or aryl, wherein any said C1-6alkyl, C3-8cycloalkyl, -C1-6alkyl-OH, -C1-6alkyl-NH2, -C1-6alkyl-NHC1-6alkyl), -C1-6alkyl-NH-C3-8cycloalkyl, -C1-6alkyl-NH-4- to 6-membered heterocycloalkyl, or -C1-6alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen;213 each R6is independently hydrogen, halogen, C1-6alkyl, C2-6alkenyl, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl), C2-6alkenyl, -O-C1-6alkyl, -NH2, -NH(CI-6alkyl), -N(CI-6 alkyl)(C1-6alkyl), -NCH2, or -CHNH; or R1and any R6taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, C1-6alkyl, -C1-6alkyl-C3-8cycloalkyl, haloC1-6alkyl, and C3-8cycloalkyl; each R7is independently hydrogen, halogen, C1-6alkyl, or C2-6alkenyl; or any R6and any R7taken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by one or two substituents independently selected from halogen, C1-6alkyl, haloC1-6alkyl, and C3-8cycloalkyl;R8is hydrogen, halogen, or C1-6alkyl, wherein said C1-6alkyl is optionally substituted one, two, or three times by halogen;R9is hydrogen, C1-6alkyl, -C1-6alkyl-SCh-C1-6alkyl, -C1-6alkyl-aryl, or -C1-6alkyl-5- 6-membered heteroaryl, wherein said C1-6alkyl, -C1-6alkyl-SCh-C1-6alkyl, -C1-6alkyl-aryl, or -C1-6alkyl-5-6-membered heteroaryl is optionally substituted one, two, or three times by halogen, and each R10is independently halogen, C1-6alkyl, C3-8cycloalkyl, - ■CCNN,, -C1-6alkyl-OH, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl), -OH, C1-4alkoxy, -O-C3-8cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein C1-6alkyl, C3-8cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, or C1-4alkoxy.

[0108] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 11.TABLE 11215WO2022152852 | GSK

[0109] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 152852, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (XI):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is hydrogen, halogen, C1-6alkyl, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl),-C1-6alkyl~N(C1-6alkyl)(C1-6alkyl), -C1-6alkyl-Ca-s cycloalkyl, -C1-6alkyl-aryl, 5- or 6- membered heteroarylC1-4alkyl-, C3-8cycloalkyl, C2-6alkenyl, - C2-6alkenyl-C3-8cycloalkyl,-OH, C1-6alkoxy, -O-C2-6alkenyl, -O-C1-6alkyl-C3-8cycloalkyl), -O-C3-8cycloalkyl, -O-aryl,-O-heteroaryl, -CO2H, -CO2C1-6alkyl, -CO2C3-8cycloalkyl, -O2CC1-6alkyl,216-O2CC3-8cycloalkyl, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)(C1-6alkyl), aryl, or 5-6 membered heteroaryl, wherein the C1-6alkyl, -C1-6alkyl-Cs-8 cycloalkyl, C1-6alkoxy, -O-aryl, -O-heteroaryl, aryl, or 5-6 membered heteroaryl ofR1is optionally substituted one, two, or three times by R8; each R2is independently hydrogen, hydroxyl, halogen, or C1-6alkyl; each R3and R4is independently selected from hydrogen, -CN, C1-6alkyl, C3-8cycloalkyl, -OH, C1-6alkoxy, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)(C1-6alkyl), 5-membered heteroaryl, 5-6 membered heterocycloalkyl or 5-6 membered lactam, wherein the C1-6alkyl, 5-membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered lactam of R3or R4is optionally substituted one, two, or three times by R9; each of R5a, R5b, R6aand R6bis independently hydrogen, halogen, C1-6alkyl, -C1-6alkyl-NH2, -C1-6alkyl-NH(C1-6alkyl), -C1-6alkyl-N(C1-6alkyl)(C1-6alkyl), C2-6alkenyl, -NH2, -NH(CI-6alkyl), -N(CI-6 alkyl)(C1-6alkyl), -NCH2, or -CHNH; or R1and R5aor R5btaken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, C1-6alkyl, -C1-6alkyl-C3-8cycloalkyl, haloC1-6alkyl, and C3-8cycloalkyl; or any of R5aR5b, R6aand R6btaken together with the atoms to which they are attached, form a 5-, 6-, or 7-membered ring optionally containing one, two, or three heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally substituted by oonnee or two substituents independently selected from halogen, C1-6alkyl, haloC1-6alkyl, and C3-8cycloalkyl; each of R7aand R7bis independently selected from hydrogen, halogen, -OH or C1-6alkyl optionally substituted one, two, or three times by halogen; each R8is independently halogen, C1-6alkyl, C3-8cycloalkyl, -OH, C1-6alkoxy, -O-C3-8cycloalkyl, aryl, or 5-6 membered heteroaryl, wherein any said C1-6alkyl, C3-8cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted one, two, or three times by halogen; each R9is independently halogen, C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, -C1-6alkyl-aryl, or -OH, wherein any said -C1-6alkyl-aryl is optionally substituted one, two, or three times by C1-6alkoxy;R10is hydrogen, C1-6alkyl, or C1-6alkoxy;217R11is hydrogen, C1-6alkyl, or C1-6alkoxy; andR12is CO2-(C i-6 alkyl), C(=O)-(C1-6alkyl) optionally substituted with 1, 2 or 3 halogen atoms or SO2-C1-6alkyl.

[0110] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 12.218219220221222WO2022152853 | GSK

[0111] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2022 / 152853, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (XII):223 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:X is C(R2)2, O orNR3;X1is CH or N; n is 0 or 1 ;R1is -O-R4or a halogen; each R2is independently H or a halogen;R3is H, halogen, -CO2C1-6alkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloalkyl, -CO-(3 -6-membered cycloalkyl), C1-6alkyl, CO-NHC1-6alkyl, COOC1-6alkyl or CN, wherein any C1-6alkyl of R3is optionally substituted 1, 2 or 3 times with a halogen or CN; and wherein the or 5- or 6-membered heteroaryl of R3is optionally substituted with halogen, Ci -6 alkyl or CN;R4is phenyl or pyridinyl wherein each phenyl or pyridinyl is optionally substituted with 1, 2 or 3 halogen atoms; andR7is H, pyridinyl or pyridone wherein the pyridinyl of R7is optionally substituted with O or the pyridinyl nitrogen is optionally an N-oxide.

[0112] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 13.224225226US2021128561 | Katholieke Universiteit Leuven

[0113] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in US 2021 / 1128561, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (XIII):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:K means =0 or =S or =NH, W means -CR1=, and L means -R2; orK means -R2, W means -CR1=, and L means =0; orK means -Rl, W means ~N=, and L means -R2; or227K means -Rl, W means -CH=, and L means -R2;X means -N= and Y means -NR3-; orX means -NR4- and Y means -N=; orX means -NR4- and Y means -CR0=; orX means -N= and Y means -S-; orX means -O- and Y means -N=; orX means -S- and Y means -N=; orX means -N= and Y means -N=;RO, Rl, R2, R3, R4independently of one another mean -H; -C1-6alkyl; -C1-6-cycloalkyl; -phenyl; C1-6alkyl-phenyl; -heteroaryl selected from the group consisting of thienyl, furanyl and pyrrolyl;-C(=O)OH; -C(=O)O-C1-6alkyl; -CN; -OH; -O-C1-6alkyl, -NH2, -S-C1-6alkyl; -F, -Cl, -Br, or -I; or Rl and R2together with the atoms to which they are attached form a six membered saturated unsubstituted alicyclic ring;R9 and RIO independently of one another mean --HH,, -C1-6alkyl, CN, OH, -O-C1-6alkyl, -F, -Cl, -Br, -I; or R9 and RIO together with the carbon atoms to which they are attached form a phenyl ring optionally substituted with R5, R6, R7 and R8; wherein R5, R6, R7 and R8 independently of one another mean -H, -C1-6alkyl, -CN, -OH, -O-C1-6alkyl, -F, -Cl, -Br, -I; or R6 and R7 together with the carbon atoms to which they are attached form an unsubstituted phenyl ring; wherein in each case the C1-6alkyl may be linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from -CN, -C(=O)OH,C(=O)O-C1-6alkyl, OH, O-C1-6alkyl, -NH2, -NH-C1-6alkyl, -N(Ci.6alkyl)2, -N3, -F, Cl, -Br, -I; wherein in each case the C1-6-cycloalkyl may be linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from -CN, -C(=O)OH, -C(=O)O-C1-6alkyl, -OH, -Q-C1-6alkyl, -NH2, -NH-C1-6alkyl, -N(CI-6alkyl)2, -N3, -F, -Cl,Br, -I; wherein in each case the phenyl may be unsubstituted, mono- or disubstituted with a substituent independently selected from -CN, -C(=O)OH, -C(=O)-C1-6alkyl, OH, -O-C1-6alkyl, -NH2, -NH-C1-6alkyl, -N(CI-6alkyl)2, -N3, -F, -Cl, -Br, -I; wherein in each case the heteroaryl may be linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from -CN, -C(=O)OH,228C(=0)0-C1-6alkyl, OH, O-C1-6alkyl, NH2, -NH-CI-6 alkyl, -N(CI-6 alkyl)2, -N3, -F,Cl, -Br, -I.

[0114] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 14.229230231232

[0115] In another embodiment, the small molecule MRGPRX2 modulator is:or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.233WO2020223255 | Solent Therapeutics

[0116] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2020 / 223255, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (XIV):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:L is selected from a bond and C 1-4 alkanediyl;R1is selected from:(a) C1-4alkyl which is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C1-4alkoxy, amino and aminocarbonyl, wherein each of the C1-4alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with from 0 to 2 substituents independently selected from C1-4alkyl; and(b) a cyclic group selected from C3-8cycloalkyl, C2-9 heterocyclyl, Ce-14 aryl and Ci -9 heteroaryl, wherein the cyclic group is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C1-4alkyl, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the C1-4alkyl and C1-4alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with from 0 to 2 substituents independently selected from C1-4alkyl;R2is selected from:(a) Ci-4 alkyl which is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C1-4alkoxy and amino; and(b) a cyclic group selected from C3-8cycloalkyl, C2-9 heterocyclyl, Ce-14 aryl and Ci -9 heteroaryl, wherein the cyclic group is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C1-4alkoxy, amino, C3-8cycloalkyl and C3-5 heterocyclyl, provided the cyclic group has no more than one optional substituent which234 is selected from C3-8cycloalkyl and C3-5 heterocyclyl, and wherein each of the C1-4alkyl, C1-4alkoxy, C3-8cycloalkyl and C3-5 heterocyclyl optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein the amino optional substituent is independently substituted with from 0 to 2 substituents independently selected from C1-4alkyl; andR3, R4, and R5are each independently selected from hydrogen, halo, cyano, and C1-3alkyl; wherein each of the aforementioned heterocyclyl and heteroaryl moieties independently has 1 to 4 heteroatoms as ring members, each independently selected from N, O, and S.

[0117] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 15.239240242244

[0118] In another embodiment, the small molecule MRGPRX2 modulator is:or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.US 2022 / 0401435 | University of Hong Kong

[0119] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in US 2022 / 401435, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (XV):245or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:(a) wherein n is an integer from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or 0 or 1 ;(b) wherein R' and R" are independently a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, an amido, an amino, an oxo, a phosphonium, a phosphanyl, a phosphonyl, a silyl, a sulfinyl, a sulfonyl, a thiol, a hydroxyl, or a halogen;(c) wherein A' and Z' are independently a substituted or unsubstituted polyaryl or a substituted or unsubstituted polyheteroaryl; and(d) wherein the substituents are independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, a halogen, a hydroxyl, a phenoxy, an aroxy, an alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, an carboxyl, an amino, an amido, an oxo, a silyl, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, or a thiol.

[0120] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 16.246WO 2023 / 039448 | University of North Carolina

[0121] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2023 / 039448, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the stmcture of Formula (XVI):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:X is S or O;Ring A is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;L1is substituted or unsubstituted alkylene;unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or247 substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B, R1C, and R1Dare independently hydrogen, halogen, -CCh, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH,CONH2, -N02, SH, SO3H, OSO3H, SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2,NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, - NNHHOOHH,, -OCCI3, OCBr3, OCF3,OCI3, -OCH2CI, -OCH2B1-, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or un substituted heteroaryl;X1is independently -F, -Cl, -Br, or -I; nl is an integer from 0 to 4; ml and vl are independently 1 or 2; and zl is an integer from 0 to 4.

[0122] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 17.248CN112076185 | Xi'an Jiaotong University

[0123] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in CN 112076185, the entirety of which is incorporated herein by reference. In another249 embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (XVII):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1, R2, R3, and R4are each, individually, hydrogen, fluorine, chlorine, bromine or trifluoromethyl; andR1', R2', R3', and R4' are each, individually, hydrogen, fluorine, chlorine, bromine or trifluoromethyl.

[0124] In one embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of a compound of Table 18.250W02025042730 | Incyte

[0125] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2025 / 042730, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4; provided that at least one of X3and X4is N;X5is N or CR5;X6is N or CR6;251R1, R2, R3, R4, R5, and R6are each independently selected from H, D, C1-6alkyl, C2- 6 alkenyl, C2-6alkynyl, Cnshaloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NORal)Rbl, C(=NRel)NRclRdl, NRclC(=NR61)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(O)(=NH)Rbl, S(O)2NRclRdl, P(O)(NH2)Rbl, or P(O)(NH2)ORal; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R1, R2, R3, R4, R5, and R6are each optionally substituted with 1, 2, 3, or 4 substituents each independently selected from R10A; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming R1, R2, R3, R4, R5, and R6are each optionally substituted with 1, 2, 3, or 4 substituents each independently selected from R10B;R7and R8are each independently selected from H, D, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cue haloalkyl, C3-10cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C3-10cycloalkyl and 4-10 membered heterocycloalkyl forming R7and R8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20A; and wherein the C1-6alkyl, C2-6alkenyl, andC2-6alkynyl forming R7and R8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20B;A is a group of the Formula (A);wherein represents the point of attachment of A to the remainder of the molecule;R9Aand R9B, together with the carbon atom to which they are both attached, form a C3-12 cycloalkane or 4-12 membered heterocycloalkane ring, wherein the C3-12 cycloalkane or 4-12 membered heterocycloalkane ring formed by R9Aand R9Bis optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from RA;Cy is a ring selected from C6-10aryl and 5-10 membered heteroaryl; wherein the C6-10aryl and 5-10 membered heteroaryl forming Cy are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy;252 each RAis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NORal)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(O)2NRclRdl, S(O)(=NRel)Rbl, P(O)(ORal)(ORal), P(O)(ORal)Rbl, P(O)(NH2)Rbl, P(O)(NH2)(ORal), and B(ORal)(ORal); wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl- C1-3alkylene forming RAare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA1; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RAare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA2; each RA1is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and RA2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RA1are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA2, each RA2is independently selected from C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-Cn 3 alkylene, halo, CN, ORa3, SR33, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, S(O)2NRc3Rd3, S(O)(=NRe3)Rb3, P(O)(ORa3)(ORa3), P(O)(ORa3)Rb3, P(O)(NH2)Rb3,P(O)(NH2)(ORa3), and B(ORa3)(ORa3); wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl- C1-3alkylene forming RA2are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA3; each RA3is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORa8, SRa8, C(O)Rb8, C(O)NRc8Rd8, C(O)ORa8, OC(O)Rb8, OC(O)NRc8Rd8, NRc8Rd8, NRc8C(O)Rb8, NRc8C(O)ORa8,253NRc8C(O)NRc8Rd8, C(=NRe8)Rb8, C(=NORa8)Rb8, C(=NRe8)NRc8Rd8, NRc8C(=NRe8)NRc8Rd8, NRc8S(O)Rb8, NRc8S(O)2Rb8, NRc8S(O)2NRc8Rd8, S(O)Rb8, S(O)NRc8Rd8, S(O)2Rb8, and S(O)2NRc8Rd8; wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming RA3are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RA3are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; each RCyis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NORa2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming RCyare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCyl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RCyare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2; each RCylis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and RCy2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RCylare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2; each RCy2is independently selected from C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-Cl-3 alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-Ci- 3 alkylene, halo, CN, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, Oslo aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3254 alkylene forming RCy2are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; each R10Ais independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and R10B; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming R10Aare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10B; each R10Bis independently selected from C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-Ci- 3 alkylene, halo, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NORa5)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5; wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R10Bare each optionally substituted with 1,2, 3, or 4 substituents independently selected from R11; each R11is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R11are each optionally substituted with 1, 2,3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, andC2-6alkynyl forming R11are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; each R20Ais independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming R20Aare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20B; each R20Bis independently selected from C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10255 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-Ci- 3 alkylene, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)ORa7, NRc7S(O)Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, and S(O)2NRc7Rd7; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, Ce- 10 aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R20Bare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; each Ral, Rcl, Rdl, Ra2, Rc2, Rd2, R33, Rc3, Rd3, Ra4, Rc4, Rd4, Ra5, Rc5, Rd5, Ra6, Rc6, Rd6, Ra7, RC?RCP Ra8, RC8,anj pd8 jsincjepencjently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl forming Ral, Rcl, Rdl, Ra2, Rc2, Rd2, Ra3, Rc3, Rd3, Ra4, Rc4, Rd4, Ra5, Rc5, Rd5, Ra6, Rc6, Rd6, Ra7, Rc7, Rd7, Ra8, Rc8, and Rd8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming Ral, Rcl, Rdl, Ra2, Rc2, Rd2, Ra3, Rc3, Rd3, Ra4, Rc4, Rd4, Ra5, Rc5, Rd5, Ra6, Rc6, Rd6, Ra7, Rc7, Rd7, Ra8, Rc8, and Rd8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; or any Rcland Rdlattached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc5and Rd5attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl;256 or any Rc6and Rd6attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc7and Rd7attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc8and Rd8attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; each Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from C1-6alkyl, C2- 6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, Ce- 10 aryl and 5-10 membered heteroaryl forming Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; each Rel, Re2, Re3, Re5, and Re8is independently selected from H, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylcarbonyl, C1-6alkylaminosulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, aminosulfonyl, C1-6alkylaminosulfonyl and di(C1-6alkyl)aminosulfonyl; each Rglis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and Rg2; and each Rg2is independently selected from D, OH, NO2, CN, halo, C3-6 cycloalkyl, HO-C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-2 alkylene, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl-Ci-2 alkylene, C1-6alkoxy, C1-6haloalkoxy, C1-3alkoxy-C1-3alkyl, C1-3alkoxy- C1-3alkoxy, HO-C1-3alkoxy, HO-C1-3alkyl, cyano-C1-3alkyl, H2N-C1-3alkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, Cl-6 alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, Cl-6 alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino;257 wherein at each occurrence, a heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the N and S ring-forming heteroatoms of the heterocycloalkyl group are optionally oxidized; and a ringforming carbon atom of the heterocycloalkyl group is optionally substituted by oxo to form a carbonyl group; at each occurrence, a heterocycloalkane ring has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the N and S ringforming heteroatoms of the heterocycloalkane ring are optionally oxidized; and a ring- forming carbon atom of the heterocycloalkane ring is optionally substituted by oxo to form a carbonyl group; and at each occurrence, a heteroaryl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the N and S ringforming heteroatoms of the heteroaryl group are optionally oxidized; and a ring-forming carbon atom of the heteroaryl group is optionally substituted by oxo to form a carbonyl group.

[0126] In some embodiments, the compound of Formula (I) is selected from:4-(((7-chloro-2-(trifluoromethyl)imidazo[l,2-a]pyrimidin-5-yl)amino)methyl)-4- phenylpiperidine-1 -carboxamide;4-phenyl-4-(((2-(trifhioromethyl)imidazo[l,2-c]pyrimidin-5-yl)amino)methyl)piperidine- 1 -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylpyrrolidine-1 -sulfonamide;(R)-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylpyrrolidine-1 -sulfonamide;(S)-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylpyrrolidine-1 -sulfonamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylpyrrolidine-1 -carboxamide;(R)-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylpyrrolidine-1 -carboxamide;(S)-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylpyrrolidine-1 -carboxamide;4-(((7-chloro-2-(trifluoromethyl)imidazo[l,2-c]pyrimidin-5-yl)amino)methyl)-4- phenylpiperidine- 1 -sulfonamide;2584-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- phenylpiperidine- 1 -sulfonamide;4-(((5-methyl-2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- phenylpiperidine- 1 -carboxamide;2-methyl-N-((4-phenylpiperidin-4-yl)methyl)-5-(trifluoromethyl)pyrazolo[l,5- a]pyrimidin-7-amine;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4-fluoro- lH-pyrazol-l-yl)azetidine-l -sulfonamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4-fluoro-1 H-py razol - 1 -y l)azeti dine- 1 -carb oxami de;3-(4-fluoro-lH-pyrazol-l-yl)-3-(((2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-5- yl)amino)methyl)azetidine- 1 -sulfonamide;3-(4-fluoro-lH-pyrazol-l-yl)-3-(((2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-5- yl)amino)methyl)azetidine- 1 -carboxamide;N-methyl-4-phenyl-4-(((2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-5- yl)amino)methyl)piperidine- 1 -carboxamide; methyl 4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- phenylpiperidine-1 -carboxylate;4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-N-methyl-4- phenylpiperidine-1 -carboxamide;4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- phenylpiperidine-1 -carboxamide;N-((l-methyl-4-phenylpiperidin-4-yl)methyl)-2,5-bis(trifluoromethyl)pyrazolo[l,5- a]pyrimidin-7-amine;N-methyl-4-(((5-methyl-2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-phenylpiperidine-l -carboxamide;(3,3-difluoroazetidin-l-yl)(4-phenyl-4-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5- yl)amino)methyl)piperidin- 1 -yl)m ethanone; l-(4-phenyl-4-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5-yl)amino)methyl)piperidin- l-yl)ethan-l-one;N-methyl-4-phenyl-4-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5- yl)amino)methyl)piperidine- 1 -carboxamide;2594-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4-(5- fluoropyri din-2 -yl)piperi dine- 1 -carboxamide;2-(4-(5-fluoropyridin-2-yl)-4-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5- yl)amino)methyl)piperidin- 1 -yl)ethan- 1 -ol;3-(4-(5-fluoropyridin-2-yl)-4-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5- yl)amino)methyl)piperidin-l-yl)-3 -oxopropanenitrile;3-(((7-chloro-2-(trifluoromethyl)imidazo[l,2-a]pyridin-5-yl)amino)methyl)-3-(5- fluoropyri din-2 -yl)-N-methylazeti dine- 1 -carboxamide;N-methyl-4-(((2-(perfluoroethyl)imidazo[l,2-a]pyridin-5-yl)amino)methyl)-4- phenylpiperidine-1 -carboxamide;4-(((7-chloro-2-(trifluoromethyl)imidazo[l,2-a]pyridin-5-yl)amino)methyl)-N-methyl-4- phenylpiperidine-1 -carboxamide;N-methyl-4-(((7-methyl-2-(trifluoromethyl)imidazo[l,2-a]pyridin-5-yl)amino)methyl)-4- phenylpiperidine- 1 -carboxamide;4-(((2-isopropylimidazo[l,2-a]pyridin-5-yl)amino)methyl)-N-methyl-4-phenylpiperidine- 1 -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -sulfonamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide;3-(4-fluorophenyl)-3-(((2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-5- yl)amino)methyl)azetidine- 1 -sulfonamide;3-(4-fluorophenyl)-3-(((2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-5- yl)amino)methyl)azetidine-l -carboxamide; 3-(4-fluorophenyl)-3-(((2-(trifluoromethyl)imidazo[l,2-a]pyri din-5- yl)amino)methyl)azetidine-l -sulfonamide;3-(4-fluorophenyl)-3-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5- yl)amino)methyl)azetidine- 1 -carboxamide;N-((l-(4-fluorophenyl)cyclobutyl)methyl)-2-(trifluoromethyl)imidazo[l,2-a]pyri din-5- amine;N-((l-(pyridin-4-yl)cyclobutyl)methyl)-2-(trifluoromethyl)imidazo[l,2-a]pyri din-5- amine;N-((l-(4-bromophenyl)cyclobutyl)methyl)-2-(trifluoromethyl)imidazo[l,2-a]pyri din-5- amine; and260N-((4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)methyl)-2- (trifluoromethyl)imidazo[l,2-a]pyridin-5-amine; or a pharmaceutically acceptable salt of any of the aforementioned compounds.

[0127] In some embodiments, the compound of Formula (I) is selected from:6-(4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4-(4- fluorophenyl)piperidin-l-yl)-2-methylpyridazin-3(2H)-one;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4-fluoro- IH-pyrazol- 1 -yl)-N-methylazetidine- 1 -carboxamide;N-((l-(5-amino-lH-l,2,4-triazol-3-yl)-4-phenylpiperidin-4-yl)methyl)-5- (difluoromethyl)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-((3-(4-methylpiperazin-l-yl)-l-phenylcyclobutyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-(((ls,3s)-3-(4-methylpiperazin-l-yl)-l-phenylcyclobutyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-(((lr,3r)-3-(4-methylpiperazin-l-yl)-l-phenylcyclobutyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-((3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylcyclobutyl)amino)ethan- 1 -ol;2-(((ls,3s)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-phenylcyclobutyl)amino)ethan-l-ol;2-(((lr,3r)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-phenylcyclobutyl)amino)ethan-l-ol;5-(3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidin- 1 -yl)pyrazine-2-carbonitrile;N-((3-(4-fluorophenyl)-l-(l-methyl-lH-l,2,3-triazol-4-yl)azetidin-3-yl)methyl)-2,5- bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;6-(3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidin-l-yl)picolinamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lr,3r)-3-hydroxycyclobutyl)azetidine-l-carboxamide;261(R)-(4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4-(4- fluorophenyl)piperidin-l-yl)(l-methylazetidin-2-yl)methanone;4-(3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidin-l-yl)-l-cyclopropylpyridin-2(lH)-one;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((ls,3s)-3-hydroxy-3-methylcyclobutyl)azetidine-l -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lR,3R)-3-hydroxycyclopentyl)azetidine-l-carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((l s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)azetidine- 1 -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lr,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)azetidine-l-carboxamide;4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4-(4- fluorophenyl)-N-((lR,3R)-3-hydroxycyclopentyl)piperidine-l-carboxamide;3-(((2-chloro-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide;3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- chlorophenyl)azetidine- 1 -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(5- fluoropyri din-2 -yl)azeti dine- 1 -sulfonamide;2-(azetidin-l-yl)-l-(4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-(4-fluorophenyl)piperidin- 1 -yl)ethan- 1 -one;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(5- fluoropyri din-2 -yl)-N-(methyl-d3)azetidine-l-carboxamide;3-(((2-(difluoromethyl)-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-(4-fluorophenyl)-N-(methyl-d3)azetidine-l -carboxamide;N-cyclopropyl-3-(((2-(difluoromethyl)-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-(4-fluorophenyl)azetidine-l -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-N-(3- cyanobicyclo[l.l.l]pentan-l-yl)-3-(5-fluoropyri din-2 -yl)azetidine-l -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-N-(3- cy anobicy clo[ 1.1.1 ]pentan- 1 -y 1 ) - 3 -(3 ,5 -difluorophenyl)azetidine- 1 -carboxamide;2623-(((5-chloro-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide;3-(4-fluorophenyl)-3-(((5-methyl-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimi din-7- yl)amino)methyl)azetidine- 1 -carboxamide;3-(((5-ethyl-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide;3 -(((5 -cy clopropyl-2-(trifluoromethyl)pyrazol o[ 1 , 5 -a]pyrimidin-7-yl)amino)methyl)-3- (4-fluorophenyl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l -carboxamide;3-(4-fluorophenyl)-3-(((5-(methyl-d3)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)azetidine- 1 -carboxamide; and3-(((5-ethyl-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-(2,2,2-trifluoroethyl)azetidine-l -carboxamide; or a pharmaceutically acceptable salt of any of the aforementioned.

[0128] In some embodiments, the compound of Formula (I) is selected from: l-amino-4-(((5-ethyl-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- (4-fluorophenyl)cyclohexane-l -carbonitrile; l-((3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)cyclobutyl)amino)-2-methylpropan-2-ol; l-((4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4-(4- fluorophenyl)cyclohexyl)amino)-2-methylpropan-2-ol;N-((( 1 s, 3 s)-3 -methoxy- 1 -phenylcyclobutyl)methyl)-2, 5 -bi s(trifluoromethyl)pyrazolo[ 1,5- a]pyrimidin-7-amine;1-amino-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)cy clobutane- 1 -carboxamide,2-methyl-N-((3-phenyltetrahydrofuran-3-yl)methyl)-5-(trifluoromethyl)pyrazolo[l,5- a]pyrimidin-7-amine;5-iodo-2-methyl-N-((3-phenyltetrahydrofuran-3-yl)methyl)pyrazolo[l,5-a]pyrimidin-7- amine;3-(((7-chloro-2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-5-yl)amino)methyl)-3- phenylazetidine-1 -carboxamide;3-(((2,7-bis(trifluoromethyl)imidazo[l,2-a]pyrimidin-5-yl)amino)methyl)-3-(4- fluorophenyl)cyclobutan- 1 -ol;2633-((4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- phenylcyclohexyl)amino)propanenitrile;2-bromo-N-((l-phenylcyclopent-3-en-l-yl)methyl)-5-(trifluoromethyl)pyrazolo[l,5- a]pyrimidin-7-amine;2-bromo-N-((4-(methylamino)-l-phenylcyclohexyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylcy cl opentan- 1 -ol ;N-(4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- phenylcyclohexyl)-N-methylacetamide;3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- (pyridin-4-yl)cy cl opentan- 1 -ol ;2-bromo-N-((3-(methylamino)-l-(pyridin-3-yl)cyclopentyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;(2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-2- (pyridin-2-yl)cyclopropyl)methanol;(2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-2- phenylcyclopropyl)methanol;4-(3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidin- 1 -yl)- 1 -methylpyrimidin-2(lH)-one;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lr,3r)-3-hydroxy-3-methylcyclobutyl)azetidine-l-carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-(((lr,3r)-3-hydroxycyclobutyl)methyl)azetidine-l -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lS,2S)-2-hydroxycyclobutyl)azetidine-l -carboxamide;3 -(((2-cy clopropyl-5 -(trifluoromethyl)pyrazol o[ 1 , 5 -a]pyrimidin-7-yl)amino)methyl)-3- (IH-pyrazol-l-yl)azetidine-l-sulfbnamide;3 -(((2-cy ano-5 -(trifluoromethyl)pyrazolo[ 1 , 5 -a]pyrimidin-7 -yl)amino)methyl)-3 -( 1 H- pyrazol- 1 -yl)azetidine- 1 -sulfonamide;3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l -carboxamide;2643-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(6- methylpyri din-3 -yl)azetidine- 1 -sulfonamide;3-(((2-(difluoromethyl)-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-(4-fhiorophenyl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l-carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(5- fluoropyri din-2 -yl)-N-((lr,4r)-4-hydroxycy cl ohexyl)azeti dine- 1 -carboxamide;3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(3,4- difluorophenyl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l -carboxamide;3-(4-fluorophenyl)-N-(methyl-d3)-3-(((2-(trifluoromethyl)imidazo[l,2-a]pyridin-5- yl)amino)methyl)azetidine- 1 -carboxamide;3 -(4-fluorophenyl)-N-(( 1 r,4r)-4-hy droxy cy clohexyl)-3 -(((2-(trifluoromethyl)imidazo[l,2- a]pyridin-5-yl)amino)methyl)azetidine-l-carboxamide;3-(4-fluorophenyl)-N-(methyl-d3)-3-(((2-(trifluoromethyl)-[l, 2, 4]tri azolof l,5-a]pyridin- 5-yl)amino)methyl)azetidine- 1 -carboxamide;5-chloro-7-(((4-phenylpiperidin-4-yl)methyl)amino)pyrazolo[l,5-a]pyrimidine-2- carbonitrile;3-(((5-(dimethylamino)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-(4-fluorophenyl)azetidine-l -sulfonamide;3-(4-fluorophenyl)-3-(((5-methoxy-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)azetidine- 1 -sulfonamide;3 -(((5 -cy clopropyl-2-(trifluoromethyl)pyrazol o[ 1 , 5 -a]pyrimidin-7-yl)amino)methyl)-3 - (4-(dimethylcarbamoyl)phenyl)-N-(methyl-d3)azetidine-l-carboxamide;3-(((5-cyclobutyl-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-(methyl-d3)azetidine-l-carboxamide;3-(4-fluorophenyl)-3-(((5-(methyl-d3)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-N-(2,2,2-trifluoroethyl)azetidine-l-carboxamide;N-(2,2-difluoroethyl)-3-(4-fluorophenyl)-3-(((5-(methyl-d3)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)azetidine-l-carboxamide;3-(((5-(ethyl-d5)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide; and3-(((5-(ethyl-d5)-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3-(4- fluorophenyl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l -carboxamide; or a pharmaceutically acceptable salt of any of the aforementioned.265

[0129] In some embodiments, the compound of Formula (I) is selected from:2-bromo-N-(((ls,3s)-3-(4-methylpiperazin-l-yl)-l-phenylcyclobutyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-(((lr,3r)-3-(4-methylpiperazin-l-yl)-l-phenylcyclobutyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-(((ls,3s)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-phenylcyclobutyl)amino)ethan-l-ol;2-(((lr,3r)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-phenylcyclobutyl)amino)ethan-l-ol;(ls,4s)-l-amino-4-(((5-ethyl-2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-(4-fluorophenyl)cyclohexane-l -carbonitrile;( 1 r,4r)- 1 -amino-4-(((5 -ethyl-2-(trifluoromethyl)pyrazolo[ 1 , 5 -a]pyrimidin-7- yl)amino)methyl)-4-(4-fluorophenyl)cyclohexane-l -carbonitrile; l-(((lr,3r)-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- (4-fluorophenyl)cyclobutyl)amino)-2-methylpropan-2-ol; l-(((ls,3s)-3-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- (4-fluorophenyl)cyclobutyl)amino)-2-methylpropan-2-ol; l-(((lr,4r)-4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- (4-fluorophenyl)cyclohexyl)amino)-2-methylpropan-2-ol;1-(((ls,4s)-4-(((2,5-bis(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-4- (4-fluorophenyl)cyclohexyl)amino)-2-methylpropan-2-ol;3-(((lr,4r)-4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-phenylcyclohexyl)amino)propanenitrile;3-(((ls,4s)-4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-phenylcyclohexyl)amino)propanenitrile;2-bromo-N-(((lr,4r)-4-(methylamino)-l-phenylcyclohexyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-((( Is, 4s)-4-(m ethylamino)- 1-phenylcycl ohexyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;(lR*,3S*)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-phenylcyclopentan-l-ol;(lS*,3S*)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-phenylcyclopentan-l-ol;266(lR,3S)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 3 -phenylcyclopentan- 1 -ol;(lS,3R)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 3 -phenylcyclopentan- 1 -ol;(lS,3S)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3- phenylcyclopentan- l-ol;(lR,3R)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 3 -phenylcyclopentan- 1 -ol;N-((lr,4r)-4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-phenylcyclohexyl)-N-methylacetamide;N-((ls,4s)-4-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-4-phenylcyclohexyl)-N-methylacetamide;(lR*,3R*)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-(pyridin-4-yl)cyclopentan-l-ol;(lR*,3S*)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-3-(pyridin-4-yl)cyclopentan-l-ol;(lR,3R)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 3 -(pyndin-4-y l)cy cl opentan- 1 -ol ;(lS,3S)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 3 " (pyridin-4-yl)cycl opentan- 1 -ol;(lR,3S)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-3 -(pyridin-4-y l)cy cl opentan- 1 -ol ;(lS,3R)-3-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 3 -(pyndin-4-y l)cy cl opentan- 1 -ol ;2-bromo-N-(((lR*,3R*)-3-(methylamino)-l-(pyridin-3-yl)cyclopentyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-(((lS*,3R*)-3-(methylamino)-l-(pyridin-3-yl)cyclopentyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-(((lR,3R)-3-(methylamino)-l-(pyridin-3-yl)cyclopentyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2-bromo-N-(((lS,3S)-3-(methylamino)-l-(pyridin-3-yl)cyclopentyl)methyl)-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine; 2-bromo-N-(((lR,3S)-3-(methylamino)-l- (pyridin-3-yl)cyclopentyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;2672-bromo-N-(((lS,3R)-3-(methylamino)-l-(pyridin-3-yl)cyclopentyl)methyl)-5- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-amine;((lR*,2S*)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-2-(pyridin-2-yl)cyclopropyl)methanol;((lR*,2R*)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-2-(pyridin-2-yl)cyclopropyl)methanol;((lR,2S)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 2-(pyridin-2-yl)cyclopropyl)methanol;((lS,2R)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 2-(pyridin-2-yl)cyclopropyl)methanol;((lR,2R)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 2-(pyridin-2-yl)cyclopropyl)methanol;((lS,2S)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 2-(pyri din-2 -yl)cyclopropyl)methanol;((lR*,2R*)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-2-phenylcyclopropyl)methanol;((lR*,2S*)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7- yl)amino)methyl)-2-phenylcyclopropyl)methanol;((lR,2R)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 2-phenylcyclopropyl)methanol;((lS,2S)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)-2-phenylcyclopropyl)methanol; ((lR,2S)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5- a]pyrimidin-7-yl)amino)methyl)- 2-phenylcyclopropyl)methanol;((lS,2R)-2-(((2-bromo-5-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)methyl)- 2-phenylcyclopropyl)methanol; or a pharmaceutically acceptable salt of any of the aforementioned.WO2025042736 | Incyte

[0130] In one embodiment, the small molecule MRGPRX2 modulator is a compound disclosed in WO 2025 / 042736, the entirety of which is incorporated herein by reference. In another embodiment, the small molecule MRGPRX2 modulator is a compound having the structure of Formula (I):268or a pharmaceutically acceptable salt thereof, wherein: X1is N or CR1; and R5are each independently selected from H, D, C1-6alkyl, C2-6alkenyl,C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)ORal, NRclC(O)NRclRdl, C(=NRel)Rbl, C(=NORal)Rbl, C(=NRel)NRclRdl, NRclC(=NRel)NRclRdl, NRclS(O)Rbl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(O)(=NH)Rbl, S(O)2NRclRdl, P(O)(NH2)Rbl, or P(O)(NH2)ORal, wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R1, R2, R3, R4, and R5are each optionally substituted with 1, 2, 3, or 4 substituents each independently selected from R10A; and wherein the Cue alkyl, C2-6alkenyl, and C2-6alkynyl forming R1, R2, R3, R4, and R5are each optionally substituted with 1, 2, 3, or 4 substituents each independently selected from R10B;R6is C1-6haloalkyl;R7and R8are each independently selected from H, D, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cue haloalkyl, C3-10cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C3-10cycloalkyl and 4-10 membered heterocycloalkyl forming R7and R8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20A; and wherein the C1-6alkyl, C2-6alkenyl, andC2-6alkynyl forming R7and R8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20B;A is a group of the Formula (A);269wherein represents the point of attachment of A to the remainder of the molecule;R9Aand R9B, together with the carbon atom to which they are both attached, form a C3-12 cycloalkane or 4-12 membered heterocycloalkane ring, wherein the C3-12 cycloalkane or 4-12 membered heterocycloalkane ring formed by R9Aand R9Bis optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from RA;Cy is a ring selected from C6-10aryl and 5-10 membered heteroaryl; wherein the C6-10aryl and 5-10 membered heteroaryl forming Cy are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RAis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl,membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl- C1-3alkylene forming RAare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA1; and wherein the C1-6alkyl, C2- e alkenyl, and C 2-6 alkynyl forming RAare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA2; each RA1is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cue haloalkyl, and R '2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RA1are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RA2; each RA2is independently selected from C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene,270 the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl -C1-3alkylene forming RA2are each optionally substituted with 1,2, 3, or 4 substituents independently selected from RA3; each RA3is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORa8, SRa8, C(O)Rb8, C(O)NRc8Rd8, C(O)ORa8, OC(O)Rb8, OC(O)NRc8Rd8, NRc8Rd8, NRc8C(O)Rb8, NRc8C(O)ORa8, NRc8C(O)NRc8Rd8, C(=NRe8)Rb8, C(=NORa8)Rb8, C(=NRe8)NRc8Rd8, NRc8C(=NRe8)NRc8Rd8, NRc8S(O)Rb8, NRc8S(O)2Rb8, NRc8S(O)2NRc8Rd8, S(O)Rh8, S(O)NRc8Rd8, S(O)2Rb8, and S(O)2NRc8Rd8; wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming RA3are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RA3are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; each RCyis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NORa2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming RCyare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCyl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RCyare each optionally substituted with 1, 2,3, or 4 substituents independently selected from RCy2; each RCylis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and RCy2; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming RCylare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2; each RCy2271 is independently selected from C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4S(O)Rb4, NRc4S(O)2Rh4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming RCy2are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; each R1OAis independently selected from Cue alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and R10B; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming R10Aare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R10B; each R10Bis independently selected from C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-Ci- 3 alkylene, halo, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NORa5)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5; wherein the C3-10cycloalkyl, 4-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-12 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R10Bare each optionally substituted with 1,2, 3, or 4 substituents independently selected from R11; each R11is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, NRc5Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6S(O)Rb6, NRc5S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Rd6; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl-C1-3alkylene forming R11are each optionally substituted with 1, 2,3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and272C2-6alkynyl forming R11are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; each R20Ais independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6haloalkyl; wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming R20Aare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R20B; each R20Bis independently selected from C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene, 5-10 membered heteroaryl-C1-3alkylene, halo, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)ORa7, NRc7S(O)Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, and S(O)2NRc7Rd7; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, Ce- 10 aryl, 5-10 membered heteroaryl, C3-10cycloalkyl-C1-3alkylene, 4-10 membered heterocycloalkyl-C1-3alkylene, C6-10aryl-C1-3alkylene and 5-10 membered heteroaryl -C1-3alkylene forming R20Bare each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; each Ral, Rcl, Rdl, Ra2, Rc2, Rd2, Ra3, Rc3, Rd3, Ra4, Rc4, Rd4, Ra5, Rc5, Rd5, Ra6, Rc6, Rd6, Ra7, RC?Rd7, Ra8, RC8,ancj j^ds js£ncjepencientiy selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl forming Ral, Rcl, Rdl, Ra2, Rc2, Rd2, Ra3, Rc3, Rd3, Ra4, Rc4, Rd4, Ra5, Rc5, Rd5, Ra6, Rc6, Rd6, Ra7, Rc7, Rd7, Ra8, Rc8, and Rd8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming Ral, Rcl, Rdl, Ra2, Rc2, Rd2, Ra3, Rc3, Rd3, Ra4, Rc4, Rd4, Ra5, Rc5, Rd5, Ra6, Rc6, Rd6, Ra7, Rc7, Rd7, Ra8, Rc8, and Rd8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; or any Rcland Rdlattached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc2and Rd2attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl;273 or any Rc3and Rd3attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc4and Rd4attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc5and Rd5attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc6and Rd6attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc7and Rd7attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; or any Rc8and Rd8attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; each Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from C1-6alkyl, C2- 6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl; wherein the C3-10cycloalkyl, 4-10 membered heterocycloalkyl, C6-10aryl and 5-10 membered heteroaryl forming Rbl, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rgl; and wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl forming Rbl, Rb2, Rb3, Rb4, Rb5, RM, j^b7,anj j^bxare eac]1 Optionapy substituted with 1, 2, 3, or 4 substituents independently selected from Rg2; each Rel, Re2, Re5, and Re8is independently selected from H, CN, C1-6alkyl, C1-6haloalkyl, Cue alkylthio, C1-6alkylsulfonyl, C1-6alkylcarbonyl, C1-6alkylaminosulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, aminosulfonyl, C1-6alkylaminosulfonyl and di(C1-6alkyl)aminosulfonyl; each Rglis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, and Rg2; and274 each Rg2is independently selected from D, OH, NO2, CN, halo, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-2 alkylene, C1-6alkoxy, Cue haloalkoxy, C1-3alkoxy-C1-3alkyl, C1-3alkoxy-C1-3alkoxy, HO-C1-3alkoxy, HO-C1-3alkyl, cyano-C1-3alkyl, H2N-C1-3alkyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkyl sulfonyl, carbamyl, C1-6alkylcarbamyl, di (Cue alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkoxy carbonyl, C1-6alkylcarbonylamino, Cue alkyl sulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C C1l--66 alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino; wherein at each occurrence, a heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the N and S ring-forming heteroatoms of the heterocycloalkyl group are optionally oxidized; and a ringforming carbon atom of the heterocycloalkyl group is optionally substituted by oxo to form a carbonyl group; at each occurrence, a heterocycloalkane ring has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the N and S ringforming heteroatoms of the heterocycloalkylene group are optionally oxidized; and a ring-forming carbon atom of the heterocycloalkylene group is optionally substituted by oxo to form a carbonyl group; and at each occurrence, a heteroaryl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the N and S ringforming heteroatoms of the heteroaryl group are optionally oxidized; and a ring-forming carbon atom of the heteroaryl group is optionally substituted by oxo to form a carbonyl group.

[0131] In some embodiments, the compound of Formula (I) is selected from:3-(((2,6-bis(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4 fluorophenyl)azetidine -1- sulfonamide;3-(4-fluorophenyl)-3-(((6-methyl-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -sulfonamide;3-(((6-bromo-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -sulfonamide;3-(((6-chloro-2-(perfluoroethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -sulfonamide;2753-(((6-chloro-2-(difluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -sulfonamide;3-(((6-bromo-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyri din-2- yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N'-cyano-3-(4- fluorophenyl)azetidine-l-carboximidamide;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-phenylpyrrolidin-2-one;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N'-cyano-4- phenylpiperidine-l-carboximidamide;3 -(4-fluoro- 1 H-pyrazol- 1 -y 1 )- 3 -(((6-fluoro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -sulfonamide;4-(((6-fluoro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-phenylpiperidine-l- sulfonamide;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-phenylpiperidine-l- sulfonamide;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-phenylpiperidine-l- carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-methyl-3- phenylpyrrolidine-1 -carboxamide;6-chloro-N-((l-methyl-4-phenylpiperidin-4-yl)methyl)-2-(trifluoromethyl)quinolin-4- amine; 6-chloro-N-((3-phenyltetrahydrofuran-3-yl)methyl)-2-(trifluoromethyl)quinolin-4-amine;6-chloro-N-((4-phenyltetrahydro-2H-pyran-4-yl)methyl)-2-(trifluoromethyl)quinolin-4- amine;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(3-fluoro-lH-pyrazol-l- yl)azetidine-l -sulfonamide;3 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-(3 , 3 - difluorocyclobutyl)-3-(5-fluoropyridin-2-yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)pyrrolidine-l-carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)-N-isopropylazetidine- 1 -carboxamide;3 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-(3 , 3 - difluorocyclobutyl)-3 -(4-fluoro- IH-pyrazol- 1 -yl)azetidine- 1 -carboxamide;2763-(((6-fluoro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)azetidine-l -sulfonamide;3-(((6-fluoro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide;3 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3 -(4-fluoro- 1 H-pyrazol- 1 - yl)-N-(methyl-d3)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-cyclopropyl-3-(4- fluoro- lH-pyrazol-l-yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-chloropyri din-2- yl)azetidine-l -sulfonamide;3-(4-chloro-lH-pyrazol-l-yl)-3-(((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)-N-(methyl-d3)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(3- fluorophenyl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- chlorophenyl)azetidine- 1 -sulfonamide;3 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methy l)-3 -(3,4- difluorophenyl)azetidine- 1 -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(2-chloropyri din-4- yl)azetidine-l -sulfonamide;3-(4-chloro-lH-pyrazol-l-yl)-3-(((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -sulfonamide;3-(4-chloro-lH-pyrazol-l-yl)-3-(((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-phenylazetidine-l- sulfonamide;2773-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-phenylazetidine-l- carboxamide;3-(4-bromo-lH-pyrazol-l-yl)-3-(((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(2-chloropyri din-4- yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(3-fluoropyridin-2- yl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)-N-methylazetidine-l -carboxamide;5-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-5-phenylpyrrolidin-2-one;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyri din-2- yl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyri din-2- yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifhioromethyl)quinolin-4-yl)amino)methyl)-N-methyl-3- phenylazetidine- 1 -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2-yl)- N- methylpyrrolidine- 1 -carboxamide;6-chloro-N-((3-(4-fluorophenyl)oxetan-3-yl)methyl)-2-(trifluoromethyl)quinolin-4- amine; 3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2-yl)-N- methylazetidine- 1 -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-methyl-3-(lH-pyrazol- l-yl)azetidine-l-carboxamide,6-chloro-N-((2-(4-fluorophenyl)-l,4-dioxan-2-yl)methyl)-2-(trifluoromethyl)quinolin-4- amine;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-cyano-lH-pyrazol-l- yl)azetidine-l -sulfonamide; or a pharmaceutically acceptable salt of any of the aforementioned.

[0132] In some embodiments, the compound of Formula (I) is selected from:2786-chloro-N-((3 -(methylamino)- 1-phenylcy cl opentyl)methyl)-2 (trifluoromethyl)quinolin- 4-amine;3-(5-fluoropyridin-2-yl)-3-(((6-methyl-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -carboxamide;3-(((7-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)azetidine-l -carboxamide;3-(((6-cyano-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)azetidine-l -carboxamide;3-(((7-fluoro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)azetidine-l -carboxamide;3-(((5-fluoro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)azetidine-l -carboxamide;3-(5-fluoropyridin-2-yl)-3-(((7-methyl-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -carboxamide;3 -(5 -fluoropyridin-2-yl)-3 -(((5 -methyl-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)azetidine- 1 -carboxamide;3-(((2,7-bis(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)azetidine-l -carboxamide,3-(((8-cyano-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5-fluoropyridin-2- yl)azetidine-l -carboxamide,3-(4-fluorophenyl)-3-(((2-(tri fluoromethyl)- 1, 6-naphthyridin-4- yl)amino)methyl)azetidine- 1 -carboxamide;3 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3 -phenyl- 1 - (trifluoromethyl)cy clobutan- 1 -ol ;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-phenylcyclohexane-l- carboxylic acid;6-chloro-2-(trifluoromethyl)-N-((3-(3-(trifluoromethyl)-lH-pyrazol-l-yl)azeti din-3- yl)methyl)quinolin-4-amine;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5,6- dihydrocyclopenta[c]pyrazol-l(4H)-yl)-N-(methyl-d3)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-(difluoromethyl)-lH- pyrazol- 1 -yl)-N-(methyl-d3)azetidine- 1 -carboxamide;2793 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-(cy anomethyl)- 1H- pyrazol- 1 -yl)-N-(methyl-d3)azetidine- 1 -carboxamide;6-chloro-N-((l-(5-fluoropyridin-2-yl)-3-((l-methyl-lH-pyrazol-5- yl)amino)cyclobutyl)methyl)-2-(trifluoromethyl)quinolin-4-amine;N-((3-aminosulfonylamino-l-phenylcyclobutyl)methyl)-6-chloro-2-(trifluoromethyl)quinolin-4-amine;N-(3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3- phenylcyclobutyl)cyclopropane- 1 , 1 -dicarboxamide;N-(3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-phenylcyclobutyl)-l- methylazetidine-3-carboxamide;N-(3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-phenylcyclobutyl)-1- methylpiperidine-4-carboxamide;N-(3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-phenylcyclobutyl)-3,3,3 -trifluoro-2-hy droxypropanamide;N-((l-(6-aminopyridazin-3-yl)-4-phenylpiperidin-4-yl)methyl)-6-chl oro-2- (trifluoromethyl)quinolin-4-amine;N-((l-(5-amino-l-(2-morpholinoethyl)-lH-l,2,4-triazol-3-yl)-4-phenylpiperi din-4- yl)methyl)-6-chloro-2-(trifluoromethyl)quinolin-4-amine;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(quinolin-2-yl)azetidine- 1 -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-methylthiazol-2- yl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(l-methyl-lH-indazol-5- yl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(l-methyl-lH-indazol-5- yl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(l-methyl-lH-indazol-6- yl)azetidine-l -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(5- fluorobenzo[d]thiazol-2-yl)azetidine- 1 -sulfonamide;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-(4-fluorophenyl)-N- ((lr,3r)-3-hydroxycyclobutyl)piperidine-l-carboxamide;2804-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-(4-fluorophenyl)-N- ((lr,4r)-4-hydroxycyclohexyl)piperidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)-N-((lr,4r)-4-hydroxycyclohexyl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)-N-((ls,4s)-4-hydroxy-4-methylcyclohexyl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluorophenyl)-N- ((lR,3R)-3-hydroxycyclopentyl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-((lr,4r)-4- cyanocyclohexyl)-3-(4-fluorophenyl)azetidine-l -carboxamide;6-chloro-N-((3 -(4-fluorophenyl)- 1 -(2-methoxy ethyl)azeti din-3 -yl)methyl)-2- (trifluoromethyl)quinolin-4-amine;N-((l-((lH-pyrazol-4-yl)methyl)-3-(4-fluorophenyl)azetidin-3-yl)methyl)-6-chl oro-2- (trifluoromethyl)quinolin-4-amine;6-chloro-N-((3-(4-fluorophenyl)-l-((2-methyl-lH-imidazol-4-yl)methyl)azetidin-3- yl)methyl)-2-(trifluoromethyl)quinolin-4-amine;4-((3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4- fluorophenyl)azetidin- 1 -yl)methyl)pyridine 1 -oxide,N-((3-amino-l-phenylcyclobutyl)methyl)-6-chloro-2-(trifluoromethyl)quinolin-4-amine;3-(((6-bromo-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)-N-(methyl-d3)azetidine-l -carboxamide;3-(4-chloro-lH-pyrazol-l-yl)-3-(((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)-N-methylazetidine-l -carboxamide;3-(4-bromo-lH-pyrazol-l-yl)-3-(((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)methyl)-N-methylazetidine-l -carboxamide;4-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-4-(5-fluoropyri din-2- yl)piperidine- 1 -sulfonamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-cyano-lH-pyrazol-l- yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-methoxy-lH-pyrazol- l-yl)azetidine-l-carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(3-methyl-lH-pyrazol-l- yl)azetidine-l -carboxamide;2813 -(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3 -(3 -cy ano- IH-pyrazol- 1 - yl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(3,5-dimethyl-lH- pyrazol- 1 -yl)azetidine- 1 -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(4-fluoro-lH-pyrazol-l- yl)-N-(3-hydroxycyclobutyl)azetidine-l -carboxamide;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-N-cyclobutyl-3-(4-fluoro-1 H-py razol - 1 -y l)azeti dine- 1 -carb oxami de;2-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-2-phenyl-5,7- diazaspiro[3.4]octane-6, 8-dione;3-(((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)methyl)-3-(3-fluoro-lH-pyrazol-l- yl)-N-(methyl-d3)azetidine-l -carboxamide; or a pharmaceutically acceptable salt of any of the aforementioned.Pharmaceutical Compositions

[0133] In certain embodiment, also disclosed herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof. In some embodiments, the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid eesstteerrss,, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.282

[0134] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice ofPharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in2013.

[0135] In other embodiments, there are provided methods of making a composition of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.

[0136] As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose,283 hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0137] The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and / or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired.

[0138] The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.

[0139] Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and / or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and / or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by referenceCombination Therapy

[0140] In another embodiment, the method of treating a subject having a MRGPRX2 dependent condition (e.g., an itch associated condition, a pain associated condition, a pseudo- allergic reaction, or an inflammatory or autoimmune disorder) described herein further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent. In one embodiment, the itch associated condition is a pseudo-allergic condition.

[0141] In one embodiment, the second therapeutic agent is an antihistamine, such as an Hl receptor antagonist or an H2 receptor antagonist. In one embodiment, the second therapeutic284 agent is an Hl receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is a H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or leukotriene synthesis inhibitor, such as Montelukast, Zafirlukast, Pranlukast, or 5 -lipoxygenase inhibitor (e.g., Zileuton, hypericum perforatum). In one embodiment, the second therapeutic agent is an immunomodulatory agent such as Omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, betamethasone, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricyclic antidepressant that can relieve itch such as doxepin, amitriptyline or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory dmg such as dapsone, sulfasalazine, hydroxychloroquine or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant such as cyclosporine, methotrexate, mycophenolic acid or tacromilus. In one embodiment, the second therapeutic agent is a BTK inhibitor.

[0142] The second therapeutic agent may be administered simultaneously, separately, or sequentially with the compounds of the present disclosure. If administered simultaneously, the second therapeutic agent and compound of the present disclosure may be administered in separate dosage forms or in the same dosage form.Routes of Administration

[0143] The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intratarsal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.285Kits

[0144] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of MRGPRX2 associated diseases or disorders, and other diseases referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.EXAMPLESEXAMPLE 1SYNTHESIS OF COMPOUND l-X-30

[0145] 3-chloro-N-((lR,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)-l-(2,2,2-trifluoroethyl)-lH-pyrazole-4-carboxamide was prepared in a manner similar to the general procedure disclosed for Example 30 in WO 2023 / 192901.

[0146] LCMS-ESI (m / z) calculated for C22H19CI2F6N5O: 553.09 found 553.8 [M+H]+.

[0147] 'HNMR (400 MHz, DMSO-d6) 5 8.60 (d, J= 10.9 Hz, 1H), 8.35 (s, 1H), 8.06 (d,J= 7.9 Hz, 1H), 7.90 (d, J= 9.0 Hz, 1H), 7.74 (dd, J= 9.0, 2.3 Hz, 1H), 7.48 (d, J= 7.9 Hz, 1H),5.21 (q, J= 9.0 Hz, 1H), 4.01-3.83 (m, 2H), 2.17 (d, J = 12.0 Hz, 1H), 2.00-1.78 (m, 3H), 1.61-1.21 (m, 4H).286EXAMPLE 2SYNTHESIS OF COMPOUND l-X-32

[0148] W e was prepared in a manner similar to thegeneral procedure disclosed for Example 32 in WO 2023 / 192901.

[0149] LCMS (m / z) calculated for C23H19CIF6N6O: 544.1; found 545.1 [M+H]+.EXAMPLE 3SYNTHESIS OF COMPOUND 5-10-1B

[0151] hiadiazine 1, 1-dioxide was prepared in a manner similar tothe general procedure disclosed for Examples 9 and 10 in U.S. Ser. No. 63 / 588,638.

[0152] LCMS (m / z) calculated for 446.1; found 447.1 [M+H]+.287

[0153] 'H NMR (400 MHz, DMSO-de) 8 = 10.56 (bs, 1H), 8.48 (d, 7=4.7 Hz, 1H), 8.11 (bs, 1H), 7.81 (ddd, 7=9.9, 8.3, 1.3 Hz, 1H), 7.40-7.20 (m, 2H), 7.66 (dd, 7=8.7, 5.5 Hz, 1H), 7.57 (d, 7=7.9 Hz, 1H), 7.51 (dd, 7=8.6, 4.5 Hz, 1H), 7.40-7.20 (m, 2H), 7.11 (ddd, 7=11, 8, 1.4 Hz, 1H), 7.01 (dd, 7=11.1, 8.7 Hz, 1H), 4.73 (bs, 1H), 1.71 (d, 7=7.0 Hz, 3H).EXAMPLE 4SYNTHESIS OF COMPOUND 8-211Synthesis of / V-(5-fluoropyridin-2-yl)-2,2,3,3-tetramethylcyclopropane-l-carboxamide

[0154] / V-(5-fluoropyridin-2-yl)-2,2,3,3-tetramethylcyclopropane-l-carboxamide was prepared in a manner similar to the general procedure disclosed for compounds E201 and E211 in WO 2021 / 092262.

[0155] LCMS (m / z) calculated for C13H17FN2O: 236.3; found 237.2 [M+H]+.

[0156] *H NMR (400 MHz, DMSO-d6) 8 = 10.48 (s, 1H), 8.27 (d, J= 3.1 Hz, 1H), 8.08(dd, 7 = 4.3, 9.1 Hz, 1H), 7.66 (dt, 7= 3.1, 8.8 Hz, 1H), 1.52 (s, 1H), 1.23 (s, 6H), 1.16 (s, 6H).EXAMPLE 5SYNTHESIS OF COMPOUND 8-224Synthesis of JV-(5-(3,4-difluorophenoxy)pyrazin-2-yI)-2,2,3,3-tetramethyIcyclopropane-1-carboxamide

[0157] -(5-(3,4-difluorophenoxy)pyrazin-2-yl)-2,2,3,3-tetramethylcyclopropane-l- carboxamide was prepared in a manner similar to the general procedure disclosed for compounds E217 and E224 in WO 2021 / 092262.

[0158] LCMS (m / z) calculated for C18H19F2N3O2: 347.4; found 347.9 [M+H]+.288

[0159] 'HNMR (400 MHz, DMSO-d6) 5 ppm 10.67 (s, 1 H), 8.84 (d, J- 1.38 Hz, 1 H), 8.29 (d, J= 1.25 Hz, 1 H), 7.45 - 7.54 (m, 1 H), 7.41 (ddd, J= 11.69, 6.94, 3.00 Hz, 1 H), 7.00 - 7.08 (m, 1 H), 1.55 (s, 1 H), 1.24 (s, 6 H), 1.18 (s, 6 H).EXAMPLE 6SYNTHESIS OF COMPOUND 10-129Synthesis of 4-((S)-l-((S)-l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-l-oxopropan- 2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide

[0160] 4-((S)-l-((S)-l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)amino)-l-oxopropan-2-yl)- 4,4-difluoropiperidin-3-yl)pyridine 1-oxide was prepared in a manner similar to the general procedure disclosed in Example 132 in WO 2022 / 073904.

[0161] LCMS (m / z) calculated for C23H21F4N5O3: 491.4; found 492.2 [M+H]+.

[0162] 'H NMR (400 MHz, DMSO-d6) 5 ppm 10.57 (s, 1 H), 8.82 (d, J = 1.4 Hz, 1 H), 8.46 (bs, 1 H), 8.19 (m, 2 H), 7.55-7.40 (m, 4 H), 7.19 (m, 1 H), 3.71 (m, 1 H), 3.6-3.4 (m, 1 H), 3.1-2.8(m, 3 H), 2.6-2.0 (m, 3 H), 1.23 (d, J= 6.8 Hz, 3 H).289Synthesis of 3-ethyl-2-isopropylbenzo[4,5]imidazo[l,2-a]pyrimidin-4(10H)-one

[0163] 3-ethyl-2-isopropylbenzo[4,5]imidazo[l,2-a]pyrimidin-4(10H)-one was prepared in a manner similar to Method F of US 2021 / 0128561, using 5,6-difluoro-lH-benzo[d]imidazole- 2-amine and ethyl 2-ethyl-4-methyl-3-oxopentanoate to form the title compound.

[0164] LCMS (m / z) calculated for C15H17N3O: 255.3; found 255.9 [M+H]+.

[0165] NMR (400 MHz, DMSO-d6) 5 = 12.57 (br s, 1H), 8.43 (br d, J= 7.8 Hz, 1H), 7.41 (br s, 2H), 7.25 (br s, 1H), 3.25 - 3.15 (m, 1H), 2.59 (br d, J- 7.0 Hz, 2H), 1.22 (br d, J- 5.8 Hz, 6H), 1.07 (br t, J= 6.0 Hz, 3H).EXAMPLE 8SYNTHESIS OF COMPOUND 15-16

[0166] 5-(2-chlorophenyl)-7-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][l,2,4]thiadiazine 1,1-dioxide was prepared in a manner similar to Example 3 and Example 16 of WO 2020 / 223255, using 3-chloro-5-(2-chlorophenyl)-7-fluro-4 / 7- benzo[e][l,2,4]thiadiazine 1,1-dioxide, (3-fluoropyridin-2-yl)methanamine, and EtiN to form the title compound.

[0167] LCMS (m / z) calculated for C19H13CIF2N4O2S: 434.8; found 435.0 [M+H]+.

[0168] 'HNMR (400 MHz, DMSO-d6) 5 = 9.43 (s, 1H), 8.40 (br d, J= 4.3 Hz, 1H), 8.21- 8.04 (m, 1H), 7.79 - 7.72 (m, 1H),7.7O (d, J= 7.8 Hz, 1H), 7.64 (dd, J= 2.9, 7.3 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.57 - 7.53 (m, 1H), 7.52 - 7.48 (m, 1H), 7.45 (td, J = 4.4, 8.5 Hz, 1H), 7.40 (dd, J = 2.7, 8.8 Hz, 1H), 4.63 (br s, 2H).290EXAMPLE 9SYNTHESIS OF 3-(((2,5-BIS(TRIFLUOROMETHYL)PYRAZOLO[1,5-A]PYRIMIDIN-7-YL)AMINO)METHYL)-3-(4- FLUOROPHENYL)-N-((1R,3R)-3-HYDROXYCYCLOBUTYL)AZETIDINE-1 -CARBOXAMIDE

[0169] The title compound was prepared according to the procedure described in Example48 of W02025 / 042730, using (lr,3r)-3-aminocyclobutan-l-ol instead of (lr,4r)-4- aminocyclohexan-l-ol as starting material.

[0170] LCMS calc, for C23H22F7N6O2 (M+H)+: m / z=547.2; found: 547.2.

[0171] 1HNMR (500 MHz, DMSO) 6 9.12 (s, 1H), 7.21-7.15 (m, 2H), 7.13 (s, 1H), 7.00 (t, 1=8.7 Hz, 2H), 6.54 (d, 1=7.1 Hz, 1H), 5.85 (s, 1H), 4.87 (d, 1=5.2 Hz, 1H), 4.28-4.23 (m, 2H), 4.23-4.18 (m, 1H), 4.16-4.05 (m, 1H), 4.03-3.96 (m, 4H), 2.14-2.06 (m, 2H), 2.06-1.98 (m, 2H) ppm.EXAMPLE 10SYNTHESIS OF 3-(((6-CHLORO-2-(TRIFLUOROMETHYL)QUINOLIN-4-YL)AMINO)METHYL)-3-(4-FLUORO- 1 H-PYRAZOL- 1 - YL)-N-(METHYL-D3)AZETIDINE- 1 -CARBOXAMIDE

[0172] The title compound was prepared according to the procedures described in Example 22 of WO2025 / 042736, with methyl-d3 -amine hydrochloride replacing 3,3- difluorocyclobutanamine hydrochloride in step 4.

[0173] LCMS calc, for C19H15D3C1F4N6O (M+H)+: m / z=460.1; found: 460.1.291EXAMPLE 11SYMPTOMATIC DERMOGRAPHISMFRICTEST

[0175] 10 patients with symptomatic dermographism were recruited. Visit 1 (Screening) occurred between Day -30 and Day -14 (inclusive). Initial dosing of l-X-30 occurred at Visit 2 (Enrollment or DI). l-X-30 was administered by mouth, each day for 4 weeks for a total of 28 doses. Capsules containing 75 mg of l-X-30 were supplied in bottles. Each subject took two 75 mg l-X-30 capsules per dose. Visit 2 (Enrollment or DI) was followed by 4 weekly clinic visits (Visit 3 to Visit 6).

[0176] The total IgE of each patient was determined at Visit 2 before treatment with l-X- 30 to determine a baseline level. Total IgE level for each patient was determined by the FDA approved ImmunoCAP™ Total IgE fluoroenzymeimmunoassay test.

[0177] FricTest® is a validated, easy to use dermographometer for diagnosing patients with symptomatic dermographism (urticaria tactitial or dermographic urticaria) and for measuring their trigger thresholds and disease activity.

[0178] The comb-like, four-pronged FricTest® was placed vertically so that the four tips were touching the skin, and then stroked once with moderate pressure across the width of the volar surface of the forearm for a distance of approximately 6 centimeters, which allowed for simultaneous dermal stimulation with four tips of different lengths exerting four different provocation levels, from I (the weakest) to IV (the strongest).

[0179] A positive response is defined by a palpable wheal of > 3 mm in width (the diameter of FricTest® tips) at 10 min (± 2 min) after provocation. A FricTest® was conducted on each patient to determine a baseline score, with four indicating that each prong produced a positive response, three indicating that three prongs produced a positive response, two indicating that two prongs produced a positive result, one indicating that one prong produced a positive response, and zero indicating that no prongs produced a positive result.

[0180] A baseline critical friction threshold (CFT) was determined for each patient during a screening period from 14 to 30 days before first dosage administration and again at baseline prior to initing dosing (DI) of l-X-30. The CFT was then determined each week for four weeks after292 starting dosing. The CFT Response was calculated by finding the difference between the final FricTest® score at week 4 and the Baseline FricTest® score at day 1. A reduction of the FricTest® score by less than or equal to 1 (ACFT < 1) indicates no response to treatment by the reference compound. A reduction of the FricTest® score by less than or equal to two but greater than 1 (ACFT = 2 or 3 (if CFT 0)) indicates a partial response to treatment by the reference compound. A complete response is indicated if the FricTest® score is zero. Table 19 indicates that low IgE may predict complete response and complete response sustained over time.EXAMPLE 12COLD URTICARIAPROVOCATION TEMPERATURE TEST

[0181] 2 patients with cold urticaria were recruited. Visit 1 (Screening) occurred betweenDay -30 and Day -14 (inclusive). Initial dosing of l-X-30occurred at Visit 2 (Enrollment or DI). l-X-30 was administered by mouth, each day for 4 weeks for a total of 28 doses. Capsules containing 75 mg of l-X-30 were supplied in bottles. Each subject took two 75 mg l-X-30 capsules per dose. Visit 2 (Enrollment or DI) was followed by 4 weekly clinic visits (Visit 3 to Visit 6).

[0182] The total IgE of each patient was determined at Visit 2 before treatment with l-X- 30 to determine a baseline level. Total IgE level for each patient was determined by the FDA approved ImmunoCAP™ Total IgE fluoroenzymeimmunoassay test.293

[0183] The cold urticaria provocation test is a diagnostic procedure used to confirm the presence of cold urticaria and determine thresholds of stimulation temperature in cold urticaria patients. TempTest® is a cold provocation device that allows exposure of the skin to thermal elements with defined temperatures.

[0184] The patients placed the inner forearm on an aluminum temperature applicator on a TempTest® device for 5 minutes. The TempTest® produces temperatures from 4° to 44°C continuously. After 10 more minutes (± 2 min), the wheals appearing on the arm were compared to the stencil and the critical temperature threshold (CTT) was determined by the highest temperature on the stencil corresponding to the end of the wheal.

[0185] A baseline CTT was determined for each patient during a screening period from 14 to 30 days before first dosage administration and again at baseline prior to dosing (DI). The TempTest® was repeated each week for four weeks after initial dosing. The CTT Response was calculated by finding the difference between the final TempTest® score (CTT) at week 4 and the initial TempTest® score (CTT) at day 1. Formation of no wheals or itch after TempTest® provocation is a negative reaction and thus has a CTT Response of less than 4 °C (CTT < 4 °C) and is a complete response to treatment by the reference compound. A reduction of the TempTest® critical threshold temperature (i.e., CTT Response) by greater than or equal to 4 °C (ACTT > 4 °C) indicates a partial response to treatment by the reference compound. Table 20 indicates that low IgE may predict complete CTT response.294EXAMPLE 13BIOLOGICAL ASSAYSMast cell P-hexosaminidase release assay for MRgprx2 inhibition measurement

[0186] Human LAD2 cells (NIH) were maintained in an incubator at 37°C with 5% CO2and cultured in StemPro-34 serum-free media (Gibco 10639011) supplemented with 2 mM L- glutamine, 100 U / ml penicillin, 50 mg / ml streptomycin and 100 ng / ml SCF (Invitrogen PEP0860), at a concentration of 2-5 x 105cells / mL, with hemidepletion every 1-2 weeks.

[0187] Cells were transferred to SCF-Free medium at 2.5 x 105cells / mL and kept in an incubator overnight. On the day of the assay, cells were washed twice in Assay Buffer (final concentrations lO mM HEPES, 137 mM NaCl, 5.6 mM D-glucose, 2.7 mMKCl, 1 mMMgCl, 1.8 mM CalCh, 0.4 mM Na2HPO4.7H2O, 0.04% BSA, pH = 7.4) and plated in a 96-well v-bottom plate at 20,000 cells per well in 80 pL Assay Buffer. Antagonist compounds solubilized at 10 mM in DMSO were diluted in Assay Buffer to 10X final desired concentrations as a 10-point curve (10 pM final top concentration with 1 :3 serial dilutions) and 10 pL added per well. Plates were then incubated for 1 hour at 37°C. Agonists were diluted in Assay Buffer to 10X desired concentrations and 10 pL of the appropriate agonist added to each well. The final concentration of Cortistatin-14 (Tocris 3374) used in antagonist assays was 500 nM. Final concentrations of DMSO were kept consistent across the plate. Plates were then incubated in a warm air oven for 30 minutes at 37°C, followed by centrifugation at 4°C for 5 minutes at 450 x g. 50 pL supernatant from each well was then transferred to a 96-well flat bottom plate containing 100 pL substrate solution per well (3.5 mg / mL / j-Nitrophenyl-N-acetyl-P-D-glucosaminide (Sigma 487052) in Citrate Buffer containing a final concentration of 40 mM Citric Acid, 20 mM Na2HPO4.7H2O, pH = 4.5). To the cell pellets left in the remaining assay buffer, 150 pL 0.1% Triton-X-100 was then added to each well, resuspended by pipetting up and down, and 50 pL cell lysates transferred to a second 96-well flat bottom plate containing 100 pL substrate solution per well. Plates containing transferred supernatant and cell lysates were then incubated in a warm air oven for 90 minutes at 37°C. After incubation, 50 pL of 400 mM Glycine buffer (pH 10.7) was added into each well and the plate was read on a Molecular Devices SpectraMax iD5 plate reader (absorbance at 405 nm with reference fdter at 620 nm). After background subtraction, the percentage degranulation (percent beta-hexosaminidase release) was calculated as 100 x (supernatant values) / (supernatant + lysate values), followed by analysis using GraphPad Prism software to calculate an ICso value for each compound. The ICso values are reported in Table 21.295Mast cell p-hexosaminidase release assay for IgE inhibition measurement

[0188] Human LAD2 cells (NIH) were maintained in an incubator at 37°C with 5% CO2and cultured in StemPro-34 serum-free media (Gibco 10639011) supplemented with 2 mM L- glutamine, 100 U / ml penicillin, 50 mg / ml streptomycin and 100 ng / ml SCF (Invitrogen PEP0860), at a concentration of 2-5 x 105cells / mL, with hemidepletion every 1-2 weeks.

[0189] Cells were transferred to SCF-Free medium at 2.5 x 105cells / mL and kept in an incubator overnight. For IgE, cells were also treated overnight with biotin-conjugated IgE (Abbiotec 250206) at 400 ng / rnL. On the day of the assay, cells were washed twice in Assay Buffer (final concentrations 10 mM HEPES, 137 mM NaCl, 5.6 mM D-glucose, 2.7 mM KC1, 1 mM MgCl, 1.8 mM CalCh, 0.4 mM Na2HPO4.7H2O, 0.04% BSA, pH = 7.4) and plated in a 96-well v-bottom plate at 20,000 cells per well in 80 pL Assay Buffer. Antagonist compounds solubilized at 10 mM in DMSO were diluted in Assay Buffer to 10X final desired concentrations as a 10-point curve (10 pM final top concentration with 1 :3 serial dilutions) and 10 pL added per well. Plates were then incubated for 1 hour at 37°C. Agonists were diluted in Assay Buffer to 10X desired concentrations and 10 pL of the appropriate agonist added to each well. The final concentration of Streptavidin (Thermo Scientific 21122) used was 200 ng / rnL. Final concentrations of DMSO were kept consistent across the plate. Plates were then incubated in a warm air oven for 30 minutes at 37°C, followed by centrifugation at 4°C for 5 minutes at 450 x g. 50 pL supernatant from each well was then transferred to a 96-well flat bottom plate containing 100 pL substrate solution per well (3.5 mg / mL / ?-Nitrophenyl-N-acetyl-[3-D-glucosaminide (Sigma 487052) in Citrate Buffer containing a final concentration of 40 mM Citric Acid, 20 mM Na2HPO4.7H2O, pH = 4.5). To the cell pellets left in the remaining assay buffer, 150 pL 0.1% Triton-X-100 was then added to each well, resuspended by pipetting up and down, and 50 pL cell lysates transferred to a second 96- well flat bottom plate containing 100 pL substrate solution per well. Plates containing transferred supernatant and cell lysates were then incubated in a warm air oven for 90 minutes at 37°C. After incubation, 50 pL of 400 mM Glycine buffer (pH 10.7) was added into each well and the plate was read on a Molecular Devices SpectraMax iD5 plate reader (absorbance at 405 nm with reference filter at 620 nm). After background subtraction, the percentage degranulation (percent beta-hexosaminidase release) was calculated as 100 x (supernatant values) / (supernatant + lysate values), followed by analysis using GraphPad Prism software to calculate an IC50 value for each compound. The IC50 values are reported in Table 21.296EXAMPLE 14HUMAN STUDY

[0190] This example provides an overview of a Phase lb, open-label study in approximately 30 participants with chronic inducible urticaria (CIndU) to evaluate the safety, tolerability, and pharmacodynamics (PD) of 150 mg Compound l-X-30 administered orally (PO), once daily (QD) over 4 weeks. Approximately 15 participants were to have symptomatic dermographism (SDerm) and approximately 15 participants were to have cold urticaria (ColdU).

[0191] As shown in Figure 9, the study included a Screening Period of at least 2 weeks and up to 30 days to assess participant eligibility; a 4-week open-label treatment period when all participants received a 150 mg dose of Compound l-X-30 PO, QD; and an 8-week off-treatment follow-up period after administration of the last dose of Compound l-X-30 for a total study duration of up to approximately 16 weeks for each participant. The study included men and women, aged 18 to 80 years (inclusive), with a diagnosis of SDerm or typical ColdU for >3 months. Participants with SDerm had a critical friction threshold (CFT) >2 pins via FricTest® atScreening and a baseline CFT <1 pin different from Screening. Participants with ColdU had a critical temperature threshold (CTT) of >10°C via TempTest® at Screening and a baseline CTT<20% different from Screening.297

[0192] Each 150 mg dose of Compound l-X-30 (also referred to herein as “study drug”) consisted of two 75 mg capsules. Study drug was swallowed whole. Capsules were not permitted to be split, opened, or chewed. Study drug was taken with approximately 240 mL (8 fluid ounces) of water on an empty stomach. The first dose of study drug was administered at the site on Day 1 after all baseline study procedures were completed. Biopsy was permitted to be conducted after the first dose. Study drug was taken QD for 4 weeks at approximately the same time of the day after a fast of at least 4 hours. Participants refrained from eating for at least 2 hours post-dose. On the days of clinic visits, the time of study drug administration may have differed depending on the scheduled visit time. For visits with provocation testing during the treatment period, study drug was administered after provocation testing.

[0193] A total of 33 participants were enrolled in the study, all of whom received at least1 dose of study drug. Of these, 30 (90.9%) participants met study eligibility criteria and had no protocol deviations that might impact the assessment of PD measurements. Additionally, all 33 (100.0%) participants received at least 1 dose of study drug and provided adequate blood samples for bioanalysis. Of the 33 participants who received treatment, 32 (97.0%) completed treatment through Week 4 and completed the study. One participant with SDerm discontinued treatment and the study due to not meeting eligibility criteria.

[0194] Plasma samples were analyzed by Celerion (Lincoln, NE) for the determination of study drug concentrations. The plasma samples were assayed by high-performance liquid chromatography -tandem mass spectrometry methods. Blood samples for pharmacokinetics (PK) of study drug were collected predose and at 3 and 4 hours postdose relative to the dose of the study drug on Day 1 and Week 4; predose on Weeks 1, 2, and 3; and at the Follow-Up Visits.

[0195] On both Day 1 and Week 4, plasma study drug concentrations were higher 3 hours postdose compared to 4 hours postdose, consistent with the previously observed time to maximum concentration of 3.2 hours in a prior study with study drug. Mean plasma study drug trough concentrations exceeded 2000 nM after 1 week of dosing and remained above 2000 nM until Week 8. By Week 12 (8 weeks after the final dose), study drug concentrations had declined but remained detectable.

[0196] For participants with SDerm, a 4-pronged FricTest was placed vertically so that all 4 tips were touching the skin, and then stroked once with moderate pressure across the width of the volar surface of the forearm for at least 6 cm. The CFT was measured as the number of prongs (0 to 4) that elicited a wheal response of >3 mm (i.e, the diameter of the prongs) approximately 10 minutes after provocation. As shown in Figure 10, CFT values decreased progressively over298 the Treatment Period, with a mean standard error (SE) change from baseline to Week 4 of -1.7 (0.4), indicating a potential improvement in participants' tolerance to mechanical stimuli. Notably, mean CFT values remained stable during the Off-Treatment Follow-Up Period, indicating a sustained effect after at least 8 weeks of treatment discontinuation.

[0197] For participants with ColdU, the participant’s forearm was placed on an electronic testing device that maintained continuous temperatures of 4°C to 44°C for 5 minutes. The CTT was measured as the highest temperature that elicited a wheal response approximately 10 minutes after provocation. As shown in Figure 11, mean CTT values decreased progressively over the Treatment Period, with a mean (SE) change from baseline to Week 4 of -3.6 (1.2)°C, indicating a potential improvement in participants' tolerance to cold temperatures. Following the discontinuation of treatment, mean CTT values increased during the Off-Treatment Follow-Up Period but remained below the mean baseline value.

[0198] Subgroup analyses were conducted for the secondary PD endpoints by baseline total IgE levels (<100 kU / L vs. >100 kU / L). In participants with a baseline total IgE >100 kU / L, the mean CFT gradually declined throughout the Treatment Period, with the decline continuing into the Off-Treatment Follow-Up Period (see Figure 12). In participants with a baseline total IgE <100 kU / L, the mean CFT showed a sharper decline than the >100 kU / L subgroup, reaching its lowest point at Week 4 (see Figure 12). Subsequently, mean CFT values slightly increased during the Off-Treatment Follow-Up Period but remained below the mean values for the first 3 weeks of treatment. The proportion of participants who achieved a complete response or any response (complete and partial) was higher among participants with a baseline total IgE <100 kU / L than those with a baseline total IgE >100 kU / L at every timepoint. One participant was excluded from the subgroup analysis due to a missing baseline IgE level. This participant's Week 4 IgE level was 3 kU / L, and they consistently achieved complete responder status from Week 1 through Week 8 Figure 13 shows individual CFT responses (rather than the mean shown in Figure 12) and for two essential timepoints: before (baseline) and after treatment (week 4), wherein the dashed line = complete response, the dotted line = partial response, and solid line = no response.

[0199] Although participants in both subgroups experienced a mean decrease in CTT from baseline to Week 4, this reduction was more pronounced in participants with baseline total IgE <100 kU / L than for participants with baseline total IgE >100 kU / L (see Figure 14). Following treatment discontinuation, a rebound in CTT was observed for both subgroups but remained below each respective mean baseline value. A complete response was achieved at only 3 timepoints, all of which occurred in the baseline total IgE <100 kU / L subgroup. This represented a small299 proportion of participants (1 per timepoint) and was only observed at the end of treatment and during the Off-Treatment Follow-Up Period. The proportion of participants achieving any response (complete and partial) was consistently higher in the baseline total IgE <100 kU / L subgroup compared to those with a baseline total IgE >100 kU / L from Week 2 onward. Figure 15 shows individual CTT responses (rather than the mean shown in Figure 14) and for two essential timepoints: before (baseline) and after treatment (week 4), wherein the line code is dashed line = complete response, dotted line = partial response, and solid line = no response.

[0200] In summary, subgroup analysis based on baseline total IgE levels revealed differential responses to treatment. Participants with baseline IgE <100 kU / L exhibited greater reductions in CFT and CTT throughout the Treatment Period and into the Off-Treatment Follow- Up Period compared to those with baseline IgE >100 kU / L. The proportion of responders (complete and partial) was also consistently higher in the <100 kU / L subgroup, suggesting that baseline IgE levels predict better treatment outcomes for patients administered a small molecule MRGPRX2 modulator.

[0201] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0202] These and other changes can be made to the embodiments in light of the abovedetailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

[0203] This application claims the benefit of priority to U.S. Application No. 63 / 636,478, filed April 19, 2024, which application is hereby incorporated by reference in its entirety.

Claims

300CLAIMS1. A method of treating an MRGPRX2 dependent condition in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of a small molecule MRGPRX2 modulator when the patient has been selected based on the presence of a blood serum IgE level at or below an IgE reference level.

2. The method of claim 1, wherein the IgE reference level is about 150 U / L.

3. The method of claim 1 or 2, wherein the IgE reference level is about 100 U / L.

4. The method of any one of claims 1-3, wherein the MRGPRX2 dependent condition is a pseudo-allergic reaction, an itch associated condition, a pain associated condition, a cancer associated condition, or an inflammatory or autoimmune condition.

5. The method of claim 4, wherein the pseudo-allergic reaction is caused by secretagogues, cationic peptidergic drugs, anionic peptidergic drugs, neutral peptidergic drugs, non-steroidal antagonist drugs, neuropeptides, antimicrobial peptides, MCD peptide, Substance P, VIP, PACAP, dynorphin, somatostatin, Compound 48 / 80, cortistatin-14, mastoparan, melettin, cathelicidin peptides, ciprofloxacin, vancomycin, leuprolide, goserelin, histrelin, triptorelin, cetrorelix, ganirelix, degarelix, octreotide, lanreotide, pasireotide, sermorelin, tesamorelin, icatibant, glatiramer acetate, teriparatide, pramlintide, bleomycin, exenatide, glucagon, liraglutide, enfuvirtide, colistimethate, succinylcholine, tubocurarine, atracurium, mivacurium, and rocuronium6. The method of claim 4, wherein the itch associated condition is chronic itch, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chicken pox, end-stage renal failure, hemodialysis, chronic urticaria, chronic spontaneous urticaria, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, food allergy, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iodinated contrast dye allergy, iron deficiency anemia, kidney disease, leukemia, porphyrias, lymphoma, malignancy, mastocystosis, multiple myeloma,301 neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia rubra vera, prurigo nodularis, lichen planus, lichen sclerosis, pruritus ani, pseudorabies, psoriasis, chronic prurigo / prurigo nodularis, rectal prolapse, sarcoidosis granulomas, scabies, schistosomiasis, scleroderma, severe stress, stasia dermatitis, swimmer's itch, thyroid disease, tinea cruris, rosacea, cutaneous amyloidosis, scleroderma, acne, wound healing, burn healing, ocular itch, or urticaria.

7. The method of claim 6, wherein the itch associated condition is chronic urticaria, chronic spontaneous urticaria, urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, chronic prurigo / prurigo nodularis, contact dermatitis, or eczema.

8. The method of claim 4, wherein the pain associated condition is acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet’s disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn’s disease, degenerative disc disease, dental pain, Dercum’s disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headaches, herniated disc, hydrocephalus, intercostal neuraligia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatositis (dermatomyositis), knee injury, leg pain, loin pain-haematuria syndrome, lupus, Lyme disease, medullary sponge kidney (MSK), meralgia paresthetica, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget’s disease, Parsonage Turner syndrome, pelvic pain, periodontitis pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, post hemiorraphy pain syndrome, post mastectomy, postoperative pain, pain syndrome, post stroke pain, post thorocotomy pain syndrome, postherpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud’s disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosi, Scheuemann’s kyphosis disease, sciatica, scoliosis, shingles (herpes zoster), Sjogren’s syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinal302 cerebellum ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov cysts, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain, or vulvodynia.

9. The method of claim 4, wherein the cancer associated condition is adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxiatelangiectasia, Beckwith-Wiedemann syndrome, cholangiocarcinoma, Birt-Hogg-Dube syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), prostrate, basal cell, melanoma, colon, colorectal, bladder, kidney cancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lung cancer (non-small cell, small cell), leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T cell lymphocytic, eosinophilic), liver cancer, Li-Fraumei syndrome, lymphoma (Hodgkin and non-Hodgkin), Lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma, multiple endocrine neoplasia, multiple myeloma, MUTYH-associated polyposis, myelodyspastic syndrome, nasal cavity and paranasal sinus cancer, neurobastoma, neuroendocrine tumors, neurofibromatosis, penile cancer, parathyroid cancer, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary gland tumor, pleupulmonary blastoma, oral and oropharyngeal , thyroid, uterine, pancreatic, Carney complex, brain and spinal cord cancer, cervical cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplatic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary, leiomyomastosis and renal cell cancer, hereditary pancreatitis, herediatary papillary renal carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS related cancers, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, vulver cancer, Werner syndrome, or xeroderma pigmentosum.

10. The method of claim 4, wherein the inflammatory or autoimmune condition is chronic inflammation, mast cell activation syndrome, multiple sclerosis, Steven Johnson’s syndrome, toxic epidermal necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps),303 rhinitis, tendonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, allergic rhinitis, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, Crohn’s Disease, ulcerative colitis, lupus erythematous, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, permanent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, eosinophilic gastroenteritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin- exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatoisis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, reflux nephropathy, polycystic kidney disease, liver fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic hepatitis B and C virus, liver tumors and cancer, alcoholic liver disease, polycystic liver disease, liver cholangiocarcinoma, neuromyelitis optica spectum disorder, cardiovascular disease, inflammation induced by bacterial or viral infection, inflammation associated with SARS-CoV-2 infection or its variants and coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome, pneumonia, long / long-term / chronic COVID, post-acute sequelae of COVID-19 (PASC), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS “Brain Fog”), or vasculitis.

11. The method of claim 10, wherein the inflammatory or autoimmune condition is asthma, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, or nasal polyposis.

12. The method of claim 10 or 11, wherein the asthma is moderate to severe persistent asthma.

13. The method of any one of claims 1-12, wherein the MRGPRX2 modulator is a compound having the structure of Formula (I):304or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, -(CH=CH)nQ, or-CQ(R)2, where Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CH2C(0)0R, -C(O)OR, -C(O)NHR,and where R1and / or Q is optionally substituted with one or more Rq;each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -N(R)2, alkylamino, -(CH2)nR', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups together with the atom to which it is attached forms a double bond, carbocycle or heterocycle, wherein R is optionally substituted with one or more of X, haloalkyl, or haloalkoxy; each Rqis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl,Q’ is optionally substituted with one or more RY;R2, R3, R4, R5, and R6are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C(X)2R, -C(X)(R)2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; each Rxis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(0)2R, or S(O)2R, or Rxtogether with R1forms a heterocyclic ring; each RYis independently C1-6alkyl, cycloalkyl, oxo, X, - OR, or -C(O)OR;305Rwis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rzis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each R’ is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each X is independently F, Cl, Br, or I; and each n is independently 0, 1, 2, 3, 4 or 5.

14. The method of any one of claims 1-13, wherein the MRGPRX2 modulator is a compound having the structure of Formula (I-A):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, -(CH=CH)nQ, or-CQ(R)2, where Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CH2C(O)OR, ~C(O)OR, -C(O)NHR, -OC(O)R, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, and where R1and / or Q is optionally substituted with one or more Rq; each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -N(R)2, alkylamino, -(CH2)nR', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups together with the atom to which it is attached forms a double bond, carbocycle or heterocycle, wherein R is optionally substituted with one or more of X, haloalkyl, or haloalkoxy; each Rqis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, oxo, -OR, -SR, -O(CH2)nR, -OX3, -OX2H, -0(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(O)2, =NH, -N(R)2, -N(R)C(O)R, N(R)S(O)2R, S(O)2R, B(OR)2, C(H)Q'R, O(CH2)nQ', or (CH2)nQ', where Q' is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', X, -CX3, -CX2H, -C(X)H2,306-C(CH3)2X, -C(CH3)2OH, -CN, -N(R')2, -N(R')C(O)R', or -N(R')S(O)2R', and where Rqand / or Q’ is optionally substituted with one or more RY;R2, R3, R4, R5, and R6are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C(X)2R, -C(X)(R)2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; each Rxis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)3R, or Rxtogether with R1forms a heterocyclic ring; each RYis independently C1-6alkyl, cycloalkyl, oxo, X, -CX3, -OR, or -C(O)OR;W is N or CRW;Z is N or CRZ;Rwis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rzis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each R' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR, aryl, cycloalkyl, heteroaryl, or heterocyclyl; each X is independently F, Cl, Br, or I; and each n is independently 0, 1, 2, 3, 4 or 5.

15. The method of any one of claims 1-14, wherein the MRGPRX2 modulator has the structure of a compound of Table 1, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

16. The method of any one of claims 1-15, wherein the MRGPRX2 modulator isor a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.30717. The method of any one of claims 1-12, wherein the MRGPRX2 modulator is a compound having the structure of Formula (I-B):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2where Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -OR, -CH2C(O)OR, -C(O)OR, -C(0)NHR, -OC(O)R, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(0)R, -N(R)C(0)0R, or -N(R)S(0)2R, where R1and / or Q is optionally substituted with one or more Rq; each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, alkylamino, -(CH2)nR', X, aryl, cycloalkyl, heteroaryl, or heterocyclyl, or two R groups together with the atom to which it is attached forms a carbocycle; each Rqis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -O(CH2)„R, -OX3, -0X2H, -0(X)H2, -C(O)OR, -C(O)R, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(0)R, -N(R)S(O)2R, -S(O)2R, -C(H)QR, or -(CH2)nQ' where Q' is selected from C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', -CX3, -CX2H, -C(X)H2, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(O)2R';R2, R4, and R5are at each occurrence, independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -C(X)2R, -C(X)(R)2, -CN, -N(R)2, -N(R)C(0)R, -N(R)S(O)2R, or -S(O)2R;R3is at each occurrence, independently C1-6alkyl, C2-6alkenyl, H, OH, F, Br, I, -N(R)2, -N(R)C(0)R, -N(R)C(0)0R, or -N(R)S(0)2R;R6is at each occurrence, independently H, C1-6alkyl, C2-6alkenyl, X, CF3, -CF2H, -C(F)H2, -C(F)2R, or -C(F)(R)2;308 each Rxis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, X, -CX3, -CX2H, -C(X)H2, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, and -S(O)2R; each R' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;W is N or CRW;Z is N or CRZ;Rwis C1-6alkyl, C2-6alkenyl, C2-6alkynyl, H, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rzis C1-6alkyl, C2-6alkenyl, H, OH, F, Br, I, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or N(R)S(O)2R; each X is independently F, Cl, Br, and I; and n is independently 0, 1, 2, 3, 4 and 5.

18. The method of claim 17, wherein the MRGPRX2 modulator has the structure of a compound of Table 2.

19. The method of any one of claims 1-12, wherein the MRGPRX2 modulator is a compound having the structure of Formula (II):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2, wherein R1is optionally substituted with one or more Rql;Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -CH2C(O)OR, C(O)OR, -C(O)NHR, trihalomethyl, dihalomethyl, -CN, -N(R)2, -N(R)C(O)R, N(R)C(O)OR, or -N(R)S(O)2R, wherein Q is optionally substituted with one or more Rq2;309Rqland Rq2are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -0(CH2)nR, haloalkoxy, -C(O)OR, -C(O)R, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(=NH)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -C(H)Q'R, or -CH2)nQ' where Q’ is selected from C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', haloalkyl, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(O)2R';each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(O)NHR', amino, -(CH2)nR', halo, aryl, cycloalkyl, heteroaryl or heterocyclyl, or two R groups taken together with the atom to which they are attached form a carbocycle or heterocycle; is H, C1-6alkyl, haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, ■CN, halo, -C(O)R, aryl, cycloalkyl, heteroaryl, or heterocyclyl; is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, ■CN, halo, -C(O)R, aryl, cycloalkyl, heteroaryl, or heterocyclyl; is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, CN, halo, ~C(O)R, aryl, cycloalkyl,heteroaryl, or heterocyclyl; each n is independently 0, 1, 2, 3, 4 or 5; when D is CRd, W is CRW, and Z is CRZ, then R2is H, C1-6alkyl, C2-6alkenyl, cycloalkyl, -OR, -C(O)OR, -OC(O)R, halo, -CF3, -CF2H, -C(F)H2, "C(F)2R, -C(F)(R)2, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; or when at least one of D, W or Z is N, then R2is C1-6alkyl, C2-6alkenyl, cycloalkyl, -OR, -C(O)OR, -OC(O)R, halo, -CF3, -CF2H, -C(F)H2, -C(F)2R, -C(F)(R)2, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R, and each R3is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R.

20. The method of any one of claims 1-12 or 19, wherein the MRGPRX2 modulator is a compound having the structure of Formula (II- A):310or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

21. The method of any one of claims 1-12 or 19, wherein the MRGPRX2 modulator is a compound having the structure of Formula (II-B):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

22. The method of any one of claims 19-21, wherein the MRGPRX2 modulator has the structure of a compound of Table 3.

23. The method of any one of claims 1-12, wherein the MRGPRX2 modulator is a compound having the structure of Formula (III):311or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:R1is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2, wherein R1is optionally substituted with one or more Rql;Q is C1-6alkyl, aryl, cycloalkyl, heterocyclyl, -CH2C(0)0R, -C(O)OR, -C(O)NHR, haloalkyl, -CN, -N(R)z, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(0)2R, wherein Q is optionally substituted with one or more Rq2;Rqland Rq2are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -0(CH2)nR, haloalkoxy, -C(O)OR, -C(O)R, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -S(O)2R, -C(H)Q'R, or -(CH2)nQ' where Q' is selected from C1-6alkyl, aryl, cycloalkyl, heterocyclyl, OR', -C(O)OR', -OC(O)R', haloalkyl, -CN, -N(R')2, -N(R')C(O)R', and -N(R')S(O)2R';each R is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, alkylamino, -(CH2)nR', halo, aryl, cycloalkyl, heteroaryl or heterocyclyl, or two R groups taken together with the atom to which they are attached form a carbocycle or heterocycle;312R' is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;Rais H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rbis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rcis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rdis either absent, or when present, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Reis either absent, or when present, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rsis either absent, or when present, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rwis either absent, or when present, H, C1-6alkyl, C 2-6 alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Ryis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R;Rzis H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)zR; n is independently 0, 1, 2, 3, 4 and 5;R6is Ci-4 alkyl, phenyl, -C(O)R, - (CH2)nOR, -CN, F, Cl, Br, CF3, CF2H or CFH2, with the proviso that R is not H;313 each R8is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)s, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; andR2, R3, R4, R5and R7are the same or different and either absent or, when present, independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, -OR, -C(O)OR, -OC(O)R, halo, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or -S(O)2R; wherein: adjacent atoms on either the “a” ring or “b” ring may be joined together by single bonds to form a 9 atom carbocyclic or heterocyclic ring structure; or atoms 1 and 2, 3 and 4, 5 and 6 and 8 and 9 on rings “a” ring and “b” ring may be joined together by double bonds to form an aromatic 9 atom carbocyclic or heterocyclic ring structure; or atoms 1 and 2, 3 and 4, 6 and 7 and 8 and 9 on rings “a” ring and “b” ring may be joined together by double bonds to form an aromatic 9 atom carbocyclic or heterocyclic ring structure.

24. The method of any one of claims 1-12 or 23, wherein the MRGPRX2 modulator is a compound having the structure of Formula (III-A):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

25. The method of any one of claims 1-12 or 23-24, wherein the MRGPRX2 modulator is a compound having the structure of Formula (III-A- 1) or Formula (III-A-2):314or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

26. The method of any one of claims 1-12 or 23, wherein the MRGPRX2 modulator is a compound having the structure of Formula (III-B):or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

27. The method of any one of claims 1-12, 23, or 26, wherein the MRGPRX2 modulator is a compound having the structure of Formula (III-B-1) or Formula (III-B-2):315or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

28. The method of any one of claims 23-27, wherein the MRGPRX2 modulator has the structure of a compound of Table 4.

29. The method of any one of claims 1-12, wherein the MRGPRX2 modulator is a compound having the structure of Formula (IV):or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: -R1is C1-6alkyl, carbocycle or heterocycle, wherein R1is substituted with -(R5)n;R2is halo, C1-6alkyl, carbocycle or heterocycle, wherein R2is substituted with -(R6)P;R3is H or C1-6alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring;316R4is, at each occurrence, independently halo, -CN, OR7, -N(R7)2, C1-6alkyl, C1-6haloalkyl;R5is, at each occurrence, independently halo, -CN, -OR7, -N(R7)2, -S(O)2-R7, C1-6alkyl, C1-6haloalkyl, carbocycle, or heterocycle;R6is, at each occurrence, independently halo, -CN, -OR7, -N(R7)2, -SR7, -C(O)OR7, -N(R8)C(O)R7, -N(R8)C(O)OR7, -C(O)N(R8)2, -S(O)2-R7, -C1-6alkyl-R7, C1-6haloalkyl, carbocycle substituted with -(R7)x, or heterocycle substituted with -(R7)x;R7is, at each occurrence, independently H, -OR8, -N(R8)2, -C(O)OR8, -NHC(O)OR8, -C1-6alkyl-R8, C1-6haloalkyl, carbocycle substituted with -(R8)y, or heterocycle substituted with -(R8)y;R8is, at each occurrence, independently H, OR, NR2, -C1-6alkyl-R, carbocycle substituted with -(R)z, or heterocycle substituted with — (R)z;R' and R" are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6alkyl, or C1-6alkenyl, or, independently, at each occurrence of R' and R" attached to the same carbon atom, R' and R", together with the carbon to which they are attached, form a cycloalkyl;Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl;R is, at each occurrence, independently H, halo, -CN, -OH, -NH2, or C1-6alkyl; m is 0-5; n is 0-5; p is 0-5 q is 1-3; u is, at each occurrence, independently 0-3, v is, at each occurrence, independently 0-3; w is 0-3; x is 0-3; y is 0-3 ; and z is 0-3.

30. The method of claim 29, wherein the MRGPRX2 modulator has the structure of a compound of Table 5.31731. The method of any one of claims 1-30, wherein the patient is a human.

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