FIELD OF THE INVENTION

This invention relates to compounds which are antagonists of MrgX2 (Mas-related Gene X2) and thus are useful as therapeutic agents.

BACKGROUND OF THE INVENTION

Mature mammalian mast cells ordinarily reside: Near blood vessels or nerves; beneath or within epithelia; within airways, gastrointestinal, and genitourinary tracts; and near smooth muscle and mucus-producing glands. Classically, mast cells are activated by IgE antibodies, secreting a wide range of substances with local and systemic effects, including histamine, serotonin, proteases, chemokines, and cytokines. Indeed, mast cells are implicated in the progression and/or maintenance of many diseases (Nature Immunology, 6, 135-142 (2005)).

Recent work has emphasized the role of the Mas-related G protein-coupled receptor (MRGPR) family, specifically, Mrgprb2, in mast cell activation (Nature, 519, 237-241 (2015)). Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2 (Adv. Immunol., 136, 123-62 (2017)). To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain populations of mast cells (Nature Immunology, 17, 878-887 (2016); Annu. Rev. Immunol., 38, 49-77 (2020)). This knowledge provides the opportunity to target mast cell degranulation in a very precise manner.

Natural endogenous ligands of Mrgprb2/MRGPRX2 have been reported and are mostly neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP), Corti statin- 14, and pituitary adenylate cyclase activating polypeptide (PACAP). Others include β-defensin, cathelicidin (LL-37), and proadrenomedullin N-terminal 20 peptide (PAMP9-20) (Journal of Allergy and Clinical Immunology, 138, 700-710 (2016); J. Immunol., 191, 345-352 (2013); BBRC, 349, 1322-28 (2006)). Given the close proximity between mast cells and sensory nerves in various pathological conditions, it follows that neuropeptide-activated MRGPRX2 could contribute to symptoms of neurogenic inflammation including pain, swelling and pruritus. Various observations using knock-out (KO) mice are consistent with the Mrgprb2/MRGPRX2 receptors playing a role in mast cell-mediated neurogenic inflammation. For instance, Mrgprb2/MRGPRX2 agonists induce various symptoms such as flushing, swelling and itch in wild type mice, but not in Mrgprb2-deficient mice (Nature, 519, 237-241 (2015); Immunity, 50, 1163-1171 (2019)). Mrgprb2-deficent mice have also demonstrated significant reductions in inflammation (leukocyte infiltration, including mast cells), swelling, pain and overall clinical score in various disease models (Neuron, 101, 412-420 (2019); Immunity, 50, 1163-1171 (2019); Nature Immunology, 20, 1435-1443 (2019)). An important and relevant observation was the demonstration that Substance P injection could stimulate the infiltration of leukocytes in wild type and NKR1 (canonical Substance P receptor) KO mice whereas the response was substantially blunted in Mrgprb2 null mice (Neuron, 101, 412-420 (2019)). This observation extends the role of Mrgprb2/MRGPRX2 as a key receptor in mediating Substance P-induced inflammatory responses, including pain (Neuron, 101, 353-355, (2019)). Indeed, a Substance P / Mrgprb2 sensory cluster was demonstrated to be critical in driving the clinical score of a severe preclinical model of atopic dermatitis (Nature Immunology, 20, 1435-1443 (2019)).

In addition to the various reports using Mrgprb2-deficient mice, further evidence suggests a role for various ligands of MRGPRX2 in human disease. For example, in addition to the number of MRGPRX2-expressing mast cells being significantly increased in severe chronic urticaria (Clinical and Molecular Allergy 16, 24 (2018)), PACAP nerve fibers were demonstrated to be in close proximity to tryptase-positive mast cells, providing the morphological basis for increased mast cell - sensory interactions (J. Allergy Clin. Immunol., 134, 622-633 (2014)). In support of this, patients with urticaria exhibit enhanced wheal reactions vs healthy individuals to MRGPRX2 agonists (e.g., Substance P) when injected intradermally (Allergy, 54, 46-56 (1999)). In addition, PACAP and the antimicrobial peptide, LL-37, which is implicated in cutaneous inflammation, were both demonstrated to be upregulated in rosacea (J. Invest. Dermatol., 15, 53-62, (2011)). Indeed, mast cell-deficient mice do not develop inflammation/flushing following LL-37 injection (J. Inv. Derm., 134, 2728 (2014)) thus inferring a role for Mrgprb2.

In addition to skin disorders, mast cell involvement has been highlighted for inflammatory bowel disease (IBD) and arthritis (Immunol. Rev., 217, 38-52 (2007); Pharmacology and Therapeutics, 116, 207-235 (2007)) as well as asthma (Respiratory Research, 19, 1 (2018)) and migraine. In patients with rheumatoid arthritis (RA), the number of degranulated mast cells is increased in synovial tissue and is correlated with disease activity, as it is for patients with IBD. A positive correlation between serum Substance P levels and chronic pain intensity has been noted in both osteoarthritic and RA patients (PLOS ONE, 10, e0139206 ((2015)) and a recent article suggested that the SP- MRGPRX2 axis may play a role in the pathogenesis of RA, especially in the regulation of inflammation and pain (Allerg. Intern., 26, S9-S20 (2017)). Finally, there is a growing body of evidence for a role of PACAP in migraine pathogenesis and that it is mediated via activation of mast cells (Frontiers in Cellular Neuroscience, 13, 1-11 (2019)).

In summary, a potent, selective antagonist of MRGPRX2 that blocks IgE- independent mast cell de-granulation is expected to provide therapeutic benefit in mast-cell driven pathologies including skin disorders such as urticaria, atopic dermatitis and rosacea as well as additional indications like inflammatory bowel disease, arthritis and migraine.

SUMMARY OF THE INVENTION

The present invention relates to compounds according to Formula (I) or pharmaceutically acceptable salts thereof: wherein: each X ¹ is independently N or CR ⁶ ; each X ² is independently N or CR ⁷ ; Y ¹ is N or CR ⁸ ;

Y ² is N or CR ⁸ ;

Z is

R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH((C ₁ -

C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-aryl, 5- or 6-membered heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )cycloalkyl, (C ₂ - C ₆ )alkenyl, -(C ₂ -C ₆ )alkenyl-(C ₃ -C ₈ )cycloalkyl, -OH, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ - C ₈ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl-aryl, -O-(C ₁ -C ₆ )alkyl-5-6 membered heteroaryl, -O-(C ₂ - C ₆ )alkenyl, -O-(C ₃ -C ₈ )cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO ₂ H, -CO ₂ (C ₁ - C ₆ )alkyl, -CO ₂ (C ₃ -C ₈ )cycloalkyl, -O ₂ C(C ₁ -C ₆ )alkyl, -O ₂ C(C ₃ -C ₈ )cycloalkyl, -NH ₂ , -NH(C ₁ -C ₆ )alkyl, -N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), aryl, or 5-6 membered heteroaryl, wherein any said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-aryl, (C ₁ - C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₃ -C ₈ )cycloalkyl, -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 R ¹⁰ ;

R ² is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₄ )alkoxy;

R ³ is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₄ )alkoxy;

R ⁴ is hydrogen, (C ₁ -C ₆ )alkyl, or -OH;

R ⁵ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₄ )alkoxy, -(C ₁ - C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-O-(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ - C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)- OH, -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ - C ₆ )alkyl)-OH, -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl- NHC(O)-((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -NH-(C ₁ - C ₆ )alkyl, -CN, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ )alkyl), -C(O)N(C ₁ -C ₆ )alkyl) (C ₁ -C ₆ )alkyl), - NH ₂ , -NH(C ₁ -C ₆ )alkyl, -N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -SO ₂ ((C ₁ -C ₆ )alkyl), -SO ₂ -NH((CI- C ₆ )alkyl), or aryl, wherein any said (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen; each R ⁶ is independently hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, -(C ₁ - C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ - C ₆ )alkyl), (C ₂ -C ₆ )alkenyl, -O-(C ₁ -C ₆ )alkyl, -NH ₂ , -NH((C ₁ -C ₆ )alkyl), -N((C ₁ - C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -NCH ₂ , or -CHNH; or R ¹ and any R ⁶ taken 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, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl; each R ⁷ is independently hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₂ -C ₆ )alkenyl; or any R ⁶ and any R ⁷ taken 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, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl;

R ⁸ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen;

R ⁹ is hydrogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-aryl, or -(C ₁ -C ₆ )alkyl-5-6-membered heteroaryl, wherein said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ - C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-aryl, or -(C ₁ -C ₆ )alkyl-5-6-membered heteroaryl is optionally substituted one, two, or three times by halogen; and each R ¹⁰ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -CN, -(C ₁ -C ₆ )- OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N((C ₁ - C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, (C ₁ -C ₄ )alkoxy,-O-(C ₃ -C ₈ )cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-O-(C ₁ -C ₆ )alkyl, or (C ₁ - C ₄ )alkoxy.

This invention also relates to a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

This invention relates to a method of treating MrgX-mediated diseases or disorders in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising of a compound of Formula (I).

Another aspect of this invention relates to a method of treating MrgX2 -mediated diseases or disorders in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. Another aspect of this invention relates to a method of treating MrgX2 -mediated diseases or disorders in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain. Another aspect of this invention relates to the method of treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine. Another aspect of the invention relates to the method of treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

In another aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2 -mediated disease or disorder.

In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. In another aspect, there is provided a compound of Formulae (I) and (II) or a pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2- mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the use in the treatment of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. In another aspect, there is provided a compound of Formula (I) or pharmaceutically acceptable salt thereof for the use in the treatment of chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an MrgX2-mediated disease or disorder.

In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug- induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an MrgX2 -mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain. In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine. In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of the Formula (I) as defined above or pharmaceutically acceptable salts thereof. This invention further relates to compounds of the Formula (II) or pharmaceutically acceptable salts thereof wherein: each X ¹ is independently N or CR ⁶ ; each X ² is independently N or CR ⁷ ; Y ¹ is N or CR ⁸ ;

Y ² is N or CR ⁸ ;

Z is

R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH((C ₁ - C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-aryl, 5- or 6-membered heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )cycloalkyl, (C ₂ - C ₆ )alkenyl, -(C ₂ -C ₆ )alkenyl-(C ₃ -C ₈ )cycloalkyl, -OH, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ - C ₈ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl-aryl, -O-(C ₁ -C ₆ )alkyl-5-6 membered heteroaryl, -O-(C ₂ - C ₆ )alkenyl, -O-(C ₃ -C ₈ )cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)-aryl, -CO ₂ H, -C02(C ₁ - C ₆ )alkyl, -CO ₂ (C ₃ -C ₈ )cycloalkyl, -O ₂ C(C ₁ -C ₆ )alkyl, -O ₂ C(C ₃ -C ₈ )cycloalkyl, -NH ₂ , -NH(C ₁ -C ₆ )alkyl, -N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), aryl, or 5-6 membered heteroaryl, wherein any said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-aryl, (C ₁ - C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₃ -C ₈ )cycloalkyl, -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 R ¹⁰ ;

R ² is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₄ )alkoxy;

R ³ is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₄ )alkoxy;

R ⁴ is hydrogen, (C ₁ -C ₆ )alkyl, or -OH;

R ⁵ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₄ )alkoxy, -(C ₁ - C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-O-(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ - C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)- OH, -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ - C ₆ )alkyl)-OH, -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl- NHC(O)-((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -NH-(C ₁ - C ₆ )alkyl, -CN, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ )alkyl), -C(O)N(C ₁ -C ₆ )alkyl) (C ₁ -C ₆ )alkyl), - NH ₂ , -NH(C ₁ -C ₆ )alkyl, -N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -SO ₂ ((C ₁ -C ₆ )alkyl), -SO ₂ -NH((CI- C ₆ )alkyl), or aryl, wherein any said (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen; each R ⁶ is independently hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, -(C ₁ - C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ - C ₆ )alkyl), (C ₂ -C ₆ )alkenyl, -O-(C ₁ -C ₆ )alkyl, -NH ₂ , -NH((C ₁ -C ₆ )alkyl), -N((C ₁ - C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -NCH ₂ , or -CHNH; or R ¹ and any R ⁶ taken 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, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl; each R ⁷ is independently hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₂ -C ₆ )alkenyl; or any R ⁶ and any R ⁷ taken 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, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl;

R ⁸ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen;

R ⁹ is hydrogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-aryl, or -(C ₁ -C ₆ )alkyl-5-6-membered heteroaryl, wherein said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ - C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-aryl, or -(C ₁ -C ₆ )alkyl-5-6-membered heteroaryl is optionally substituted one, two, or three times by halogen; and each R ¹⁰ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -CN, -(C ₁ -C ₆ )- OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N((C ₁ - C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, (C ₁ -C ₄ )alkoxy,-O-(C ₃ -C ₈ )cycloalkyl, -aryl, 5-6 membered heteroaryl, wherein (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-O-(C ₁ -C ₆ )alkyl, or (C ₁ - C ₄ )alkoxy.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein each X ¹ is independently N. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein each X ¹ is independently CR ⁶ , wherein each R ⁶ is independently hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, -NCH ₂ , or -CHNH. In some embodiments, each X ¹ is independently CR ⁶ , wherein each R ⁶ is independently hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₂ -C ₆ )alkenyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein each X ¹ is independently CR ⁶ , wherein each R ⁶ is independently hydrogen or halogen. In some embodiments, each X ¹ is independently CR ⁶ , wherein each R ¹⁰ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein both X ¹ is CR ⁶ , wherein R ⁶ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein one X ¹ is N and the other X ¹ is CR ⁶ , wherein R ⁶ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein each X ² is independently N. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein each X ² is independently CR ⁷ , wherein each R ¹¹ is independently hydrogen or halogen. In some embodiments, each X ² is independently CR ⁷ , wherein each R ⁷ is hydrogen. In some embodiments, each X ² is independently CR ⁷ , wherein each R ⁷ is halogen. In some embodiments, this invention relates to compounds of Formula (I) and (II), wherein one X ² is N and the other X ² is CR ⁷ , wherein C ⁷ is hydrogen.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Y ¹ is N. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Y ¹ is CR ⁸ , wherein R ⁸ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Y ¹ is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl. In some embodiments, Y ¹ is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen. In some embodiments, Y ¹ is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is substituted one time by fluorine. In some embodiments, Y ¹ is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is substituted two times by fluorine. In some embodiments, Y ¹ is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is substituted three times by fluorine. In some embodiments, Y ¹ is -CF ₃ .

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Y ² is N. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Y ² is CR ⁸ , wherein R ⁸ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Y ² is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl. In some embodiments, Y ² is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen.

In some embodiments, Y ² is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is substituted one time by fluorine. In some embodiments, Y ² is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is substituted two times by fluorine. In some embodiments, Y ² is CR ⁸ , wherein R ⁸ is (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is substituted three times by fluorine. In some embodiments, Y ² is -CF ₃ .

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is wherein R ⁹ is hydrogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ - C ₆ )alkyl-aryl, or -(C ₁ -C ₆ )alkyl-5-6-membered heteroaryl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen. In some embodiments, R ⁹ is (C ₁ -C ₆ )alkyl. -(C ₁ -C ₆ )alkyl-aryl, -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, or -(C ₁ -C ₆ )alkyl-5-6- membered heteroaryl. In some embodiments, R ⁹ is (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-aryl, -(C ₁ - C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, or -(C ₁ -C ₆ )alkyl-5-6-membered heteroaryl, wherein said (C ₁ - C ₆ )alkyl is substituted three times by halogen In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁹ is hydrogen. In some embodiments, R ⁹ is (C ₁ -C ₆ )alkyl is substituted one time by halogen. In some embodiments, R ⁹ is (C ₁ - C ₆ )alkyl is substituted two times by halogen. In some embodiments, R ⁹ is (C ₁ -C ₆ )alkyl is substituted three times by halogen. In some embodiments, R ⁹ is (C ₁ -C ₆ )alkyl is substituted three times by fluorine. In some embodiments, R ⁹ is -(C ₁ -C ₆ )alkyl-aryl. In some embodiments, R ⁹ is -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl. In some embodiments, R ⁹ is -(C ₁ - C ₆ )alkyl-5-6-membered heteroaryl. In some embodiments, R ⁹ is methyl, ethyl, isopropyl, - CF ₃ , -CH ₂ CF ₃ , benzyl, -CH ₂ CH ₂ SO ₂ CH ₃ , -CFF-pyridine, or -CH ₂ -oxazole. In some embodiments, R ⁹ is methyl, ethyl, or isopropyl. In some embodiments, R ⁹ is -CH ₂ CF ₃ . In some embodiments, R ⁹ is benzyl. In some embodiments, R ⁹ is -CH ₂ CH ₂ SO ₂ CH ₃ . In some embodiments, R ⁹ is -CH ₂ - pyridine or -CHz-oxazole.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is and R ⁵ is hydrogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-

NHC(O)-((C ₁ -C ₆ )alkyl), or -C(O)NH ₂ , wherein any said (C ₁ -C ₆ )alkyl or -(C ₁ -C ₆ )alkyl-OH is optionally substituted one, two, or three times by halogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is and R ⁵ is hydrogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl- NHC(O)-((C ₁ -C ₆ )alkyl), or -C(O)NH ₂ , wherein any said (C ₁ -C ₆ )alkyl or -(C ₁ -C ₆ )alkyl-OH is optionally substituted three times by halogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is , and R ⁵ is hydrogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl- NHC(O)-((C ₁ -C ₆ )alkyl), or -C(O)NH ₂ , wherein any said (C ₁ -C ₆ )alkyl or -(C ₁ -C ₆ )alkyl-OH is optionally substituted three times by fluorine. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is and R ⁵ is hydrogen, methyl, -CH ₂ CF ₃ , -CH ₂ OH, -CH(OH)CF ₃ ,

-C(O)NH ₂ , -CH ₂ NHC(O)CH ₃ . In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is and R ⁵ is hydrogen, methyl, -CH ₂ CF ₃ , -CH ₂ OH, -CH(OH)CF ₃ ,

-C(O)NH ₂ , -CH ₂ NHC(O)CH ₃ . In some embodiments, Z is , and R ⁵ is hydrogen.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is , and R ⁵ is hydrogen or -C(O)NH ₂ .

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is , and R ⁵ is hydrogen, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-4- to 6- membered heterocycloalkyl, -C(O)NH ₂ , wherein any said -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is , and R ⁵ is hydrogen, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-4- to 6- membered heterocycloalkyl, -C(O)NH ₂ , wherein any said -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl is optionally substituted two or three times by fluorine.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is , and R is hydrogen, -CH ₂ NH ₂ , -CFF-azetidine, or -C(O)NH ₂ , wherein

-CH ₂ -azetidine is substituted two times by fluorine. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein Z is , and R is hydrogen.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ is halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, - (C ₁ -C ₆ )alkyl-aryl, 5- or 6-membered heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )cycloalkyl, (C ₂ - C ₆ )alkenyl, -(C ₂ -C ₆ )alkenyl-(C ₃ -C ₈ )cycloalkyl, -OH, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ - C ₈ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl-5-6 membered heteroaryl, -O-(C ₃ -C ₈ )cycloalkyl, -O-aryl, - O-heteroaryl, -C(O)-aryl, , -CO ₂ (C ₃ -C ₈ )cycloalkyl, -NH ₂ , aryl, or 5-6 membered heteroaryl, wherein any said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl- aryl, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₃ -C ₈ )cycloalkyl, -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 R ¹⁰ ; and each R ¹⁰ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -CN, -(C ₁ - C ₆ )-OH, -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, (C ₁ -C ₄ )alkoxy, 5-6 membered heteroaryl, wherein (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-O-(C ₁ -C ₆ )alkyl, or (C ₁ - C ₄ )alkoxy.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ is halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, - (C ₁ -C ₆ )alkyl-aryl, 5- or 6-membered heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )cycloalkyl, (C ₂ - C ₆ )alkenyl, -(C ₂ -C ₆ )alkenyl-(C ₃ -C ₈ )cycloalkyl, -OH, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ - C ₈ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl-5-6 membered heteroaryl, -O-(C ₃ -C ₈ )cycloalkyl, -O-aryl, - O-heteroaryl, -C(O)-aryl, , -CO ₂ (C ₃ -C ₈ )cycloalkyl, -NH ₂ , , aryl, or 5-6 membered heteroaryl, wherein any said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl- aryl, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₃ -C ₈ )cycloalkyl, -O-aryl, -O- 5-6-membered heteroaryl, -C(O)-aryl, aryl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R ¹⁰ ; and each R ¹⁰ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -CN, -(C ₁ - C ₆ )-OH, -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, (C ₁ -C ₄ )alkoxy, 5-6 membered heteroaryl, wherein (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen or (C ₁ -C ₆ )alkyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ is halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-aryl, 5- or 6-membered heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )cycloalkyl, -(C ₂ -C ₆ )alkenyl-(C ₃ - C ₈ )cycloalkyl, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl-5-6 membered heteroaryl, -O-(C ₃ -C ₈ )cycloalkyl, -O-aryl, -O-heteroaryl, -C(O)- aryl, -CO ₂ (C ₃ -C ₈ )cycloalkyl, aryl, or 5-6 membered heteroaryl, wherein any said (C ₁ - C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-aryl, (C ₁ -C ₄ )alkoxy, -O-(C ₁ - C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₃ -C ₈ )cycloalkyl, -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 R ¹⁰ ; and each R ¹⁰ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -CN, -(C ₁ - C ₆ )-OH, -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, (C ₁ -C ₄ )alkoxy, 5-6 membered heteroaryl, wherein (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, aryl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen or (C ₁ -C ₆ )alkyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ is halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, - (C ₁ -C ₆ )alkyl-phenyl, 5- or 6-membered heteroaryl(C ₁ -C ₄ )alkyl-, (C ₃ -C ₈ )cycloalkyl, (C ₂ - C ₆ )alkenyl, -(C ₂ -C ₆ )alkenyl-(C ₃ -C ₈ )cycloalkyl, -OH, (C ₁ -C ₄ )alkoxy, -O-(C ₁ -C ₆ )alkyl-(C ₃ - C ₈ )cycloalkyl, -O-(C ₁ -C ₆ )alkyl-5-6 membered heteroaryl, -O-(C ₃ -C ₈ )cycloalkyl, -O- phenyl, -O-heteroaryl, -C(O)-phenyl, -CO ₂ (C ₃ -C ₈ )cycloalkyl, -NH ₂ , aryl, or 5-6 membered heteroaryl, wherein 5-6 membered heteroaryl is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl; wherein any said (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-phenyl, (C ₁ -C ₄ )alkoxy, -O- (C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, -O-(C ₃ -C ₈ )cycloalkyl, -O-phenyl, -0-5-6-membered heteroaryl, -C(O)-phenyl, phenyl, or 5-6 membered heteroaryl is optionally substituted one, two, or three times by R ¹⁰ , wherein 5-6 membered heteroaryl is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl. and each R ¹⁰ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -CN, -(C ₁ - C ₆ )-OH, -(C ₁ -C ₆ )alkyl-N((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -OH, (C ₁ -C ₄ )alkoxy, 5-6 membered heteroaryl, wherein (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, phenyl, or 5-6 membered heteroaryl is further optionally substituted by one, two, or three substituents independently selected from halogen or (C ₁ -C ₆ )alkyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ is halogen or -O-aryl, wherein -O-aryl is optionally substituted one, two, or three times by R ¹⁰ ; wherein R ¹⁰ is halogen. In some embodiments, R ¹ is halogen or -O-aryl. In some embodiments, R ¹ is halogen or -O-aryl, wherein -O-aryl is substituted two or three times by R ¹⁰ ; wherein R ¹⁰ is halogen. In some embodiments, R ¹ is fluorine or -O-phenyl, wherein -O-phenyl is optionally substituted one, two, or three times by R ¹⁰ ; wherein R ¹⁰ is fluorine. In some embodiments, R ¹ is fluorine or -O-phenyl. In some embodiments, R ¹ is fluorine or -O-phenyl, wherein -O-phenyl is substituted two or three times by R ¹⁰ ; wherein R ¹⁰ is fluorine.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ and any R ⁶ taken 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, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ and any R ⁶ taken together with the atoms to which they are attached, form furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, or phenyl, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ¹ and any R ⁶ taken together with the atoms to which they are attached, form an oxazolyl, dihydropyrrole, pyrrolyl, pyridinyl, or phenyl, wherein said ring is optionally substituted by one or two substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-(C ₃ -C ₈ )cycloalkyl, halo(C ₁ -C ₆ )alkyl, and (C ₃ -C ₈ )cycloalkyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ² is hydrogen or (C ₁ -C ₆ )alkyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ² is (C ₁ -C ₆ )alkyl. In some embodiments, R ² is hydrogen or methyl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is methyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ³ is hydrogen or (C ₁ -C ₆ )alkyl. In some embodiments, R ³ is hydrogen or methyl. In some embodiments, R ³ is hydrogen.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ² is hydrogen and R ³ is (C ₁ -C ₆ )alkyl. In some embodiments, R ² is hydrogen and R ³ is methyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ² is (C ₁ -C ₆ )alkyl and R ³ is hydrogen. In some embodiments, R ² is methyl and R ³ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ² and R ³ are (C ₁ -C ₆ )alkyl. In some embodiments, R ² and R ³ are methyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁴ is hydrogen. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁴ is (C ₁ -C ₆ )alkyl. In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁴ is -OH. In some embodiments, R ⁷ is methyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁵ is hydrogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl- NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ - C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-OH, -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), - (C ₁ -C ₆ )alkyl-NH-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl-NHC(O)-((C ₁ -C ₆ )alkyl), - (C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -NH-(C ₁ -C ₆ )alkyl, -CN, -C(O)NH ₂ , - NH ₂ , -SO ₂ ((C ₁ -C ₆ )alkyl), -SO ₂ -NH((C ₁ -C ₆ )alkyl), or aryl, wherein any said (C ₁ -C ₆ )alkyl, - (C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH- (C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C ₁ -C ₆ )alkyl- 4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁵ is hydrogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl- NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ - C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-OH, -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), - (C ₁ -C ₆ )alkyl-NH-(C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl-4- to 6-membered heterocycloalkyl, -(C ₁ -C ₆ )alkyl-NHC(O)-((C ₁ -C ₆ )alkyl), - (C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ -NH-(C ₁ -C ₆ )alkyl, -CN, -C(O)NH ₂ , - NH ₂ , -SO ₂ ((C ₁ -C ₆ )alkyl), -SO ₂ -NH((C ₁ -C ₆ )alkyl), or aryl, wherein any said (C ₁ -C ₆ )alkyl, - (C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH- (C ₃ -C ₈ )cycloalkyl, -(C ₁ -C ₆ )alkyl-NH-4- to 6-membered heterocycloalkyl, or -(C ₁ -C ₆ )alkyl- 4- to 6-membered heterocycloalkyl is optionally substituted one, two, or three times by halogen, wherein aryl is phenyl and 4- to 6-membered heterocycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4- dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, or 1,4-dithianyl.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁵ is hydrogen, (C ₁ -C ₆ )alkyl, cyclopropyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-NH ₂ , - (C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-N-((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl), -(C ₁ - C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-OH, -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl)-O-(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH-cyclobutyl, -(C ₁ -C ₆ )alkyl-piperidinyl, -(C ₁ -C ₆ )alkyl-morpholinyl, -(C ₁ -C ₆ )alkyl-NHC(O)-((C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-SO ₂ -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkyl-SO ₂ - NH-(C ₁ -C ₆ )alkyl, -CN, -C(O)NH ₂ , -NH ₂ , -SO ₂ ((C ₁ -C ₆ )alkyl), -SO ₂ -NH((C ₁ -C ₆ )alkyl), or phenyl, wherein any said (C ₁ -C ₆ )alkyl, cyclopropyl, -(C ₁ -C ₆ )alkyl-OH, -(C ₁ -C ₆ )alkyl-NH ₂ , -(C ₁ -C ₆ )alkyl-NH(C ₁ -C ₆ )alkyl), -(C ₁ -C ₆ )alkyl-NH-cyclobutyl, or -(C ₁ -C ₆ )alkyl-piperidinyl is optionally substituted one, two, or three times by halogen.

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein R ⁵ is hydrogen or -C(O)NH ₂ .

In some embodiments, this invention relates to compounds of Formulae (I) and (II), wherein: each X ¹ is independently N or CR ⁶ ; each X ² is independently N or CR ⁷ ;

Y ¹ is N or CR ⁸ ;

Y ² is N or CR ⁸ ;

Z is

R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₄ )alkoxy, -O-phenyl, wherein any said (C ₁ -C ₆ )alkyl, (C ₁ -C ₄ )alkoxy, -O-phenyl is optionally substituted one, two, or three times by R ¹⁰ ;

R ² is hydrogen or (C ₁ -C ₆ )alkyl;

R ³ is hydrogen or (C ₁ -C ₆ )alkyl;

R ⁴ is hydrogen or (C ₁ -C ₆ )alkyl;

R ⁵ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₄ )alkoxy, -C(O)NH ₂ , -C(O)NH((C ₁ - C ₆ )alkyl), -C(O)N(C ₁ -C ₆ )alkyl)(C ₁ -C ₆ )alkyl), wherein any said (C ₁ -C ₆ )alkyl, (C ₁ - C ₄ )alkoxy, -C(O)NH ₂ , -C(O)NH((C ₁ -C ₆ )alkyl), -C(O)N(C ₁ -C ₆ )alkyl)(C ₁ -C ₆ )alkyl) is optionally substituted one, two, or three times by halogen; each R ⁶ is independently hydrogen, halogen, or (C ₁ -C ₆ )alkyl; each R ⁷ is independently hydrogen, halogen, or (C ₁ -C ₆ )alkyl; R ⁸ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen;

R ⁹ is hydrogen or (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted one, two, or three times by halogen; and

R ¹⁰ is halogen.

Specific compounds of this invention include:

4-((S)-4-((S)- 1 -((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2- yl)morpholin-2-yl)pyridine 1 -oxide;

4-((S)-4-((S)-l-((5-(2,4-difluorophenoxy)pyrazin-2-yl)ami no)-l-oxopropan-2- yl)morpholin-2-yl)pyridine 1 -oxide;

4-(4-(l-((5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl)a mino)-l-oxopropan-2- yl)morpholin-2-yl)pyridine 1 -oxide;

4-(4-(l -((5-(4-fluorophenoxy )pyri din-2 -yl)amino)-l -oxopropan-2 -yl)morpholin-2- yl)pyridine 1 -oxide;

2-carbamoyl-4-((S)-4-((S)-l-((5-(2,4-difluorophenoxy)pyri din-2-yl)amino)-l- oxopropan-2-yl)morpholin-2-yl)pyridine 1 -oxide;

2-carbamoyl-4-(4-(l-((5-fluoropyri din-2 -yl)amino)-l -oxopropan-2-yl)morpholin-2- yl)pyridine 1 -oxide;

2-carbamoyl-4-((S)-4-((S)-l-((5-(2,4-difluorophenoxy)pyra zin-2-yl)amino)-l- oxopropan-2-yl)morpholin-2-yl)pyridine 1 -oxide;

(S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-((S)-2-(6-o xo-l,6-dihydropyridin-3- yl)morpholino)propanamide; and

(S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-((S)-2-(6-o xo-l,6-dihydropyridin-3- yl)morpholino)propanamide; or pharmaceutically acceptable salts thereof.

In one embodiment, the compound of Formula (I) is selected from:

4-((S)-4-((S)- 1 -((5 -(2,4-difluorophenoxy)pyridin-2-yl)amino)- 1 -oxopropan-2- yl)morpholin-2-yl)pyridine 1-oxide and 4-((S)-4-((S)-l-((5-(2,4-difluorophenoxy)pyrazin- 2-yl)amino)-l -oxopropan -2 -yl)morpholin-2-yl)pyri dine 1-oxide; or a pharmaceutically acceptable salt thereof.

It is to be understood that the references herein to a compound of Formulae (I) and (II) or a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of Formulae (I) and (II). In another embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of Formulae (I) and (II). In a further embodiment, the invention is directed to a compound of Formulae (I) and (II) or a pharmaceutically acceptable salt thereof.

Another aspect of this invention relates to a pharmaceutical composition comprising a compound of Formulae (I) and (II) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Another aspect of this invention relates to a method of treating an MrgX2-mediated disease or disorder in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of Formulae (I) or (II) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising of a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Another aspect of this invention relates to a method of treating an MrgX2-mediated disease in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria.

Another aspect of this invention relates to a method of treating an MrgX2-mediated disease or disorder in a human in need thereof, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

Another aspect of this invention relates to the method of treating chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. Another aspect of the invention relates to the method of treating chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain. In another aspect, the invention provides a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof for use in therapy. In another aspect, there is provided a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2 -mediated disease or disorder. In another aspect, there is provided a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2 -mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. In another aspect, there is provided a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof for use in the treatment of an MrgX2-mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain. In another aspect, there is provided a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof for the use in the treatment of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, or migraine. In another aspect, there is provided a compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof for the use in the treatment of chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

In another aspect, there is provided the use of a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an MrgX2-mediated disease or disorder. In another aspect, there is provided the use of a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an MrgX2- mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. In another aspect, there is provided the use of a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an MrgX2 -mediated disease or disorder, wherein the disease or disorder is chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

In another aspect, there is provided the use of a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic spontaneous urticaria, mastocytosis, cold urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, fibromyalgia, nasal polyps, neuropathic pain, inflammatory pain, chronic itch, drug-induced anaphlactoid reactions, metabolic syndrome, oesophagus reflux, asthma, cough, migraine, chronic inducible urticaria, chronic pruritus, acute pruritus, prurigo nodularis, osteoarthritis, pseudo anaphalaxis, or contact urticaria. In another aspect, there is provided the use of a compound of Formulae (I) or (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic spontaneous urticaria, atopic dermatitis, rosacea, Crohns disease, ulcerative colitis, irritable bowel syndrome, neuropathic pain, or inflammatory pain.

Because of its potential use in medicine, it will be appreciated that a salt of a compound of Formulae (I) or (II) is ideally pharmaceutically acceptable.

Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 66, 1-19, (1977) or those listed in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCH/VHCA (2011) (see http://www.wiley.com/WileyCDA/WileyTitle/productCd-390639051 9.html).

Suitable pharmaceutically acceptable salts can include acid or base addition salts. Such base addition salts can be formed by reaction of a compound of Formulae (I) and (II) (which, for example, contains a 1H-tetrazole or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

Such acid addition salts can be formed by reaction of a compound of Formulae (I) and (II) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

Salts may be prepared in situ during the final isolation and purification of a compound of Formulae (I) and (II). If a basic compound of Formulae (I) and (II) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base. Similarly, if a compound of Formulae (I) and (II) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid.

It will be understood that if a compound of Formulae (I) and (II) contains two or more basic moi eties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.

Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formulae (I) and (II) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, di succinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, mucate, naphthalene-l,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p- aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenyl acetate, phenyl ethy lb arbiturate, phosphate, polygalacturonate, propionate, -toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)- 1,3 -propanediol (TRIS), arginine, benethamine (N-benzylphenethylamine), benzathine (N, N ’-dibenzylethylenediamine), bis- (2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-l’-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine fV-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t- butylamine, tromethamine (tris(hydroxymethyl)aminomethane), and zinc.

The compound of Formulae (I) and (II) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that a compound or salt of Formulae (I) and (II) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.

The subject invention also includes isotopically-labeled compounds, which are identical to those recited in Formulae (I) and (II) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ C1, ¹²³ I, and ¹²⁵ I.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H, ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵ I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formulae (I) and (II) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formulae (I) and (II) or pharmaceutically acceptable salt thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of Formulae (I) and (II) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art. Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).

When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a “quick-dissolve” medicine.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.

It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formulae (I) and (II) or salt thereof with at least one excipient.

The present invention also provides a method of treatment in a mammal, especially a human.

Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the Formulae (I) and (II), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art. DEFINITIONS

Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.

As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms. The term "(C ₁ -C ₆ )alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl.

"Alkoxy" refers to a group containing an alkyl radical, defined hereinabove, attached through an oxygen linking atom. The term “(C ₁ -C ₄ )alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary “(C ₁ -C ₄ )alkoxy” groups useful in the present invention include methoxy, ethoxy, //-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

When the term "alkyl" is used in combination with other substituent groups, such as "halo(C ₁ -C ₄ )alkyl", "aryl(C ₁ -C ₄ )alkyl-", or " (C ₁ -C ₄ )alkoxy(C ₁ -C ₄ )alkyl-", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety. The term "halo(C ₁ -C ₄ )alkyl" is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical. Examples of "halo(C ₁ -C ₄ )alkyl" groups useful in the present invention include, but are not limited to, -CF ₃ (trifluoromethyl), -CCI ₃ (trichloromethyl), 1,1 -difluoroethyl, 2-fluoro-2- methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Examples of "aryl(C ₁ -C ₄ )alkyl" or “phenyl(C ₁ -C ₄ )alkyl” groups useful in the present invention include, but are not limited to, benzyl and phenethyl. Examples of "(C ₁ -C ₄ )alkoxy(C ₁ -C ₄ )alkyl-" groups useful in the present invention include, but are not limited to, methoxymethyl, methoxyethyl, methoxyisopropyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, isopropoxyisopropyl, /- butoxymethyl, t-butoxy ethyl, and t-butoxyisopropyl.

As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. The term

(C ₃ -C ₈ )cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary "(C ₃ -C ₈ )cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, "4- to 6-membered heterocycloalkyl" represents a group or moiety comprising a non aromatic, monovalent monocyclic radical, which is saturated or partially unsaturated, containing 4, 5, or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 4- to 6- membered heterocycloalkyl groups useful in the present invention include, but are not limited to azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1, 3 -oxathiol anyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4- oxathiolanyl, 1,4-oxathianyl, and 1,4-dithianyl.

"Aryl" refers to optionally substituted monocyclic, fused bicyclic, or fused tricyclic groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Huckel's Rule. Examples of “aryl” groups are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like.

"Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryls useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotri azolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8- naphthyridinyl, and pteridinyl. Examples of 5-membered "heteroaryl" groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of 6-membered "heteroaryl" groups include oxo-pyridyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl. Examples of 6,6-fused “heteroaryl” groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6- naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 6,5- fused “heteroaryl” groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.

As used herein, "5- or 6-membered heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

The terms "halogen" and "halo" represent fluoro, chloro, bromo, or iodo substituents. "Hydroxy" or “hydroxyl” is intended to mean the radical -OH.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.

"Pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "treatment" refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.

The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formulae (I) and (II), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

Compound Preparation

Abbreviations

AcOH or HO Ac acetic acid

AgNO ₃ silver nitrate aq aqueous

BOC or /-BOC or Boc tret-butoxy carbonyl

BOC-anhydride or Boc-anhydride di-tert-butyldicarbonate CDCI ₃ deuteriochloroform

CD3OD or methanol-d ₄ deuteriomethano

CPME cyclopentyl methyl ether

CS ₂ CO ₃ cesium carbonate

Cui copper(I) iodide

DCC N,N-dicyclohexylcarbodiimide

DCM dichloromethane

DIAD diisopropyl azodi carb oxy late

DIPEA or DIEA N,N-diisopropylethylamine

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

DMF N(N-dimethylformamide

DMSO dimethylsulfoxide

DMSO-d ₆ hexadeuteriodimethylsulfoxide eq equivalent(s)

ES electrospray mass spectroscopy

EtOAc ethyl acetate

Et2O or ether diethyl ether

EtOH ethanol

Fe iron h hour(s)

HBr hydrobromic acid

HC1 hydrochloric acid

¹ H NMR proton nuclear magnetic resonance H ₂ O ₂ hydrogen peroxide

HPLC high performance liquid chromatography

K ₂ CO ₃ potassium carbonate

LCMS liquid chromatography-mass spectroscopy m-CPBA or mCPBA meta-chloroperbenzoic acid

MeCN or CH ₃ CN or ACN or AcCN acetonitrile

MeOH methanol

MgSO ₄ magnesium sulfate

MS mass spectrum m/z mass-to-charge ratio

Na ₂ CO ₃ sodium carbonate

NaHCCE sodium bicarbonate

NaOH sodium hydroxide

Na ₂ SO ₄ sodium sulfate

NBS A-bromosuccinimide

NH ₄ C1 ammonium chloride

NH ₄ HCO ₃ ammonium bicarbonate

PS-PPh ₃ polymer-bound triphenylphosphine rt room temperature or retention time sat. saturated

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran TMSCN or TMS-CN trimethyl silyl cyanide

EXPERIMENTALS

The following guidelines apply to all experimental procedures described herein. All reactions were conducted under a positive pressure of nitrogen, unless otherwise indicated. Temperatures designated are external (i.e. bath temperatures) and are approximate. Air and moisture-sensitive liquids were transferred via syringe. Reagents were used as received. Solvents utilized were those listed as “anhydrous” by vendors. Molarities listed for reagents in solutions are approximate and were used without prior titration against a corresponding standard. All reactions were agitated by stir bar, unless otherwise indicated. Heating was conducted using heating baths containing silicon oil, unless otherwise indicated. Reactions conducted by microwave irradiation (0 - 400 W at 2.45 GHz) were done so using a Biotage® Initiator 2.0 instrument with Biotage® microwave EXP vials (0.2 - 20 mL) and septa and caps. Irradiation levels utilized (i.e. high, normal, low) based on solvent and ionic charge were based on vendor specifications. Cooling to temperatures below -70 °C was conducted using dry ice/acetone or dry ice/2- propanol. Magnesium sulfate and sodium sulfate used as drying agents were of anhydrous grade, and were used interchangeably. Solvents described as being removed “in vacuo” or “under reduced pressure” were done so by rotary evaporation.

Preparative normal phase silica gel chromatography was carried out using either a Teledyne ISCO® CombiFlash Companion instrument with RediSep or ISCO® Gold silica gel cartridges (4 g-330 g), or an Analogix® IF280 instrument with SF25 silica gel cartridges (4 g - 3-00g), or a Biotage® SP1 instrument with HP® silica gel cartridges (10g - 100 g), unless otherwise indicated. Purification by reverse phase HPLC was conducted usiin a YMC-pack column (ODS-A 75x30mm) as solid phase, unless otherwise noted. A mobile phase of 25mL/min A (CH ₃ CN-0.1% TFA): B (water-0.1% TFA), 10-80% gradient A (10 min) was utilized with UV detection at 214 nM, unless otherwise noted.

PE Sciex® API 150 single quadrupole mass spectrometer (PE Sciex, Thornhill, Ontario, Canada) was operated using electrospray ionization in the positive ion detection mode. The nebulizing gas was generated from a zero air generator (Balston Inc., Haverhill, MA, USA) and delivered at 65 psi and the curtain gas was high purity nitrogen delivered from a Dewar liquid nitrogen vessel at 50 psi. The voltage applied to the electrospray needle was 4.8 kV. The orifice was set at 25 V and mass spectrometer was scanned at a rate of 0.5 scan/sec using a step mass of 0.2 amu and collecting profile data.

'H-NMR spectra were recorded at 250 MHz or 400 MHz using a Bruker® AVANCE 400 MHz instrument, with ACD Spect manager v. 10 used for reprocessing. Multiplicities indicated are: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sxt = sextet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, and br indicates a broad signal. J indicates the NMR coupling constant measured in Hertz.

LCMS Methods:

LC/MS Method 1 : UPLC was conducted on an Acquity UPLC CSH C18 column (30mm x 2.1mm i.d. 1.7pm packing diameter) eluting with 10 mM ammonium bicarbonate in water adjusted to pH 10 with 25% ammonium hydroxide solution (solvent A) and acetonitrile (solvent B), using the following elution gradient 0-1.85 min.: 0% to 100% B, 1.9 to 2.0 min. 100% B, at a flow rate of 1.3 mL/ min. at 45°C. Mass spectrum was recorded on a Waters Acquity QDa mass detector using alternative-scan positive and negative mode

LC/MS Method 2: UPLC was conducted on an Acquity UPLC CSH C18 column (30mm x 2.1mm i.d. 1.7pm packing diameter) eluting with 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), using the following elution gradient 0-1.85 min.: 1% to 100% B, 1.9 to 2.0 min. 100% B, at a flow rate of 1.3 mL/ min. at 45°C. Mass spectrum was recorded on a Waters Acquity QDa mass detector using alternative- scan positive and negative mode electrospray ionisation, scan range of 100 to 1000 AMU, with targeted sample frequency of 8 Hz.

LC/MS Method 3: was conducted on a CORTECS C18 column (50mm x 2.1 mm i.d. 2.7 pm packing diameter) eluting with water/0.05%TFA (solvent A) and ACN/0.05%TFA (solvent B), using the following elution gradient: 0.01-1.10 min.: 5% to 100% B, 1.80-1.90 min. to 5% B at a flow rate of 1.0 mL/ min. at 40°C.

Intermediates Intermediate 1

2-bromo-A-(5-fluoropyri din-2 -yl)propanamide

A mixture of 2-bromopropanoic acid (16.3 g, 107.2 mmol, 1.2 eq), DCM (200 mL), DCC (27.6 g, 134.0 mmol, 1.5 eq) and 5-fhioropyridin-2-amine (10.0 g, 89.3 mmol, 1.0 eq) was stirred for 2.0 h at 25 °C, filtered, concentrated and dissolved in DCM (50 ml). Silica (100- 200 mesh, 60.0 g) was added, and the mixture was concentrated and loaded onto a silica gel column (330 g, 100-200 mesh), eluting with ethyl acetate/petroleum ether (1/9) to give 2-bromo-A-(5-fluoropyridin-2-yl)propanamide (20.0 g, purity: 90%, yield: 90%) as yellow oil. LCMS: (ES, m/z): 247 [M+H] ⁺ . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.22 (d, J=3.2 Hz, 1H), 8.18-8.15 (m, 1H), 7.64-7.59 (m, 1H), 4.76-4.69 (m, 1H), 1.84 (d, J=6.8 Hz, 3H).

Intermediate 2

(R)-2-bromo-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propan amide

Step 1

A mixture of 5-bromopyrazin-2-amine (33.0 g, 190 mmol), 2,4-difluorophenol (29.6 g, 228 mmol), dimethylglycine (3.91 g, 37.9 mmol), cesium carbonate (93.0 g, 284 mmol) and copper(I) iodide (7.22 g, 37.9 mmol) in dioxane (600 mL) was heated at 110 °C. After 2 h, the mixture was concentrated, diluted with EtOAc, washed with sat’d aq sodium carbonate solution (2 x 100 mL) and brine (1 x 100 mL), dried over magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in MeCN (200 mL), water was added (500 mL), and the mixture was stirred at rt for 1 h. The resulting solid precipitate was collected by filtration, dissolved in EtOAc concentrated onto silica gel and purified by column chromatography, eluting with 0-100% ethyl acetate in heptane give 17.0 g (purity: 100%, yield: 40%) of 5-(2,4-difluorophenoxy)pyrazin-2-amine as a white solid. LCMS rt = 0.72 min, Method 2, (ES, m/z 224 [M+H] ⁺ . 'H NMR: (400 MHz, DMSO-d ₆ ) 5 ppm 7.92 (d, J=1.5 Hz, 1H), 7.45-7.38 (m, 2H), 7.28 (td, J=9.2, 5.6 Hz, 1H), 7.13-7.05 (m, 1H), 6.16 (s, 2H).

Step 2

A mixture of 5-(2,4-difluorophenoxy)pyrazin-2-amine (40 g, 179 mmol), (R)-2- bromopropanoic acid (32.9 g, 215 mmol) and silver nitrate (4.57 g, 26.9 mmol) in DCM (700 mL) was treated portionwise with DCC (44.4 g, 215 mmol), maintaining a temperature betwen 15 and 20 °C using a cold water bath. The resulting mixture was stirred at rt overnight, filtered and loaded onto a silica gel column, eluting with 5-40% ethyl acetate in heptane to give a yellow solid which was triturated with heptane to give 43 g (purity: 97%, yield: 67%) (R)-2-bromo-A-(5-((5-chloropyridin-2-yl)oxy)pyridin-2- yl)propanamide as a pale yellow solid. LCMS (ES, m/z) 358 [M+H] ⁺ , rt = 1.03 min, Method 5. Analytical Chiral HPLC (Chiral IG 150 x 4.6 mm, 70:30 EtOH: Heptane): 3.43 min (desired product, major isomer) and 4.35 min (minor isomer), % ee = 92%. 'H NMR: (400 MHz, DMSO-d ₆ ) 5 11.16 (s, 1H), 8.80 (d, J=1.0 Hz, 1H), 8.47 (d, J=1.5 Hz, 1H), 7.58-7.36 (m, 2H), 7.28-7.06 (m, 1H), 4.86 (q, J=6.8 Hz, 1H), 1.75 (d, J=6.8 Hz, 3H).

Intermediate 3

(R)-2-bromo-A-(5-(2,4-difluorophenoxy)pyridin-2-yl)propan amide

Step 1

2,4-Difluorophenol (2.2 ml, 22.80 mmol) was added to a slurry of 5-chloro-2-nitropyridine (3.23 g, 20.37 mmol) and cesium carbonate (8.867 mg, 27.2 mmol) in acetonitrile (50.93 ml). After stirring overnight, additional 2,4-difluorophenol (0.4 ml, 4.19 mmol) and cesium carbonate (1.328 mg, 4.07 mmol) were added. The reaction was stirred overnight, adsorbed onto isolate and purified via normal phase chromatography (silica gel), eluting with 0-100% EtOAc in heptane followed by 20% MeOH in DCM to give 5-(2,4- difluorophenoxy)-2-nitropyridine (4.710 g, yield: 92%). LCMS: (ES, m/z): 253 [M+H] ⁺ , rt = 0.92 min, LC/MS Method 2.

Step 2 Ammonium chloride (9.99 g, 187 mmol) and iron (10.431 g, 187 mmol) were added to a solution 5-(2,4-difluorophenoxy)-2-nitropyridine (4710.5 mg, 18.68 mmol) in ethanol (29.9 ml) and water (7.47 ml). The reaction was stirred at 70 °C for 2 h, rt overnight, then at 90 °C for 8 h. Additional iron (10.95 g, 196 mmol) was added, and the reaction was reheated to 90 °C. After 2 h, the EtOH was removed in vacuo , and EtOAc (50 mL) was added. The mixture was stirred for 10 min, filtered through C ₆ lite, adsorbed onto isolate and purified via silica chromatography, eluting with 0-100% EtOAc in heptane to give 5- (2,4-difluorophenoxy)pyridin-2-amine (3.13 g, 14.09 mmol, 75 % yield). LCMS: (ES, m/z): 223 [M+H] ⁺ . ¹ H NMR: (400 MHz, DMSO-d ₆ ) 5 7.75 (d, J=2.93 Hz, 1H), 7.37-7.45 (m, 1H), 7.20 (dd, J=8.80, 2.93 Hz, 1H), 6.99-7.08 (m, 2H), 6.48 (d, J=8.31 Hz, 1H), 5.86 (s, 2H).

Step 3

To DCC (371 mg, 1.800 mmol) in DCM (5 ml) was added (R)-2-bromopropanoic acid (275 mg, 1.800 mmol). After 15 m, 5-(2,4-difluorophenoxy)pyridin-2-amine (200 mg, 0.900 mmol) in DCM (3 mL) was added dropwise, followed by three tiny crystals of DMAP. After 3 h the mixture was filtered through C ₆ lite, concentrated and purified over silica (40 g column), eluting with 0-60% EtOAc in heptane to afford (R)-2-bromo-A-(5- (2,4-difluorophenoxy)pyridin-2-yl)propanamide (283 mg, 0.792 mmol, 88 % yield) as a colorless oil. LCMS: (ES, m/z): 356 [M+H] ⁺ , rt = 1.08 min, LC/MS Method 1. ¹ H NMR: (400 MHz, CDCI ₃ ) δ 8.70 (br. s., 1H), 8.19 (d, J=9.05 Hz, 1H), 8.09 (d, J=2.69 Hz, 1H), 7.33 (dd, J=9.05, 2.93 Hz, 1H), 7.10 (td, J=8.99, 5.50 Hz, 1H), 7.00 (ddd, J=10.70, 8.13, 2.93 Hz, 1H), 6.90 (dddd, J=9.08, 7.55, 2.93, 1.71 Hz, 1H), 4.54 (q, J=6.93 Hz, 1H), 1.97 (d, J=7.09 Hz, 3H). Intermediate 4 was synthesized in an analogous manner.

Intermediate 5

2-bromo-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-yl) propanamide

Step 1

A mixture of 6-aminopyridin-3-ol (215 mg, 1.952 mmol), 2,3,5-trifluoropyridine (0.182 mL, 2.050 mmol) and C _S2 CO ₃ (763 mg, 2.343 mmol) in acetonitrile (8 mL) was stirred at 60 °C overnight, diluted with EtOAc, filtered, concentrated, and purified by normal phase chromatography (40 g golden column), eluting with 0-45 % EtOAc in DCM to give 5- ((3,5-difjuoropyridin-2-yl)oxy)pyridin-2-amine (147 mg, 0.659 mmol, yield: 34%). LCMS (m/z) 224 (M+H) ⁺ , retention time: 0.66 min, LC/MS Method 1. ¹ H NMR: (400 MHz, CDCL) 5 8.01 (d, J=2.45 Hz, 1H), 7.81 (d, J=2.69 Hz, 1H), 7.31-7.37 (m, 2H), 6.56-6.61 (m, 1H), 4.49 (br. s., 2H).

Step 2

To 5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2-amine (178 mg, 0.798 mmol) and 2- bromopropanoic acid (0.086 mL, 0.957 mmol) in DCM (4 mL) were added DCC (247 mg, 1.196 mmol) and DMAP (9.74 mg, 0.080 mmol). After 2.5 h, the reaction was filtered, concentrated and purified by column chromatography (ISCO 24 g Gold), eluting with 0- 5% EtOAc in DCM to provide 2-bromo-N-(5-((3,5-difluoropyridin-2-yl)oxy)pyridin-2- yl)propanamide (247 mg, 0.690 mmol, 86 % yield) as a colorless, sticky oil. LCMS (m/z) 360 (M+H) ⁺ , retention time: 0.98 min, LC/MS Method 1. ¹ H NMR: (400 MHz, CDCI ₃ ) δ 9.08 (br. s., 1H), 8.33 (d, J=9.05 Hz, 1H), 8.24 (d, J=2.69 Hz, 1H), 7.83 (d, J=2.45 Hz, 1H), 7.64 (dd, J=9.05, 2.69 Hz, 1H), 7.35-7.43 (m, 1H), 4.58 (q, J=6.85 Hz, 1H), 1.98 (d, J=7.09 Hz, 3H).

Examples Example 1 4-((8)-4-((8)-l-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino) -l-oxopropan-2- yl)morpholin-2-yl)pyridine 1 -oxide

Step 1

To 2-(pyridin-4-yl)morpholine (450 mg, 2.74 mmol) in acetonitrile (5 mL) at 22°C was added Boc-anhydride (0.764 mL, 3.29 mmol), followed by TEA (0.764 mL, 5.48 mmol). After 1 h, the reaction was partitioned between NH4CI (sat) and EtOAc, and stirred for 10 min. The layers were separated, and the aqueous layer was back extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated to a afford 716 mg (2.438 mmol, 89 % yield) tert-butyl 2-(pyridin-4-yl)morpholine-4- carboxylate, which was used without further purification. LCMS (ES, m/s): 265.2 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.61-8.47 (m, 2H), 7.42-7.33 (m, 2H), 4.54- 4.40 (m, 1H), 4.04-3.89 (m, 2H), 3.84-3.74 (m, 1H), 3.63-3.50 (m, 1H), 3.08-2.87 (m, 1H), 2.86-2.58 (m, 1H), 1.44-1.40 (m, 9H).

Step 2

To tert-butyl 2-(pyridin-4-yl)morpholine-4-carboxylate (710 mg, 2.69 mmol) in DCM (20 mL) in an ice bath was added in m-CPBA (77% purity, 722 mg, 3.22 mmol). After 30 min the bath was removed, and the reaction was stirred at rt for 2-3 hr. DCM (50 ml), NaHCOs (sat, 50 mL) and 10% Na ₂ CO ₃ (10 mL) were added, and the mixture was stirred for 15 min. The layers were separated, and the aqueous layer was back extracted with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and purified via silica gel column, eluting with 5-65% 3: 1 EtOAc: EtOH (+2% NH4OH) in heptane to afford 532 mg (1.803 mmol, 67.1 % yield) 4-(4-(tert-butoxycarbonyl)morpholin-2- yl)pyridine 1 -oxide. LCMS (ES, m/s): 281.2 [M+H]+. 'H NMR (400 MHz, DMSO-d ₆ ) 5 8.24-8.15 (m, 2H), 7.45-7.36 (m, 2H), 4.46 (dd, J=10.5, 2.7 Hz, 1H), 3.99-3.72 (m, 3H), 3.61-3.49 (m, 1H), 3.05-2.86 (m, 1H), 2.82-2.58 (m, 1H), 1.45-1.34 (m, 9H).

Step 3

To 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)pyridine 1-oxide (532 mg, 1.898 mmol) in ethyl acetate (10 mL) and methanol (1.00 mL) at 22 °C was slowly added HC1 (3 M in CPME, 6.33 mL, 18.98 mmol). The reaction was stirred overnight and concentrated to give 438 mg (1.920 mmol, quantitative yield) 4-(morpholin-2-yl)pyridine 1-oxide hydrochloride, which was used without further purification. LCMS (ES, m/s): 181.1 [M+H]+. ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 10.18-9.14 (m, 2H), 8.65-8.49 (m, 2H), 7.69 (d, J=6.8 Hz, 2H), 4.99 (dd, J=11.2, 2.4 Hz, 1H), 4.19-4.11 (m, 1H), 4.01 (td, J=12.3, 2.2 Hz, 1H), 3.57 (br d, J=12.7 Hz, 1H), 3.24 (br d, J=12.7 Hz, 1H), 3.15-2.90 (m, 2H).

Step 4

To (R)-2-bromo- N-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanamide (200 mg, 0.590 mmol) in DMF (5 mL) was added 4-(morpholin-2-yl)pyridine 1-oxide hydrochloride (141 mg, 0.649 mmol) and TEA (0.205 mL, 1.474 mmol). The reaction was stirred over the weekend, then partitioned between NH ₄ C1 (sat’d, 50 mL) and DCM (25 mL). The aqueous layer was isolated and back extracted DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and purified via silica gel column, eluting with 5- 85% 3 : 1 EtOAc: EtOH (+2% NH4OH) in heptane to afford a mixture of isomers (120 mg, 0.260 mmol, 44.1 % yield). Chiral purification of the mixture (Column: Chromegachiral CCC, 5 micron; 30 x 250 mm; 35:65 heptane: ethanol; Flow rate: 45 mL/min) gave 4 isomer peaks at retention times of 8.5, 10.2, 13.6, and 16.5 min. The fractions corresponding to the peak at 16.5 min retention time were concentrated to give 51 mg (28% yield) 4-((S-4-(S)-l-((5-(2,4-difluorophenoxy)pyridin-2-yl)amino)-l -oxopropan-2- yl)morpholin-2-yl)pyridine 1-oxide. LCMS (ES, m/s): 457.3 [M+H]+, rt = 0.64 Method 2. 'H NMR (400 MHz, DMSO-d ₆ ) 5 10.33-10.27 (m, 1H), 8.21-8.08 (m, 4H), 7.55-7.46 (m, 2H), 7.37 (d, J=6.8 Hz, 2H), 7.30 (td, J=9.3, 5.4 Hz, 1H), 7.18-7.07 (m, 1H), 4.60-4.52 (m, 1H), 3.99-3.92 (m, 1H), 3.68 (td, J=11.1, 2.2 Hz, 1H), 3.59-3.51 (m, 1H), 3.02-2.94 (m, 1H), 2.76-2.68 (m, 1H), 2.46-2.38 (m, 1H), 2.37-2.30 (m, 1H), 1.27-1.15 (m, 3H).

Examples 2-4 were prepared in an analogous manner using the designated intermediate in

Example 5 -carbamoyl-4-((S)-4-((S)-l-((5-(2,4-difluorophenoxy)pyridin- 2-yl)amino)-l-oxopropan-2- yl)morpholin-2-yl)pyridine 1 -oxide

Step 1

TMS-CN (1.339 mL, 9.99 mmol) was added to 4-(4-(tert-butoxycarbonyl)morpholin-2- yl)pyridine 1-oxide (Example 1, Step 2) (2 g, 7.13 mmol) in DCM (36 mL), followed by dimethylcarbamoyl chloride (0.918 mL, 9.99 mmol). After 72 h, the reaction was partitioned between DCM (60 mL) and saturated K ₂ CO ₃ solution (10 mL) with water (10 mL). After stirring 10 min, the layers were separated, and the organic layer was washed with water (20 mL) and brine (20 mL), then dried over Na ₂ SO ₄ . Organic solvents were removed in vacuo, and the residue was purified by column chromatography (ISCO 80 g column), eluting with 0-50% EtOAc in heptane to give 1.82 g, (6.29 mmol, 88 % yield) tert-butyl 2-(2-cyanopyridin-4-yl)morpholine-4-carboxylate. LCMS: (ES, m/z): 290.3 [M+H] ⁺ , rt = 1.00 min, LC/MS Method 1.

Step 2

To a solution of tert-butyl 2-(2-cyanopyridin-4-yl)morpholine-4-carboxylate (500 mg, 1.728 mmol) in methanol (8 mL) was added pH 7.4 buffer (5 mL) and hydrogen peroxide (0.353 mL, 3.46 mmol). After stirring overnight, the reaction was treated with saturated NaHCO ₃ solution (20 mL) and extracted with DCM (3 X 25 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified over silicon column (ISCO 24 g), eluting with 30-100% EtOAc in heptane to give 148 mg (0.458 mmol, 26.5 % yield) 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)-2-carbamoylpyridin e 1- oxide. LCMS: (ES, m/z): 324.2 [M+H] ⁺ . flT NMR (400 MHz, DMSO-d ₆ ) 5 ppm 8.41 (d, J=6.85 Hz, 2H), 8.29 (br d, J=4.40 Hz, 1H), 8.22 (d, J=2.93 Hz, 1H), 7.61 (dd, J=6.60, 2.69 Hz, 1H), 4.57 (dd, J=10.27, 2.93 Hz, 1H), 3.93-4.02 (m, 2H), 3.78 (br d, J=13.20 Hz, 1H), 3.58 (td, J=11.62, 2.69 Hz, 1H), 2.99 (br s, 2H), 1.42 (s, 9H).

Step 3

To 4-(4-(tert-butoxycarbonyl)morpholin-2-yl)-2-carbamoylpyridin e 1-oxide (132 mg, 0.408 mmol) DCM (3 mL) was added TFA (0.3 mL, 3.89 mmol). After 4 h the reaction was concentrated to give 138 mg (0.408 mmol, 100 % yield) 2-carbamoyl-4-(morpholin-2- yl)pyridine 1-oxide, trifluoroacetic acid salt, which was used without further purification. LCMS: (ES, m/z): 224.2 [M+H] ⁺ , rt = 0.32 min, LC/MS Method 1.

Step 4

To (R)-2-bromo-A-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanami de (71.4 mg, 0.200 mmol) in DMA (2 ml) was added 2-carbamoyl-4-(morpholin-2-yl)pyridine 1-oxide, trifluoroacetic acid salt (67.5 mg, 0.2 mmol) followed by TEA (0.167 mL, 1.20 mmol). The mixture was stirred at rt for 16 h, then heated to 50 °C for another 3 h. The reaction was diluted with EtOAc and washed with satd. K2CO3 solution, a mix of satd. K2CO3 solution and brine, then dried over Na2SO4, filtered and concentrated. The sample was purified by reverse phase chromatography: Xselect CSH Prep Cl 8 5uM OBD (Gradient 15% to 55% B over 19 min, flow rate 40 mL/min, A: Water with 0.1% Formic Acid/B: Acetonitrile with 0.1% Formic Acid) to give 2-carbamoyl-4-(4-(l-((5-(2,4- difluorophenoxy)pyridin-2-yl)amino)-l-oxopropan-2-yl)morphol in-2-yl)pyridine 1-oxide (64.9 mg, 0.127 mmol, 63.7 % yield) (mixture of 4 diasteomers). Further purification by chiral chromatography (Column: Lux C ₆ ll 2, 5 micron, 30 x 250mm; Flow Rate: 45 mL/min, Mobile Phase: 85: 15 acetonitrile: methanol, modifier: 0.1% isopropylamine) gave 4 peaks. Peak 2 was collected to give 2-carbamoyl-4-((S)-4-((S)-l-((5-(2,4- difluorophenoxy)pyridin-2-yl)amino)-l-oxopropan-2-yl)morphol in-2-yl)pyridine 1-oxide (14.3 mg, 0.028 mmol, 23.75 % yield). LCMS (ES, m/s): 500.3 [M+H] ⁺ , rt = 0.97 min, Method 1. flT NMR (400 MHz, DMSO-d ₆ ) 5 10.24-10.39 (m, 2H), 8.38 (d, J=6.85 Hz, 1H), 8.28 (br d, J=4.40 Hz, 1H), 8.04-8.23 (m, 3H), 7.58 (dd, J=6.85, 2.93 Hz, 1H), 7.45-

7.55 (m, 2H), 7.30 (td, J=9.29, 5.87 Hz, 1H), 7.08-7.17 (m, 1H), 4.66 (br d, J=7.82 Hz, 1H), 3.99 (br d, J=11.25 Hz, 1H), 3.65-3.75 (m, 1H), 3.51-3.62 (m, 1H), 3.05 (br d, J=11.25 Hz, 1H), 2.72 (br d, J=10.76 Hz, 1H), 2.39-2.48 (m, 1H), 2.30-2.39 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

Examples 6 and 7 were synthesized in an analogous manner, using the designated

Intermediate in Step 4.

Example 8 (S)-A-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-((S)-2-(6-oxo- l,6-dihydropyridin-3- yl)morpholino)propanamide

Step 1

A mixture of 2-methoxy-5-vinylpyridine (1.04 g, 7.70 mmol, 1.00 eq) in tert-butanol (20 mL) and water (20 mL) was treated with NBS (1.37 g, 7.70 mmol, 1.00 eq), and the reaction was stirred at 40 °C for 17 h. The mixture was cooled in an ice bath, treated with 5 N NaOH (4.63 mL, 23.1 mmol, 3 eq) and was allowed to warm to rt while stirring for 4 h. The reaction was quenched with water (30 mL) and was extracted with DCM (2 x 40 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and loaded onto a silica gel column, eluting with 0-70% EtOAc in heptane to give 0.781 g (purity: 88%, yield: 59%) of 2-methoxy-5-(oxiran-2-yl)pyridine as a clear liquid. LCMS: (ES, m/z) 170 (M+H ₂ 0+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.19 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.3, 2.4 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 3.94 (dd, J=3.9, 2.4 Hz, 1H), 3.85 (s, 3H), 3.12 (dd, J=5.1, 4.2 Hz, 1H), 3.00-2.89 (m, 1H).

Step 2

A mixture of 2-methoxy-5-(oxiran-2-yl)pyridine (0.76 g, 5.0 mmol) in ethanol (20 mL) was treated with ethanolamine (0.31 mL, 5.1 mmol, 1.0 eq), stirred for 18 h, then treated with triethylamine (0.70 mL, 5.0 mmol, 1.0 eq). After 3 h, the reaction was heated to 80 °C for 3 h, cooled to room temperature, treated with di-tert-butyl di carbonate (1.1 g, 5.0 mmol, 1.0 eq) and stirred for 16 h. Additional di-tert-butyl dicarbonate (0.12 g, 5.0 mmol, 0.11 eq) was added, and the reaction was stirred for 1 h. The mixture was quenched with water (30 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and loaded onto a silica gel column, eluting with 0-70% EtOAc in heptane to give 0.78 g (purity: 99%, yield: 37%) of tert-butyl (2- hydroxy-2-(6-methoxypyridin-3-yl)ethyl)(2-hydroxyethyl)carba mate as a yellow oil. LCMS: (ES, m/z) 330 (M+H) ⁺ . 'H NMR (400 MHz, CDCI ₃ ) δ 8.26-8.11 (m, 1H), 7.78- 7.60 (m, 1H), 6.79 (d, J=8.3 Hz, 1H), 5.14-4.98 (m, 1H), 4.04-3.95 (m, 4H), 3.80 (br d, J=8.8 Hz, 2H), 3.62 (br s, 1H), 3.56-3.07 (m, 4H), 1.51 (s, 9H).

Step 3

A mixture of tert-butyl (2-hydroxy-2-(6-methoxypyridin-3-yl)ethyl)(2- hydroxyethyl)carbamate (0.590 g, 1.89 mmol) and polymer-bound triphenylphosphine (100-200 mesh) (0.761 g, 2.28 mmol) in toluene (20 mL) was treated with diisopropyl azodi carb oxy late (0.450 mL, 2.31 mmol) and stirred for 21 h. Additional polymer bound triphenylphosphine (100-200 mesh) (0.125 g, 0.375 mmol) and diisopropyl azodi carb oxy late (0.074 mL, 0.38 mmol) were added, and the resulting mixture was stirred for an additional 5 h. The reaction was filtered, concentrated and loaded onto a silica gel column, eluting with 0-100% EtOAc in heptane to give 0.120 g (purity: 66%, yield: 14%) of tert-butyl 2-(6-methoxypyri din-3 -yl)morpholine-4-carboxylate as a yellow oil. LCMS: (m/z) 295 (M+H) ⁺ . 'H NMR (400 MHz, CDCI ₃ ) 6 8.20 (d, J=2.4 Hz, 1H), 7.66 (dd, J=8.6, 2.2 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.41 (br dd, J=10.5, 2.2 Hz, 1H), 4.21-3.87 (m, 6H), 3.69 (td, J=11.6, 2.7 Hz, 1H), 3.15-3.00 (m, 1H), 2.94-2.74 (m, 1H), 1.50 (s, 9H). Step 4

A solution of tert-butyl 2-(6-methoxypyridin-3-yl)morpholine-4-carboxylate (120 mg, 0.408 mmol, 1.00 eq) in DCM (3 ml) was treated with TFA (0.5 mL, 6.49 mmol, 15.9 eq), and the resulting mixture was stirred at 25 °C for 1 h. The reaction was concentrated, and the crude residue was taken onto the next step without further purification. LCMS (ES, m/z): 195 [M+H] ⁺ .

Step 5

A mixture of 2-(6-m ethoxypyri din-3 -yl)morpholine, tri fluoroacetic acid salt (80.0 mg, 0.260 mmol) in DMF (1 mL) was treated with silver nitrate (44.5 mg, 0.262 mmol, 1.01 eq), (R)-2-bromo-A-(5-(2,4-difluorophenoxy)pyridin-2-yl)propanami de (94.5 mg, 0.265 mmol, 1.02 eq), and tri ethylamine (0.181 mL, 1.30 mmol, 5.00 eq), and the resulting mixture was stirred at 60 °C for 3 h. The reaction was filtered, concentrated and purified by reverse phase HPLC (Column XSelect CSH Prep OBD C18 30x150mm, 5pm OBD); Mobile Phase A: water (10 mmol/L NH4HCO3 and 0.075% NH4OH), Mobile Phase B: MeCN ; Flow Rate 40 mL/ min; Gradient 50% B to 99% B over 17 min) to give 0.0719 g (purity: 93%, yield: 54.8%) of (2S)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(2-(6- methoxypyridin-3-yl)morpholino)propanamide as a presumed mix of enantiomers. LCMS (ES, m/z): 471 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCI ₃ ) δ 8.26-8.08 (m, 3H), 7.63 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (br dd, J = 8.8, 2.9 Hz, 1H), 7.13-7.06 (m, 1H), 7.04-6.97 (m, 1H), 6.94-6.87 (m, 1H), 6.77 (dd, J = 8.6, 4.2 Hz, 1H), 4.21-4.07 (m, 1H), 3.95 (d, J = 3.4 Hz, 3H), 2.04 (s, 3H), 1.69-1.53 (m, 4H), 1.50-1.26 (m, 3H).

Step 6

A solution of (28)-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)-2-(2-(6-methoxy pyridin-3- yl)morpholino)propanamide (69.2 mg, 0.147 mmol, 1.00 eq) and 33% HBr in acetic acid (2 mL) was stirred at 90 °C for 5 h. The mixture was quenched with water (20 mL) and sat. aqueous NaHCCL solution (50 mL), and was extracted with DCM (4 x 20 mL). The combined organic phases were dried over MgSO ₄ , filtered, concentrated and loaded onto a silica gel column, eluting with 0-20% MeOH in DCM to give 61.0 mg (purity: 90% , yield: 81% yield) of (28)-A-(5-(2,4-difluorophenoxy)pyri din-2 -yl)-2-(2-(6-oxo- 1,6- dihydropyridin-3-yl)morpholino)propanamide as a white solid. The mixture was then further purified by chiral chromatography (Column: Chiralpak IC 20x250 mm, 5 pm; Mobile Phase: 40 : 60 Heptane : Ethanol; Flow Rate: 20 mL/min) to give two peaks at 6.2 min and 9.6 min. The peak with retention time 9.6 min was collected to give 12.7 mg (purity: 99%, yield: 19%, chiral purity: 99.6%) of (S)-N-(5-(2,4-difluorophenoxy)pyridin- 2-yl)-2-((S)-2-(6-oxo-l,6-dihydropyridin-3-yl)morpholino)pro panamide as a white solid. LCMS (m/z) 475 (M+H) ⁺ . 'H NMR (400 MHz, CDCI ₃ ) 8 13.06 (br s, 1H), 9.65 (br s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.49 (dd, J=9.3, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.33-7.24 (m, 1H), 7.09 (td, J=9.0, 5.4 Hz, 1H), 7.03-6.95 (m, 1H), 6.90 (br dd, J=2.9, 1.5 Hz, 1H), 6.58 (d, J=9.8 Hz, 1H), 4.46 (br d, J=9.3 Hz, 1H), 4.05 (dd, J=11.5, 1.7 Hz, 1H), 3.97-3.85 (m, 1H), 3.32 (br s, 1H), 2.94-2.73 (m, 2H), 2.68 (br d, J=9.3 Hz, 1H), 2.29 (br t, J=10.8 Hz, 1H), 1.35 (br d, J=6.8 Hz, 3H).

Example 9 (S)-N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-((S)-2-(6-oxo- l,6-dihydropyridin-3- yl)morpholino)propanamide Step 1

A racemic mixture of tert-butyl 2-(6-m ethoxypyri din-3 -yl)morpholine-4-carboxylate (Example 8, Step 3) (260 mg) was separated by Prep-Chiral SFC (Column: Chiralpak IG, 20x250 mm, 5p; Co-solvent: 15% MeOH; Flow rate: 50 g/min; Rtl : 5.1-6.1 min (undesired R isomer), Rt2: 6.4-7.8 min (desired S isomer) to give 153 mg (ee: 99.6%, 41% yield) of tert-butyl (S)-2-(6-m ethoxypyri din-3 -yl)morpholine-4-carboxylate as a white solid. LCMS: (ES, m/z) 295 [M+H] ⁺ ; rt = 0.88 min, LCMS Method 2. ¹ H NMR: (400 MHz, DMSO-d ₆ ) 5 8.18 (d, J=2.4 Hz, 1H), 7.72 (dd, J=8.8, 2.4 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 4.40 (dd, J=10.5, 2.7 Hz, 1H), 3.94 (br dd, J=11.5, 2.7 Hz, 1H), 3.85 (s, 3H), 3.79 (br d, J=12.7 Hz, 1H), 3.54 (td, J=11.7, 2.4 Hz, 1H), 3.08-2.71 (m, 2H), 1.42 (s, 9H). (One hydrogen peak likely obscured by solvent peak).

Step 2

A solution of tert-butyl (S)-2-(6-methoxypyridin-3-yl)morpholine-4-carboxylate (150 mg, 0.52 mmol) in DCM (4 mL) was treated with trifluoroacetic acid (1.0 mL, 13 mmol), and the resulting mixture was stirred at room temperature for 20 h and concentrated to give the crude trifluoroacetic acid salt of (S)-2-(6-methoxypyridin-3-yl)morpholine 0.52 mmol) as a clear film, which was used without further purification. LCMS: (ES, m/z) 195 [M+H] ⁺ ; rt = 0.28 min LCMS Method 2.

Step 3

A solution of crude (S)-2-(6-m ethoxypyri din-3 -yl)morpholine, trifluoroacetic acid salt (0.52 mmol) and (S)-2-bromo-A-(5-(2,4-difluorophenoxy)pyrazin-2-yl)propanami de (220 mg, 0.62 mmol) in DMA (0.5 ml) at 0 °C was treated with tri ethylamine (0.51 ml, 3.6 mmol), and the resulting mixture was stirred at room temperature for 21 h. The reaction was diluted with water and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (x 3), washed with brine, dried over MgSCU, filtered and concentrated. The resulting residue was loaded onto a silica gel column, eluting with 0- 100% EtOAc in heptane to give 110 mg (purity: 100%, 44% yield) of (S)-N-(5-(2,4- difluorophenoxy)pyrazin-2-yl)-2-(CS')-2-(6-methoxypyridin-3- yl)morpholino)propanamide as a clear gum. LCMS: (ES, m/z) 472 [M+H] ⁺ ; rt = 0.75 min, LCMS Method 2. 'H NMR (400 MHz, CDCI ₃ ) δ 9.68 (s, 1H), 9.05 (d, J=1.5 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.62 (dd, J=8.8, 2.4 Hz, 1H), 7.23 (td, J=8.8, 5.9 Hz, 1H), 7.03-6.89 (m, 2H), 6.75 (d, J=8.8 Hz, 1H), 4.67 (br d, J=8.3 Hz, 1H), 4.15-4.08 (m, 1H), 3.94 (s, 3H), 3.93-3.85 (m, 1H), 3.32 (q, J=6.8 Hz, 1H), 2.83 (br d, J=11.2 Hz, 1H), 2.73-2.64 (m, 1H), 2.57 (br t, J=10.8 Hz, 2H), 1.37 (d, J=6.8 Hz, 3H).

Step 4

A solution of (S)-A-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-((S)-2-(6-meth oxypyridin-3- yl)morpholino)propanamide (110 mg, 0.23 mmol) in 33% HBr in HOAc (2 ml, 12 mmol) was heated at 90 °C for 3 h. The reaction was concentrated, and the resulting residue was diluted with EtOAc and neutralized with sat. aq. NaHCO ₃ solution. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (x 3), washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was loaded onto a silica gel column, eluting with 0-100% MeOH in EtOAc to give 90 mg (purity: 100%, 87% yield) of S)-N- (5-(2,4-difluorophenoxy)pyrazin-2-yl)-2-((S)-2-(6-oxo-l,6-di hydropyridin-3- yl)morpholino)propanamide as a white solid. LCMS: (ES, m/z) 458 [M+H] ⁺ ; rt = 0.61 min, LCMS Method 2. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86 (d, J=1.5 Hz, 1H), 8.27 (d, J=1.5 Hz, 1H), 7.64 (dd, J=9.5, 2.7 Hz, 1H), 7.47-7.41 (m, 1H), 7.32 (td, J=8.9, 5.6 Hz, 1H), 7.14 (ddd, J=10.9, 8.2, 2.9 Hz, 1H), 7.06-6.96 (m, 1H), 6.60-6.48 (m, 1H), 4.50 (dd, J=10.0, 2.2 Hz, 1H), 4.05-3.98 (m, 1H), 3.84 (td, J=11.2, 2.4 Hz, 1H), 3.40 (q, J=6.8 Hz, 1H), 2.96-2.88 (m, 1H), 2.75 (dd, J=11.5, 1.7 Hz, 1H), 2.54-2.39 (m, 2H), 1.33 (d, J=6.8 Hz, 3H).

Assay Protocol

A Ca ²⁺ mobilization assay was used to assess the activity of the compounds of this invention. A HEK293 cell line with stably expressing human MRGPRX2 and mouse Galphal5 genes was used in the assay. Briefly, cells were seeded into black clear-bottomed 384-well plates at 1.5 x 10 ⁴ cells/well and culture at 37°C for 24 hours prior to assay. On the day of assay, cells were loaded with Ca ²⁺ indicator dye in 20 pL Hank's buffered saline solution containing 25 mmol/L HEPES, pH 7.2 (assay buffer) supplemented with 2 pmol/L Fluo-4 dye (Molecular Probes), 2.5 mmol/L probenecid (Sigma) & 0.5 mmol/L Brilliant Black (MP Biomedicals). Activation of human MRGPRX2 by a peptide agonist, Cortistatin-14 (PCKNFFWKTFSSCK, Disulfide Bridge: 2-13, TFA salt, GeneScript), was measured on FLIPR ^TETRA (Molecular Devices) instrument as increased fluorescence intensity (488 nm excitation/530 nm emission) upon receptor binding, leading to G-protein activation and Ca ²⁺ mobilization. An activation dose response curve was produced for Cortistatin-14 to determine the EC50 value of the agonist on the day of assay. Compounds of this invention were prepared as 1 mM or 10 mM solution in DMSO. Serial dilutions of 11 concentrations at 3 -folds were made in DMSO for each compound and then diluted in assay buffer prior to addition onto the dye-loaded cells (final testing concentration range of 100 pmol/L-100 pmol/L for compounds with final 1% DMSO in assay buffer). After 30 min incubation at 37°C, agonist Cortistatin-14 was added to the cell culture at 4xEC50 final concentration. Fluorescence intensity was measured on FLIPR ^TETRA for compounds’ ability to inhibit agonist mediated MRGPRX2 activation. Dose dependent inhibition curves were fitted in ActivityBase (IDBS) data analysis platform to report a pIC50 value for each individual compound dilution series.

The pIC50s for each compound of this invention were averaged to determine a mean value, for a minimum of 2 experiments. For instance, the compounds of Examples 1 - 304 inhibited MRGPRX2 activation in the above method with a pIC50 value between approximately 9.0 and 4.5.

Biological Data

The exemplified compounds were tested according to the FLIPR ^TETRA assay described above and were found to be MrgX2 antagonists with pIC50 > 5.0.

As determined using the above method, the compounds of Examples 1-9 exhibited a pIC _5o between approximately 9.0-5.0

The compounds of Examples 5, and 7-9 exhibited a pIC ₈ o > 8.0.

The compounds of Examples 1 and 2 exhibited a pIC ₈ o 8.0 > pIC ₈ o > 7.0. The compounds of Example 3 and 4 exhibited a pIC ₈ o 7.0 > pIC ₈ o > 5.0. The compounds of Example 6 exhibited 5.5 > pIC ₈ o > 4.5.