Mrgprx2 modulators and related methods of treatment

Abstract

Disclosed herein are compounds having the structure of Formula (I): (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L1, L2, R1, R2, R3, R4, and m are as defined herein. Pharmaceutical compositions comprising them, processes for preparing them, and uses of them to treat or prevent diseases, disorders, and conditions are also provided. The compounds are modulators of MRGPRX2 or the MRGPRX2 ortholog and are useful in the treatment of diseases, disorders, and conditions related to MRGPRX2 or the MRGPRX2 ortholog activity.

Description

[0001] MRGPRX2 MODULATORS AND RELATED METHODS OF TREATMENT BACKGROUND Technical Field [1] The invention relates to modulators of the Mas-related G-protein coupled receptor X2, to products containing the same, as well as to methods of their use and preparation. Description of the Related Art [2] Mas-related G-protein receptors (MRGPRs) are a group of orphan receptors with limited expression in very specialized tissues. Very little is known about the function of most of these receptors. In humans, there are eight members in the MRGPR family of receptors. Of these, four members (MRGPRD, E, F and G) have readily identifiable orthologs in mammals. [3] The other four receptors (MRGPR X1, X2, X3 and X4) have counterparts in higher species including dogs and horses, but they do not have a single corresponding ortholog in rodents. [4] Mas-related G protein-coupled receptor X2 (MRGPRX2) is an orphan, seven transmembrane G protein-coupled receptor that is almost exclusively expressed on connective tissue mast cells. MRGPRX2 belongs to a G protein-coupled receptor subfamily X, comprised of four members X1-X4, specific to humans and primates. MRGPRX2 is a low affinity promiscuous receptor for cyclic and polybasic structure ligands that mediates mast cell degranulation in response to multiple endogenous and exogenous stimuli. [5] Mast cells constitute an integral part of the human immune system. They are important modulators of inflammatory and physiological processes. MRGPRX2 receptor plays a pivotal role in itch, allergy and inflammation. Activation of the receptor by neuropeptides, antimicrobial host defense peptides as well as numerous FDA-approved drugs leads to mast cell degranulation and release of inflammatory mediators through immunoglobulin-independent pathway (M. Thapaliya, et al., Curr. Allergy Asthma Rep., 2021, 21(1), 3). [6] Activation of MRGPRX2 receptor drives non-histaminergic itch in chronic refractory pruritus and MRGPRX2 has also been implicated in senile itch (A. He, et al. Biomed. Res. Int., 2017, 4790810; J. Meixiong, et al., Immunity, 2019, 50(5), 1163-71). There is an increased MRGPRX2 gene expression on mast cells in the skin of patients with severe chronic urticaria (hives) (H. Ali, J. Immunobiol., 2016, 1(4), 115; D. Fujisawa, et al., J. Allergy Clin. Immunol. 2014, 134(3), 622-33). Additionally, activation of MRGPRX2 by elevated levels of proadrenomedullin N-terminal 20 peptide (PAMP1-20) in the skin of patients with allergic contact dermatitis (ACD) leads to intensely itchy eczematous skin rash (J. Meixiong, et al., Immunity, 2019, 50(5):1163-71). MRGPRX2 is also involved in the pathogenesis of acne rosacea where dysregulation of the host defense mechanism due to excessive LL-37 antimicrobial peptide production leads to enhanced mast cell activation through MRGPRX2 (H. Ali, Adv. Immunol., 2017, 136, 123-62). MRGPRX2 is also implicated in systemic mastocytosis and in neurogenic inflammation, pain and itch. Substance P released from nerve endings and directly from mast cells in sickle cell anemia patients activates mast cells via MRGPRX2 causing painful crisis (H. Subramanian, et al., J. Allergy Clin. Immunol., 2016, 138(3), 700-10). [7] The role of MRGPRX2 in mast cell biology is further supported by the fact that naturally occurring missense MRGPRX2 variants: G165E, D184H, W243R, and H259Y inhibit mast cell degranulation in response to endogenous neuropeptides and drugs (I. Alkanfari, et al., J. Immuol., 2018, 201(2), 343-49). [8] Taken together, these findings suggest that MRGPRX2 plays a critical role in itch, pain, and inflammation. Potential disease indications for MRGPRX2 antagonist encompass chronic urticaria and pruritus (hives / itch), acne rosacea, and systemic mastocytosis. These clinical indications present high unmet medical need, particularly in antihistamine-refractory patients. Therefore, targeting of MRGPRX2 receptor can be useful in the clinical treatment of mast-cell mediated diseases. [9] There remains a need for new compounds that are effective as modulators, antagonists or inhibitors of MRGPRX2. BRIEF SUMMARY

[0010] This invention is based, in part, on the identification of MRGPRX2 or MRGPRX2 ortholog modulator compounds. Among rodent orthologs, mouse mrgprb2 and rat mrgprb3 correspond functionally to human MRGPRX2 in mast cells. MRGPRX2 and its ortholog receptors mediate disorders including pseudo-allergic drug reactions, chronic itch (e.g., pruritus), inflammation disorders, pain disorders, a cancer associated condition, skin disorders, wound healing, cardiovascular disease, and lung inflammation / COPD. In one embodiment, expression of MRGPRX2 and its orthologs is largely restricted to mast cells. Mast cells are innate immune cells that primarily reside at sites exposed to the external environment, such as the skin, oral / gastrointestinal mucosa and respiratory tract. Mast cells express numerous receptors that respond to mechanical and chemical stimuli. Upon activation, classically by IgE, mast cells release pre-formed mediators from granules (e.g., histamine, proteases, and heparin) and newly synthesized mediators (e.g., thromboxane, prostaglandin D2, leukotriene C4, tumor necrosis factor alpha, eosinol chemotactor factor, and platelet-activating factor) that elicit allergic and inflammatory responses. Histamine dilates post-capillary venules, activates the endothelium, and increases blood vessel permeability. This causes local edema, warmth, redness, and chemotaxis of other inflammatory cells to the site of release. Histamine also contributes to neuronal sensitization that leads to pain or itch. MRGPRX2 and its orthologs mediate immunoglobulin E (IgE) independent activation of mast cells. MRGPRX2 and its orthologs are receptors for (or sensitive to activation by) various ligands, including basic secretagogues (small cationic molecules), certain drugs (e.g., cationic peptidergic drugs), neuropeptides, and antimicrobial peptides, and thus are important for non-IgE mediated pseudo-allergic reactions, inflammation, pain, and itch conditions. Mast cells may also contribute to the progression of autoimmune disorders by promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a Th17 immune response. Thus, modulating MRGPRX2 or MRGPRX2 orthologs allows for treatment of autoimmune diseases, pseudo-allergic drug reactions, pain, itch, and inflammatory disorders such as inflammatory bowel disease, urticaria, sinusitis, asthma, rosacea, endometriosis, and other MRGPRX2 or MRGPRX2 ortholog dependent conditions as explained in more detail below.

[0011] In one embodiment is provided a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of the pharmaceutical composition of the modulator compounds of the present invention.

[0012] Accordingly, in an embodiment, is provided a compound having structure (I): or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof, wherein L1, L2, R1, R2, R3, R4, and m are as defined herein.

[0013] In other embodiments, compounds are provided having formula (II), (III), (III-A), or (III-B) as defined herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0014] In yet other embodiments, pharmaceutical compositions are provided comprising a carrier or excipient and a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or isotope thereof.

[0015] In another embodiment, methods are provided for treating an MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a compound having structure (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

[0016] In some embodiments, the MRGPRX2 or a MRGPRX2 ortholog dependent condition is one or more of a pseudo-allergic reaction, itch associated condition, a pain associated condition, a cancer associated condition, an inflammation-associated condition, or an autoimmune disorder.

[0017] In another embodiment, compounds are provided having one or more of the structures disclosed herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. DETAILED DESCRIPTION

[0018] As mentioned above, the invention relates to modulators of MRGPRX2 (or MRGPRX2 ortholog), to products containing the same, as well as to methods of their use and preparation. This invention is based, in part, on the identification of MRGPRX2 modulator compounds and MRGPRX2 ortholog modulator compounds. MRGPRX2 and MRGPRX2 orthologs are expressed in mast cells. MRGPRX2 and MRGPRX2 orthologs are receptors for (or sensitive to activation by) a diverse group of ligands, including basic secretagogues, certain drugs, neuropeptides, antimicrobial peptides, and thus are important for pseudo-allergic reactions, itch, pain, or inflammatory disorders upon exposure.

[0019] MRGPRs appear to be sensory receptors that recognize their external environment to exogenous or endogenous signals / chemicals. These receptors likely respond to multiple chemical ligands / agonists. For example, MRGPRX2 recognizes Compound 48 / 80, Substance P, Mastoparan, Icatibant, Ciprofloxacin, and atracurium as agonist signals. In certain embodiments, molecules of this invention modulate MRGPRX2 by functioning as inverse agonists that are capable of blocking multiple chemical entities, and / or as competitive antagonists that can specifically block individual ligands. In one embodiment, such modulations are selective against other MRGPRs, such as MRGPR X1, X3, X4 and / or D.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and is not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0021] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.

[0022] Reference in the specification to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.

[0023] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0024] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about 100µL" means "about 100µL" and also "100µL." In some embodiments, about means within 5% of the value. Hence, "about 100 µL" means 95–105 μL. In some embodiments, about means within 4% of the value. In some embodiments, about means within 3% of the value. In some embodiments, about means within 2% of the value. In some embodiments, about means within 1% of the value. Generally, the term "about" includes an amount that would be expected to be within experimental error. Compounds

[0025] One embodiment provides a compound having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: L1is –(CR′R′′)q−, –(CR′R′′)u−CR′=CR′−(CR′R′′)v−, –(CR′R′′)u−C≡C−(CR′R′′)v−, −(CR′R′′)u−O−(CR′R′′)v−, −(CR′R′′)u−NR′−(CR′R′′)v−, −(CR′R′′)u−C(O)−(CR′R′′)v−; L2is –(CRaRb)w−; R1is C1-6 alkyl, carbocycle or heterocycle, wherein R1is substituted with –(R5)n; R2is halo, C1-6 alkyl, carbocycle or heterocycle, wherein R2is substituted with –(R6)p; R3is H or C1-6 alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −C(O)N(R8)2, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NHC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl; m is 0–5; n is 0–5; p is 0–5 q is 1–3; u is, at each occurrence, independently 0–3; v is, at each occurrence, independently 0–3; w is 0–3; x is 0–3; y is 0–3; and z is 0–3; wherein R2is carbocycle or heterocycle when L1is −C(R′R′′)q−.

[0026] “Alkyl” means a saturated or unsaturated straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 3 carbon atoms. Examples of saturated straight chain alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. An unsaturated alkyl includes alkenyl and alkynyl as defined below.

[0027] “Alkenyl” means a straight chain or branched alkenyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. Alkenyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0028] “Alkynyl” means a straight chain or branched alkynyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to 3 carbon atoms. Alkynyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0029] “Halo” or “halogen” refers to fluorine, chlorine, bromine, and iodine.

[0030] “Hydroxy” refers to −OH.

[0031] “Cyano” refers to −CN.

[0032] Amino refers to –NH2, -NHalkyl or N(alkyl)2, wherein alkyl is as defined above. Examples of amino include, but are not limited to – NH2, -NHCH3, –N(CH3)2, and the like.

[0033] “Haloalkyl” refers to alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, −CF3, −CHF2, and the like.

[0034] “Alkoxy” refers to alkyl as defined above joined by way of an oxygen atom (i.e., −O−alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0035] “Haloalkoxy” refers to haloalkyl as defined above joined by way of an oxygen atom (i.e., −O−haloalkyl). Examples of lower haloalkoxy groups include, but are not limited to, −OCF3, and the like.

[0036] “Cycloalkyl” refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0037] “Aryl” groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Representative aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The terms “aryl” and “aryl groups” include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.

[0038] “Carbocycle” refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring may give rise to aromaticity. In one embodiment, carbocycle includes cycloalkyl as defined above. In another embodiment, carbocycle includes aryl as defined above.

[0039] “Heterocycle” refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.

[0040] Heterocyclyl groups also include fused ring species including those having fused aromatic and non-aromatic groups. A heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring members. A heterocyclyl group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0041] In one embodiment, heterocyclyl includes heteroaryl.

[0042] “Heteroaryl” refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups” include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydro indolyl.

[0043] In one embodiment is provided a compound of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is carbocycle or heterocycle.

[0044] In one embodiment, R1is heterocycle. In one embodiment, R1is heterocycloalkyl. In one embodiment, R1is aziridinyl, oziranyl, thiranyl, azetidinyl, 1,2-dihydroazotyl, oxetanyl, 2H- oxetyl, thietanyl, 2H-thietyl, pyrrolidinyl, 4,5-dihydro-1H-imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, 2H-pyranyl, 3,4-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, morpholinyl, thianyl, 1,4-dithianyl, 2H-thiopyranyl, azepanyl, 1,4-diazepanyl, oxepanyl, or thiepanyl. In one embodiment, R1is tetrahydro-2H-pyranyl.

[0045] In one embodiment, R1is heteroaryl. In one embodiment, R1is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,3,4-thiatriazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, [1,2,3]triazolo[4,5-b]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-purinyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-c]pyriminyl, pyrrolo[1,2-b]pyrdazinyl, imidazo[4,5-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, pyrido[3,4-d]pyridazinyl, 1,5-naphtyridinyl, 1,8-natphyridinyl, 9H-carbazolyl, benzoxazolyl, dibenzofuranyl, benzothiophenyl, or dibenzothiophenyl. In one embodiment, R1is pyridinyl, furanyl, thiazolyl, pyrazolyl, or indolyl.

[0046] In one embodiment, R1is carbocycle. In a further embodiment, R1is cycloalkyl. In one embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In one embodiment, R1is cyclohexyl. In another embodiment, R1is aryl. In one embodiment, R1is naphthyl, tetrahydronaphthalenyl, or phenyl.

[0047] In one embodiment, R1is C1-6 alkyl.

[0048] In one embodiment is provided a compound having the structure of Formula (II): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: L1is –(CR′R′′)q−, –(CR′R′′)u−CR′=CR′−(CR′R′′)v−, –(CR′R′′)u−C≡C−(CR′R′′)v−, −(CR′R′′)u−O−(CR′R′′)v−, −(CR′R′′)u−NR′−(CR′R′′)v−, −(CR′R′′)u−C(O)−(CR′R′′)v−; L2is –(CRaRb)w−; R2is carbocycle or heterocycle, wherein R2is substituted with –(R6)p; R3is H or C1-6 alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl; m is 0–5; n is 0–5; p is 0–5 q is 1–3; u is, at each occurrence, independently 0–3; v is, at each occurrence, independently 0–3; w is 0–3; x is 0–3; y is 0–3; and z is 0–3; wherein R2is carbocycle or heterocycle when L1is −C(R′R′′)q−.

[0049] In one embodiment is provided a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is carbocycle or heterocycle.

[0050] In one embodiment, R2is heterocycle. In a further embodiment, R2is heterocycloalkyl. In one embodiment, R2is aziridinyl, oziranyl, thiranyl, azetidinyl, 1,2- dihydroazotyl, oxetanyl, 2H-oxetyl, thietanyl, 2H-thietyl, pyrrolidinyl, 4,5-dihydro-1H-imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, 2H-pyranyl, 3,4-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, morpholinyl, thianyl, 1,4-dithianyl, 2H-thiopyranyl, azepanyl, 1,4-diazepanyl, oxepanyl, thiepanyl, or 2,3-dihydrobenzo[1,4]dioxinyl, dihydrobenzofuranyl, or benzo[1,3]dioxolyl. In one embodiment, R2is tetrahydrofuranyl, 2,3- dihydrobenzo[1,4]dioxinyl, benzo[1,3]dioxolyl, or dihydrobenzofuranyl.

[0051] In another embodiment, R2is heteroaryl. In one embodiment, R2is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,3,4-thiatriazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, [1,2,3]triazolo[4,5-b]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-purinyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-c]pyriminyl, pyrrolo[1,2-b]pyrdazinyl, imidazo[4,5-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, pyrido[3,4-d]pyridazinyl, 1,5-naphtyridinyl, 1,8-natphyridinyl, 9H-carbazolyl, benzoxazolyl, dibenzofuranyl, benzothiophenyl, or dibenzothiphenyl. In one embodiment, R2is pyridinyl, pyrimidinyl, oxazolyl, isothiazolyl, thiazolyl, isoquinolinyl, indolyl, benzo[d]oxazolyl, quinolinyl, pyrazinyl, or indazolyl. In one embodiment, R2is pyridinyl.

[0052] In one embodiment, R2is carbocycle. In a further embodiment, R2is cycloalkyl. In one embodiment, R2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In another embodiment, R2is aryl. In one embodiment, R2is naphthyl or phenyl.

[0053] In one embodiment is provided a compound having the structure of Formula (III): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: L1is –(CR′R′′)q−, –(CR′R′′)u−CR′=CR′−(CR′R′′)v−, –(CR′R′′)u−C≡C−(CR′R′′)v−, −(CR′R′′)u−O−(CR′R′′)v−, −(CR′R′′)u−NR′−(CR′R′′)v−, −(CR′R′′)u−C(O)−(CR′R′′)v−; L2is –(CRaRb)w−; Q1, Q2, and Q3are, at each occurrence, independently CR6or N; R3is H or C1-6 alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl m is 0–5; n is 0–5; p is 0–5 q is 1–3; u is, at each occurrence, independently 0–3; v is, at each occurrence, independently 0–3; w is 0–3; x is 0–3; y is 0–3; and z is 0–3.

[0054] In one embodiment is provided a compound of Formula (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1, Q2, and Q3are each CR6. In another embodiment is provided a compound of Formula (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1is N and Q2and Q3are each CR6. In another embodiment is provided a compound of Formula (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q2is N and Q1and Q3are each CR6. In another embodiment is provided a compound of Formula (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q3is N and Q1and Q2are each CR6.

[0055] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein w is 0.

[0056] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein w is 1. In a further embodiment, Rais H. In another embodiment, Rais C1-6 alkyl. In a further embodiment, Rais methyl. In one embodiment, Rbis H. In one embodiment, Rbis C1-6 alkyl. In a further embodiment, Rbis methyl. In one embodiment, Raand Rb, together with the carbon atom to which they are attached, form a cycloalkyl. In one embodiment, Raand Rb, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, or cyclopentyl.

[0057] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein w is 2 or 3. In a further embodiment, at least one Rais H. In another embodiment, at least one Rais C1-6 alkyl. In a further embodiment, at least one Rais methyl. In one embodiment, at least one Rbis H. In one embodiment, at least one Rbis C1-6 alkyl. In a further embodiment, at least one Rbis methyl. In one embodiment, at least one Raand Rb, together with the carbon atom to which they are attached, form a cycloalkyl. In a further embodiment, at least one Raand Rb, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, or cyclopentyl.

[0058] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is –(CR′R′′)q−. In one embodiment, q is 1. In another embodiment, q is 2. In one embodiment, each R′ is H. In another embodiment, at least one R′ is C1-6 alkyl. In one embodiment, at least one R′ is methyl. In one embodiment, each R′′ is H. In another embodiment, at least one R′′ is C1-6 alkyl. In one embodiment, at least one R′′ is methyl. In another embodiment, at least one R′′ is C1-6 alkenyl. In one embodiment, at least one R′′ is vinyl. In another embodiment, at least one occurrence of R′ and R′′ attached to the same carbon atom form a cycloalkyl together with the carbon to which they are attached. In one embodiment, at least one occurrence of R′ and R′′ attached to the same carbon atom form a cyclopropyl or a cyclobutyl together with the carbon to which they are attached.

[0059] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−CR′=CR′−(CR′R′′)v−. In one embodiment, L1is −CR′=CR′−. In one embodiment, each R′ is H. In another embodiment, at least one R′ is C1-6 alkyl. In one embodiment, at least one R′ is methyl.

[0060] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−C≡C−(CR′R′′)v−. In one embodiment, L1is −C≡C−.

[0061] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−O−(CR′R′′)v−. In one embodiment, u is 0. In another embodiment, u is 1. In one embodiment, v is 0. In another embodiment, v is 1. In one embodiment, L1is −O−.

[0062] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−NR′−(CR′R′′)v−. In one embodiment, u is 0. In another embodiment, u is 1. In one embodiment, v is 0. In another embodiment, v is 1. In one embodiment, L1is −NR′−. In one embodiment, R′ is H. In another embodiment, R′ is C1-6 alkyl. In one embodiment, R′ is methyl, ethyl, or propyl.

[0063] In one embodiment is provided a compound of any one of Formula (I), (II), or (III), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−C(O)−(CR′R′′)v−. In one embodiment, u is 0. In another embodiment, u is 1. In one embodiment, v is 0. In another embodiment, v is 1. In one embodiment, L1is −C(O)−.

[0064] In one embodiment is provided a compound having the structure of Formula (III-A) or Formula (III-B): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q1, Q2, and Q3are, at each occurrence, independently CR6or N; R3is H or C1-6 alkyl; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NRC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl m is 0–5; n is 0–5; p is 0–5 x is 0–3; y is 0–3; and z is 0–3.

[0065] In one embodiment is provided a compound having the structure of Formula (III-A) or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1, Q2, and Q3are each CR6. In another embodiment, Q1is N and Q2and Q3are each CR6. In another embodiment, Q2is N and Q1and Q3are each CR6. In another embodiment, Q3is N and Q1and Q2are each CR6.

[0066] In one embodiment is provided a compound having the structure of Formula (III-A) or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais H. In another embodiment, Rais C1-6 alkyl. In one embodiment, Rais methyl.

[0067] In one embodiment is provided a compound having the structure of Formula (III-A) or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis H. In another embodiment, Rbis C1-6 alkyl. In one embodiment, Rbis methyl.

[0068] In one embodiment is provided a compound having the structure of Formula (III-A) or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Raand Rb, together with the carbon atom to which they are attached, form a cycloalkyl. In one embodiment, Raand Rb, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, or cyclopentyl.

[0069] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0. In another embodiment, m is 1 or 2. In another embodiment, m is 1. In another embodiment, m is 2.

[0070] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R4is C1-6 alkyl. In one embodiment, at least one R4is methyl.

[0071] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is halo. In one embodiment, at least one R4is Cl or F.

[0072] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is −CN.

[0073] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is C1-6 alkoxy. In one embodiment, at least one R4is −OCH3.

[0074] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0. In another embodiment, n is 1, 2, or 3. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.

[0075] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is C1-6 alkyl. In one embodiment, at least one R5is methyl, ethyl, propyl, or butyl. In one embodiment, at least one R5is methyl. In one embodiment, at least one R5is ethyl. In one embodiment, at least one R5is propyl. In one embodiment, at least one R5is butyl.

[0076] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is halo. In one embodiment, at least one R5is Cl or F. In one embodiment, at least one R5is Cl. In another embodiment, at least one R5is F.

[0077] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is −CN.

[0078] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is C1-6 alkoxy. In one embodiment, at least one R5is methoxy.

[0079] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is carbocycle. In one embodiment, at least one R5is phenyl.

[0080] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein p is 0. In another embodiment, p is 1, 2, or 3. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3.

[0081] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is halo. In one embodiment, at least one R6is Cl or F. In one embodiment, at least one R6is Cl. In another embodiment, at least one R6is F.

[0082] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −CN.

[0083] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −OR7. In one embodiment, at least one R7is H, −C1-6 alkyl−R8, or C1-6 haloalkyl. In one embodiment, at least one R7is H. In one embodiment, at least one R7is −C1-6 alkyl−R8. In one embodiment, at least one R8is H, −C1-6 alkyl−R8, or carbocycle. In one embodiment, at least one R7is C1-6 haloalkyl. In one embodiment, at least one R6is:

[0084] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −N(R7)2. In one embodiment, at least one R7is H or −C1-6 alkyl−R8. In one embodiment, at least one R8is H, −C1-6 alkyl−R8, or carbocycle. In one embodiment, at least one R6is:

[0085] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −SR7or −S(O)2R7. In one embodiment, at least one R7is −N(R8)2, −C1-6 alkyl−R8, or carbocycle substituted with –(R8)y. In one embodiment, at least one R8is H, −C1-6 alkyl−R8, or carbocycle. In one embodiment, at least one R6is:

[0086] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, or −C(O)N(R8)2. In one embodiment, at least one R7is H or −C1-6 alkyl−R8. In one embodiment, at least one R8is H, −C1-6 alkyl−R8, or carbocycle. In one embodiment, at least one R8is H, −C1-6 alkyl−R8, or carbocycle. In one embodiment, at least one R6is:

[0087] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −C1-6 alkyl−R7. In one embodiment, R7is H. In one embodiment, at least one R6is methyl, ethyl, propyl, or butyl. In another embodiment, R7is −OR8, −N(R8)2, −C(O)OR8, −NHC(O)OR8, or heterocycle substituted with –(R8)y. In one embodiment, at least one R8is H, −C1-6 alkyl−R8, or carbocycle. In one embodiment, at least one R6is:

[0088] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −C1-6 haloalkyl. In one embodiment, at least one R6is −CHF2 or −CF3.

[0089] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is carbocycle substituted with −(R7)x. In one embodiment, at least one R6is phenyl substituted with −(R7)x. In one embodiment, x is 0. In another embodiment, x is 1, 2, or 3. In one embodiment, x is 1. In one embodiment, x is 2. In one embodiment, x is 3.

[0090] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is heterocycle substituted with −(R7)x. In one embodiment, at least one R6is pyrazolyl, thiophenyl, or tetrazolyl substituted with −(R7)x. In one embodiment, x is 0. In another embodiment, x is 1, 2, or 3. In one embodiment, x is 1. In one embodiment, x is 2. In one embodiment, x is 3. In one embodiment, at least one R6is pyrazolyl, thiophenyl, or tetrazolyl.

[0091] In one embodiment is provided a compound having the structure of Formula (I), (II), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R3and one R6, together with the atoms to which they are attached, form a ring. In one embodiment, R3and one R6, together with the atoms to which they are attached, form a 6-membered ring fused with R2.

[0092] In one embodiment is provided a compound having the structure of Formula (III-C), or Formula (III-D), Formula (III-E), or Formula (III-F): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R’, R”, Ra, Rb, R3, R4, R5, R6, Q1, Q2, Q3, n, m, and p are as defined above in the context of Formulas (I), (II), (III), (III-A), or (III-B).

[0093] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H.

[0094] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R” is H.

[0095] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is alkyl.

[0096] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is methyl.

[0097] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R” is alkyl.

[0098] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R” is methyl.

[0099] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ and R” are H.

[0100] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is alkyl and R” is H.

[0101] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is methyl and R” is H.

[0102] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H and R” is alky.

[0103] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H and R” is methyl.

[0104] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais H.

[0105] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rbis H.

[0106] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais alkyl.

[0107] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais methyl.

[0108] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rbis alkyl.

[0109] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rbis methyl.

[0110] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Raand Rbare H.

[0111] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais alky and Rbis H.

[0112] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais methyl and Rbis H.

[0113] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais H and Rbis alkyl.

[0114] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), Rais H and Rbis methyl.

[0115] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is H, Rais H and Rbis H.

[0116] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is alkyl, R” is H, Rais H and Rbis H.

[0117] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is methyl, R” is H, Rais H and Rbis H.

[0118] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is alkyl, Rais H and Rbis H.

[0119] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is methyl, Rais H and Rbis H.

[0120] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is H, Rais alkyl and Rbis H.

[0121] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is H, Rais methyl and Rbis H.

[0122] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is H, Rais H and Rbis alkyl.

[0123] In another embodiments of Formulas (III-C), (III-D), (III-E) and (III-F), R’ is H, R” is H, Rais H and Rbis methyl.

[0124] Representative compounds of Formula (I), and Formulas (II), (III), (III-A), (III-B), (III-C), (III-D), (III-E) and (III-F) as applicable, include the compounds having the structure of those listed in Table 1 and Examples 1–20, below, as well as pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof. To this end, representative compounds are identified herein by their respective “Compound Number”, which is sometimes abbreviated as “Compound No.”, “Cmpd. No.”, “Cpd. No.”, or “No.” TABLE 1

[0125] "Isomer" is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. However, when a particular stereochemistry or isomeric form is indicated herein, the particular form is meant to indicate an assumed stereochemistry or isomeric form unless it is specifically indicated that the particular stereochemistry or isomeric form has been definitively determined. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers”. Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S). The term also encompasses isomers arising from substitution patterns across double bonds, in particular (E)- and (Z)- isomers, or cis- and trans- isomers. E–Z configuration describes the absolute stereochemistry across double bonds having two, three or four substituents. Following the Cahn-Ingold-Prelog priority rules (CIP rules), each substituent on a double bond is assigned a priority, and the positions of the higher of the two substituents on each carbon determined. If the two groups of higher priority are on the same side of the double bond (cis to each other), the bond is assigned Z ("zusammen", German for "together"). If the two groups of higher priority are on opposite sides of the double bond (trans to each other), the bond is assigned E ("entgegen", German for "opposite"). Each isomer may be isolated separately or exist as mixtures. The mixtures may be predominantly one isomer, e.g.99.9%, or 99% or 90%, predominantly the other isomer, enriched in one or the other of the isomer (e.g. an 80 / 20 mixture, or a 40 / 60 mixture), or be approximately equal mixtures.

[0126] "Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.

[0127] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0128] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (i.e., will not rotate plane- polarized light in either direction since its constituent enantiomers cancel each other out).

[0129] A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

[0130] A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

[0131] "Isotope" refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has several isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and / or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and / or tritium, and / or wherein one or more fluorine atoms are replaced by fluorine-19.

[0132] In one embodiment is provided an isotope of a compound of Table 1 or of any one of Formulas (I), (II), (III), (III-A), or (III-B). In one embodiment, the isotope comprises at least one deuterium atom. In another embodiment, an isotope is provided wherein L2is −CD2−. In another embodiment, an isotope is provided wherein at least one R4, R5, or R6is D.

[0133] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts."

[0134] The term "pharmaceutically acceptable" refers to an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to nontoxic inorganic or organic acid and / or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).

[0135] Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0136] Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, βhydroxybutyric, salicylic, -galactaric, and galacturonic acid.

[0137] Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the Synthesis of the compounds described herein, for example in their purification by recrystallization.

[0138] In some embodiments, the compounds are pharmaceutically acceptable salts. In some embodiments, the compounds are isomers. In some embodiments, the compounds are racemates. In some embodiments, the compounds are solvates. In some embodiments, the compounds are hydrates. In some embodiments, the compounds are isotopes. Pharmaceutical Compositions

[0139] In certain embodiment, also disclosed herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof. In some embodiments, the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0140] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0141] In other embodiments, there are provided methods of making a composition of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.

[0142] As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0143] The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and / or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired.

[0144] The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.

[0145] Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and / or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and / or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by reference. Modulating MRGPRX2 Activity and Treating Diseases Associated with MRGPRX2

[0146] In certain embodiments, described herein, are methods for modulating the activity of at least one Mas-related G protein coupled receptor (MRGPR) comprising contacting the MRGPR with a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof. In some embodiments, the MRGPR is MRGPRX2. In certain embodiments, methods of treating a subject having a disease or disorder associated with the activity of MRGPRX2 are disclosed, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof.

[0147] “Modulating” MRGPRX2 means that the compound interacts with MRGPRX2 or MRGPRX2 orthologs in a manner such that it functions as an inverse agonist to the receptor, and / or as a competitive antagonist to the receptor. In one embodiment, such modulation is partially or fully selective against other MRGPRs, such as MRGPR X1, X3, X4 and / or D.

[0148] “MRGPR” refers to one or more of the Mas-related G protein coupled receptors, which are a group of orphan receptors with limited expression in very specialized tissues (e.g., in mast cells and dorsal root ganglia) and barrier tissues. There are eight related receptors in this class expressed in humans. Of these, four members (MRGPRD, E, F and G) have readily identifiable orthologs in mammals. The other four receptors (MRGPR X1, X2, X3 and X4) have no single ortholog, based on homology, in non-human species. Among rodent receptors, mouse mrgprb2 and rat mrgprb3 correspond functionally to human MRGPRX2 on mast cells.

[0149] “MRGPRX2,” also referred to as “MRGX2,” or “MGRG3,” refers to a member of the MRGPR family that is expressed on mast cells and capable of mediating IgE independent activation (e.g., mast cell degranulation) in response to ligand binding. An exemplary human MRGPRX2 amino acid sequence is set forth in Uniprot Q96LB1.

[0150] As used herein, the term "administering" or "administration" refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.

[0151] As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well- being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed. The terms cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development: and / or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0152] As used herein, the term “subject” refers to an animal (e.g., a mammal, such as a human, dog or horse), and thus veterinary use is an application specifically contemplated herein. A subject to be treated according to the methods described herein may be one who has been diagnosed with a MRGPRX2 dependent condition or MRGPRX2 ortholog dependent condition, such as a pseudo-allergic reaction, an itch associated condition, a pain associated condition, a cancer associated condition, an inflammatory or autoimmune disorder. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. The term “patient” may be used interchangeably with the term “subject.” A subject may refer to an adult or pediatric subject.

[0153] The Federal Food, Drug, and Cosmetic Act defines “pediatric” as a subject aged 21 or younger at the time of their diagnosis or treatment. Pediatric subpopulations are further characterized as: (i) neonates – from birth through the first 28 days of life; (ii) infants – from 29 days to less than 2 years; (iii) children – 2 years to less than 12 years; and (iv) adolescents – aged 12 through 21. Despite the definition, depending on the susceptible patient population and clinical trial evaluation, an approved regulatory label may include phrasing that specifically modifies the range of a pediatric population, such as, for example, pediatric patients up to 22 years of age.

[0154] As used herein, the term "effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.

[0155] As used herein, the term "therapeutically effective amount" or “"pharmaceutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of a compound of the present invention in combination with other active ingredients effective to act as a modulator of MRGPRX2 or effective to treat or prevent a disease or disorder associated with MRGPRX2.

[0156] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the MRGPRX2 ortholog with a compound of Formula (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having MRGPRX2, as well as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing MRGPRX2.

[0157] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0158] As used herein, the phrase “MRGPRX2 dependent condition” means a condition where the activation, over sensitization, or desensitization of MRGPRX2 or its orthologs by a natural or synthetic ligand initiates, mediates, sustains, or augments a pathological condition. For example, it is known that some cationic peptidergic drugs cause pseudo-allergic reactions in patients where MRGPRX2 is sensitive to (or activated by) secretagogues, cationic peptidergic drugs, including Icatibant, Leuprolide, or Ganirelix, neutral and anionic peptidergic drugs (e.g., Exenatide, Glucagon, Liraglutide, Enfuvirtide, Colistimethate), non-steroidal agonist (atracurium mivacurium), non-steroidal antagonist drugs, neuropeptides, and antimicrobial peptides. Moreover, overexpression of MRGPRX2 and / or overactivity MRGPRX2 may also render mast cells more susceptible to activation by endogenous and / or exogenous ligands. Without being limited by theory, it is to be understood that by modulating MRGPRX2, pseudo-allergic reactions, itch, pain, inflammatory or autoimmune disorders can be eased.

[0159] In some embodiments, the MRGPRX2 dependent condition is a condition that is caused by IgE independent activation of MRGPRX2 or its orthologs. IgE independent activation of MRGPRX2 is capable of inducing mast cell degranulation. For example, IgE independent mast cell activation is associated with some cases of chronic urticaria and other mast cell mediated conditions, which are not responsive to current anti-IgE or antihistamine therapies. Thus, the compounds of the present disclosure may be used for treating an MRGPRX2 dependent condition caused by IgE independent activation of MRGPRX2 and that would benefit from modulating MRGPRX2.

[0160] In some embodiments, the MRGPRX2 dependent condition is an itch associated condition, a pain associated condition, a cancer associated condition, a pseudo-allergic reaction, or an autoimmune or inflammatory disorder in humans or other mammals.

[0161] As used herein the phrase “pseudo-allergic reaction” refers to an IgE-independent allergic reaction, characterized by histamine release, inflammation, airway contraction, or any combination thereof. A pseudo-allergic reaction may be an anaphylactic reaction. A pseudo- allergic reaction may be caused by a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. Thus, in one embodiment, the method of present invention is provided to treat a pseudo-allergic reaction, such as pseudo-allergic reactions caused by secretagogues, cationic peptidergic drugs, anionic peptidergic drugs, neutral peptidergic drugs, non-steroidal antagonist drugs, neuropeptides, and antimicrobial peptides. In one embodiment, the pseudo-allergic reaction is caused by MCD peptide, Substance P, VIP, PACAP, dynorphin, somatostatin, Compound 48 / 80, Cortistatin-14, Mastoparan, Melettin, Cathelicidin Peptides, Ciprofloxacin, Vancomycin, Leuprolide, Goserelin, Histrelin, Triptorelin, Cetrorelix, Ganirelix, Degarelix, Octreotide, Lanreotide, Pasireotide, Sermorelin, Tesamorelin, Icatibant, Glatiramer Acetate, Teriparatide, Pramlintide, Bleomycin, Exenatide, Glucagon, Liraglutide, Enfuvirtide, Colistimethate, Succinylcholine, Tubocurarine, Atracurium, Mivacurium, And Rocuronium.

[0162] As used herein, the phrase “itch associated condition” means pruritus (including acute and chronic pruritus) associated with any condition. The itch sensation can originate, e.g., from the peripheral nervous system (e.g., dermal or neuropathic itch) or from the central nervous system (e.g., neuropathic, neurogenic or psychogenic itch). Thus, in one embodiment, the method of present invention is provided to treat an itch associated condition, such as acne, allergic blepharitis, anaphylaxis, anaphylactoid drug reactions, anaphylactic shock, anemia, atopic dermatitis, bullous pemphigoid, burn healing, candidiasis, chicken pox, cholestatic pruritis, chronic itch, chronic urticaria, contact dermatitis, cutaneous amyloidosis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, end-stage renal failure, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, food allergy, folliculitis, fungal skin infection, hemodialysis, hemorrhoids, herpes, HIV infection, Hodgkin’s disease, hyperthyroidism, iodinated contrast dye allergy, iron deficiency anemia, kidney disease, leukemia, porphyria, lymphoma, mast cell activation syndrome, malignancy, mastocytosis, multiple myeloma, neurodermatitis, ocular itch, onchocerciasis, Paget’s disease, pediculosis, polycythemia rubra vera, prurigo nodularis, lichen planus, lichen sclerosis, pruritus ani, pseudo-allergic reactions, pseudorabies, psoriasis, rectal prolapse, rosacea, sarcoidosis granulomas, scabies, schistosomiasis, scleroderma, severe stress, Stasia dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, urticaria and wound healing.

[0163] As used herein, the phrase “pain associated condition” means any pain due to a medical condition. Thus, in one embodiment, the method of present invention is provided to treat a pain associated condition, such as acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet’s Disease (Syndrome), bladder pain, burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, chronic pelvic pain syndrome, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn’s disease, degenerative disc disease, dental pain, Dercum’s disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headaches, herniated disc, hydrocephalus, intercostal neuralgia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatosis and dermatomyositis, knee injury, leg pain, loin pain-haematuria syndrome, lupus, Lyme disease, medullary sponge kidney (MSK), meralgia paresthetica, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget’s disease, Parsonage Turner syndrome, pelvic pain, periodontitis pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney disease, polymyalgia rheumatica, polymyositis, porphyria, post herniorrhaphy pain syndrome, post mastectomy, postoperative pain, pain syndrome, post stroke pain, post thoracotomy pain syndrome, postherpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud’s Disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosis, Scheuermann’s Kyphosis disease, sciatica, scoliosis, shingles (herpes zoster), Sjogren’s syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinal cerebellum ataxia (SCA Ataxia), spinal cord injury, spinal stenosis, syringomyelia, Tarlov cysts, transverse myelitis, trigeminal neuralgia, ulcerative colitis, vascular pain and vulvodynia.

[0164] As used herein, the term “autoimmune disorder”, or “inflammatory disorder” means a disease or disorder arising from and / or directed against an individual’s own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom. Typically, various clinical and laboratory markers of autoimmune diseases may exist including, but not limited to, hypergammaglobulinemia, high levels of autoantibodies, antigen-antibody complex deposits in tissues, clinical benefit from corticosteroid or immunosuppressive treatments, and lymphoid cell aggregates in affected tissues. Thus, in one embodiment, the method of present invention is provided to treat an autoimmune disorder, such as chronic inflammation, mast cell activation syndrome, Multiple Sclerosis, Steven Johnson’s Syndrome, Toxic Epidermal Necrolysis, acne vulgaris, appendicitis, bladder infection, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, rosacea, tendonitis, tonsillitis, sinusitis, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, allergic rhinitis, autoinflammatory disease, celiac disease, chronic prostatitis, Crohn’s Disease, diverticulitis, endometrial pain, epithelial intestinal disorder, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, lupus erythematous, meningitis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, permanent sputum eosinophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, eosinophilic gastroenteritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, schwannomatosis, tubulointerstitial nephritis, ulcerative colitis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, reflux nephropathy, polycystic kidney disease, liver fibrosis / cirrhosis, autoimmune liver disease, biliary atresia, acute and chronic Hepatitis B and C virus, Liver tumors and cancer, alcoholic liver disease, polycystic liver disease, liver cholangiocarcinoma, neuromyelitis optica spectrum disorder, cardiovascular disease, inflammation induced by bacterial or viral infection, inflammation associated with SARS-CoV-2 infection or its variants and Coronavirus Disease 2019 (COVID-19), acute respiratory distress syndrome, pneumonia, Long / Long-Term / Chronic COVID, Post-Acute Sequelae of COVID-19 (PASC), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS “Brain Fog”) and vasculitis.

[0165] As used herein the phrase “cancer associated condition” means any disease arising from the proliferation of malignant cancerous cells. Thus, in one embodiment, the method of present invention is provided to treat a cancer / tumor associated condition, such as adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia- telangiectasia, Beckwith Wiedemann syndrome, Birt-Hogg-Dubee syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), cholangiocarcinoma, prostrate, basal cell, melanoma, colon, colorectal, bladder, kidney cancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lung cancer (non-small cell, small cell), leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T cell lymphocytic, eosinophilic), Liver Cancer, Li-Fraumeni syndrome, lymphoma (Hodgkin and non-Hodgkin), lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma, multiple endocrine neoplasia, multiple myeloma, MUTYH-associated polyposis, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, neuroblastoma, neuroendocrine tumors, neurofibromatosis, penile cancer, parathyroid cancer, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary gland tumor, pleuropulmonary blastoma, oral and oropharyngeal , thyroid, uterine, pancreatic, carney complex, brain and spinal cord cancer, cervical cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary, leiomyomatosis and renal cell cancer, hereditary pancreatitis, hereditary papillary renal carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS related cancers, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, culver cancer, Werner syndrome and Xeroderma pigmentosum.

[0166] In another embodiment, a method of treating a subject having an itch associated condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the itch associated condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema. In another embodiment, a method of treating a subject having an inflammation or autoimmune associated condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the inflammation or autoimmune associated condition is sinusitis, asthma, rosacea, or endometriosis.

[0167] In another embodiment, a method of treating a subject having a pain associated condition is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition thereof. In one embodiment, the pain associated condition is chronic pelvic pain syndrome, endometriosis pain, fibromyalgia, migraine or postoperative pain. Combination Therapy

[0168] In another embodiment, the method of treating a subject having a MRGPRX2 dependent condition (e.g., an itch associated condition, a pain associated condition, a pseudo- allergic reaction, or an inflammatory or autoimmune disorder) described herein further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent. In one embodiment, the itch associated condition is a pseudo-allergic condition.

[0169] In one embodiment, the second therapeutic agent is an antihistamine, such as an H1 receptor antagonist or an H2 receptor antagonist. In one embodiment, the second therapeutic agent is an H1 receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is a H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or leukotriene synthesis inhibitor, such as Montelukast, Zafirlukast, Pranlukast, or 5-lipoxygenase inhibitor (e.g., Zileuton, hypericum perforatum). In one embodiment, the second therapeutic agent is an immunomodulatory agent such as Omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, betamethasone, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricyclic antidepressant that can relieve itch such as doxepin, amitriptyline or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory drug such as dapsone, sulfasalazine, hydroxychloroquine or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant such as cyclosporine, methotrexate, mycophenolic acid or tacromilus.

[0170] The second therapeutic agent may be administered simultaneously, separately, or sequentially with the compounds of the present disclosure. If administered simultaneously, the second therapeutic agent and compound of the present disclosure may be administered in separate dosage forms or in the same dosage form. Routes of Administration

[0171] The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intratarsal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Kits

[0172] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of MRGPRX2 associated diseases or disorders, and other diseases referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. Compound Synthesis

[0173] Compounds having the structure of Formulas (I) can be synthesized using standard synthetic techniques known to those of skill in the art.

[0174] Modifications to the methods described herein will be apparent to one skilled in the art. To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates, or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed.

[0175] Unless otherwise indicated, conventional methods of mass spectroscopy (MS), liquid chromatography-mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or readily prepared. EXAMPLES General Methods

[0176] 1H NMR (400 MHz) spectra were obtained in solution of deuterochloroform (CDCl3), deuteromethanol (CD3OD) or dimethyl sulfoxide-D6 (DMSO-D6). HPLC retention times, purities and mass spectra (LCMS) were obtained using one of the following methods:

[0177] Purity Method 1: Shimadzu system equipped with a Halo C18, 5 μm, 3.0 x 30 mm column using H2O with 0.0375% trifluoroacetic acid as mobile phase A, and acetonitrile with 0.01875% trifluoroacetic acid as mobile phase B. The gradient was 5-95% mobile phase B over 0.5 min, held at 95% mobile phase B for 0.3 min, returned to 5% mobile phase B for 0.205 min. The flow rate was 1.5 mL / min.

[0178] Purity Method 2: Shimadzu system equipped with a Kinetex EVO C18, 5 μm, 2.1 x 30 mm column using H2O with 0.025% NH4OH as mobile phase A, and acetonitrile as mobile phase B. The gradient was 0-60% mobile phase B over 0.8 min, held at 60% mobile phase B for 0.4 min, returned to 0% mobile phase B for 0.35 min. The flow rate was 1.5 mL / min.

[0179] Purity Method 3: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column, using H2O with 0.1% formic acid as mobile phase A, and MeCN with 0.1% formic acid as mobile phase B. The gradient was 10-95% mobile phase B over 12 min, held at 95% for 2 min, then returned to 10% mobile phase B over 1 min. The flow rate was 1 mL / min. An ESI detector in positive mode was used.

[0180] Purity Method 4: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column, using H2O with 0.1% formic acid as mobile phase A, and MeCN with 0.1% formic acid as mobile phase B. The gradient was 5-95% mobile phase B over 5 min, 95-20% mobile phase B over 1.5 min, then returned to 10% mobile phase B over 0.5 min. The flow rate was 1 mL / min. An ESI detector in positive mode was used.

[0181] Chiral Purity Method 1: Shimadzu system equipped with a Chiralcel OJ-3, 3 μm, 4.6 x 50 mm column at 35 °C column temp using MeOH (0.05%DEA) in CO2 from 5% to 40% gradient over 3 min. The flow rate was 3 mL / min. A PDA detector was used.

[0182] Chiral Purity Method 2: Shimadzu system equipped with a Chiralcel OJ-3, 3 μm, 4.6 x 50 mm column at 35 °C column temp using EtOH (0.05%DEA) in CO2 from 5% to 40% gradient over 3 min. The flow rate was 3 mL / min. A PDA detector was used.

[0183] The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedures were from Aldrich Sure-Seal bottles kept under nitrogen (N2). All reactions were stirred magnetically, and temperatures are external reaction temperatures. Chromatographies were typically carried out using a Combiflash Rf flash purification system (Teledyne Isco) equipped with Redisep (Teledyne Isco) Rf Gold Normal-Phase silica gel (SiO2) columns or by using a similar system.

[0184] Preparative HPLC purifications were typically performed using one of the following systems: 1) Waters System equipped with a Waters 2489 uv / vis detector, an Aquity QDA detector, a Waters xBridge Prep C185 μm OBD, 30 X 150 mm column, and eluting with various gradients of H2O / MeCN (0.1% formic acid) at a 30 mL / min flow rate, 2) Teledyne Isco ACCQPrep® HP150 UV system equipped with a Waters xBridge Prep C185 μm OBD, 30 X 150 mm column, and eluting with various gradients of H2O / MeCN (0.1% formic acid) at a 42.5 mL / min flow rate, or 3) column: Phenomenex Synergi C18150X30 mm- 4μm; mobile phase: [H2O (0.225%formic acid)- MeCN];B%: 55%-85%,12min) and were typically concentrated using a Genevac EZ-2.

[0185] The following additional abbreviations are used: ethyl acetate (EA), triethylamine (TEA), dimethyl sulfoxide (DMSO), silica gel (SiO2), azobisisobutyronitrile (AIBN), diisobutylaluminium hydride (DIBAL), trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP), diphenylphosphoryl azide (DPPA), benzoyl peroxide (BPO), 1,1'- bis(diphenylphosphino)ferrocene (dppf), bis(pinacolato)diboron (B2pin2), tetrahydrofuran (THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), hydroxybenzotriazole (HOBt), N-methyl morpholine (NMM), N-Bromosuccinimide (NBS), diisopropylethyl amine (DIPEA), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 2-[2- (dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos), triflic acid (TfOH), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), isopropanol (IPA), dimethylformamide (DMF), dimethyl acetamide (DMA), dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile (MeCN or ACN), 1,1’-thiocarbonyldiimidazole (TCDI), petroleum ether (PE), not determined (ND), retention time (RT), molecular weight (mw), room temperature (rt), hour (h), and not applicable (N / A). EXAMPLE 1 Synthesis of Representative Compound 1-15 Reagents: (i) Base (K2CO3, Cs2CO3 or (KOtBu), solvent (MeCN); (ii) Fe, solvent (EtOH / AcOH / H2O); (iii.) ClSO2NCO, solvent (nitromethane) then AlCl3; (iv) N,N-diethylaniline, solvent (POCl3); (v) Base (Et3N), solvent (EtOH) or Base (DIPEA), solvent (NMP) Step 1-1. Synthesis of 1-fluoro-2-(2-fluorophenoxy)-3-nitrobenzene (INT-1A)

[0186] To 2-fluorophenol (0.500 g, 1 Eq, 4.46 mmol) in MeCN (10 mL) was added Potassium carbonate (616 mg, 261 μL, 1 Eq, 4.46 mmol) and 1,2-difluoro-3-nitrobenzene (710 mg, 1 Eq, 4.46 mmol). The reaction vial was capped and heated at 80 °C overnight. After the reaction was completed, water (10 mL) was added. The aqueous layer was extracted with EtOAc (3 x 10 mL), and the organics were concentrated in vacuo to afford crude material. The crude material was purified by silica gel chromatography (0-50% EtOAc / hexanes) to afford 1-fluoro-2-(2- fluorophenoxy)-3-nitrobenzene INT 1A (1.04 g, 4.14 mmol, 93 % yield). Step 1-2. Synthesis of 3-fluoro-2-(2-fluorophenoxy)aniline (INT-1B)

[0187] To a vigorously stirred solution of INT 1A (1.04 g, 1 Eq, 4.14 mmol) in EtOH (6 mL), H2O (6 mL), and AcOH (6 mL) was added iron powder (925 mg, 4 Eq, 16.6 mmol). The reaction vial was capped and heated at 100 °C overnight. The reaction mixture was filtered through Celite, rinsed with EtOAc, concentrated in vacuo, and purified by silica gel chromatography (0- 100% EtOAc / hexanes) to afford 3-fluoro-2-(2-fluorophenoxy)aniline INT 1B (871 mg, 3.94 mmol, 95 % yield). Step 1-3. Synthesis of 6-fluoro-5-(2-fluorophenoxy)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 1C)

[0188] To a solution of sulfurisocyanatidic chloride (668 mg, 1.2 Eq, 4.72 mmol) in nitromethane (15 mL) at 0 °C was added dropwise a solution of INT 1B (870 mg, 1 Eq, 3.93 mmol) in nitromethane (15 mL). The reaction mixture was stirred at 0 °C for 30 minutes. Aluminum trichloride (1.57 g, 3 Eq, 11.8 mmol) was added and the reaction mixture was heated to 105 °C for 45 minutes. The reaction mixture was cooled some and slowly poured onto ice water (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL) and concentrated in vacuo to afford crude material. The crude material was purified by silica gel chromatography (0à100% 10% MeOH in EtOAc / hexanes) to afford 6-fluoro-5-(2-fluorophenoxy)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 1C (590 mg, 1.81 mmol, 46% yield) Step 1-4. Synthesis of 3-chloro-6-fluoro-5-(2-fluorophenoxy)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 1D)

[0189]

[0190] To a stirring solution of INT 1C (590 mg, 1 Eq, 1.81 mmol) was added Phosphorus oxychloride (11.1 g, 6.67 mL, 40 Eq, 72.3 mmol) and N,N-diethylaniline- (270 mg, 289 μL, 1 Eq, 1.81 mmol). The reaction mixture was stirred and heated at 125 °C for 18 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (0 to100% 10% MeOH in EtOAc / hexanes) to afford 3-chloro-6-fluoro-5-(2-fluorophenoxy)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 1D (549.8 mg, 1.595 mmol, 88% yield). Step 1-5. Synthesis of 6-fluoro-5-(2-fluorophenoxy)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 1-15)

[0191] To INT 1D (80 mg, 1 Eq, 0.23 mmol) in EtOH (2 mL) was added triethylamine (70 mg, 97 μL, 3 Eq, 0.70 mmol) and (3-fluoropyridin-2-yl)methanamine (59 mg, 2 Eq, 0.46 mmol). The reaction vial was capped and heated at 65 °C for 15h. The reaction mixture was concentrated in vacuo and purified by reversed phase HPLC (35-55% 0.1% formic acid in MeCN / 0.1% formic acid in H2O) that was lyophilized to afford 6-fluoro-5-(2-fluorophenoxy)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 1-15 (19 mg, 43 μmol, 18 %). LCMS (m / z) calculated for C19H13F3N4O3S: 434.0; found 435.0 [M+H] +, tR = 7.797 min (Escient Purity 1).1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.43 (d, J = 4.6 Hz, 1H), 8.02 (s, 1H), 7.78 (t, J = 9.2 Hz, 1H), 7.74 – 7.60 (m, 1H), 7.56 – 7.36 (m, 2H), 7.29 (t, J = 9.7 Hz, 1H), 7.17 (dt, J = 15.5, 6.8 Hz, 2H), 6.99 (t, J = 8.2 Hz, 1H), 4.68 (d, J = 4.7 Hz, 2H).19F NMR (376 MHz, DMSO- d6) δ -123.16, -126.49, -133.79. Synthesis of Scheme 1 Compounds

[0192] Alternatively for Step 1-4, the following compounds were synthesized without the addition of N,N-diethylaniline: 1-59, 1-60, 1-61, 1-64, 1-65, 1-66, 1-67, 1-89, 1-99, 1-100, 1-101, 1-102, 1-103, 1-104, 1-105, 1-106, 1-107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-113, 1-114, 1-115, 1-116, 1-117, 1-118, 1-119, 1-120, 1-121, 1-122, 1-123, 1-124, 1-125, 1-126, 1-127, 1-128, 1-129, 1-130, 1-131, 1-132, 1-133, 1-134, 1-135, 1-136, 1-137, 1-138, 1-139, 1-140, 1-141, 1-142, 1-143, 1-144, 1-145, 1-146, 1-147, 1-148, 1-149, 1-150, 1-151, 1-152, 1-153, 1-163, 1-164.

[0193] Alternatively for Step 1-5, the following compounds were made using 3 eq of DIPEA in NMP at 90 °C for 3 h: 1-62, 1-63, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-81, 1-82, 1-83, 1-84, 1-85, 1-86, 1-87, 1-88, 1-90, 1-91, 1-92, 1-93, 1-94, 1-95, 1-96.

[0194] Alternatively for Step 1-5, the following compounds were made using 3 eq of DIPEA in NMP at 120 °C for 3 h: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-11, 1-12, 1-13, 1-14, 1-20, 1-21, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-49, 1-52, 1-22, 1-101, 1-102, 1-103, 1-104, 1-105, 1-106, 1-107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-113, 1-114, 1-115, 1-116, 1-117, 1-118, 1-119, 1-120, 1-121, 1-122, 1-123, 1-124, 1-125, 1-126, 1-127, 1-128, 1-129, 1-130, 1-131, 1-132, 1-133, 1-134, 1-135, 1-136, 1-139, 1-140, 1-141, 1-142, 1-143, 1-144, 1-145, 1-146, 1-147, 1-148, 1-149, 1-150, 1-151, 1-152, 1-153, 1-163, 1-164.

[0195] Alternatively for Step 1-5, the following compounds were made using 3 eq of DIPEA in NMP at 130 °C for 18 h: 1-200, 1-201, 1-202, 1-203, 1-204, 1-205, 1-206, 1-207, 1-208, 1-209, 1-234, 1-246, 1-247, 1-248, 1-249, 1-254, 1-259, 1-260, 1-261, 1-262, 1-268, 1-269, 1-270, 1-271, 1-272, 1-273, 1-274, 1-275, 1-276, 1-277, 1-278, 1-279.

[0196] Alternatively for Step 1-5, the following compounds were made using 3 eq of DIPEA in DMA at 130 °C for 16 h: 1-64, 1-65, 1-66, 1-67, 1-89.

[0197] Alternatively for Step 1-5, the following compounds were made using 3 eq of DIPEA in DMF at 120 °C for 2 h: 1-97, 1-98.

[0198] Alternatively for Step 1-5, the following compounds were made using 3 eq of DIPEA in THF at 70 °C for 18 h: 1-53, 1-59, 1-60, 1-61, 1-99, 1-100, 1-137, 1-138.

[0199] The compounds listed in Table 2 were made using the procedures of Scheme 1. TABLE 2 EXAMPLE 2 Synthesis of Representative Compound 2-1 Scheme 2 Reagents: (i) Base (Cs2CO3 or K2CO3), solvent (MeCN); (ii) SnCl2•2H2O, solvent (EtOAc); (iii.) ClSO2NCO, solvent (nitromethane) then AlCl3; (iv) N,N-diethylaniline, solvent (POCl3); (v) Base (DIPEA), solvent (DMA) or Base (DBU), solvent (DMF), reagent (BOP) Step 2-1. Synthesis of 2-(2-chlorophenoxy)-1-fluoro-3-nitrobenzene (INT 2A)

[0200] To a stirring solution of 1,2-difluoro-3-nitro-benzene (3.0 g, 18.86 mmol, 8.19 mL, 1.2 eq) and 2-chlorophenol (2.02 g, 15.71 mmol, 1.60 mL, 1 eq) in MeCN (200 mL) was added Cs2CO3 (10.2 g, 31.4 mmol, 2 eq). The reaction mixture was heated and stirred at 80 °C for 14h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated in vacuo to afford crude material. The crude material was purified by silica gel chromatography (0- 3% EtOAc / petroleum ether) to afford 2-(2-chlorophenoxy)-1-fluoro-3-nitro-benzene INT 2A (3.1 g, 11.6 mmol, 74% yield).1H NMR (400 MHz, DMSO-d6) δ = 8.04 (td, J = 1.5, 8.4 Hz, 1H), 7.88 (ddd, J = 1.5, 8.6, 10.3 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.31 - 7.24 (m, 1H), 7.16 (dt, J = 1.4, 7.7 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H). Step 2-2. Synthesis of 2-(2-chlorophenoxy)-3-fluoroaniline (INT 2B)

[0201] To a solution of 2-(2-chlorophenoxy)-1-fluoro-3-nitro-benzene INT 2A (3.1 g, 11.6 mmol, 1 eq) in EA (25 mL), was added SnCl2•2H2O (15.7 g, 69.5 mmol, 6 eq). The mixture was heated and stirred at 50 °C for 16h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated in vacuo to afford crude material. The crude material was purified by silica gel chromatography (0-5% EtOAc / petroleum ether) to afford 2-(2- chlorophenoxy)-3-fluoroaniline INT 2B (2.5 g, 10.2 mmol, 88% yield). LCMS (m / z) calculated for C12H9ClFNO: 237.0; found 238.0 [M+H] +, tR = 0.543 min (Purity Method 1). Step 2-3. Synthesis of 5-(2-chlorophenoxy)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 2C)

[0202] To a solution of N-(oxomethylene)sulfamoyl chloride INT 2B (2.28 g, 16.1 mmol, 1.40 mL, 1.5 eq) in nitrobenzene (30 mL) at 0 °C, was added 2-(2-chlorophenoxy)-3-fluoro-aniline (2.5 g, 10.5 mmol, 3.2 mL, 1 eq). The mixture was stirred at 0 °C for 0.5 h. Then, AlCl3 (2.10 g, 15.8 mmol, 862 µL, 1.5 eq) was added. The mixture was heated and stirred at 120 °C for 1.5h. The reaction solution was cooled to room temperature and then diluted with aqueous saturated NH4Cl solution (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude material. The crude material was diluted with petroleum ether (300 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and then dried under vacuum to afford 5-(2-chlorophenoxy)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 2C) (3.0 g, 5.16 mmol, 49% yield) that was used without further purification. Step 2-4. Synthesis of 3-chloro-5-(2-chlorophenoxy)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 2D).

[0203] To a solution of 5-(2-chlorophenoxy)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 2C (1.5 g, 4.38 mmol, 1 eq) in POCl3 (10 mL), was added N,N-diethylaniline (980 mg, 6.56 mmol, 1.05 mL, 1.5 eq) . The mixture was heated and stirred at 120 °C for 16h. The reaction mixture was cooled to room temperature and poured into water (150 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The mixture was then extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The aqueous mixture was adjusted to pH = 7 by KOH and then discarded. The crude residue was purified by silica gel chromatography (0à30% EtOAc / petroleum ether) to afford 3-chloro-5-(2-chlorophenoxy)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 2D (630 mg, 1.73 mmol, 39% yield). LCMS (m / z) calculated for C13H7Cl2FN2O3S: 360.0; found 361.0 [M+H] +, tR = 0.527 min (Purity Method 1). Step 2-5. Synthesis of 5-(2-chlorophenoxy)-6-fluoro-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 2-1).

[0204] To a solution of (3-fluoro-2-pyridyl)methanamine (124 mg, 623 µmol, 1.5 eq, 2HCl) and DIPEA (161 mg, 1.25 mmol, 217 µL, 3 eq) in DMA (2 mL), was added 3-chloro-5-(2- chlorophenoxy)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 2D (150 mg, 415 µmol, 1 eq) . The reaction mixture was heated and stirred at 120 °C for 14 h. After returning to room temperature, the crude mixture was filtered through filter paper and concentrated in vacuo. The crude residue was purified by preparative HPLC (column: Phenomenex Luna C18 150x25mmx10µm; 38%-68% MeCN and 0.1% formic acid in water over 10 min) and lyophilized to afford 5-(2-chlorophenoxy)-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide 2-1 (74 mg, 156 µmol, 38% yield). LCMS (m / z) calculated for C19H13ClF2N4O3S: 450.0; found 451.0 [M+H] +, tR = 0.516 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.80 (br s, 1H), 8.43 (br d, J = 4.0 Hz, 1H), 8.07 (br s, 1H), 7.82 - 7.74 (m, 1H), 7.70 (dd, J = 5.2, 8.8 Hz, 1H), 7.63 (dd, J = 1.5, 7.9 Hz, 1H), 7.48 (td, J = 4.4, 8.5 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.24 - 7.16 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.69 (br d, J = 3.8 Hz, 2H). Synthesis of Scheme 2 Compounds

[0205] Alternatively for step 2-1, the following compounds were made using K2CO3 as base instead of Cs2CO3: 2-7.

[0206] Alternatively for step 2-5, the following compounds were made using THF as solvent instead of DMA at a reaction temperature of 60 °C: 2-3, 2-9, 2-13.

[0207] Alternatively for step 2-5, the following compounds were made using 1.3 Eq of BOP reagent with 3.4 Eq of DBU as base and DMF as solvent at 80 °C for 15 h: 2-7.

[0208] Alternatively for step 2-5, the following compounds were made using 1.3 Eq of BOP reagent with 3.4 Eq of DBU as base and MeCN as solvent at 80 °C for 15 h: 2-12.

[0209] The compounds listed in Table 3 were made using the procedures of Scheme 2. TABLE 3 EXAMPLE 3 Synthesis of Representative Compound 3-1

[0002] Scheme 3 Reagents: (i) Base (Cs2CO3) solvent (MeCN); (ii) SnCl2•2H2O, solvent (EtOAc); (iii.) ClSO2NCO, solvent (nitromethane) then AlCl3; (iv) CuCN, solvent (DMSO); (v) N,N- diethylaniline, solvent (POCl3); (vi) Base (DIPEA), solvent (THF) Step 3-1. Synthesis of 1-bromo-2-(2-fluorophenoxy)-3-nitrobenzene (INT3A)

[0210] To a solution of 1-bromo-2-fluoro-3-nitro-benzene (5.0 g, 23 mmol, 1 eq) and 2- fluorophenol (2.68 g, 23.9 mmol, 2.21 mL, 1.05 eq) in MeCN (50 mL), was added Cs2CO3 (16.3 g, 50.0 mmol, 2.2 eq). The reaction mixture was heated and stirred at 80 °C for 14 h. Upon cooling, the crude mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0à100% EtOAc / petroleum ether) to afford 1-bromo-2- (2-fluorophenoxy)-3-nitrobenzene (INT3A) (5.5 g, 15.0 mmol, 66% yield) that was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 8.19 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 8.2 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.18 - 7.06 (m, 2H), 6.72 (dt, J = 2.1, 8.2 Hz, 1H). Step 3-2. Synthesis of 3-bromo-2-(2-fluorophenoxy)aniline (INT3B)

[0211] To a solution of 1-bromo-2-(2-fluorophenoxy)-3-nitro-benzene INT 3A (5.5 g, 17.6 mmol, 1 eq) in EtOAc (50 mL), was added SnCl2•2H2O (19.88 g, 88.12 mmol, 5 eq). The mixture was heated and stirred at 50 °C for 3 h. The reaction mixture was poured into an aq. sat. NaHCO3 solution (300 mL) while stirring. The mixture was extracted with EtOAc (2 x 200 mL). The combined organic phase was washed with brine (3 x 80 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (0 to15% EtOAc / petroleum ether) to afford 3-bromo-2-(2-fluorophenoxy)aniline (4.5 g, 13.4 mmol, 76% yield) INT 3B that was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.35 - 7.27 (m, 1H), 7.06 - 6.97 (m, 2H), 6.96 - 6.91 (m, 1H), 6.82 (d, J = 8.1 Hz, 2H), 6.52 - 6.44 (m, 1H), 5.35 (s, 2H). Step 3-3. Synthesis of 6-bromo-5-(2-fluorophenoxy)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 3C)

[0212] To a solution of N-(oxomethylene)sulfamoyl chloride (3.42 g, 24.2 mmol, 2.1 mL, 1.52 eq) in nitrobenzene (50 mL) at 0 °C, was added 3-bromo-2-(2-fluorophenoxy)aniline INT 3B (4.5 g, 16 mmol, 1 eq). The mixture was stirred at 0 °C for 0.5 hr. Then, AlCl3 (3.2 g, 24.0 mmol, 1.31 mL, 1.5 eq) was added. The mixture was heated and stirred at 120 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated NH4Cl aqueous solution (500 mL). The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude brown oil. The obtained brown oil was diluted with petroleum ether (300 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and then dried under vacuum to give a yellow solid. The yellow solid was triturated in EtOH (10 mL) and collected by filtration to afford 6-bromo-5-(2-fluorophenoxy)-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 3C (3.9 g, 9.0 mmol, 56% yield) that was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 11.47 (s, 1H), 7.74 - 7.63 (m, 2H), 7.41 - 7.33 (m, 1H), 7.14 - 6.99 (m, 2H), 6.59 (t, J = 8.0 Hz, 1H). Step 3-4. Synthesis of 5-(2-fluorophenoxy)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine- 6-carbonitrile 1,1-dioxide (INT3D)

[0213] To a solution of 6-bromo-5-(2-fluorophenoxy)-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 3C (1.58 g, 4.08 mmol, 1 eq) in DMSO (15 mL), was added CuCN (804 mg, 8.98 mmol, 1.96 mL, 2.2 eq). The mixture was stirred at 100 °C for 14 h. The mixture was then heated and stirred at 110 °C for 3 h. The reaction mixture was poured into ammonia water (1%, 40 mL) and a brown precipitate was formed. The mixture was filtered. The filtrate was extracted with EtOAc (2 x 30 mL). The aqueous phase was acidified with 1N HCl to pH = 5. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 5-(2- fluorophenoxy)-3-hydroxy-1,1-dioxo-4H-1,2,4-benzothiadiazine-6- carbonitrile INT 3D (500 mg, 945 μmol, 23% yield) that was used without further purification. Step 3-5. Synthesis of 3-chloro-5-(2-fluorophenoxy)-4H-benzo[e][1,2,4]thiadiazine-6- carbonitrile 1,1-dioxide (INT 3E)

[0214] To a solution of 5-(2-fluorophenoxy)-3-hydroxy-1,1-dioxo-4H-1,2,4- benzothiadiazine-6-carbonitrile INT 3D (500 mg, 1.50 mmol, 1 eq) in POCl3 (5 mL), was added N,N-diethylaniline (373 mg, 2.50 mmol, 0.4 mL, 1.67 eq). The reaction mixture was heated and stirred at 120 °C for 2 h. The reaction solution was poured into water (50 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude material. The crude material was purified by prep-TLC silica gel (3:1 EtOAc / petroleum ether) to afford 3-chloro-5-(2- fluorophenoxy)-1,1-dioxo-4H-1,2,4-benzothiadiazine-6- carbonitrile INT 3E (150 mg, 332 μmol, 22% yield). The aqueous mixture was adjusted to pH = 7 by KOH and then discarded.

[0003] Step 3-6. Synthesis of 3-(((3-chloropyridin-2-yl)methyl)amino)-5-(2-fluorophenoxy)- 4H-benzo[e][1,2,4]thiadiazine-6-carbonitrile 1,1-dioxide (Compound 3-1)

[0215] To a solution of (3-chloro-2-pyridyl)methanamine INT 3E (182 mg, 1.28 mmol, 3 eq) and 3-chloro-5-(2-fluorophenoxy)- 1,1-dioxo-4H-1,2,4-benzothiadiazine-6-carbonitrile (150 mg, 426 μmol, 1 eq) in THF (5 mL) was added DIPEA (275.58 mg, 2.13 mmol, 371.40 μL, 5 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (30 mL). The product was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150x25mmx5µm; mobilephase: [A-B: water(NH4HCO3)-ACN]; gradient: 28%-58% B over 9 min) and lyophilized to afford3-(((3-chloropyridin-2-yl)methyl)amino)-5-(2-fluorophenoxy)-4H-benzo[e][1,2,4]thiadiazine-6- carbonitrile 1,1-dioxide (3-1) (33.3 mg, 72.7 µmol, 17% yield). LCMS (m / z) calculated for C20H13ClF2N5O3S: 457.0; found 458.2 [M+H] +, tR = 0.516 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 11.13 (s, 2H), 8.54 (br d, J = 4.4 Hz, 1H), 8.23 (br t, J = 4.1 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.81 - 7.69 (m, 2H), 7.48 - 7.41 (m, 2H), 7.26 (br d, J = 1.0 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.05 - 6.96 (m, 1H), 4.70 (d, J = 4.4 Hz, 2H).

[0216] 1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.42 (m, 1H), 7.87 (br d, J = 7.9 Hz, 1H), 7.79 (br d, J = 8.3 Hz, 1H), 7.68 - 7.53 (m, 1H), 7.38 - 7.26 (m, 2H), 7.25 - 7.06 (m, 2H), 6.99 - 6.88 (m, 1H), 4.77 (br s, 2H). Synthesis of Scheme 3 Compounds

[0217] Alternatively for step 3-5, the following compounds were made using 1.3 Eq of BOP reagent with 2 Eq of DBU as base and DMF as solvent at 80 °C for 15 h: 3-2.

[0218] The compounds listed in Table 4 were made using the procedures of Scheme 3. TABLE 4 EXAMPLE 4 Synthesis of Representative Compound 4-1

[0004] Scheme 4 Reagents: (i) Base (K2CO3), catalyst (Pd(PPh3)4, solvent (1,4-dioxanes / H2O); (ii) ClSO2NCO, solvent (nitromethane) then AlCl3; (iv) 2,6-lutidine, solvent (POCl3); (v) Base (DIPEA), solvent (NMP) Step 4-1. Synthesis of 2-(2-chlorobenzyl)-3-fluoroaniline (INT 4A)

[0219] To a solution of (2-amino-6-fluorophenyl)boronic acid (980 mg, 1.3 Eq, 6.32 mmol) and 1-(bromomethyl)-2-chlorobenzene (1000 mg, 1 Eq, 4.9 mmol) in 1,4-dioxane (6 mL) and water (4 mL), potassium carbonate (2.02 g, 3 Eq, 14.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.01 Eq, 49 μmol) were added. The reaction mixture was degassed and then heated at 100 °C while stirring for 3 h. The reaction mixture was passed through a syringe filter, concentrated in vacuo and purified by silica gel chromatography (0à100% 10% MeOH in EtOAc / hexanes) to afford 2-(2-chlorobenzyl)-3-fluoroaniline INT 4A (789 mg, 3.35 mmol, 69 % yield). LCMS (m / z) calculated for C13H11ClFN: 235.0; found 236.1 [M+H]+, tR = 5.67 min (Purity method 4).1H NMR (400 MHz, DMSO) δ 7.56 – 7.33 (m, 1H), 7.21 (tt, J = 7.4, 5.5 Hz, 2H), 7.01 (td, J = 8.1, 6.7 Hz, 1H), 6.80 (dd, J = 7.0, 2.3 Hz, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.36 (ddd, J = 9.5, 8.1, 1.1 Hz, 1H), 5.26 (s, 2H), 3.92 (d, J = 1.9 Hz, 2H). Step 4-2. Synthesis of 5-(2-chlorobenzyl)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 4B)

[0220] To sulfurisocyanatidic chloride (540 mg, 1.2 Eq, 3.82 mmol) was added nitromethane (5 mL). The mixture was cooled to 0 °C. A solution of INT 4A (750 mg, 1 Eq, 3.18 mmol) in nitromethane (5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 15 minutes and then aluminum trichloride (1.70 g, 4 Eq, 12.7 mmol) was added. The reaction mixture was heated to 115 °C for 3 hours. The reaction mixture was cooled to room temperature and poured into ice cold water (20 mL). The resultant precipitate was filtered, washed with water (3 x 5 mL) then hexane (3 x 5 mL). The crude material was purified by silica gel chromatography (0à100% 10% MeOH in EtOAc / hexanes) to afford obtained 5-(2-chlorobenzyl)-6-fluoro-3- hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 4B (451 mg, 1.32 mmol, 42 % yield).

[0005] Step 4-3. Synthesis of 3-chloro-5-(2-chlorobenzyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 4C)

[0221] To INT 4B (550 mg, 1 Eq, 1.61 mmol) in a sealed tube was added POCl3 (2.47 g, 1.50 mL, 10 Eq, 16.1 mmol) and 2,6-dimethylpyridine (173 mg, 1 Eq, 1.61 mmol). The tube was sealed and heated at 105 °C while stirring for 18 h. The reaction mixture was concentrated in vacuo to afford 3-chloro-5-(2-chlorobenzyl)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 4C that was used without further purification. LCMS (m / z) calculated for C14H9Cl2FN2O2S: 358.0; found 358.2 [M]+, tR = 5.04 min (Purity method 3). Step 4-4. Synthesis of 6-fluoro-5-(2-fluorobenzyl)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 4-1)

[0222] To a solution of 3-chloro-5-(2-chlorobenzyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 4C (20 mg, 1 Eq, 56 μmol) in NMP (2 mL) in a sealed tube was added (3-fluoropyridin-2-yl)methanamine (8.4 mg, 1.2 Eq, 67 μmol) and N-ethyl-N- isopropylpropan-2-amine (22 mg, 3 Eq, 0.17 mmol). The tube was sealed and heated at 120 °C while stirring for 3 h. The reaction mixture was cooled to room temperature and purified by reversed phase HPLC (A-B gradient: 35-55%, A: 0.1% formic acid in MeCN and B: 0.1% formic acid in H2O) to afford 5-(2-chlorobenzyl)-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide 4-1 (9.3 mg, 21 μmol, 37% yield). LCMS (m / z) calculated for C20H15ClF2N4O2S: 448.1; found 449.0 [M+H]+, tR = 8.537 min (Purity method 3).1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.79 (ddd, J = 10.9, 7.7, 5.3 Hz, 2H), 7.55 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 (dt, J = 8.7, 4.5 Hz, 1H), 7.38 – 7.10 (m, 3H), 6.83 – 6.60 (m, 1H), 4.67 (d, J = 5.2 Hz, 2H), 4.19 (s, 2H). Synthesis of Scheme 4 Compounds

[0223] The compounds listed in Table 5 were made using the procedures of Scheme 4. TABLE 5 EXAMPLE 5 Synthesis of Representative Compound 5-1 Scheme 5 Reagents: (i) KOAc, catalyst (Pd(dppf)Cl2), solvent (DMF); (ii) base (K2CO3), catalyst (Pd(PPh3)4), solvent (dioxanes / H2O); (iii) ClSO2NCO, solvent (nitromethane) then AlCl3; (iv) N,N-diethylaniline, solvent (POCl3); (v) Base (DIPEA), solvent (THF) Step 5-1. Synthesis of 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (INT 5A)

[0224]

[0225] To a solution of 2-bromo-3-fluoro-aniline (10 g, 52.6 mmol, 1 eq) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (26.7 g, 105 mmol, 2 eq) in DMF (200 mL) were added KOAc (25.8 g, 263 mmol, 5 eq) and Pd(dppf)Cl2 (3.85 g, 5.26 mmol, 0.1 eq). The reaction mixture was heated and stirred at 80 °C for 15h. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (0à50% EtOAc and petroleum ether) to afford 3-fluoro-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)aniline INT 5A (12 g, 45.6 mmol, 87% yield) that was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.14 - 7.06 (m, 1H), 6.39 (d, J = 8.3 Hz, 1H), 6.15 (dd, J = 8.3, 9.6 Hz, 1H), 5.83 (s, 2H), 1.28 (s, 12H). Step 5-2. Synthesis of 2-(2,6-dimethylbenzyl)-3-fluoroaniline (INT 5B)

[0226] To a solution of 2-(bromomethyl)-1,3-dimethyl-benzene (5.04 g, 25.3 mmol, 1.2 eq) and 3-fluoro-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline INT 5A (5.0 g, 21.1 mmol, 1 eq) in dioxane (40 mL) and H2O (10 mL) were added K2CO3 (5.83 g, 42.2 mmol, 2 eq) and Pd(PPh3)4 (2.44 g, 2.11 mmol, 0.1 eq). The mixture was heated and stirred at 80 °C for 15 h. The reaction mixture was cooled, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (0à10% EtOAc / petroleum ether) to afford 2-(2,6- dimethylbenzyl)-3-fluoroaniline INT 5B (800 mg, 3.14 mmol, 15% yield) that was used without further purification. Step 5-3. Synthesis of 5-(2,6-dimethylbenzyl)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 5C)

[0227] To a solution of N-(oxomethylene)sulfamoyl chloride (648.13 mg, 4.58 mmol, 398.60 μL, 1.4 eq) in nitrobenzene (5 mL) was added 2-[(2,6-dimethylphenyl)methyl]-3-fluoro- aniline (750 mg, 3.27 mmol, 1 eq) at 0 °C for 0.5 h. Then AlCl3 (654.23 mg, 4.91 mmol, 268.13 μL, 1.5 eq) was added. The mixture was stirred at 60 °C for 1.5 h. The reaction mixture was quenched by the addition of water 50 mL, and then adjusted to pH>7 with sodium hydroxide. A brown precipitate was formed. It was collected by filtration and dried under high vacuum to afford 5-(2,6-dimethylbenzyl)-6-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 5C (400 mg, crude) that was used without further purification. Step 5-4. Synthesis of 3-chloro-5-(2,6-dimethylbenzyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 5D)

[0228] A mixture of 5-[(2,6-dimethylphenyl)methyl]-6-fluoro-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 5C (330 mg, 986.95 μmol, 1 eq) and N,N-diethylaniline (307.88 mg, 2.06 mmol, 329.99 μL, 2.09 eq) in POCl3 (5 mL) was heated and stirred at 120 °C for 4 h. The mixture was concentrated in vacuo, the residue was slowly quenched by saturated NaHCO3 aqueous solution to pH ~8, then extracted EtOAc (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by prep-TLC (2 / 1 EtOAc / petroleum ether) to afford 3-chloro-5-(2,6-dimethylbenzyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 5D (150 mg, 140 µmol, 14% yield) that was used without further purification. Step 5-5. Synthesis of 5-(2,6-dimethylbenzyl)-6-fluoro-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 5-1)

[0229] To a solution of 3-chloro-5-[(2,6-dimethylphenyl)methyl]-6-fluoro-4H-1,2,4- benzothiadiazine 1,1-dioxide INT 5D (150.0 mg, 140.30 μmol, 1 eq) in THF (5 mL) and DIPEA (35 mg, 271 μmol, 47.2 μL, 1.93 eq) was added (3-fluoro-2- pyridyl)methanamine (25 mg, 198 μmol, 1.41 eq). The reaction mixture was heated and stirred at 80 °C for 15h. The crude was purified by prep-HPLC (column: Waters Xbridge 150x25mmx5um; A-B mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 9 min) to afford 5-(2,6-dimethylbenzyl)-6-fluoro- 3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 5-1 (15 mg, 33 μmol, 24% yield). LCMS (m / z) calculated for C22H20F2N4O2S: 442.1; found 443.2 [M+H]+, tR = 0.580 min (Purity Method 2).1H NMR (400 MHz, DMSO-d6) δ = 10.53 (br s, 1H), 8.47 (d, J = 4.6 Hz, 1H), 8.17 (br s, 1H), 7.80 (t, J = 9.3 Hz, 1H), 7.64 (br dd, J = 5.6, 8.3 Hz, 1H), 7.49 (td, J = 4.4, 8.4 Hz, 1H), 7.07 - 6.90 (m, 4H), 4.72 (br d, J = 4.0 Hz, 2H), 4.08 (s, 2H), 2.18 (s, 6H).

[0230] 19F NMR (376 MHz, DMSO-d6) δ = -106.26 (s, 1F), -126.41 (s, 1F). Synthesis of Scheme 5 Compounds

[0231] The compounds listed in Table 6 were made using the procedures of Scheme 5. TABLE 6 EXAMPLE 6 Synthesis of Representative Compound 6-1 Reagents: (i) ClSO2NCO, solvent (nitromethane) then AlCl3; (ii) 2,6-lutidine, solvent (POCl3); (iii) Base (DIPEA), solvent (NMP); (iv) Base (Cs2CO3), catalyst (Pd(dppf)Cl2), solvent (dioxanes / H2O); Step 6-1. Synthesis of 5-bromo-6-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 6A)

[0232] To a solution of sulfurisocyanatidic chloride (0.89 g, 1.2 Eq, 6.3 mmol) in nitromethane (15 mL) at 0°C was added a solution of 2-bromo-3-fluoroaniline (1.0 g, 1 Eq, 5.3 mmol) in nitromethane (15 mL) dropwise. The reaction mixture was stirred at 0 °C for 15 minutes and then aluminum trichloride (2.1 g, 3 Eq, 16 mmol) was added. The reaction mixture was heated at 105 °C for 3 h. The reaction mixture was cooled to room temperature and added to ice cold water (50 mL). The resultant precipitate was filtered, washed with water (3 x 15 mL) and hexane (3 x 15 mL) to afford 5-bromo-6-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide (INT 6A) that was used without further purification. Step 6-2. Synthesis of 5-bromo-3-chloro-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide (INT 6B)

[0233] To crude 5-bromo-3-chloro-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 6A was added POCl3 (7.4 mL, 15 Eq, 79 mmol) and 2,6-lutidine (0.73 mL, 1.2 equivalents, 6.3 mmol). The reaction vessel was sealed and heated at 130 °C with stirring overnight. The reaction mixture was cooled to room temperature and poured into ice cold water (30 mL). The resultant precipitate was filtered, washed with water (3 x 10 mL) and hexane (3 x 10 mL) to afford 5-bromo-3-chloro-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 6B (0.83 g, 2.6 mmol, 49% yield) that was used without further purification. LCMS (m / z) calculated for C7H3BrClFN2O2S: 311.9; found 331.0 [M+H]+, tR = 3.67 min (Purity Method 4).1H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 7.71 (dd, J = 8.7, 6.1 Hz, 1H), 7.21 (t, J = 8.6 Hz, 1H). Step 6-3. Synthesis of 5-bromo-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 6C)

[0234] To a stirring solution of 5-bromo-3-chloro-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 6B (100 mg, 1 Eq, 319 μmol) in NMP (2 mL) was added (3-fluoropyridin-2- yl)methanamine (40.2 mg, 1 Eq, 319 μmol). The reaction vial was capped and heated at 100 °C while stirring for 3 h. The reaction mixture was cooled to room temperature and purified by reversed phase HPLC (Gradient: 35-55% A; A-B mobile phase: [0.1% formic acid in MeCN - 0.1% formic acid in H2O]) to afford 5-bromo-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 6C (38 mg, 94 μmol, 30% yield). LCMS (m / z) calculated for C13H9BrF2N4O2S: 402.0; found 402.2 [M+H]+, tR = 9.391 min (Purity Method 3).1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.64 (s, 1H), 8.47 (d, J = 4.7 Hz, 1H), 7.79 (t, J = 9.1 Hz, 2H), 7.49 (dt, J = 8.6, 4.5 Hz, 1H), 7.31 (t, J = 8.6 Hz, 1H), 4.70 (dd, J = 5.0, 1.8 Hz, 2H). Step 6-4. Synthesis of 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5-phenethyl- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 6-1)

[0235] To a solution of 5-bromo-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 6C (15 mg, 1 Eq, 37 μmol) in 1,4-dioxane (2 mL) and water (2 mL) was added cesium carbonate (24 mg, 2 Eq, 74 μmol), phenethylboronic acid (17 mg, 3 Eq, 0.11 mmol), Pd(dppf)Cl2 (2.7 mg, 0.1 Eq, 3.7 μmol). The mixture was degassed and heated at 90 °C for 3 h while stirring. The reaction mixture was cooled to room temperature, passed through a syringe filter, and concentrated in vacuo to afford crude material. The crude material was purified by reversed phase HPLC (Gradient: 35-55% A; A-B mobile phase: [0.1% formic acid in MeCN - 0.1% formic acid in H2O]) to afford 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5- phenethyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 6-1 (0.7 mg, 2 μmol, 4% yield). LCMS (m / z) calculated for C21H18F2N4O2S: 428.1; found 429.0 [M+H]+, tR = 8.66 min (Purity Method 3). Synthesis of Scheme 6 Compounds

[0236] Alternatively for Step 6-4, the following compounds were made using 2 Eq. of boronic acid, 3 Eq. of potassium phosphate tribasic, and 0.1 Eq. Pd(PPh3)4 at 110 °C for 14h: 6-2, 6-4, 6-5, 6-18.

[0237] The compounds listed in Table 7 were made using the procedures of Scheme 6. TABLE 7 EXAMPLE 7 Synthesis of Representative Compound 7-7 Scheme 7 Reagents: (i) NH2NHTos, solvent (MeOH); (ii) Base (t-BuOLi), solvent (dioxanes), catalyst (XPhos-Pd-G2); (iii) catalyst (Pd / C), H2 (50 psi), solvent (MeOH); (iv) ClSO2NCO, solvent (nitromethane) then AlCl3; (v) N,N-diethylaniline, solvent (POCl3); (vi) Base (DIPEA), solvent (DMA) Step 7-1. Synthesis of (E)-N'-(1-(2-fluorophenyl)ethylidene)-4- methylbenzenesulfonohydrazide (INT 7A)

[0238] To a solution of 1-(2-fluorophenyl)ethanone (50.0 g, 362 mmol, 44.0 mL, 1 eq) in MeOH (500 mL), was added 4-methylbenzenesulfonohydrazide (68.1 g, 366 mmol, 1.01 eq). The mixture was heated and stirred at 60 °C for 14h. The reaction mixture was concentrated in vacuo. The residue was triturated with MeOH (100 mL) and collected by filtration to afford (E)-N'-(1-(2- fluorophenyl)ethylidene)-4-methylbenzenesulfonohydrazide INT 7A (80 g, 261 mmol, 72% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.66 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.49 - 7.38 (m, 3H), 7.37 - 7.26 (m, 1H), 7.26 - 7.09 (m, 2H), 2.37 (s, 3H), 2.18 (d, J = 2.5 Hz, 3H). Step 7-2. Synthesis of 3-fluoro-2-(1-(2-fluorophenyl)vinyl)aniline (INT 7B)

[0239] To a mixture of 2-bromo-3-fluoro-aniline (10 g, 52.6 mmol, 1 eq), N-[(E)-1-(2- fluorophenyl)ethylideneamino]-4- methyl-benzenesulfonamide INT 7A (20.0 g, 65.3 mmol, 1.24 eq) and t-BuOLi (8.50 g, 106 mmol, 9.57 mL, 2.02 eq) in dioxane (600 mL) was added XPhos-Pd- G2 (4.00 g, 5.08 mmol, 0.10 eq), then it was stirred at 100 °C for 15 h. The mixture was concentrated in vacuo. The residue was added to 200 mL of water. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 to10% EtOAc / petroleum ether) to afford 3-fluoro-2-(1-(2-fluorophenyl)vinyl)aniline INT 7B (21.5 g, 87.4 mmol, 83% yield). Step 7-3. Synthesis of 3-fluoro-2-(1-(2-fluorophenyl)ethyl)aniline (INT 7C)

[0240] A mixture of 3-fluoro-2-[1-(2-fluorophenyl)vinyl]aniline INT 7B (25 g, 108 mmol, 1 eq) and 10% Pd / C (2.5 g) in MeOH (300 mL) was degassed and purged with N23 times. The reaction mixture was stirred at 50 °C for 45 h under an H2 atmosphere (50 psi). The reaction mixture was filtered and concentrated in vacuo to afford 3-fluoro-2-(1-(2-fluorophenyl)ethyl)aniline INT 7C (16.9 g, 63.9 mmol, 70% yield) that was used without further purification. LCMS (m / z) calculated for C14H13F2N: 233.1; found 234.2 [M+H]+, tR = 0.552 min (Purity Method 1). Step 7-4. Synthesis of 6-fluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 7D)

[0241] To a solution of 3-fluoro-2-[1-(2-fluorophenyl)ethyl]aniline INT 7C (4.0 g, 17.2 mmol, 1 eq) in Nitrosobenzene (60 mL) at 0 °C, was added N-(oxomethylene)sulfamoyl chloride (3.59 g, 25.3 mmol, 2.20 mL, 1.48 eq). The mixture was stirred at 0 °C for 0.5 h. Then AlCl3 (3.44 g, 25.8 mmol, 1.41 mL, 1.5 eq) was added. The mixture was heated and stirred at 60 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated NH4Cl aqueous solution (300 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oil was diluted with petroleum ether (600 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and dried under vacuum to give 6-fluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 7D l (4.5 g, 11.8 mmol, 69% yield) that was used without further purification. LCMS (m / z) calculated for C15H12F2N2O3S: 338.1; found 337.0 [M-H], tR = 0.629 min (Purity Method 2). Step 7-5. Synthesis of 3-chloro-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 7E)

[0242] To a solution of 6-fluoro-5-[1-(2-fluorophenyl)ethyl]-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 7D (1.5 g, 4.4 mmol, 1 eq) in POCl3 (10 mL), was added N,N- diethylaniline (1.03 g, 6.88 mmol, 1.10 mL, 1.55 eq). The reaction mixture was heated and stirred at 120 °C for 16h. The reaction mixture was cooled to room temperature and poured into water (100 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 hr. The mixture was extracted with EtOAc (3 x 60 mL). The combined organic phase was washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The aqueous mixture was adjusted to pH = 7 by KOH and then discarded. The crude residue was purified by silica gel chromatography (0 to 65% EtOAc / petroleum ether) to afford 3- chloro-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 7E) (1.1 g, 2.6 mmol, 59% yield) that was used without further purification. LCMS (m / z) calculated for C15H11ClF2N2O2S: 356.0; found 355.0 [M-H], tR = 0.538 min (Purity Method 2). Step 7-6. Synthesis of 3-((3-chloro-4-fluorobenzyl)amino)-6-fluoro-5-(1-(2- fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 7-7)

[0243] To a stirring solution of (3-chloro-4-fluoro-phenyl)methanamine (34 mg, 210 μmol, 1.5 eq) in DMA (1 mL) was added 3-chloro-6-fluoro-5-[1-(2- fluorophenyl)ethyl]-4H-1,2,4- benzothiadiazine 1,1-dioxide INT 7E (50 mg, 140 μmol, 1 eq) and DIPEA (54 mg, 420 μmol, 73 μL, 3 eq). The mixture was stirred at 120 °C for 2 h. The crude mixture was filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC (column: Welch Xtimate C18150x25mmx5um; gradient: 43%-73% MeCN / 0.1% formic acid in water over 10 min) and lyophilized to afford 3-((3-chloro-4-fluorobenzyl)amino)-6-fluoro-5-(1-(2- fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 7-7 (13.7 mg, 28.3 μmol, 20% yield). LCMS (m / z) calculated for C22H17ClF3N3O2S: 479.1; found 480.1 [M+H]+, tR = 0.540 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 7.75 (br t, J = 5.2 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.55 (br t, J = 7.7 Hz, 1H), 7.49 - 7.37 (m, 2H), 7.35 - 7.27 (m, 1H), 7.27 - 7.21 (m, 1H), 7.09 (dd, J = 8.3, 10.0 Hz, 1H), 7.01 (dd, J = 8.9, 11.1 Hz, 1H), 4.65 (q, J = 6.7 Hz, 1H), 4.59 - 4.44 (m, 2H), 1.69 (d, J = 7.1 Hz, 3H). Synthesis of Scheme 7 Compounds

[0244] Alternatively for step 7-3, the following compounds were made using 0.2 Eq of tris(triphenylphosphine)rhodium(I) chloride in THF with H2 (50 psi) at a reaction temperature of 80 °C for 72 h: 7-2.

[0245] Alternatively for step 7-3, the following compounds were made using 0.05 Eq of PtO2 in MeOH with H2 (1 atm) at room temperature for 24 h: 7-1.

[0246] The compounds listed in Table 8 were made using the procedures of Scheme 7. TABLE 8 EXAMPLE 8 Synthesis of Representative Compound 8-3 Scheme 8 Reagents: (i) NH2NHTos, solvent (MeOH); (ii) Base (t-BuOLi), solvent (dioxanes), catalyst (XPhos-Pd-G2); (iii) catalyst (PtO2), H2 (15 psi), solvent (MeOH); (iv) N,N-diethylaniline, solvent (POCl3); (v) Base (DIPEA), solvent (THF) Step 8-1. Synthesis (E)-N'-(1-(2,3-dichlorophenyl)ethylidene)-4- methylbenzenesulfonohydrazide (INT 8A)

[0247] To a solution of 1-(2,3-dichlorophenyl)ethanone (2.0 g, 10.6 mmol, 1 eq) in MeOH (20 mL) was added 4- methylbenzenesulfonohydrazide (2.17 g, 11.6 mmol, 1.1 eq). The reaction mixture was heated and stirred at 60 °C for 15h. The reaction mixture was cooled to room temperature and the resultant precipitate was filtered. The precipitate was washed with MeOH and dried under high vacuum to afford (E)-N'-(1-(2,3-dichlorophenyl)ethylidene)-4- methylbenzenesulfonohydrazide INT 8A (3.3 g, 9.13 mmol, 86% yield). LCMS (m / z) calculated for C15H14Cl2N2O2S: 355.0; found 480.1 [M-H], tR = 0.443 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.77 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 1.5, 8.1 Hz, 1H), 7.43 - 7.31 (m, 3H), 7.15 (dd, J = 1.5, 7.6 Hz, 1H), 2.37 (s, 3H), 2.16 (s, 3H). Step 8-2. Synthesis 5-(1-(2,3-dichlorophenyl)vinyl)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 8B)

[0248] To a solution of N-[(E)-1-(2,3-dichlorophenyl)ethylideneamino]-4-methyl- benzenesulfonamide INT 8A (1.54 g, 4.32 mmol, 1.5 eq) and 5-bromo-6-fluoro-1,1-dioxo-4H- 1,2,4-benzothiadiazin-3-ol INT 6A (850 mg, 2.88 mmol, 1 eq) in dioxane (16 mL) was added lithium, 2-methylpropan-2-olate (692 mg, 8.64 mmol, 779 μL, 3 eq) and XPhos-Pd-G2 (227 mg, 288 μmol, 0.1 eq). The reaction mixture was heated and stirred at 100 °C for 15 h. After returning to room temperature, water (15 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (3 x 15 mL). The aqueous phase was adjusted to pH = 5 by diluted hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organics were washed with aqueous saturated brine solution (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150x40mmx10um; A-B mobile phase: [water( NH4HCO3)-ACN]; gradient: 10%-40% B over 15 min) to afford 5-(1-(2,3-dichlorophenyl)vinyl)- 6-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 8B (180 mg, 440 μmol, 15% yield). LCMS (m / z) calculated for C15H9Cl2FN2O3S: 386.0; found 384.9 [M-H], tR = 0.518 min (Purity Method 2). Step 8-3. Synthesis 5-(1-(2,3-dichlorophenyl)ethyl)-6-fluoro-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 8C)

[0249] A solution of 5-[1-(2,3-dichlorophenyl)vinyl]-6-fluoro-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 8B (340 mg, 878 μmol, 1 eq) in MeOH (20 mL) was degassed and purged with N23 times. PtO2 (200 mg) was added and degassed and purged with N23 times. The reaction mixture was then put under an H2 atmosphere (15 psi) and stirred for 4h at room temperature. The reaction mixture was concentrated in vacuo to give 5-(1-(2,3-dichlorophenyl)ethyl)-6-fluoro-3- hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 8C that was used without further purification. LCMS (m / z) calculated for C15H11Cl2FN2O3S: 388.0; found 386.8 [M-H], tR = 0.514 min (Purity Method 2). Step 8-4. Synthesis 3-chloro-5-(1-(2,3-dichlorophenyl)ethyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 8D)

[0250] To a solution of 5-[1-(2,3-dichlorophenyl)ethyl]-6-fluoro-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 8C (280 mg, 719 μmol, 1 eq) in POCl3 (2 mL) was added N,N- diethylaniline (161 mg, 1.08 mmol, 173 μL, 1.5 eq). The mixture was heated and stirred at 120 °C for 2h. The reaction mixture was cooled to room temperature and quenched by the addition of sodium bicarbonate solution (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL), and the combined organic layer was washed with brine (2 x 20 mL), filtered, and concentrated in vacuo to give a crude residue. The crude residue was purified by silica gel chromatography (0à100% EtOAc / petroleum ether) to afford 3-chloro-5-(1-(2,3-dichlorophenyl)ethyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 8D (220 mg, 453 μmol, 63% yield) that was used without further purification. LCMS (m / z) calculated for C15H10Cl3FN2O2S: 406.0; found 404.9 [M-H], tR = 0.587 min (Purity Method 2). Step 8-5. Synthesis of 5-(1-(2,3-dichlorophenyl)ethyl)-6-fluoro-3-((3-fluoro-2- methylbenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 8-3)

[0251] To a solution of 3-chloro-5-[1-(2,3-dichlorophenyl)ethyl]-6-fluoro-4H-1,2,4- benzothiadiazine 1,1-dioxide INT 8D (220 mg, 540 μmol, 1 eq) and (3-fluoro-2-methyl- phenyl)methanamine (350 mg, 2.51 mmol, 4.66 eq) in THF (3 mL) was added DIPEA (209 mg, 1.62 mmol, 282 μL, 3 eq). The mixture was heated and stirred at 60 °C for 15 h. The reaction mixture was concentrated in vacuo to give a crude residue. The crude residue was purified by prep- HPLC (column: Welch Xtimate C18150x25mmx5um; A-B mobile phase: [water(FA)-ACN]; gradient: 50%-70% B over 10 min) to afford 5-(1-(2,3-dichlorophenyl)ethyl)-6-fluoro-3-((3- fluoro-2-methylbenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 8-3 (63.2 mg, 123.8 μmol, 23% yield). LCMS (m / z) calculated for C23H19Cl2F2N3O2S: 509.0; found 510.0 [M+H]+, tR= 0.571 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.35 (s, 1H), 7.75 - 7.61 (m, 3H), 7.58 (d, J = 7.9 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.32 - 7.22 (m, 1H), 7.21 - 7.17 (m, 1H), 7.16 - 7.09 (m, 1H), 7.01 - 6.91 (m, 1H), 4.63 - 4.46 (m, 3H), 2.26 (s, 3H), 1.68 (br d, J = 7.0 Hz, 3H). Synthesis of Scheme 8 Compounds

[0252] Alternatively for step 8-2, the following compounds were made using 3 Eq of lithium;2-methylpropan-2-olate in dioxanes with 0.1 Eq Pd(PPh3)2Cl2 at a reaction temperature of 100 °C for 15 h: 8-1.

[0253] The compounds listed in Table 9 were made using the procedures of Scheme 8. TABLE 9

[0006] EXAMPLE 9 Synthesis of Representative Compound 9-7 Reagents: (i) TMSOTf, solvent (DCM); (ii) Base (K2CO3), solvent (dioxanes / H2O), catalyst (Pd(dppf)Cl2); (iii) catalyst (Pd / C), H2 (15 psi), solvent (MeOH); (iv) ClSO2NCO, solvent (nitromethane) then AlCl3; (v) N,N-diethylaniline, solvent (POCl3); (vi) Base (DIPEA), solvent (THF) Synthesis of (6-amino-2,3-difluorophenyl)boronic acid INT 9

[0254] To a solution of 2-bromo-3,4-difluoro-aniline (5.0 g, 24 mmol, 1 eq) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (12.2 g, 48.1 mmol, 2 eq) in dioxane (100 mL) was added KOAc (7.08 g, 72.1 mmol, 3 eq) and XphosPdG4 (1.03 g, 1.20 mmol, 0.05 eq). The reaction mixture was heated and stirred at 80 °C for 15h. The reaction mixture was filtered and concentrated in vacuo to afford (6-amino-2,3- difluorophenyl)boronic acid INT 9 (4.0 g) that was used without further purification. Step 9-1. Synthesis of 1-(2-fluorophenyl)vinyl trifluoromethanesulfonate (INT 9A)

[0255] To a solution of 1-(2-fluorophenyl)ethanone (5.0 g, 36.2 mmol, 4.4 mL, 1 eq) in DCM (100 mL) at 0 °C was added 2,6-ditert-butyl-4-methyl-pyridine (8.18 g, 39.8 mmol, 1.1 eq) and trifluoromethylsulfonyl trifluoromethanesulfonate (12.25 g, 43.43 mmol, 7.17 mL, 1.2 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo. Petroleum ether was added and solid pyridinium triflate was filtered off and washed with petroleum ether. The combined petroleum ether solution was washed subsequently with cool HCl (1 M) and saturated brine. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1-(2-fluorophenyl)vinyl trifluoromethanesulfonate INT 9A (10 g) that was used without further purification. Step 9-2. Synthesis of 3,4-difluoro-2-(1-(2-fluorophenyl)vinyl)aniline (INT 9B)

[0256] To a solution of 1-(2-fluorophenyl)vinyl trifluoromethanesulfonate INT 9A (3.8 g, 14.1 mmol, 1 eq) and (6-amino-2,3- difluoro-phenyl)boronic acid INT 9 (4.0 g, 23 mmol, 1.5 eq) in dioxane (100 mL) and H2O (20 mL) was added K2CO3 (6.39 g, 46.3 mmol, 3 eq) and Pd(dppf)Cl2 (1.13 g, 1.54 mmol, 0.1 eq). The reaction mixture was heated and stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the crude residue was added aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine solution (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The crude residue was purified by silica gel chromatography (0 to 20% EtOAc / petroleum ether) to afford 3,4- difluoro-2-(1-(2-fluorophenyl)vinyl)aniline INT 9B (1.0 g, 3.39 mmol, 22% yield) that was used without further purification. LCMS (m / z) calculated for C14H10F3N: 249.1; found 250.1 [M+H]+, tR = 0.558 min (Purity Method 1). Step 9-3. Synthesis of 3,4-difluoro-2-(1-(2-fluorophenyl)ethyl)aniline (INT 9C)

[0257] A mixture of 3,4-difluoro-2-[1-(2-fluorophenyl)vinyl]aniline INT 9B (1.0 g, 4.0 mmol, 1 eq) and 10% Pd / C (4.27 g, 4.01 mmol, 1.00 eq) in MeOH (50 mL) was degassed and purged with N23 times. The reaction mixture was then stirred at 25 °C for 4 h under an H2 atmosphere (15 psi). The reaction mixture was filtered and concentrated in vacuo to afford 3,4- difluoro-2-(1-(2-fluorophenyl)ethyl)aniline INT 9C (700 mg, 2.33 mmol, 72% yield) that was used without further purification. LCMS (m / z) calculated for C14H12F3N: 251.1; found 252.2 [M+H]+, tR = 0.560 min (Purity Method 1). Step 9-4. Synthesis of 6,7-difluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 9D)

[0258] To a solution of N-(oxomethylene)sulfamoyl chloride (552 mg, 3.90 mmol, 340 μL, 1.4 eq) in nitrobenzene (3 mL) at 0 °C was added a solution of 3,4-difluoro-2-[1-(2- fluorophenyl)ethyl]aniline (700 mg, 2.79 mmol, 1 eq) in nitrobenzene (1 mL). The reaction mixture was stirred at 0 °C for 0.5 h. Then, AlCl3 (557 mg, 4.18 mmol, 1.5 eq) was added. The reaction mixture was heated and stirred at 120 °C for 1.5 h. The reaction mixture was cooled to room temperature and quenched by addition of ammonium chloride aqueous solution (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organics were concentrated in vacuo to afford a crude residue. The crude residue was washed with petroleum ether (2 x 10 mL) and filtered to give 6,7-difluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 9D (790 mg) that was used without further purification. LCMS (m / z) calculated for C15H11F3N2O3S: 356.0; found 355.1 [M-H], tR = 0.445 min (Purity Method 2). Step 9-5. Synthesis of 3-chloro-6,7-difluoro-5-(1-(2-fluorophenyl)ethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 9E)

[0259] To a solution of 6,7-difluoro-5-[1-(2-fluorophenyl)ethyl]-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 9D (400 mg, 1.12 mmol, 1 eq) in POCl3 (5 mL) was added N,N- diethylaniline (251 mg, 1.68 mmol, 269 μL, 1.5 eq). The reaction mixture was heated and stirred at 120 °C for 2 h. The reaction mixture was cooled to room temperature and quenched by the addition of an aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (0à100% EtOAc / petroleum ether) to afford 3-chloro-6,7-difluoro-5-(1-(2- fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 9E (230 mg, 487 μmol, 43% yield) that was used without further purification. LCMS (m / z) calculated for C15H10ClF3N2O2S: 374.0; found 373.0 [M-H], tR = 0.528 min (Purity Method 2) Step 9-6. Synthesis of 6,7-difluoro-5-(1-(2-fluorophenyl)ethyl)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 9-7)

[0260] To a solution of 3-chloro-6,7-difluoro-5-[1-(2-fluorophenyl)ethyl]-4H-1,2,4- benzothiadiazine 1,1-dioxide INT 9E (230 mg, 614 μmol, 1 eq) and (3-fluoro-2- pyridyl)methanamine;dihydrochloride (244 mg, 1.23 mmol, 2 eq) in THF (3 mL) was added DIPEA (397 mg, 3.07 mmol, 534 μL, 5 eq). The mixture was heated and stirred at 60 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx5um; A-B mobile phase: [water(NH4HCO3)-ACN]; gradient: 32%-62% B over 9 min) to afford 6,7-difluoro-5-(1-(2- fluorophenyl)ethyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide 9-7 (33.6 mg, 71.3 μmol, 12% yield). LCMS (m / z) calculated for C21H16F4N4O2S: 464.1; found 465.1 [M-H], tR = 0.533 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.60 (br s, 1H), 8.47 (br d, J = 3.4 Hz, 1H), 8.12 (br s, 1H), 7.80 (t, J = 9.3 Hz, 1H), 7.73 (br t, J = 8.3 Hz, 1H), 7.60 (br t, J = 7.6 Hz, 1H), 7.50 (td, J = 4.4, 8.4 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.30 - 7.23 (m, 1H), 7.17 - 7.08 (m, 1H), 4.79 (br d, J = 5.9 Hz, 1H), 4.71 (br d, J = 3.8 Hz, 2H), 1.72 (br d, J = 7.0 Hz, 3H). Synthesis of Scheme 9 Compounds

[0261] The compounds listed in Table 10 were made using the procedures of Scheme 9. TABLE 10 EXAMPLE 10 Chiral Separation Chiral Separation of Compound 9-6 into Compound 10-3A and Compound 10-3B

[0262] SFC separation conditions of 9-6: (column: DAICEL CHIRALCEL OD (250mmx30mm,10um); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; 40% i-PrOH (0.1% NH3H2O), isocratic elution mode) to afford 10-3A and 10-3B.

[0263] The above-mentioned chiral column was used for each chiral separation. Chiral Separation of Compound 9-1 into Compound 10-1A and Compound 10-1B

[0264] SFC separation conditions of 9-1: mobile phase: [CO2-EtOH (0.1% NH3H2O)]; 35% EtOH (0.1% NH3H2O), isocratic elution mode) to afford 10-1A and 10-1B. Chiral Separation of Compound 9-5 into Compound 10-2A and Compound 10-2B

[0265] SFC separation conditions of 9-5: mobile phase: [CO2-EtOH (0.1% NH3H2O)]; 30% EtOH (0.1% NH3H2O), isocratic elution mode) to afford 10-2A and 10-2B. Chiral Separation of Compound 8-2 into Compound 10-4A and Compound 10-4B

[0266] SFC separation conditions of 8-2: mobile phase: [CO2-EtOH]; 25% EtOH (0.1% NH3H2O), isocratic elution mode) to afford 10-4A and 10-4B. Chiral Separation of Compound 9-4 into Compound 10-5A and Compound 10-5B

[0267] SFC separation conditions of 9-4: mobile phase: [CO2-EtOH]; 35% EtOH (0.1% NH3H2O), isocratic elution mode) to afford 10-5A and 10-5B. Chiral Separation Table

[0268] The compounds listed in Table 11 were separated using the conditions set forth above.

[0007] TABLE 11 EXAMPLE 11 Synthesis of Representative Compound 11-1 Step 11-1. Synthesis of (E)-2-(2-chlorostyryl)-3-fluoroaniline (INT 11A)

[0269] To a solution of 2-bromo-3-fluoro-aniline (2.5 g, 13.2 mmol, 1 eq) and 1-chloro-2- vinyl-benzene (2.74 g, 19.7 mmol, 1.5 eq) in DMF (40 mL) was added Pd(dppf)Cl2(481 mg, 656 μmol, 0.05 eq) and TEA (2.91 g, 28.7 mmol, 4 mL, 2.2 eq). The reaction mixture was heated and stirred at 120 °C for 14 h. The reaction mixture was cooled to room temperature and poured into water (40 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (0 to15% EtOAc / petroleum ether) to afford (E)-2-(2-chlorostyryl)-3-fluoroaniline INT 11A (3.0 g, 9.7 mmol, 74% yield) that was used without further purification. LCMS (m / z) calculated for C14H11ClFN: 247.1; found 248.0 [M+H]+, tR = 0.618 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 8.00 (dd, J = 1.2, 7.8 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.42 - 7.34 (m, 2H), 7.33 - 7.25 (m, 1H), 7.11 (d, J = 16.4 Hz, 1H), 7.00 - 6.95 (m, 1H), 6.51 (d, J = 8.1 Hz, 1H), 6.40 - 6.35 (m, 1H), 5.73 (s, 2H). Step 11-2. Synthesis of 2-(2-chlorophenethyl)-3-fluoroaniline (INT 11B)

[0270] To a solution of 2-[(E)-2-(2-chlorophenyl)vinyl]-3-fluoro-aniline INT 11A (3.00 g, 12.1 mmol, 1 eq) in MeOH (80 mL) was added Pd / C (0.2 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with N23 times. The mixture was stirred under an atmosphere of H2 (15 Psi) at 25 °C for 2 h. The crude mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0à20% EtOAc / petroleum ether) to afford 2-(2-chlorophenethyl)-3-fluoroaniline INT 11B (2.1 g, 3.5 mmol, 29% yield) that was used without further purification. LCMS (m / z) calculated for C14H13ClFN: 249.1; found 250.1 [M+H]+, tR = 0.588 min (Purity Method 1). Step 11-3. Synthesis of 5-(2-chlorophenethyl)-6-fluoro-3-hydroxy-4H-

[0271] To a solution of N-(oxomethylene)sulfamoyl chloride (1.11 g, 7.81 mmol, 678 μL, 1.5 eq) in nitrobenzene (10 mL) at 0 °C, was added a solution of 2-[2-(2-chlorophenyl)ethyl]-3- fluoro-aniline INT 11B (1.3 g, 5.21 mmol, 1 eq) in nitrobenzene (3 mL). The mixture was stirred at 0 °C for 0.5 h. Then AlCl3 (1.04 g, 7.83 mmol, 428 μL, 1.5 eq) was added. The mixture was heated and stirred at 120 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated aqueous NH4Cl (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The obtained brown oil was diluted with petroleum ether (300 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and then dried under high vacuum to afford 5-(2-chlorophenethyl)-6- fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 11C (1.1 g, 2.3 mmol, 44% yield) that was used without further purification. LCMS (m / z) calculated for C15H12ClFN2O3S: 354.0; found 353.1 [M-H], tR = 0.420 min (Purity Method 2). Step 11-4. Synthesis of 3-chloro-5-(2-chlorophenethyl)-6-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 11D)

[0272] To a solution of 5-[2-(2-chlorophenyl)ethyl]-6-fluoro-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 11C (0.5 g, 1.4 mmol, 1 eq) in POCl3 (5 mL), was added N,N- diethylaniline (373 mg, 2.50 mmol, 0.4 mL, 1.77 eq). The reaction mixture was heated and stirred at 120 °C for 2h. The reaction mixture was cooled to room temperature and poured into water (50 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The aqueous layer was extracted with EtOAc (3 x 80 mL). The combined organics were washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc / petroleum ether) to afford 3-chloro-5-(2-chlorophenethyl)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide INT 11D (80 mg, 197 μmol, 14% yield). LCMS (m / z) calculated for C15H11ClFN2O2S: 372.0; found 371.0 [M-H], tR = 0.520 min (Purity Method 2). Step 11-5. Synthesis of 5-(2-chlorophenethyl)-6-fluoro-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 11-1)

[0273] To a solution of (3-fluoro-2-pyridyl)methanamine dihydrochloride (64.0 mg, 322 μmol, 1.5 eq) and 3-chloro-5- [2-(2-chlorophenyl)ethyl]-6-fluoro-4H-1,2,4-benzothiadiazine 1,1- dioxide INT 11D (80 mg, 214 μmol, 1 eq) in DMAC (2 mL), was added DIPEA (166 mg, 1.29 mmol, 224 μL, 6 eq). The reaction mixture was heated and stirred at 120 °C for 1h. The reaction mixture was cooled to room temperature and poured into water (40 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150x25mmx 10um; A-B mobile phase: [water(FA)-ACN]; gradient:40%-70% B over 10 min) and lyophilized to afford 5-(2- chlorophenethyl)-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide 11-1 (39.2 mg, 84.7 μmol, 40% yield). LCMS (m / z) calculated for C21H17ClF2N4O2S: 462.1; found 463.1 [M+H]+, tR = 0.528 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.40 - 9.80 (m, 1H), 8.48 (br d, J = 4.5 Hz, 1H), 8.22 - 8.03 (m, 1H), 7.80 (br t, J = 9.1 Hz, 1H), 7.61 (br dd, J = 6.3, 7.8 Hz, 1H), 7.50 (td, J = 4.4, 8.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.32 - 7.18 (m, 3H), 7.00 (br t, J = 8.8 Hz, 1H), 4.70 (br d, J = 3.6 Hz, 2H), 3.17 - 3.02 (m, 2H), 3.01 - 2.90 (m, 2H). Synthesis of Scheme 11 Compounds

[0274] The compounds listed in Table 12 were made using the procedures of Example 11. TABLE 12 EXAMPLE 12 Synthesis of Representative Compound 12-1 Scheme 12 Reagents: (i) PdCl2(dppf), solvent (1,4-dioxane / H2O); (ii) solvent (POCl3); (iii) Base (DIPEA), solvent (NMP) Step 12-1. Synthesis of 5-(2-chlorobenzyl)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 12A)

[0275] To a solution of 5-bromo-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 1 Eq, 361 µmol) and (2-chlorobenzyl)boronic acid (123 mg, 2 Eq, 722 µmol) in 1,4- Dioxane (4mL) and water (4 mL), PdCl2(dppf) (26.4 mg, 0.1 Eq, 36.1 µmol), Cs2CO3 (353 mg, 3 Eq, 1.08 mmol) were added. The mixture was degasssed with N2 and then the reaction was heated and stirred at 90 °C for 3h. The reaction mixture was cooled and passed through a syringe filter into a test tube, and the filtrate was directly loaded / purified by HPLC to yield 5-(2-chlorobenzyl)- 3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 12A (83 mg, 0.26 mmol, 71 % yield). LCMS (m / z) calculated for C14H11ClN2O3S: 322.0; found 323.0 [M+H]+, tR = 4.575 min (Purity Method 3).1H NMR (400 MHz, DMSO) δ 10.55 – 10.31 (m, 1H), 7.69 (dd, J = 7.9, 1.4 Hz, 1H), 7.56 – 7.45 (m, 1H), 7.40 – 7.28 (m, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.16 – 7.09 (m, 1H), 7.05 (dd, J = 7.8, 1.5 Hz, 1H), 4.23 (s, 2H). Step 12-2. Synthesis of 3-chloro-5-(2-chlorobenzyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 12B)

[0276] To a stirring solution of 5-(2-chlorobenzyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 12A (83 mg, 1 Eq, 0.26 mmol) was added phosphorus oxychloride (0.39 g, 0.24 mL, 10 Eq, 2.6 mmol). The mixture was heated to 125 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford 3-chloro-5-(2-chlorobenzyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 12B (24 mg, 67 µmol, 26 % yield) that was used without further purification. LCMS (m / z) calculated for C14H10Cl2N2O2S: 340.0; found 341.0 [M+H]+, tR = 6.016 min (Purity Method 3).1H NMR (400 MHz, DMSO) δ 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 – 7.48 (m, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.38 – 7.28 (m, 2H), 7.14 (ddd, J = 9.2, 6.9, 3.1 Hz, 2H), 4.33 (s, 2H). Step 12-3. Synthesis of 5-(2-chlorobenzyl)-3-((2-chlorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound 12-1)

[0277] To a stirring solution of 3-chloro-5-(2-chlorobenzyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 12B (10 mg, 1 Eq, 29 µmol) in NMP (2 mL) was added (2- chlorophenyl)methanamine (6.2 mg, 1.5 Eq, 44 µmol). The mixture was heated to 100 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and purified by reversed phase HPLC to afford 5-(2-chlorobenzyl)-3-((2-chlorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide 12-1 (5.2 mg, 12 µmol, 40 % yield). LCMS (m / z) calculated for C21H17Cl2N3O2S: 445.0; found 446.0 [M+H]+, tR = 9.284 min (Purity Method 3). Synthesis of Scheme 12 Compounds

[0278] Alternatively for Step 12-3, the following compounds were made using 3 eq of DIPEA in NMP at 120 °C for 18 h: 12-3.

[0279] Alternatively for Step 12-3, the following compounds were made using 3 eq of DIPEA in NMP at 130 °C for 18 h: 12-4, 12-5, 12-6, 12-7, 12-8, 12-9, 12-10, 12-11, 12-12, 12- , 12-14, 12-15, 12-16, 12-17, 12-18, 12-19, 12-20, 12-21, 12-22, 12-23, 12-24, 12-25, 12-26, 12- , 12-28, 12-29, 12-30, 12-31, 12-32.

[0280] The compounds listed in Table 13 were made using the procedures of Scheme 12. TABLE 13 EXAMPLE 13 Synthesis of Representative Compound 13-1 Reagents: (i) ClSO2NCO, solvent (nitromethane) then AlCl3; (ii) N,N-diethylaniline, solvent (POCl3); (iii) Base (DIPEA), solvent (DMA); (iv) base (LiOtBu), catalyst (Pd(PPh3)2Cl2), solvent (dioxanes) Step 13-1. Synthesis of 5-bromo-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 13A)

[0281] To a solution of N-(oxomethylene)sulfamoyl chloride (5.81 g, 41.1 mmol, 3.57 mL, 1.41 eq) in nitrobenzene (80 mL) was added 2-bromoaniline (5 g, 29.1 mmol, 3.16 mL, 1 eq) at 0 °C . The mixture was stirred at 0 °C for 0.5 h. Then, AlCl3 (5.81 g, 43.6 mmol, 2.38 mL, 1.5 eq) was added. The mixture was stirred at 120 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated NH4Cl aqueous solution (500 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a brown oil. The obtained brown oil was diluted with petroleum ether (300 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and then dried under vacuum to give 5-bromo-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 13A (4.0 g, 14.2 mmol, 49% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.25 (s, 1H), 7.96 (dd, J = 1.1, 7.9 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H). Step 13-2. Synthesis of 5-bromo-3-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT

[0282] To a solution of 5-bromo-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 13A (2.2 g, 7.94 mmol, 1 eq) in POCl3 (10 mL) was added N,N-diethylaniline (1.78 g, 11.9 mmol, 1.90 mL, 1.5 eq). The mixture was stirred at 120 °C for 2 h. The reaction solution was then poured into water (500 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The dark brown oil eventually formed a brown precipitate that was collected by vacuum filtration and dried under vacuum to give 5-bromo-3-chloro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 13B (2.0 g, 6.4 mmol, 80% yield) that was used without further purification. The filtrate was adjusted to pH = 7 by KOH and then discarded.1H NMR (400 MHz, DMSO-d6) δ = 7.93 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H). Step 13-3. Synthesis of 5-bromo-3-(((3-chloropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 13C)

[0283] To a solution of (3-chloro-2-pyridyl)methanamine (1.12 g, 5.21 mmol, 1.1 eq) and 5-bromo-3-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 13B (1.4 g, 4.74 mmol, 1 eq) in DMA (10 mL) was added DIPEA (1.84 g, 14.21 mmol, 2.48 mL, 3 eq). The reaction mixture was stirred at 120 °C for 4 h. The reaction mixture was poured into water (40 mL). The product was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue. The residue was purified by flash silica gel chromatography (0à90% EtOAc / petroleum ether) to afford 5-bromo-3- (((3-chloropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 13C (500 mg, 1.11 mmol, 23% yield). LCMS (m / z) calculated for C13H10BrClN4O2S: 399.9; found 401.0 [M+H]+, tR = 0.453 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.24 (br s, 1H), 8.72 (br s, 1H), 8.59 (dd, J = 1.2, 4.7 Hz, 1H), 8.02 (dd, J = 1.3, 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 4.6, 8.1 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 4.72 (d, J = 4.9 Hz, 2H). Step 13-4. Synthesis of 3-(((3-chloropyridin-2-yl)methyl)amino)-5-(1-(2- -4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (13-1)

[0284] To a solution of N-[(E)-1-(2-fluorophenyl)ethylideneamino]-4-methyl- benzenesulfonamide INT 13D (199 mg, 648 μmol, 1.45 eq) and 5-bromo-N-[(3-chloro-2- pyridyl)methyl]-1,1-dioxo-4H-1,2,4-benzothiadiazin-3-amine INT 7A (180 mg, 448 μmol, 1 eq) in dioxane (2 mL) were added lithium tert-butoxide (108 mg, 1.34 mmol, 121 μL, 3 eq) and Pd(PPh3)2Cl2 (31.4 mg, 44.8 μmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150x40mmx10um; A-B mobile phase: [water( NH4HCO3)-ACN]; B: 28%-58% over10 min) to afford 3-(((3-chloropyridin-2-yl)methyl)amino)- 5-(1-(2-fluorophenyl)vinyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 13-1 (18.8 mg, 40.4 μmol, 9% yield). LCMS (m / z) calculated for C21H16ClFN4O2S: 442.1; found 443.2 [M+H]+, tR = 0.502 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.08 (s, 1H), 8.54 (d, J J = 4.4 Hz, 1H), 8.38 (br t, J = 4.4 Hz, 1H), 8.00 (dd, J = 1.1, 8.0 Hz, 1H), 7.69 (dd, J = 3.1, 6.1 Hz, 1H), 7.49 - 7.36 (m, 2H), 7.34 - 7.15 (m, 5H), 6.14 (s, 1H), 5.67 (s, 1H), 4.69 (br d, J = 4.1 Hz, 2H), 2.07 (s, 1H). Synthesis of Scheme 13 Compounds

[0285] Alternatively for Step 13-1, the following compound was made using 2-iodoaniline instead of 2-bromoaniline: 13-2.

[0286] Alternatively for Step 13-1, the following compound was made using 2-bromo-3- fluoroaniline instead of 2-bromoaniline: 13-3.

[0287] Alternatively for Step 13-4, the following compounds were made using 0.13 eq of Xphos, 0.11 eq of Pd2(dba)3, and 1.9 eq of t-BuOLi at 100 °C for 15 h: 13-2.

[0288] Alternatively for Step 13-4 to make 13-3, 1.6 eq of synthesized 2-[1-(2- fluorophenyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was reacted with 1 eq of the synthesized 5-bromo-6-fluoro-N-[(3-fluoro-2-pyridyl)methyl]-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-amine, 2 eq of K2CO3, and 0.13 eq of Pd(dppf)Cl2 in 5:1 dioxane / H20 at 80 °C for 15 h.

[0289] The compounds listed in Table 14 were made using the procedures of Scheme 13. TABLE 14 EXAMPLE 14 Synthesis of Representative Compound 14-1 Scheme 14 Reagents: (i) ClSO2NCO, solvent (nitromethane) then AlCl3; (ii) N,N-diethylaniline, solvent (POCl3); (iii) Base (DIPEA), solvent (DMA); (iv) base (Et3N), catalyst (Pd(dppf)Cl2), solvent (DMF); Step 14-1. Synthesis of 3-hydroxy-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 14A)

[0290] To a solution of N-(oxomethylene)sulfamoyl chloride (4.52 g, 32.0 mmol, 2.78 mL, 1.4 eq) in nitrobenzene (50 mL) was added 2-iodoaniline (5.0 g, 22.8 mmol, 1 eq) at 0 °C . The mixture was stirred at 0 °C for 0.5 h. Then, AlCl3 (4.57 g, 34.2 mmol, 1.87 mL, 1.5 eq) was added. The mixture was stirred at 120 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated NH4Cl aqueous solution (500 mL); the aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The obtained brown oil was diluted with petroleum ether (300 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and then dried under vacuum to give 3-hydroxy- 5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14A (5.5 g, 8.82 mmol, 39% yield) that was used without further purification. LCMS (m / z) calculated for C7H5IN2O3S: 323.9; found 322.9 [M-H], tR = 0.062 min (Purity Method 2 negative mode). Step 14-2. Synthesis of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 14B)

[0291] To a solution of 3-hydroxy-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14A (2.0 g, 6.17 mmol, 1 eq) in POCl3 (15 mL), N,N-diethylaniline (1.38 g, 9.26 mmol, 1.48 mL, 1.5 eq) was added. The mixture was stirred at 120 °C for 5 h. The solution was cooled to 25 °C and stirred for 15h. The reaction solution was poured into water (200 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1h. The dark brown oil eventually formed a brown precipitate that was collected by vacuum filtration and dried under vacuum to give a brown solid. The precipitate was triturated in ethyl acetate (20 ml) and collected by filtration to afford 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14B (2.0 g, 4.32 mmol, 70% yield) that was used without further purification. LCMS (m / z) calculated for C7H4ClIN2O2S: 341.9; found 340.9 [M-H], tR = 0.362 min (Purity Method 2 negative mode). Step 14-3. Synthesis of 3-(((3-chloropyridin-2-yl)methyl)amino)-5-iodo-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 14C)

[0292] To a solution of (3-chloro-2-pyridyl)methanamine (616 mg, 4.32 mmol, 1 eq) and 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14B (2.0 g, 4.32 mmol, 1 eq) in DMA (10 mL) was added DIPEA (1.68 g, 13.0 mmol, 2.26 mL, 3 eq). The mixture was stirred at 120 °C for 4 h. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-80% Ethyl acetate / petroleum ether gradient at 60 mL / min) to afford 3-(((3- chloropyridin-2-yl)methyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14C (750 mg, 1.32 mmol, 31% yield) that was used without further purification. LCMS (m / z) calculated for C13H10ClIN4O2S: 447.9; found 449.2 [M+H]+, tR = 0.445 min (Purity Method 1). Step 14-4. Synthesis of (E)-3-(((3-chloropyridin-2-yl)methyl)amino)-5-(2- fluorostyryl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (14-1)

[0293] To a solution of 3-(((3-chloropyridin-2-yl)methyl)amino)-5-iodo-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14C (250 mg, 557 μmol, 1 eq) and 1-fluoro-2-vinyl- benzene (170 mg, 1.39 mmol, 2.5 eq) in DMF (2 mL) was added Pd(dppf)Cl2 (82 mg, 111 μmol, 0.2 eq) and TEA (113 mg, 1.11 mmol, 155 μL, 2 eq). The mixture was stirred at 120 °C for 14 h. The reaction mixture was poured into water (40 mL) and the product was extracted with EtOAc (2 x30 mL). The combined organic phase was washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-50% Ethyl acetate / petroleum ether gradient at 60 mL / min) to afford (E)-3-(((3- chloropyridin-2-yl)methyl)amino)-5-(2-fluorostyryl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 14-1 (15.2 mg, 33 μmol, 6% yield). LCMS (m / z) calculated for C21H16ClFN4O2S: 442.1; found 443.2 [M+H]+, tR = 0.545 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.42 (br s, 1H), 8.58 (br d, J = 4.3 Hz, 1H), 8.10 - 8.00 (m, 2H), 7.97 - 7.86 (m, 2H), 7.68 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 15.9 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.37 - 7.26 (m, 4H), 4.72 (d, J = 4.5 Hz, 2H). Synthesis of Compound 14-2 Step 14-1B. Synthesis of 5-bromo-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 14-2B)

[0294] To a solution of (3-fluoro-2-pyridyl)methanamine (855 mg, 4.29 mmol, 1.27 eq, 2HCl) in MeCN (20 mL) was added BOP (2.25 g, 5.08 mmol, 1.5 eq) and DBU (2.06 g, 13.56 mmol 2.04 mL, 4 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h.5-bromo-6-fluoro-3-hydroxy- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 6A, which was prepared in an analogous fashion to INT 14A (1.0 g, 3.39 mmol, 1 eq) was added. The mixture was stirred at 80 °C for 14 h. The reaction mixture was poured into water (40 mL). The product was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0~80% ethyl acetate / petroleum ether gradient at 60 mL / min) to afford 5-bromo-6-fluoro- 3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 14-2B) (800 mg, 1.71 mmol, 50% yield) that was used without further purification. LCMS (m / z) calculated for C13H9BrF2N4O2S: 402.0; found 403.0 [M+H]+, tR = 0.428 min (Purity Method 1). Step 14-2B. Synthesis of (E)-9-(2-fluorostyryl)-9-borabicyclo[3.3.1]nonane (INT 14- 2C)

[0295] To a solution of 1-ethynyl-2-fluoro-benzene (0.2 g, 1.66 mmol, 189 μL, 1 eq) in THF (10 mL), was added 9- borabicyclo[3.3.1]nonane (0.5 M, 10 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 16h to afford (E)-9-(2-fluorostyryl)-9-borabicyclo[3.3.1]nonane INT 14- 2C that was used as a crude solution without purification. Step 14-3B. Synthesis of (E)-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5-(2- fluorostyryl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (14-2)

[0296] To a solution of 9-[(E)-2-(2-fluorophenyl)vinyl]-9-borabicyclo[3.3.1]nonane INT 14-2C (0.4 g, 1.65 mmol, 3.33 eq) and 5- bromo-6-fluoro-N-[(3-fluoro-2-pyridyl)methyl]-1,1- dioxo-4H-1,2,4-benzothiadiazin-3-amine INT 14-2B (200 mg, 496 μmol, 1 eq) in THF (30 mL) and H2O (4 mL) were added K3PO4 (632 mg, 2.98 mmol, 6 eq) and [2-(2- aminophenyl)phenyl]- chloro-palladium tri-tert-butylphosphane (127 mg, 248 μmol, 0.5 eq). The mixture was stirred at 60 °C for 14h. The reaction mixture was poured into water (40 mL). The product was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0~100% Ethyl acetate / Petroleum ether gradient at 80 mL / min) and then repurified by preparative HPLC (column: C18 150×30mm; A-B mobile phase: [water(FA)- ACN]; gradient:48%-78% B over 7 min) and lyophilized to afford (E)-6-fluoro-3- (((3-fluoropyridin-2-yl)methyl)amino)-5-(2-fluorostyryl)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide 14-2 (35 mg, 78 μmol, 16% yield). LCMS (m / z) calculated for C21H15F3N4O2S: 444.1; found 445.1 [M+H]+, tR = 0.534 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.37 - 10.24 (m, 1H), 8.50 - 8.38 (m, 1H), 8.15 (br t, J = 4.6 Hz, 1H), 7.95 (br t, J = 7.2 Hz, 1H), 7.79 (ddd, J = 1.2, 8.5, 9.9 Hz, 1H), 7.73 (dd, J = 5.6, 8.7 Hz, 1H), 7.54 - 7.40 (m, 2H), 7.38 - 7.28 (m, 3H), 7.27 - 7.19 (m, 2H), 4.70 (br d, J = 4.0 Hz, 2H). Synthesis of Scheme 14 Compounds

[0297] Alternatively for Step 14-3B, 14-3 was synthesized using 1.4 eq of 1-fluoro-2-vinyl- benzene, 0.14 eq of [2-(2- aminophenyl)phenyl]-chloro-palladium;tritert-butylphosphane, and 2 eq of dicyclohexylamine in dioxanes at 100 °C for 15h.

[0298] The compounds listed in Table 15 were made using the procedures of Scheme 14. TABLE 15 EXAMPLE 15 Synthesis of Representative Compound 15-1 Reagents: (i) 2-bromobenzaldehyde, solvent (THF), i-PrMgClLiCl; (ii) DMP, solvent (DCM); (iii) TiCl4, ZnMe2, solvent (toluene); (iv) diphenylmethanimine; base (Cs2CO3), catalyst (Pd2(dba)3), ligand (Xantphos), solvent (toluene) (v) HCl, solvent (THF); (vi) ClSO2NCO, solvent (nitromethane) then AlCl3; (vii) N,N-diethylaniline, solvent (POCl3); (viii) Base (DIPEA), solvent (DMA) Step 15-1. Synthesis of (2-bromophenyl)(2-fluorophenyl)methanol (INT 15A)

[0299] To a solution of 1-fluoro-2-iodo-benzene (7.0 g, 32 mmol, 3.68 mL, 1 eq) in THF (50 mL) was added i-PrMgCl.LiCl (1.3 M, 24.3 mL, 1 eq). The mixture was stirred at 0 °C for 1 h. Then, 2-bromobenzaldehyde (5.83 g, 31.5 mmol, 3.65 mL, 1 eq) was added to the reaction mixture at 25 °C and stirred for 2 h. The reaction mixture was quenched with slow addition of aq. sat. NH4Cl solution (100 mL) while stirring. EtOAc (100 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 100 mL). Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-8% Ethyl acetate / petroleum ether gradient at 60 mL / min) to afford (2-bromophenyl)(2-fluorophenyl)methanol INT 15A (8.0 g, 18.5 mmol, 59% yield) that was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.62 (dd, J = 1.4, 7.8 Hz, 1H), 7.57 (dd, J = 0.9, 8.0 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.31 (ddt, J = 1.9, 5.5, 7.6 Hz, 1H), 7.26 - 7.11 (m, 4H), 6.20 - 6.10 (m, 2H). Step 15-2. Synthesis of (2-bromophenyl)(2-fluorophenyl)methanone (INT 15B)

[0300] To a solution of (2-bromophenyl)-(2-fluorophenyl)methanol INT 15A (8.0 g, 18.50 mmol, 65% purity, 1 eq) in DCM (50 mL), was added DMP (15.69 g, 36.99 mmol, 11.45 mL, 2 eq) . The mixture was stirred at 25 °C for 2h. The reaction solution was cooled to room temperature and then diluted with aq. sat. NaHCO3 solution (100 mL), then Na2SO3 (15 g) was added under stirring. The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The residue was purified by flash silica gel chromatography (Eluent of 0~8% Ethyl acetate / Petroleum ether gradient at 80 mL / min) to afford (2-bromophenyl)(2-fluorophenyl)methanone INT 15B (6.0 g, 17.4 mmol, 94% yield) that was used without further purification. LCMS (m / z) calculated for C13H8BrFO: 278.0; found 279.0 [M+H]+, tR = 0.660 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 7.77 - 7.65 (m, 3H), 7.56 - 7.44 (m, 3H), 7.42 - 7.27 (m, 2H). Step 15-3. Synthesis of 1-bromo-2-(2-(2-fluorophenyl)propan-2-yl)benzene (INT 15C)

[0301] TiCl4 (8.16 g, 43.0 mmol, 4.80 mL, 3 eq) and toluene (50 mL) were added to a dried flask under N2. The reaction was cooled to - 40 °C with stirring, and ZnMe2 (1 M, 42.99 mL, 3 eq) was added dropwise. The reaction was stirred for 30 min. A solution of (2-bromophenyl)-(2- fluorophenyl)methanone INT 15B (4.0 g, 14.3 mmol, 1 eq) in toluene (20 mL) was added dropwise to the above solution. The reaction was stirred for 3.5 h at -40 °C and stirred at 25 °C for 12 h. The reaction mixture was quenched with slow addition to water (300 mL) under stirring at 0 °C. EtOAc (300 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 200 mL). Combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0~1% Ethyl acetate / Petroleum ether gradient at 80 mL / min) to afford 1-bromo-2-(2-(2-fluorophenyl)propan-2- yl)benzene INT 15C (3.0 g, 5.73 mmol, 40% yield) that was used without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.69 (dd, J = 1.6, 8.0 Hz, 1H), 7.51 - 7.38 (m, 5H), 7.31 - 7.20 (m, 2H), 6.97 (ddd, J = 1.4, 8.0, 12.4 Hz, 1H), 5.83 (t, J = 1.0 Hz, 1H), 5.50 (s, 1H), 1.73 (s, 6H). Step 15-4. Synthesis of N-(2-(2-(2-fluorophenyl)propan-2-yl)phenyl)-1,1- diphenylmethanimine (INT 15D)

[0302] A mixture of 1-bromo-2-[1-(2-fluorophenyl)-1-methyl-ethyl]benzene INT 15C (3.0 g, 10.2 mmol, 1 eq), Cs2CO3 (10.00 g, 30.70 mmol, 3 eq), diphenylmethanimine (3.71 g, 20.5 mmol, 3.43 mL, 2 eq), Pd2(dba)3 (937 mg, 1.02 mmol, 0.1 eq), Xantphos (1.18 g, 2.05 mmol, 0.2 eq) in toluene (3 mL) was degassed and purged with N23 times, and then the mixture was stirred at 100 °C for 20 h under an N2 atmosphere. Additional Pd2(dba)3 (100 mg, 109 μmol, 1.07e-2 eq) and Xantphos (150 mg, 259.24 μmol, 2.53e-2 eq) were added, and the mixture was stirred at 100 °C for another 14 h under an N2 atmosphere. The crude mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0~1% Ethyl acetate / Petroleum ether gradient at 60 mL / min) to afford N-(2- (2-(2-fluorophenyl)propan-2-yl)phenyl)-1,1-diphenylmethanimine INT 15D (1.1 g, 2.54 mmol, 25% yield).1H NMR (400 MHz, DMSO-d6) δ = 7.49 - 7.44 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 - 7.16 (m, 6H), 7.08 - 7.00 (m, 1H), 6.99 - 6.90 (m, 2H), 6.81 (dt, J = 1.3, 7.6 Hz, 1H), 6.75 (dd, J = 1.4, 7.9 Hz, 2H), 6.64 (dt, J = 1.3, 7.6 Hz, 1H), 6.07 (dd, J = 1.3, 7.8 Hz, 1H), 1.80 (s, 6H). Step 15-5. Synthesis of 2-(2-(2-fluorophenyl)propan-2-yl)aniline (INT 15E)

[0303] To a solution of N-(2-(2-(2-fluorophenyl)propan-2-yl)phenyl)-1,1- diphenylmethanimine INT 15D (1.1 g, 2.80 mmol, 1 eq) in THF (10 mL), was added HCl (2 M, 13.98 mL, 10 eq). The mixture was stirred at 25 °C for 0.5h. The reaction mixture was poured into water (40 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-3% Ethyl acetate / petroleum ether gradient at 50 mL / min) to afford 2-(2-(2-fluorophenyl)propan-2-yl)aniline INT 15E (600 mg, 2.59 mmol, 93% yield). LCMS (m / z) calculated for C15H16FN: 229.1; found 230.2 [M+H]+, tR = 0.553 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 7.56 – 7.49 (m, 1H), 7.34 – 7.26 (m, 2H), 7.25 – 7.19 (m, 1H), 7.03 (ddd, J = 1.3, 8.0, 12.3 Hz, 1H), 6.97 – 6.89 (m, 1H), 6.64 (dt, J = 1.3, 7.5 Hz, 1H), 6.52 (dd, J = 1.1, 7.9 Hz, 1H), 3.90 (s, 2H), 1.65 (s, 6H). Step 15-6. Synthesis of 5-(2-(2-fluorophenyl)propan-2-yl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 15F)

[0304] To a solution of N-(oxomethylene)sulfamoyl chloride (813 mg, 5.74 mmol, 500 μL, 2.63 eq) in nitrobenzene (3 mL) was added 2-(2-(2-fluorophenyl)propan-2-yl)aniline INT 15E (500 mg, 2.18 mmol, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h then AlCl3 (500 mg, 3.75 mmol, 1.72 eq) was added. The mixture was stirred at 120 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated NH4Cl aqueous solution (50 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The obtained brown oil was diluted with petroleum ether (100 mL) and then stirred for 10 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (100 mL) and then dried under vacuum to afford 5-(2-(2-fluorophenyl)propan-2-yl)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 15F (500 mg, 1.05 mmol, 48% yield). LCMS (m / z) calculated for C16H15FN2O3S: 334.1; found 333.1 [M-H], tR = 0.478 min (Purity Method 2 negative mode).1H NMR (400 MHz, DMSO-d6) δ = 7.86 (br d, J = 8.1 Hz, 1H), 7.77 - 7.64 (m, 2H), 7.37 (br s, 3H), 6.97 (br s, 1H), 1.72 (s, 6H). Step 15-7. Synthesis of 3-chloro-5-(2-(2-fluorophenyl)propan-2-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 15G)

[0305] To a solution of 5-[1-(2-fluorophenyl)-1-methyl-ethyl]-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 15F (300 mg, 897 μmol, 1 eq) in POCl3 (2 mL) was added N,N- diethylaniline (280 mg, 1.88 mmol, 0.3 mL, 2.09 eq). The mixture was stirred at 120 °C for 2 h. The reaction solution was poured into water (80 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The mixture was extracted with EtOAc (3 x 80 mL). The combined organics were washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a residue. The residue was purified by prep-TLC (SiO2, PE: EtOAc = 1:3, Rf=0.40) to afford 3-chloro-5-(2-(2-fluorophenyl)propan-2-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 15G (125 mg, 294 μmol, 33% yield) that was used without further purification. LCMS (m / z) calculated for C16H14ClFN2O2S: 352.0; found 351.1 [M- H], tR = 0.412 min (Purity Method 2 negative mode).

[0008] Step 15-8. Synthesis of 3-(((3-chloropyridin-2-yl)methyl)amino)-5-(2-(2- fluorophenyl)propan-2-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (15-1)

[0306] To a solution of (3-chloro-2-pyridyl)methanamine (126 mg, 882 μmol, 3 eq) in DMA (1 mL), was added DIPEA (114 mg, 882 μmol, 154 μL, 3 eq). The mixture was stirred at 25 °C for 14h. The reaction mixture was poured into water (30 mL). The mixture was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25mm x 10um; A-B mobile phase: [water(TFA)-ACN]; gradient: 45%-75% B over 9 min) and lyophilized to afford 3-(((3- chloropyridin-2-yl)methyl)amino)-5-(2-(2-fluorophenyl)propan-2-yl)-4H-benzo[e][1,2,4]- thiadiazine 1,1-dioxide 15-1 (44 mg, 95.87 μmol, 33% yield). LCMS (m / z) calculated for C22H20ClFN4O2S: 458.1; found 459.3 [M+H]+, tR = 0.531 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 8.52 (dd, J = 0.9, 4.6 Hz, 1H), 8.31 (br s, 1H), 7.97 (br d, J = 7.8 Hz, 1H), 7.77 (br d, J = 7.8 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.52 - 7.01 (m, 6H), 4.80 - 4.20 (m, 2H), 2.07 (s, 1H), 1.79 (br s, 6H). Synthesis of Scheme 15 Compounds

[0307] The compounds listed in Table 16 were made using the procedures of Scheme 15.

[0009] TABLE 16 EXAMPLE 16 Synthesis of Representative Compound 16-1 Reagents: (i) base (LiOtBu), catalyst (Pd(PPh3)2Cl2), solvent (dioxanes); (ii) O3, solvent (DCM); (iii) N,N-diethylaniline, solvent (POCl3); (iv) Base (DIPEA), solvent (THF) Step 16-1. Synthesis of (E)-N'-(1-(2-chlorophenyl)ethylidene)-4- methylbenzenesulfonohydrazide (INT 16A)

[0308] To a solution of 1-(2-chlorophenyl)ethanone (5.0 g, 32.3 mmol, 4.21 mL, 1 eq) in MeOH (20 mL) was added 4- methylbenzenesulfonohydrazide (7.23 g, 38.8 mmol, 1.2 eq). The mixture was stirred at 60 °C for 6 h. The white precipitate was collected by filtration, air‐dried, triturated in MeOH (20 mL) and collected by filtration to afford (E)-N'-(1-(2- chlorophenyl)ethylidene)-4-methylbenzenesulfonohydrazide INT 16A (8.1 g, 24.1 mmol, 74% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.67 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.47 - 7.30 (m, 5H), 7.17 (dd, J = 1.9, 7.4 Hz, 1H), 2.37 (s, 3H), 2.16 (s, 3H). Step 16-2. Synthesis of 5-(1-(2-chlorophenyl)vinyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 16B)

[0309] To a solution of N-[(E)-1-(2-chlorophenyl)ethylideneamino]-4-methyl- benzenesulfonamide INT 16A (4.78 g, 14.8 mmol, 1.2 eq) and 5-iodo-1,1-dioxo-4H-1,2,4- benzothiadiazin-3-ol INT 14A (4.0 g, 12.3 mmol, 1 eq) in dioxane (30 mL) were added tBuOLi (2.96 g, 37.0 mmol, 3.34 mL, 3 eq) and Pd(PPh3)2Cl2 (1.73 g, 2.47 mmol, 0.2 eq). The mixture was stirred at 100 °C for 14 h. The reaction mixture was poured into water (80 mL). The mixture was extracted with EtOAc (2 x 80 mL). The combined organics were washed by brine (3 x 80 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude product (2.3 g, 6.87 mmol, 56% yield). The crude product was used directly in the next step without further purification. LCMS (m / z) calculated for C15H11ClIN2O3S: 334.0; found 333.0 [M-H], tR = 0.462 min (Purity Method 2 negative mode). Step 16-3. Synthesis of (2-chlorophenyl)(3-hydroxy-1,1-dioxido-4H- benzo[e][1,2,4]thiadiazin-5-yl)methanone (INT 16C)

[0310] A dry 100-mL round-bottomed flask containing a magnetic stirring bar was charged with 5-[1-(2-chlorophenyl)vinyl]- 1,1-dioxo-4H-1,2,4-benzothiadiazin-3-ol INT 16B (2.3 g, 6.87 mmol, 1 eq) and DCM (80 mL). A gentle stream of dry ozone was passed through the solution and the flask was immediately cooled to -78 °C. Ozonolysis was continued until the distinctive blue color of excess ozone was first observed. Ozonolysis was then terminated, and the excess ozone was removed by purging with a stream of nitrogen for 5-10 min. The solution was allowed to warm to 25 °C, and Me2S (5.92 g, 95.31 mmol, 7 mL, 13.87 eq) was added via syringe. The solution was allowed to stir at 25 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue. The residue was purified by flash silica gel chromatography (Eluent of 0-50% Ethyl acetate / Petroleum ether) to afford (2-chlorophenyl)(3-hydroxy-1,1-dioxido-4H- benzo[e][1,2,4]thiadiazin-5-yl)methanone INT 16C (1.4 g, 3.45 mmol, 50% yield). Step 16-4. Synthesis of (3-chloro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)(2- chlorophenyl)methanone (INT 16D)

[0311] To a solution of (2-chlorophenyl)(3-hydroxy-1,1-dioxido-4H- benzo[e][1,2,4]thiadiazin-5-yl)methanone INT 16C (700 mg, 2.08 mmol, 1 eq) in POCl3 (10 mL) was added N,N-diethylaniline (653 mg, 4.38 mmol, 0.7 mL, 2.11 eq). The mixture was stirred at 120 °C for 2 h. The reaction solution was poured into water (80 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The dark brown oil eventually formed a brown precipitate that was collected by vacuum filtration and dried under vacuum to give (3-chloro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)(2- chlorophenyl)methanone INT 16D (200 mg, 544 μmol, 26% yield). LCMS (m / z) calculated for C14H18Cl2N2O3S: 354.0; found 353.0 [M-H], tR = 0.320 min (Purity Method 2 negative mode). Step 16-5. Synthesis of (2-chlorophenyl)(3-(((3-chloropyridin-2-yl)methyl)amino)- 1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)methanone (16-1)

[0312] To a solution of (3-chloro-2-pyridyl)methanamine (42.2 mg, 296 μmol, 1.5 eq) and (3-chloro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)(2-chlorophenyl)methanone INT 16D (70 mg, 197 μmol, 1 eq) in THF (1.5 mL) was added DIPEA (76.4 mg, 591 μmol, 103 μL, 3 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC ( column: Phenomenex luna C18 150x25mmx 10um; A-B mobile phase: [water(FA)-ACN]; gradient: 50%-70% B over 10 min ) and lyophilized to afford (2-chlorophenyl)(3-(((3-chloropyridin-2-yl)methyl)amino)-1,1-dioxido-4H- benzo[e][1,2,4]thiadiazin-5-yl)methanone 16-1 (18 mg, 39 μmol, 20% yield). LCMS (m / z) calculated for C20H14Cl2N4O3S: 460.0; found 461.1 [M+H]+, tR = 0.516 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 11.53 (br s, 1H), 9.39 (br d, J = 3.6 Hz, 1H), 8.59 - 8.53 (m, 1H), 8.10 - 8.05 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.72 - 7.60 (m, 3H), 7.60 - 7.51 (m, 2H), 7.44 (dd, J = 4.6, 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 4.74 (br d, J = 5.0 Hz, 2H).

[0313] The compounds listed in Table 17 were made using the procedures of Scheme 16. TABLE 17 EXAMPLE 17 Synthesis of Representative Compound 17-1 Reagents: (i) 1-(bromomethyl)-2-chlorobenzene, base (Cs2CO3), solvent (NMP); (ii) N,N- diethylaniline, solvent (POCl3); (iii) base (Cs2CO3), solvent (NMP) Step 17-1. Synthesis of 5-((2-chlorobenzyl)amino)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 17A)

[0314] To a stirring solution of 5-amino-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide (100 mg, 1 Eq, 469 μmol) in NMP (5 mL) was added 1-(bromomethyl)-2-chlorobenzene (125 mg, 1.3 Eq, 610 μmol) and cesium carbonate (306 mg, 2 Eq, 938 μmol). The mixture was heated to 60 °C and stirred for 18 h. The reaction mixture was purified by HPLC to obtain 5-((2- chlorobenzyl)amino)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 17A (37 mg, 110 µmol, 23% yield). LCMS (m / z) calculated for C14H12ClN3O3S: 337.0; found 338.2 [M+H]+, tR = 3.88 min (Purity Method 4).1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 10.45 (s, 1H), 7.99 (s, 1H), 7.39 – 7.32 (m, 2H), 7.30 (dd, J = 8.0, 1.1 Hz, 1H), 7.24 (td, J = 7.0, 6.4, 3.9 Hz, 2H), 7.15 (dd, J = 7.8, 1.2 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 4.11 (s, 2H). Step 17-2. Synthesis of 3-chloro-5-((2-chlorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 17B)

[0315] To 5-((2-chlorobenzyl)amino)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide INT 17A (37 mg, 1 Eq, 110 μmol) was add 1 ml POCl3. The mixture was stirred at 105oC for 2h then concentrated in vacuo to obtain 3-chloro-5-((2-chlorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 17B (35 mg, 93 μmol, 20% yield) that was used without further purification. LCMS (m / z) calculated for C14H11Cl2N3O2S: 355.0; found 356.0 [M+H]+, tR = 3.88 min (Purity Method 4). Step 17-3. Synthesis of 5-((2-chlorobenzyl)amino)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (17-1)

[0316] To a stirring solution of 3-chloro-5-((2-chlorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 17B (8 mg, 1 Eq, 0.02 mmol) in NMP (2 mL) were added (3-fluoropyridin-2-yl)methanamine (4 mg, 1.3 Eq, 0.03 mmol) and cesium carbonate (20 mg, 3 Eq, 61 μmol). The mixture was heated to 150 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and water (4 mL) was added. The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organics were concentrated in vacuo and the crude residue was purified by silica gel chromatography (0-80% EtOAc / hexanes) to afford 5-((2- chlorobenzyl)amino)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide 17-1 (1.1 mg, 11% yield). LCMS (m / z) calculated for C20H17ClFN5O2S: 445.1; found 446.0 [M+H]+, tR = 5.798 min (Purity Method 3). Synthesis of Scheme 17 Compounds

[0317] The compounds listed in Table 18 were made using the procedures of Scheme 17. TABLE 18

[0010] EXAMPLE 18 Synthesis of Representative Compound 18-1 Scheme 18 Reagents: (i) base (Cs2CO3), catalyst (Pd(dppf)Cl2), solvent (dioxanes / water) Step 18-1. Synthesis of 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5- phenethyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (18-1)

[0318] To a solution of 5-bromo-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 14-2B (15 mg, 1 Eq, 37 μmol) and phenethylboronic acid (17 mg, 3 Eq, 0.11 mmol) in 1,4-Dioxane (2 mL) and Water (2 mL), Pd(dppf)Cl2 (2.7 mg, 0.1 Eq, 3.7 μmol) and cesium carbonate (24 mg, 2 Eq, 74 μmol) were added. The mixture was degasssed by N2 and then the reaction was stirred at 90 °C for 3 h. The reaction mixture was passed through a syringe filter into a test tube, and the filtrate was directly loaded / purified by HPLC to afford 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5-phenethyl-4H-benzo[e][1,2,4]- thiadiazine 1,1-dioxide 18-1 (0.7 mg, 2 μmol, 4% yield). LCMS (m / z) calculated for C21H18F2N4O2S: 428.1; found 429.1 [M+H]+, tR = 8.69 min (Purity Method 3).

[0319] The compounds listed in Table 19 were made using the procedures of Scheme 18. TABLE 19 EXAMPLE 19 Synthesis of Representative Compound 19-1 Scheme 19 Reagents: (i) SEMCl, base (NaH), solvent (THF); (ii) potassium hydride;trifluoro(2- phenylethynyl)boranide, base (K2CO3), catalyst (Pd(PPh3)2Cl2), solvent (dioxanes / water); (iii) TFA, solvent (DCM) Example Synthesis of Scheme 19 Compounds Step 19-1. Synthesis of 5-bromo-6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-2- ((2-(trimethylsilyl)ethoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 19A)

[0320] To a mixture of 5-bromo-6-fluoro-N-[(3-fluoro-2-pyridyl)methyl]-1,1-dioxo-2H- 1,2,4-benzothiadiazin-3-amine INT 14-2B (1.8 g, 4.46 mmol, 1 eq) in THF (30 mL) was added NaH (540 mg, 13.50 mmol, 60% purity, 3.02 eq) at 0 °C, and it was stirred at 0 °C for 0.5h. To the mixture was added SEM-Cl (2.54 g, 15.26 mmol, 2.70 mL, 3.42 eq) at 0 °C, and it was then stirred at 25 °C for 15 h. The mixture was quenched by adding 20 mL water, then extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The residue was purified by flash silica gel chromatography (0-100% Ethyl acetate / petroleum ether gradient at 40 mL / min) to afford 5-bromo- 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 19A (250 mg, 337 μmol, 8% yield) that was used without further purification. LCMS (m / z) calculated for C19H23BrF2N4OsSSi: 532.0; found 533.2 [M+H]+, tR = 0.654 min (Purity Method 2).1H NMR (400 MHz, DMSO-d6) δ = 13.03 - 12.16 (br, 1H), 8.60 - 8.35 (m, 1H), 8.02 - 7.74 (m, 2H), 7.69 - 7.49 (m, 1H), 7.43 (q, J = 8.4 Hz, 1H), 5.28 - 5.02 (m, 2H), 4.97 (br d, J = 7.1 Hz, 2H), 3.60 - 3.48 (m, 2H), 0.96 - 0.74 (m, 2H), 0.08 (m, 9H). Step 19-2. Synthesis of 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5- (phenylethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 19B)

[0321] To a mixture of 5-bromo-6-fluoro-N-[(3-fluoro-2-pyridyl)methyl]-1,1-dioxo-2-(2- trimethylsilylethoxymethyl)-1,2,4- benzothiadiazin-3-amine INT 19A (150 mg, 281 μmol, 1 eq) and potassium trifluoro(2-phenylethynyl)boranuide (90.0 mg, 433 μmol, 1.54 eq) in dioxane (10 mL) and Water (2 mL) were added K2CO3 (75.0 mg, 543 μmol, 1.93 eq) and Pd(dppf)Cl2 (22.5 mg, 30.8 μmol, 1.09e-1 eq). The reaction mixture was stirred at 60 °C for 15 h. The mixture was added to 10 mL water and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (PE / EA=1 / 1) to afford 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5- (phenylethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 19B (40 mg, 85 μmol, 30 % yield). LCMS (m / z) calculated for C27H28F2N4O3SSi: 554.2; found 555.2 [M+H]+, tR = 0.658 min (Purity Method 2). Step 19-3. Synthesis of 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5- (phenylethynyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (19-1)

[0322] To a solution of 6-fluoro-N-[(3-fluoro-2-pyridyl)methyl]-1,1-dioxo-5-(2- phenylethynyl)-2-(2- trimethylsilylethoxymethyl)-1,2,4-benzothiadiazin-3-amine INT 19B (40 mg, 46.9 μmol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 287 eq). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under vacuum to give a crude residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150x25mmx10um; A-B mobile phase: [water(FA)-ACN]; gradient: 40%-70% B over 9 min) to afford 6-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-5-(phenylethynyl)-4H-benzo[e][1,2,4]- thiadiazine 1,1-dioxide 19-1 (0.6 mg, 1.41 μmol, 3% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.33 - 10.11 (m, 1H), 8.65 - 8.50 (m, 1H), 8.45 (br d, J = 3.9 Hz, 1H), 7.88 - 7.65 (m, 4H), 7.57 - 7.42 (m, 4H), 7.33 - 7.20 (m, 1H), 4.71 (br d, J = 3.3 Hz, 2H). LCMS (m / z) calculated for C21H14F2N4O2S: 424.1; found 425.1 [M+H]+, tR = 0.536 min (Purity Method 1).

[0323] The compounds listed in Table 20 were made using the procedures of Scheme 19. TABLE 20 EXAMPLE 20 Synthesis of Representative Compound 20-1 Reagents: (i) base (LiOtBu), catalyst (Xphos-Pd-G2), solvent (dioxane); (ii) H2, catalyst (Pd / C), solvent (MeOH); (iii) N,N-diethylaniline, solvent (POCl3); (iv) base (DIPEA), solvent (THF)

[0011] Example Synthesis of Scheme 20 Compounds Step 20-1. Synthesis of (E)-N'-(1-(2-fluorophenyl)propylidene)-4- methylbenzenesulfonohydrazide (INT 20A)

[0324] A mixture of 1-(2-fluorophenyl)propan-1-one (2 g, 13.14 mmol, 1 eq) and 4- methylbenzenesulfonohydrazide (2.45 g, 13.14 mmol, 1 eq) in MeOH (40 mL) was stirred at 60 °C for 15 h. The mixture was concentrated in vacuo to afford (E)-N'-(1-(2-fluorophenyl)propylidene)- 4-methylbenzenesulfonohydrazide INT 20A (4.4 g, 11.7 mmol, 89% yield) that was used without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.92 - 7.80 (m, 2H), 7.49 - 7.37 (m, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.28 - 7.22 (m, 1H), 7.20 - 7.11 (m, 1H), 7.09 - 7.01 (m, 1H), 2.62 - 2.41 (m, 5H), 1.13 - 1.00 (m, 3H). Step 20-2. Synthesis of 6-fluoro-5-(1-(2-fluorophenyl)prop-1-en-1-yl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 20B)

[0325] To a solution of N-[(Z)-1-(2-fluorophenyl)propylideneamino]-4-methyl- benzenesulfonamide INT 20B (1.63 g, 5.08 mmol, 1.5 eq) and 5-bromo-6-fluoro-1,1-dioxo-4H- 1,2,4-benzothiadiazin-3-ol INT 14-2A (1.0 g, 3.39 mmol, 1 eq) in dioxane (20 mL) were added lithium tert-butoxide (543 mg, 6.78 mmol, 611 μL, 2 eq) and Xphos-Pd-G2 (267 mg, 339 μmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was concentrated in vacuo to give a residue. To the residue was added ammonium chloride solution (30mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150x40mmx10um; A-B mobile phase: [water(NH4HCO3)-ACN]; gradient: 12%-42% B over 20 min) to afford 6-fluoro-5-(1-(2-fluorophenyl)prop-1-en-1-yl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 20B (150 mg, 409.19 μmol, 12% yield). Step 20-3. Synthesis of 6-fluoro-5-(1-(2-fluorophenyl)propyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 20C)

[0326] A mixture of 6-fluoro-5-(1-(2-fluorophenyl)prop-1-en-1-yl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 20B (150 mg, 428 μmol, 1 eq) and Pd / C (100 mg, 10% purity) in MeOH (10 mL) was degassed and purged with N23 times, and then the mixture was stirred at 50 °C for 15 h under an H2 atmosphere (50 psi). The reaction mixture was filtered and concentrated in vacuo to afford 6-fluoro-5-(1-(2-fluorophenyl)propyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 20C (130 mg, 328 μmol, 77% yield) that was used without further purification. Step 20-4. Synthesis of 3-chloro-6-fluoro-5-(1-(2-fluorophenyl)propyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 20D)

[0327] To a solution of 6-fluoro-5-(1-(2-fluorophenyl)propyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 20C (130 mg, 369 μmol, 1 eq) in POCl3 (2 mL) was added N,N-diethylaniline (82.6 mg, 553 μmol, 89 μL, 1.5 eq). The mixture was stirred at 120 °C for 6 h. The reaction was quenched by addition of sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 15 mL), washed with brine (2 x 10 mL), filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-100% Ethyl acetate / petroleum ether gradient at 20 mL / min) to afford 3-chloro- 6-fluoro-5-(1-(2-fluorophenyl)propyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 20D (60 mg, 148 μmol, 40% yield). Step 20-5. Synthesis of 6-fluoro-5-(1-(2-fluorophenyl)propyl)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20-1)

[0328] To a solution of 3-chloro-6-fluoro-5-(1-(2-fluorophenyl)propyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 20D (60 mg, 162 μmol, 1 eq) and (3-fluoro-2- pyridyl)methanamine;dihydrochloride (64.4 mg, 324 μmol, 2 eq) in THF (2 mL) was added DIPEA (105 mg, 809 μmol, 141 μL, 5 eq). The mixture was stirred at 60 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18150×30mm; A-B mobile phase: [water(FA)-ACN]; gradient: 55%- 65% B over 7 min) to afford 6-fluoro-5-(1-(2-fluorophenyl)propyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 20-1 (10.1 mg, 21.9 μmol, 14% yield). LCMS (m / z) calculated for C22H19F3N4O2S: 460.1; found 461.1 [M+H]+, tR = 0.527 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.59 - 10.40 (m, 1H), 8.48 (br d, J = 4.5 Hz, 1H), 8.18 (br s, 1H), 7.80 (t, J = 8.8 Hz, 1H), 7.66 (dd, J = 5.6, 8.7 Hz, 1H), 7.59 (br t, J = 7.8 Hz, 1H), 7.50 (td, J = 4.5, 8.5 Hz, 1H), 7.35 - 7.21 (m, 2H), 7.15 - 7.07 (m, 1H), 7.01 (dd, J = 8.9, 11.1 Hz, 1H), 4.79 - 4.64 (m, 2H), 4.52 (br t, J = 7.3 Hz, 1H), 2.30 - 2.12 (m, 2H), 2.06 (s, 1H), 0.95 - 0.87 (m, 3H).

[0329] The compounds listed in Table 21 were made using the procedures of Scheme 20. TABLE 21 EXAMPLE 21 Synthesis of Representative Compound 21-1 Reagents: (i) base (LiOtBu), catalyst (Xphos-Pd-G2), solvent (dioxane); (ii) H2, catalyst (Pd / C), solvent (MeOH); (iii) ClSO2NCO, solvent (nitromethane) then AlCl3; (iv) N,N-diethylaniline, solvent (POCl3); (v) base (DIPEA), solvent (DMA) Example Synthesis of Scheme 21 Compounds Step 21-1. Synthesis of 2-(1-(2-fluorophenyl)prop-1-en-1-yl)aniline (INT 21A)

[0330] To a solution of N-[(E)-1-(2-fluorophenyl)propylideneamino]-4-methyl- benzenesulfonamide INT 20A (2.0 g, 5.31 mmol, 9.13e-1 eq) and 2-bromoaniline (1 g, 5.81 mmol, 1 eq) in dioxane (20 mL) were added t-BuOLi (931 mg, 11.63 mmol, 1.05 mL, 2 eq) and XPhos Pd G3 (492 mg, 581 μmol, 0.1 eq). The mixture was stirred at 100 °C for 14h. The reaction mixture was poured into water (40 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organics were washed by brine (3 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-10% Ethyl acetate / Petroleum ether gradient) to afford 2-(1-(2-fluorophenyl)prop-1-en-1- yl)aniline INT 21A (0.8 g, 3.27 mmol, 56% yield). LCMS (m / z) calculated for C15H14FN: 227.1; found 228.1 [M+H]+, tR = 0.527 min (Purity Method 1). Step 21-2. Synthesis of 2-(1-(2-fluorophenyl)propyl)aniline (INT 21B)

[0331] To a solution of 2-[(Z)-1-(2-fluorophenyl)prop-1-enyl]aniline INT 21A (0.8 g, 3.52 mmol, 1 eq) in MeOH (25 mL) was added 10% Pd / C (108 mg, 101 μmol, 0.03 eq) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under an atmosphere of H2 (50 Psi) at 50 °C for 14 h. The crude mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford 2-(1-(2-fluorophenyl)propyl)aniline INT 21B (0.8 g, crude) that was carried on without further purification. LCMS (m / z) calculated for C15H16FN: 229.1; found 230.0 [M+H]+, tR = 0.528 min (Purity Method 1). Step 21-3. Synthesis of 5-(1-(2-fluorophenyl)propyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 21C)

[0332] To a solution of 2-[1-(2-fluorophenyl)propyl]aniline INT 21B (0.8 g, 3.49 mmol, 1 eq) in nitrobenzene (12 mL) was added N-(oxomethylene)sulfamoyl chloride (741 mg, 5.23 mmol, 454 μL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, AlCl3 (582 mg, 4.36 mmol, 238 μL, 1.25 eq) was added. The mixture was stirred at 80 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with saturated NH4Cl aqueous solution (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a brown oil. The obtained brown oil was diluted with petroleum ether (150 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (60 mL) and then dried under vacuum to give a brown solid. The precipitate was triturated in toluene (3 mL) and collected by filtration to afford 5-(1-(2-fluorophenyl)propyl)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide INT 21C (0.5 g, 1.44 mmol, 41% yield). LCMS (m / z) calculated for C16H15FN2O3S: 334.1; found 333.1 [M-H], tR = 0.453 min (Purity Method 2 negative mode). Step 21-4. Synthesis of 3-chloro-5-(1-(2-fluorophenyl)propyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 21D)

[0333] To a solution of POCl3 (4.59 g, 29.9 mmol, 2.79 mL, 20 eq) in toluene (7.5 mL), were added 5-[1-(2- fluorophenyl)propyl]-1,1-dioxo-4H-1,2,4-benzothiadiazin-3-ol INT 21C (0.5 g, 1.50 mmol, 1 eq) and N,N-diethylaniline (335 mg, 2.24 mmol, 359 μL, 1.5 eq). The mixture was stirred at 110 °C for 16 h. The reaction solution was poured into water (50 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 h. The mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 50 mL),dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purifiedby flash silica gel chromatography (0-50% Ethyl acetate / petroleum ether gradient at 50 mL / min) to afford 3-chloro-5-(1-(2-fluorophenyl)propyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 21De (0.4 g, 1.05 mmol, 71% yield). LCMS (m / z) calculated for C16H14ClFN2O2S: 352.0; found 351.0 [M-H], tR = 0.520 min (Purity Method 2 negative mode). Step 21-5. Synthesis of 5-(1-(2-fluorophenyl)propyl)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (21-1)

[0334] To a solution of 3-chloro-5-[1-(2-fluorophenyl)propyl]-4H-1,2,4-benzothiadiazine 1,1-dioxide INT 21D (150 mg, 425 μmol, 1 eq), (3-fluoro-2-pyridyl)methanamine.dihydrochloride (102 mg, 510 μmol, 1.2 eq) in DMA (3 mL) was added DIPEA (281 mg, 2.18 mmol, 379 μL, 5.12 eq). The mixture was stirred at 120 °C for 14 h. The crude mixture was filtered. The residue was purified by preparative HPLC (column: Welch Xtimate C18150x25mmx5um; A-B mobile phase: [water(FA)-ACN]; gradient: 35%-65% B over 40 min) and lyophilized to afford 5-(1-(2- fluorophenyl)propyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide 21-1 (80 mg, 174 μmol, 41% yield). LCMS (m / z) calculated for C22H20F2N4O2S: 442.1; found 443.2 [M+H]+, tR = 0.56 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.24 (br s, 1H), 8.49 (d, J = 4.6 Hz, 1H), 8.19 - 8.10 (m, 1H), 7.85 - 7.77 (m, 1H), 7.60 (br t, J = 7.1 Hz, 1H), 7.56 (dd, J = 1.1, 7.6 Hz, 1H), 7.51 (td, J = 4.4, 8.5 Hz, 1H), 7.37 - 7.24 (m, 3H), 7.23 - 7.08 (m, 2H), 4.84 - 4.63 (m, 2H), 4.55 (br t, J = 7.1 Hz, 1H), 2.14 (td, J = 7.2, 14.0 Hz, 1H), 2.07 - 1.92 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H).

[0335] The compounds listed in Table 22 were made using the procedures of Scheme 21. TABLE 22

[0012] EXAMPLE 22 Synthesis of Representative Compound 22-1 Reagents: (i) N,N-diethylaniline, solvent (POCl3); (ii) Base (DIPEA), solvent (THF); (iii) base (LiOtBu), catalyst (Xphos Pd G4), solvent (dioxanes); (iv) H2, catalysts (Pd / C), solvent (MeOH / NH4OH)

[0013] Example Synthesis of Scheme 22 Compounds Step 22-1. Synthesis of 5-bromo-6-fluoro-3-((3-fluorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 22B)

[0336] To a solution of 5-bromo-3-chloro-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide INT 6B (4.8 g, 15.3 mmol, 1 eq) and (3- fluorophenyl)methanamine (2.87 g, 23.0 mmol, 2.62 mL, 1.5 eq) in THF (50 mL) was added DIPEA (5.94 g, 45.9 mmol, 8.00 mL, 3 eq). The mixture was stirred at 60 °C for 15 h. The reaction mixture was filtered and concentrated in vacuo to afford 5-bromo-6-fluoro-3-((3-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 22B (5.3 g, 13.1 mmol, 86% yield, 99.6% purity). LCMS (m / z) calculated forC14H10BrF2N3O2S: 401.0; found 401.9 [M+H]+, tR = 0.48 min (Purity Method 1).Step 22-2B. Synthesis of (E)-4-methyl-N'-(1- phenylethylidene)benzenesulfonohydrazide (INT 22C)

[0337] To a solution of 1-phenylethanone (1.0 g, 8.32 mmol, 973 μL, 1 eq) in MeOH (5 mL) , was added 4- methylbenzenesulfonohydrazide (1.57 g, 8.41 mmol, 1.01 eq). The mixture was stirred at 60 °C for 1 h. A white precipitate was formed. The crude mixture was filtered and the obtained solid was dried under vacuum to afford (E)-4-methyl-N'-(1- phenylethylidene)benzenesulfonohydrazide INT 22C (1.5 g, 5.20 mmol, 63% yield). LCMS (m / z) calculated for C15H16N2O2S: 288.1; found 289.1 [M+H]+, tR = 0.528 min (Purity Method 1). Step 22-3. Synthesis of 6-fluoro-3-((3-fluorobenzyl)amino)-5-(1-phenylvinyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 22D)

[0338] To a solution of (E)-4-methyl-N'-(1-phenylethylidene)benzenesulfonohydrazide INT 22C (72 mg, 249 μmol, 1 eq) and 5-bromo-6-fluoro-3-((3-fluorobenzyl)amino)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 22B (100 mg, 249 μmol, 1 eq) in dioxane (2 mL) were added lithium tert-butoxide (40 mg, 497 μmol, 45 μL, 2 eq) and Xphos Pd G4 (21 mg, 24.9 μmol, 0.1 eq). The mixture was stirred at 100 °C for 15 h. The reaction mixture was concentrated in vacuo. To the residue was added saturated ammonium chloride solution (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6-fluoro-3-((3-fluorobenzyl)amino)-5-(1-phenylvinyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 22D (110 mg) that was used without further purification. LCMS (m / z) calculated for C22H17F2N3O2S: 425.1; found 426.1 [M+H]+, tR = 0.533 min (Purity Method 1). Step 22-4. Synthesis of 6-fluoro-3-((3-fluorobenzyl)amino)-5-(1-phenylethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (22-1)

[0339] A mixture of 6-fluoro-3-((3-fluorobenzyl)amino)-5-(1-phenylvinyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 22D (50 mg, 118 μmol, 1 eq) , NH3.H2O (142 mg, 1.18 mmol, 156 μL, 29% purity, 10 eq) and 10% Pd / C (50 mg) in MeOH (10 mL) was degassed and purged with N23 times. The reaction mixture was then heated at 50 °C for 15 h under an H2 atmosphere (50 psi). The reaction mixture was filtered and concentrated in vacuo to give a crude residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150x25mmx5um;mobile phase: [water(FA)- ACN];gradient:40%-70% B over 40 min) to afford 6- fluoro-3-((3-fluorobenzyl)amino)-5-(1-phenylethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 22-1 (11.8 mg, 27.3 μmol, 23% yield). LCMS (m / z) calculated for C22H19F2N3O2S: 427.1; found 428.2 [M+H]+, tR = 0.533 min (Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.21 (s, 1H), 7.77 (br s, 1H), 7.67 (dd, J = 5.6, 8.7 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.35 - 7.29 (m, 2H), 7.27 - 7.19 (m, 5H), 7.16 - 7.09 (m, 1H), 7.05 (dd, J = 8.8, 11.1 Hz, 1H), 4.62 - 4.44 (m, 3H), 1.70 (br d, J = 6.8 Hz, 3H).

[0340] The compounds listed in Table 23 were made using the procedures of Scheme 22. TABLE 23 EXAMPLE 23 Synthesis of Representative Compound 23-1 Scheme 23 Reagents: (i) NH2NHTos, solvent (MeOH); (ii) Base (t-BuOLi), solvent (dioxanes), catalyst (Pd(PPh3)2Cl2); (iii) catalyst (Pd(OAc)2), cataCXium A, solvent (CD3OD / toluene), base (K3PO4); (iv) H2, catalyst (Pd / C), solvent (MeOH); (v) ClSO2NCO, solvent (nitrobenzene) then AlCl3; (vi) N,N-diethylaniline, solvent (toluene / POCl3); (vii) Base (DIPEA), solvent (DMA); (viii) chiral separation Example Synthesis of Scheme 23 Compounds Step 23-1. Synthesis of 3-bromo-2-(1-(2-fluorophenyl)vinyl)aniline (INT 23A)

[0341] To a mixture of 3-bromo-2-iodo-aniline (3.0 g, 10.1 mmol, 1 eq), N-[(E)-1-(2- fluorophenyl)ethylideneamino]-4- methyl-benzenesulfonamide INT 7A (3.0 g, 9.79 mmol, 9.72e- 1 eq), and t-BuOLi (1.5 g, 18.7 mmol, 1.7 mL, 1.9 eq) in dioxane (100 mL) was added Pd(PPh3)2Cl2 (700 mg, 997 μmol, 9.90e-2 eq). The reaction mixture was heated at 100 °C for 15h. The reaction was quenched with water (100 mL) and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude residue. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether gradient at 50 mL / min) to afford 3-bromo- 2-(1-(2-fluorophenyl)vinyl)aniline INT 23A (2.2 g, 4.59 mmol, 46% yield) that was used without further purification. LCMS (m / z) calculated for C14H11BrFN: 291.0; found 292.0 [M+H]+, tR = 0.583 min (Purity Method 1).1H NMR (400 MHz, CHLOROFORM-d) δ = 7.27 - 7.20 (m, 1H), 7.14 - 7.07 (m, 2H), 7.05 - 6.98 (m, 3H), 6.69 (dd, J = 1.5, 7.5 Hz, 1H), 6.20 (s, 1H), 5.61 (s, 1H), 3.91 (br s, 2H). Step 23-2. Synthesis of 2-(1-(2-fluorophenyl)vinyl)benzen-3-d-amine (INT 23B)

[0342] To a mixture of 3-bromo-2-(1-(2-fluorophenyl)vinyl)aniline INT 23A (2.2 g, 4.6 mmol, 1 eq), bis(1-adamantyl)-butylphosphane (61.0 mg, 170 μmol, 3.70e-2 eq) and K3PO4 (1.53 g, 7.18 mmol, 1.56 eq) in CD3OD (20 mL) and toluene (80 mL) was added Pd(OAc)2 (61.0 mg, 272 μmol, 5.91e-2 eq). The reaction mixture was heated at 50 °C for 15 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (-0-20% ethyl acetate / petroleum ether gradient at 50 mL / min) to afford the product with 78% purity. The material was further purified by prep-HPLC (column: Phenomenex luna C18150x40mmx 15um; A-B mobile phase: [water(FA)-ACN]; gradient: 45%-75% B over 15 min) to afford 2-(1-(2- fluorophenyl)vinyl)benzen-3-d-amine INT 23B (600 mg, 2.38 mmol, 52% yield) that was used without further purification. LCMS (m / z) calculated for C14H11DFN: 214.1; found 215.0 [M+H]+, tR = 0.518 min (Purity Method 1).1H NMR (400 MHz, METHANOL-d4) δ = 7.35 - 7.25 (m, 1H), 7.22 - 7.15 (m, 1H), 7.13 - 7.04 (m, 3H), 6.75 (dd, J = 1.1, 8.0 Hz, 1H), 6.71 - 6.64 (m, 1H), 5.78 (t, J = 1.4 Hz, 1H), 5.54 (t, J = 1.4 Hz, 1H). Step 23-3. Synthesis of 2-(1-(2-fluorophenyl)ethyl)benzen-3-d-amine (INT 23C)

[0343] A mixture of 2-(1-(2-fluorophenyl)vinyl)benzen-3-d-amine INT 23B (600 mg, 2.80 mmol, 1 eq) and Pd / C (100 mg, 10% purity) in MeOH (30 mL) was degassed and purged with H2 3 times, and then the mixture was stirred at 50 °C for 15h under an H2 atmosphere (50 psi). The mixture was filtered and the filtrate was concentrated in vacuo to afford 2-(1-(2- fluorophenyl)ethyl)benzen-3-d-amine INT 23C (540 mg, 2.42 mmol, 86% yield). LCMS (m / z) calculated for C14H13DFN: 216.1; found 217.2 [M+H]+, tR = 0.678 min (Purity Method 2).1H NMR (400 MHz, METHANOL-d4) δ = 7.25 - 6.95 (m, 5H), 6.80 - 6.68 (m, 2H), 4.44 (q, J = 7.0 Hz, 1H), 1.58 (d, J = 7.1 Hz, 3H). Step 23-4. Synthesis of 5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide-6-d (INT 23D)

[0344] To a mixture of 2-(1-(2-fluorophenyl)ethyl)benzen-3-d-amine INT 23C (350 mg, 1.62 mmol, 1 eq) in nitrobenzene (5.3 mL) was added N-(oxomethylene)sulfamoyl chloride (270 mg, 1.91 mmol, 166 μL, 1.18 eq) at 0 °C, and it was stirred for 0.5 h. Then, to the mixture was added AlCl3 (270 mg, 2.02 mmol, 111 μL, 1.25 eq), and it was heated at 80 °C for 4 h. Combined a previous batch to do the work-up. The reaction mixture was slowly poured into 50 mL saturated aqueous NH4Cl solution, then extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. To the residue was added 200 mL petroleum ether and the product precipitated. The precipitate was filtered, washed with petroleum ether and dried under vacuum to afford 5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide-6-d INT 23D (800 mg, 1.49 mmol, 92% yield) that was used without further purification. LCMS (m / z) calculated for C15H12DFN2O3S: 321.1; found 320.1 [M-H], tR = 0.447 min (Purity Method 2 negative mode). Step 23-5. Synthesis of 3-chloro-5-(1-(2-fluorophenyl)ethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide-6-d (INT 23E)

[0345] To a mixture of 5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H-benzo[e][1,2,4]- thiadiazine 1,1-dioxide-6-d INT 23D (400 mg, 747 μmol, 1 eq) and N,N-diethylaniline (170 mg, 1.14 mmol, 182 μL, 1.53 eq) in toluene (10 mL) was added POCl3 (2.29 g, 14.9 mmol, 1.39 mL, 20 eq). The reaction mixture was heated at 110 °C for 15 h. The reaction mixture was slowly quenched by adding 50 mL of aqueous saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient at 40 mL / min) to afford 3-chloro- 5-(1-(2-fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide-6-d INT 23E (200 mg, 512 μmol, 69% yield) that was used without further purification. LCMS (m / z) calculated for C15H11DClFN2O2S: 339.0; found 338.0 [M-H], tR = 0.538 min (Purity Method 2 negative mode).

[0014] Step 23-6. Synthesis of (S)-5-(1-(2-fluorophenyl)ethyl)-3-(((3-fluoropyridin-2- yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide-6-d (23-1)

[0346] To a mixture of 3-chloro-5-(1-(2-fluorophenyl)ethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide-6-d INT 23E (200 mg, 512 μmol, 1 eq) and DIPEA (100 mg, 774 μmol, 135 μL, 1.51 eq) in DMA (10 mL) was added (3- fluoro-2-pyridyl)methanamine (131 mg, 656 μmol, 1.28 eq, 2HCl). The reaction mixture was heated at 120 °C for 15 h. The mixture was added 10 mL water and extracted with ethyl acetate (3 x 15 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: C18 150×30mm; A-B mobile phase: [water(FA)-ACN]; gradient: 42%- 72% B over 7 min) to afford 120 mg racemic. The racemic product was further separated by SFC (column: DAICEL CHIRALCEL OD (250mmx30mm,10um); A-B mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%: 30%, isocratic elution mode) to afford two enantiomers. (S)-5-(1-(2-fluorophenyl)ethyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]- thiadiazine 1,1-dioxide-6-d 23-1 (47.4 mg, 110 μmol, 22% yield). LCMS (m / z) calculated for C21H17DClF2N4O2S: 429.1; found 430.2 [M+H]+, tR = 0.470 min (Purity Method 1). tR = 1.348 min (Chiral Purity Method 1).1H NMR (400 MHz, DMSO-d6) δ = 10.26 (br s, 1H), 8.48 (d, J = 4.6 Hz, 1H), 8.11 (br s, 1H), 7.80 (t, J = 9.3 Hz, 1H), 7.61 - 7.45 (m, 3H), 7.40 - 7.31 (m, 1H), 7.30 - 7.23 (m, 1H), 7.22 - 7.09 (m, 2H), 4.78 - 4.72 (m, 1H), 4.70 (br s, 2H), 1.59 (d, J = 7.0 Hz, 3H) and (R)-5-(1-(2-fluorophenyl)ethyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e]- [1,2,4]thiadiazine 1,1-dioxide-6-d 23-2 (2.6 mg, 1% yield). LCMS (m / z) calculated for C21H17DClF2N4O2S: 429.1; found 430.2 [M+H]+, tR = 0.470 min (Purity Method 1).

[0347] The compounds listed in Table 24 were made using the procedures of Scheme 23. TABLE 24 EXAMPLE 24 Synthesis of Representative Compound 24-1

[0015] Scheme 24 Reagents: (i) (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid, solvent (MeCN); (ii) ClSO2NCO, solvent (nitrobenzene) then AlCl3; (vi) N,N-diethylaniline, solvent (POCl3); (vii) Base (DIPEA), solvent (DMA) Step 24-1. Synthesis of (R)-3-fluoro-2-(1-(2-fluorophenyl)ethyl)aniline (INT 24A)

[0348] To a solution of 3-fluoro-2-[1-(2-fluorophenyl)ethyl]aniline INT 7C (7.2 g, 27.2 mmol, 1 eq) in MeCN (100 mL) was added (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid (4.73 g, 12.3 mmol, 0.45 eq). The mixture was stirred at 25 °C for 1 h. The mixture was then heated to 70 °C and stirred for 1 h. The mixture was cooled to 25 °C and stirred at 25 °C for 15 h. The reaction mixture was filtered and the solid was dried under reduced pressure. To the collected solid was added water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (R)-3-fluoro- 2-(1-(2-fluorophenyl)ethyl)aniline INT 24A (1.5 g, 6.43 mmol, 24% yield). The filtrate was concentrated under reduced pressure to give a residue. To the residue was added water (30 mL) and the aqueous was extracted with ethyl acetate (2 x 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 4.5 g of crude (INT 24A). To a solution of crude INT 24A (4.5 g, 17.3 mmol, 1 eq) in MeCN (63 mL) was added (2R,3R)- 2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid (2.00 g, 5.18 mmol, 0.3 eq). The mixture was stirred at 25 °C for 1 h. The mixture was then heated to 70 °C and stirred for 1 h. The mixture was cooled to 25 °C and stirred at 25 °C for 15 h. The reaction mixture was filtered and the solid was dried under vacuum. To the collected solid was added water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford additional (R)-3-fluoro-2-(1-(2-fluorophenyl)ethyl)aniline INT 24A (1.4 g, 5.97 mmol, 35% yield). LCMS (m / z) calculated for C14H13F2N: 233.1; found 234.1 [M+H]+, tR = 0.556 min (Purity Method 1); 99.2% ee, tR = 1.457 min (Chiral Purity Method 1). Step 24-2. Synthesis of (R)-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (INT 24B)

[0349] To a solution of (R)-3-fluoro-2-(1-(2-fluorophenyl)ethyl)aniline INT 24A (1.4 g, 6.00 mmol, 1 eq) in nitrobenzene (20 mL), was added N-(oxomethylene)sulfamoyl chloride (1.27 g, 9.00 mmol, 782 μL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, AlCl3 (1.00 g, 7.50 mmol, 410 μL, 1.25 eq) was added. The mixture was stirred at 80 °C for 1.5 h. The reaction solution was cooled to room temperature and then diluted with aqueous saturated NH4Cl solution (60 mL). The aqueous phase was extracted with ethyl acetate (3 x 60 mL). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The obtained brown oil was diluted with petroleum ether (200 mL) and then stirred for 30 min. The brown oil eventually formed a brown precipitate that was collected by vacuum filtration. The filter cake was washed with petroleum ether (200 mL) and then dried under vacuum to give a brown solid that was triturated in toluene (10 mL) and collected by filtration to afford (R)-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide INT 24B (4 g, crude) that was used without further purification. LCMS (m / z) calculated for C15H12F2N2O3S: 338.1; found 337.0 [M-H], tR = 0.445 min (Purity Method 2 negative mode) Step 24-3. Synthesis of (R)-3-chloro-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-4H-

[0350] To a solution of POCl3 (18.0 g, 117 mmol, 10.9 mL, 15 eq) in toluene (50 mL), was added (R)-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide INT 24B (4 g, crude) N,N-diethylaniline (1.75 g, 11.7 mmol, 1.87 mL, 1.5 eq) . The mixture was stirred at 110 °C for 16 h. The reaction mixture was poured into water (100 mL) portionwise while the temperature was kept below 35 °C. The obtained mixture was stirred for 1 hr. The aqueous layer was extracted with EtOAc (3 x 70 mL). The combined organics were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient at 80 mL / min) to afford (R)-3-chloro-6-fluoro-5-(1-(2- fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 24C (1.2 g, 3.30 mmol, 42% yield). LCMS (m / z) calculated for C15H11ClF2N2O2S: 356.0; found 355.0 [M-H], tR = 0.553 min (Purity Method 2 negative mode).

[0016] Step 24-4. Synthesis of (R)-6-fluoro-3-((2-fluorobenzyl)amino)-5-(1-(2- fluorophenyl)ethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (24-1)

[0351] To a solution of (R)-3-chloro-6-fluoro-5-(1-(2-fluorophenyl)ethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide INT 24C (70 mg, 161 μmol, 1 eq) , (2- fluorophenyl)methanamine (30.2 mg, 241 μmol, 28 μL, 1.5 eq) in DMA (1.5 mL) was added DIPEA (85.2 mg, 659 μmol, 115 μL, 4.10 eq). The mixture was heated at 120 °C for 14h. The crude mixture was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18150x25mmx 10um; A-B mobile phase: [water(FA)-ACN]; gradient: 45%-75% B over 1 min) to afford (R)-6-fluoro-3-((2-fluorobenzyl)amino)-5-(1-(2-fluorophenyl)ethyl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide 24-1 (26.4 mg, 58.9 μmol, 37% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.26 (br s, 1H), 7.71 (br s, 1H), 7.64 (br dd, J = 5.5, 8.5 Hz, 1H), 7.55 (br t, J = 7.8 Hz, 1H), 7.46 (br t, J = 7.4 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.35 - 7.21 (m, 4H), 7.16 - 7.06 (m, 1H), 7.00 (br dd, J = 9.1, 10.7 Hz, 1H), 4.74 - 4.42 (m, 3H), 1.69 (br d, J = 6.9 Hz, 3H). LCMS (m / z) calculated for C22H18F3N3O2S: 445.1; found 446.1 [M+H]+, tR = 0.538 min (Purity Method 1); 100% ee, tR = 1.221 min (Chiral Purity Method 2).

[0352] The compounds listed in Table 25 were made using the procedures of Scheme 24. TABLE 25 EXAMPLE 25 MRGPRX2 Activity

[0353] CHO cells stably transfected to express human MRGPRX2 were maintained in an incubator at 37° C with 5% CO2 and grown in F12 (HAM) media with 10% fetal bovine serum (FBS), 1% Glutamax, 1% penicillin / streptomycin, 800 µg / mL Geneticin (G418), and 300 µg / mL Hygromycin B.

[0354] Cells were plated in a 384-well assay plate at 20,000 cells per well in 12 µL of Opti- MEM and kept in an incubator overnight. On the day of the assay, compounds solubilized at 10 mM in DMSO were added as a 10-point curve (30 uM final top concentration with 1:3 serial dilutions) using a Tecan D300E digital dispenser. Agonists were diluted in assay buffer (final concentrations of 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH= 8) and 2 µL of the agonist Cortistatin-14 (CPC Scientific, catalog CORT-002) are added to each well. Final concentrations of agonists were 0.3 µM Cortistatin. Final concentrations of DMSO were kept consistent across the plate. Plates were incubated in the dark for 1 h at 37 °C and then for 1 h at room temperature. IP-1 standards and HTRF detection reagents were added according to the IP-One – Gq Kit purchased from Cisbio (part number 62IPAPEJ) and incubated in the dark for 1 h at room temperature. The plate was read on a Molecular Devices SpectraMax iD5 plate reader. The HTRF ratio was calculated from the raw data and graphed using GraphPad Prism to calculate an IC50 value for each compound.

[0355] Activity data for selected MRGPRX2 antagonists (versus 0.3 uM Cortistatin-14 agonist) are displayed in Table 26. The activity ranges are denoted as follows: “+++++” denotes antagonist activity <100 nM; “++++” denotes antagonist activity between 100 and 500 nM; “+++” denotes activity between 501 and 1000 nM; “++” denotes activity between 1001 and 2500 nM; and “+” denotes activity >2500 nM. TABLE 26 EXAMPLE 26 Mast cell beta-hexosaminidase release assay

[0356] Human LAD2 cells (NIH) were maintained in an incubator at 37°C with 5% CO2 and cultured in StemPro-34 serum-free media (Gibco 10639011) supplemented with 2 mM L- glutamine, 100 U / ml penicillin, 50 mg / ml streptomycin and 100 ng / ml SCF (Invitrogen PEP0860), at a concentration of 2-5 x 105cells / mL, with hemidepletion every 1-2 weeks.

[0357] Cells were transferred to SCF-Free medium at 2.5 x 105cells / mL and kept in an incubator overnight. On the day of the assay, cells were washed twice in Assay Buffer (final concentrations 10 mM HEPES, 137 mM NaCl, 5.6 mM D-glucose, 2.7 mM KCl, 1 mM MgCl, 1.8 mM CalCl2, 0.4 mM Na2HPO4.7H2O, 0.04% BSA, pH = 7.4) and plated in a 96-well v-bottom plate at 20,000 cells per well in 80 µL Assay Buffer. Antagonist compounds solubilized at 10 mM in DMSO were diluted in Assay Buffer to 10X final desired concentrations as a 10-point curve (10 µM final top concentration with 1:3 serial dilutions) and 10 µL added per well. Plates were then incubated for 1 hour at 37°C. Agonists were diluted in Assay Buffer to 10X desired concentrations and 10 µL of the appropriate agonist added to each well. The final concentration of Cortistatin-14 (Tocris 3374) used in antagonist assays was 500 nM. Final concentrations of DMSO were kept consistent across the plate. Plates were then incubated in a warm air oven for 30 minutes at 37°C, followed by centrifugation at 4°C for 5 minutes at 450 x g. 50 µL supernatant from each well was then transferred to a 96-well flat bottom plate containing 100 µL substrate solution per well (3.5 mg / mL p-Nitrophenyl-N-acetyl-β-D-glucosaminide (Sigma 487052) in Citrate Buffer containing a final concentration of 40 mM Citric Acid, 20 mM Na2HPO4.7H2O, pH = 4.5). To the cell pellets left in the remaining assay buffer, 150 µL 0.1% Triton-X-100 was then added to each well, resuspended by pipetting up and down, and 50 µL cell lysates transferred to a second 96-well flat bottom plate containing 100 µL substrate solution per well. Plates containing transferred supernatant and cell lysates were then incubated in a warm air oven for 90 minutes at 37°C. After incubation, 50 µL of 400 mM Glycine buffer (pH 10.7) was added into each well and the plate was read on a Molecular Devices SpectraMax iD5 plate reader (absorbance at 405 nm with reference filter at 620 nm). After background subtraction, the percentage degranulation (percent beta- hexosaminidase release) was calculated as 100 x (supernatant values) / (supernatant + lysate values), followed by analysis using GraphPad Prism software to calculate an IC50 value for each compound.

[0358] Activity data for selected MRGPRX2 antagonists in the Mast Cell Beta- Hexosaminidase Release Assay are displayed in Table 27. The activity ranges are denoted as follows: “+++++” denotes antagonist activity <100 nM; “++++” denotes antagonist activity between 100 and 500 nM; “+++” denotes activity between 501 and 1000 nM; “++” denotes activity between 1001 and 2500 nM; and “+” denotes activity >2500 nM. TABLE 27 EXAMPLE 27 Mouse Pharmacokinetic Studies

[0359] Compounds were formulated in 5% DMSO, 5% Solutol, and 90% PBS without Ca and Mg (pH 7.4) at a concentration of 0.5 mg / mL. Male C57BL / 6 mice (n=6 / compound) were administered a 50 mg / kg dose of each compound by oral gavage under a non-fasted condition. Blood samples were collected via the Submandibular vein onto K2-EDTA at 0.5, 1, 2, 4, 8 and 24 hours after dosing, and plasma was prepared and stored at -80°C until analysis. Plasma sample preparation for analysis was done by protein precipitation using acetonitrile (including Verapamil as an internal standard) followed by centrifugation. Compound concentrations were determined in extracted plasma using LC-MS / MS relative to a 12-point standard curve covering the 1 to 4000 nM range. Non-compartmental analysis using Phoenix WinNonlin was used to estimate pharmacokinetic parameters including area under the curve, clearance, and half-life. The administered dose was confirmed by analysis of residual dosing material by UPLC-UV relative to a single point calibration sample. The results of these studies are presented in Table 28. TABLE 28 EXAMPLE 28 Solubility Studies

[0360] Media according to Biorelevant Media protocols was prepared.10 μL of 10 mM in DMSO stock solutions of test compounds was added to 96-well deep plate. 490 μL of FaSSIF, FeSSIF, or FaSSGF was then added into appropriate wells of 96-well deep plate. The plate was vortexed for 2 minutes then placed on a plate shaker for 24 hours at room temperature. The plate was centrifuged for 20 minutes, then supernatant was collected and filtered with 450micron syringe filter into UPLC vials for injection into UPLC-UV system. Concentration was calculated with a 3- point standard curve. Results are shown in Table 29. TABLE 29 EXAMPLE 29 MRGPRX2 FLIPR Calcium Mobilization Assay

[0361] Chinese hamster ovary (CHO-K1) cells stably expressing human MRGPRX2 are purchased from Genescript (Piscataway, NJ). The cells are maintained in culture medium (Ham's F-12K) containing 10% (v / v) FBS, 200 µg / mL Zeocin, 100 units / mL penicillin G and 100 µg / mL streptomycin (Life Technologies, Carlsbad, CA). For the assay, the cells are harvested and resuspended with culture medium without Zeocin before plating at 8000 cells per well in 20 µL in 384-well black clear bottom cell culture plates (VWR, Radnor, PA). After 24 hour culture at 37 °C and 5% CO2, the cells are loaded with 20 µL / well of calcium dye (FLIPR Calcium 6 Assay Kit, Molecular Devices, San Jose, CA) diluted in loading buffer (1× Hank's Balanced Salt Solution (HBSS), 5  mM probenecid, 20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4, VWR, Radnor, PA) followed with 45 min. incubation at 37 °C and 40 min. at r.t. in the dark. Cells are then treated with the addition of 10uL / well test compounds with a range of increasing concentrations diluted in the assay buffer (1× HBSS, 20 mM HEPES, pH 7.4, VWR, Radnor, PA) with FLIPR Penta (Molecular Devices. San Jose, CA) and incubated for 30 min. at r.t. Ca2+release was measured with FLIPR Penta with 10 seconds basal fluorescence measurement, then 12.5 µL of 5× agonist Cortistatin-14 (Tocris, Minneapolis, MN) at final concentration corresponding to the EC80 are added followed with continued fluorescence signal monitoring for an additional 110 seconds. The base line adjusted (median of first 10s base line) max value of the Relative Fluorescence Unit (RFU) is plotted against compound concentrations. Wells with no compound serve as the positive controls, and wells with high concentration of reference antagonist are used as negative controls. IC50 curves are globally fitted with 3- or 4-parameter Hill equation in a Genedata Screener (Genedata Basel, Switzerland). EXAMPLE 30 MRGPRX2 IP1 HTRF Assay

[0362] This assay measures compound inhibition of myo-Inositol 1 phosphate (IP1) accumulation in CHO-K1 cells. Chinese hamster ovary (CHO-K1) cells stably expressing human MRGPRX2 are purchased from GenScript (Piscataway, NJ).

[0363] For the HTRF IP1 determination, an IP-One GqKit (Perkin Elmer Cisbio, Waltham, MA), which includes all reagents and buffers in this protocol, are used. The cells are maintained in culture medium (Ham's F-12K) containing 10% (v / v) FBS, and 200 µg / mL Zeocin. For the assay, the cells are harvested and resuspended in culture medium with 2% FBS and without Zeocin, then passed through a 40 µm filter. Cells are added at 20000 cells in a 5 µL / well to a 384-well white small volume cell culture plate (Greiner VWR, Radnor, PA) which contains 50 nL / well of test compound serially diluted at a selected concentration range in DMSO. 5 µL / well of prepared 2× Stimulation Buffer2 is then added to plates and incubated at 37 °C with 5% CO2 for 1 h.5 µL / well of agonist Cortistatin 14 (Bio-TechneR&D Systems, Minneapolis, MN) in 1× Stimulation Buffer 2, for a 1 µM final concentration, is then added to plates and incubated at 37 °C with 5% CO2 for 1 h.6 µL / well of 1:20 diluted Detection Reagent Mix (d2 and Cryptate) is added to the plates and incubated for 1 h in the dark. Plates are read on the PHERAstar microplate reader (BMG Labtech Cary, NC) to determine the HTRF ratio of the acceptor and donor emission signals. The IP1 concentrations are calculated from a standard curve following the IP-One GQ kit instructions. Wells with DMSO only and wells with high concentration of reference antagonist are used as controls for normalization. Compound IC50 curves are globally fitted with 3- or 4-parameter Hill equation in a Genedata Screener (Genedata Basel, Switzerland). EXAMPLE 31 MRGPRX2 β-Arrestin Assay

[0364] This assay measures compound inhibition of β-Arrestin recruitment, which is part of the G protein-independent pathway that results from the ligand-activated GPCR phosphorylation by specific GPCR kinases. The PathHunter CHO-K1 MRPGRX2 B-Arrestin Cell line stably expressing ProLink tagged MRGPRX2 and Enzyme Acceptor Tagged B-Arrestin are purchased from Eurofins DiscoverX, (Fremont, CA).

[0365] The cells are maintained in culture medium from the Europhins DiscoverX Cell Culture Kit-107 which includes FBS, hygromycin B and G418. For the assay, the cells are harvested and were resuspended with Cell Plating Reagent 2 (Eurofins DiscoverX). Cells are added 10000 cells in 25 µL / well to a 384-well black cell culture plate (Greiner VWR, Radnor, PA) which contained 125 nL / well of compound at a selected serially diluted concentration range or DMSO. The plate is incubated at 37 °C with 5% CO2 for 1 h.2 µL / well of agonist Cortistatin 14 is diluted in Protein Dilution Buffer, (Eurofins DiscoverX) for a final concentration of 0.25 µM, is added and the plate incubated at 37 °C with 5% CO2 for 90 min. 14 µL / well of Detection Reagent Mix (PathHunter Detection Kit, Eurofins DiscoverX) is added to the plates and further incubated for 1 h in the dark. Plates are read on the PHERAstar microplate reader (BMG Labtech Cary, NC) measuring luminescence 0.1 to 1 second per well. Data is normalized using DMSO only wells and wells with high concentration of reference antagonist as controls. Compound IC50 curves are globally fitted with 3- or 4-parameter Hill equation in a Genedata Screener (Genedata Basel, Switzerland). EXAMPLE 32 Caco2 Assay

[0366] Caco-2 cells are grown at 37 °C in an atmosphere of 5% CO2 in DMEM growth medium supplemented with 10% (v / v) fetal bovine serum, 1% (v / v) nonessential amino acids, penicillin (100 U / *mL), and streptomycin (100 µg / *mL). Confluent cell monolayers are subcultured every 7 days or 4 days for Caco-2 by treatment with 0.05% trypsin containing 1 µM EDTA. Caco-2 cells are seeded in 96-well Transwell plates. The seeding density for Caco-2 cells is 14,000 cells / well. DMEM growth medium is replaced every other day after seeding. Cell monolayers are used for transport assays between 22 and 25 days for Caco-2 cells.

[0367] Cell culture medium is removed and replaced with HBSS. To measure the TEER, the HBSS is added into the donor compartment (apical side) and receiver compartment (basolateral side). The TEER is measured by using a REMS Autosampler to ensure the integrity of the cell monolayers. Caco-2 cell monolayers with TEER values ≥ 300 ^⋅cm2are used for transport experiments. To determine the Papp in the absorptive direction (A-B), solution of test compound (50 μM) in HBSS is added to the donor compartment (apical side), while HBSS solution with 4% BSA is added to the receiver compartment (basolateral side). The apical volume was 0.075 mL, and the basolateral volume is 0.25 mL. The incubation period is 120 min. at 37°C in an atmosphere of 5% CO2. At the end of the incubation period, samples from the donor and receiver sides are removed and an equal volume of MeCN is added for protein precipitation. The supernatants are collected after centrifugation (3000 rpm, Allegra X-14R Centrifuge from Beckman Coulter, Indianapolis, IN) for LCMS analysis. The permeability value is determined according to the equation: Papp (cm / s)=(F * VD) / (SA * MD), where the flux rate (F, mass / time) is calculated from the slope of cumulative amounts of compound of interest on the receiver side, SA is the surface area of the cell membrane, VD is the donor volume, and MD is the initial amount of the solution in the donor chamber. EXAMPLE 33 Human Whole Blood Stability

[0368] The whole blood stability of the exemplified compounds is determined by LC- MS / MS. The 96-Well Flexi-Tier™ Block (Analytical Sales & Services, Inc, Flanders, NJ) is used for the incubation plate containing 1.0 mL glass vials with 0.5 mL of blood per vial (pooled gender, human whole blood sourced from BIOIVT, Hicksville, NY or similar). Blood is pre-warmed in water bath to 37 °C for 30 min.96-deep well analysis plate is prepared with the addition of 100 µL ultrapure water / well.50 µL chilled ultrapure water / well is added to 96-deep well sample collection plate and covered with a sealing mat.1 µL of 0.5 mM compound working solution (DMSO:water) is added to the blood in incubation plate to reach final concentrations of 1 µM, mixed by pipetting thoroughly and 50 µL is transferred 50 into the T=0 wells of the sample collection plate. Blood is allowed to sit in the water for 2 min. and then 400 µL stop solution / well is added (MeCN containing an internal standard). The incubation plate is placed in the Incu-Shaker CO2 Mini incubator (Benchmark Scientific, Sayreville, NJ) at 37 °C with shaking at 150 rpm. At 1, 2 and 4-h, the blood samples are mixed thoroughly by pipetting and 50 µL is transferred into the corresponding wells of the sample collection plate. Blood is allowed to sit in the water for 2 min. and then 400 µL of stop solution / well is added. The collection plate is sealed and vortexed at 1700 rpm for 3 min. (VX- 2500 Multi-Tube Vortexer, VWR International, Radnor, PA), and samples are then centrifuged in the collection plate at 3500 rpm for 10 min. (Allegra X-14R Centrifuge Beckman Coulter, Indianapolis, IN). 100 µL of supernatant / well is transferred from the sample collection plate into the corresponding wells of the analysis plate. The final plate is vortexed at 1700 rpm for 1 min. and analyze samples by LC-MS / MS. The peak area ratio of the 1, 2, and 4 h samples relative to T=0 is used to determine the percent remaining. The natural log of the percent remaining versus time is used determine a slope to calculate the compounds half-life in blood (t1 / 2=0.693 / slope). EXAMPLE 34 In Vitro Intrinsic Clearance Protocol

[0369] For in vitro metabolic stability experiments, test compounds are incubated with human liver microsomes at 37 °C. The incubation mixture contains test compounds (1 μM), NADPH (2 mM), and human liver microsomes (0.5 mg protein / *mL) in 100 mM phosphate buffer (pH 7.4). The mixture is pre-incubated for 2 min. at 37 °C before the addition of NADPH. Reactions are commenced upon the addition of NADPH and quenched with ice-cold MeOH at 0, 10, 20, and 30 min. Terminated incubation mixtures are analyzed using LC-MS / MS system. The analytical system consisted of a Shimadzu LC-30AD binary pump system and SIL-30AC autosampler (Shimadzu Scientific Instruments, Columbia, MD) coupled with a Sciex Triple Quad 6500+ mass spectrometer from Applied Biosystems (Foster City, CA). Chromatographic separation of test compounds and internal standard is achieved using a Hypersil Gold C18 column (50×2.1 mm, 5 µM, 175 Å) from ThermoFisher Scientific (Waltham, MA). Mobile phase A consists of 0.1% formic acid in water, and mobile phase B consists of 0.1% formic acid in MeCN. The total LC-MS / MS runtime can be 2.75 min. with a flow rate of 0.75 mL / min. Peak area integrations and peak area ratio calculations are performed using Analyst software (version 1.6.3) from Applied Biosystems.

[0370] The in vitro intrinsic clearance, CLint, in vitro, is calculated from the t1 / 2 of test compound disappearance as CLint, in vitro=(0.693 / t1 / 2)×(1 / Cprotein), where Cprotein is the protein concentration during the incubation, and t1 / 2 is determined by the slope (k) of the log–linear regression analysis of the concentration versus time profiles; thus, t1 / 2=ln2 / k. The CLint, in vitro values are scaled to the in vivo values for human by using physiologically based scaling factors, hepatic microsomal protein concentrations (45 mg protein / g liver), and liver weights (21 g / kg body weight). The equation CLint=CLint, in vitro× (*mg protein / g liver weight)×(g liver weight / kg body weight) is used. The in vivo hepatic clearance (CLH) is then calculated by using CLint and hepatic blood flow, Q (20 mL·min.−1·kg−1in humans) in the well-stirred liver model disregarding all binding from CLH=(Q×CLint) / (Q+CLint). The hepatic extraction ratio is calculated as CLH divided by Q. EXAMPLE 35 In Vivo Pharmacokinetics Protocol

[0371] For in vivo pharmacokinetic experiments, test compounds are administered to male Sprague Dawley rats or male and female Cynomolgus monkeys intravenously or via oral gavage. For intravenous (IV) dosing, test compounds are dosed at 0.5 to 1 mg / kg using a formulation of 10% dimethylacetamide (DMAC) in acidified saline via IV bolus for rat and 5 min. or 10 min. IV infusion for monkey. For oral (PO) dosing, test compounds are dosed at 1.0 to 3.0 mg / kg using 5% DMAC in 0.5% methylcellulose in citrate buffer (pH 2.5). Blood samples are collected at predose and various time points up to 24 h postdose. All blood samples are collected using EDTA as the anticoagulant and centrifuged to obtain plasma samples. The plasma concentrations of test compounds are determined by LC-MS methods. The measured plasma concentrations are used to calculate PK parameters by standard noncompartmental methods using Phoenix®WinNonlin software program (version 8.0, Pharsight Corporation).

[0372] In rats and monkeys, cassette dosing of test compounds are conducted to obtain preliminary PK parameters.

[0373] In vivo pharmacokinetic experiments with male beagle dogs may be performed under the conditions described above. EXAMPLE 36 Time Dependent Inhibition (TDI) of CYP Protocol

[0374] This assay is designed to characterize an increase in CYP inhibition as a test compound is metabolized over time. Potential mechanisms for this include the formation of a tight- binding, quasi-irreversible inhibitory metabolite complex or the inactivation of P450 enzymes by covalent adduct formation of metabolites. While this experiment employs a 10-fold dilution to diminish metabolite concentrations and therefore effects of reversible inhibition, it is possible (but not common) that a metabolite that is an extremely potent CYP inhibitor could result in a positive result.

[0375] The results are from a cocktail of CYP specific probe substrates at 4 times their Km concentrations for CYP2C9, 2C19, 2D6 and 3A4 (midazolam) using human liver microsomes (HLM). The HLMs can be pre-incubated with test compounds at a concentration 10 µM for 30 min. in the presence (+N) or absence ( -N) of a NADPH regenerating system, diluted 10-fold, and incubated for 8 min. in the presence of the substrate cocktail with the addition of a fresh aliquot of NADPH regenerating system. A calibration curve of metabolite standards can be used to quantitatively measure the enzyme activity using LC-MS / MS. In addition, incubations with known time dependent inhibitors, tienilic aicd (CYP2C9), ticlopidine (CYP2C19), paroxetine (CYP2D6), and troleandomycin (CYP3A4), used as positive controls are pre-incubated 30 min. with or without a NADPH regenerating system.

[0376] The analytical system consists of a Shimadzu LC-30AD binary pump system and SIL-30AC autosampler (Shimadzu Scientific Instruments, Columbia, MD) coupled with a Sciex Triple Quad 6500+ mass spectrometer from Applied Biosystems (Foster City, CA). Chromatographic separation of test compounds and internal standard can be achieved using an ACQUITY UPLC BEH 130A, 2.1 × 50 mm, 1.7 μm HPLC column (Waters Corp, Milford, MA). Mobile phase A consists of 0.1% formic acid in water, and mobile phase B consists of 0.1% formic acid in MeCN. The total LC-MS / MS runtime will be 2.50 min. with a flow rate of 0.9 mL / min. Peak area integrations and peak area ratio calculations are performed using Analyst software (version 1.6.3) from Applied Biosystems.

[0377] The percentage of control CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activity remaining following preincubation of the compounds with NADPH is corrected for the corresponding control vehicle activity and then calculated based on 0 min. as 100%. A linear regression plot of the natural log of % activity remaining versus time for each isozyme is used to calculate the slope. The –slope is equal to the rate of enzyme loss, or the Kobs. EXAMPLE 37 In vitro Degranulation Assay - β-Hexosaminidase Release Assay

[0378] The assay is performed essentially as described by Hermans, et al., Front. Immunol., 2021, 12, 625284. Mature mast cells are cultured in StemPro-34 medium with StemPro-34 nutrient supplement (Gibco), 2 mM L-glutamine (Gibco), 100 U / mL penicillin / 100 µg / mL streptomycin (Gibco), 100 ng / mL recombinant human stem cell factor (PeproTech) and 100 ng / mL recombinant human interleukin 6 (Peprotech). The cells are washed in HEPES-buffered Tyrode’s solution (Thermo Fisher) containing 0.1% (w / v) bovine serum albumine (further called “releasingmedium”) and seeded at 1×105 cells per well in 96-well plate in the releasing medium. Selectedwells are pretreated with predefined concentrations of MRGPRX2 antagonist for 1 h at 37 °C with 5% CO2. Then, about 10 µg / mL compound 48 / 80 (poly-p-methoxyphenethylmethylamine) or about 30 µM of substance P is added to treated wells and equal amount of releasing medium is added into negative control wells. Following 1 h incubation, the plate is centrifuged for 5 min. and 50 µL of supernatant is collected into a new 96-well plate. In a positive control group, remaining supernatant is removed and 100 µL 0.1% Triton X-100 (v / v) is added to lyse the cell at 300 g for 5 min. After that, the plate is centrifuged and 50 µL of the lysate is also transferred into the new plate. Supernatant and lysate samples are then incubated with 50 µL of p-nitrophenyl N-acetyle-B-D- glucosaminide in 0.1 M citrate buffer pH 4-4.5 (Thermo Fisher) for 1 h at 37 °C. The enzymatic reaction is stopped by the addition of 100 µL / well of 0.1 M Na2CO3 buffer pH 10 (Thermo Fisher). The absorbance is read at 405 nm. Net β-hexosaminidase release (%) is calculated as = [(stimulated release–spontaneous release) / total content in lysed cells] × 100. EXAMPLE 38 Evaluation of the MRGPRX2 Antagonist Effects on in vitro-Derived Human Mast Cells

[0379] This assay evaluates the effects of example compound on preventing mast cell degranulation via the MRGPRX2 receptor. The effects of example compounds on mast cell degranulation induced by Substance P (MRGPRX2 pathway), or IgE / anti-IgE is investigated by measuring β-hexosaminidase and mast cell specific cytokine / chemokine release into the culture media. The addition of IgE / anti-IgE serves as a differentiation for the mechanism of action of the test compound.

[0380] Mature connective tissue-type mast cells (CTMCs) are plated at 50,000 cells by well in 50 µL and stimulated as follows. IgE Sensitization (Day 0)

[0381] All CTMCs are pre-treated with 100 µM IgE before treatment to coat the Fc ^R1 receptors with IgE to resemble in vitro mast cells. In this study, CTMCs are sensitized 48 h prior to pre-treatment with example compounds and degranulation (Day 2). Pre-treatment (Day 0)

[0382] Omalizumab is added 4 h after IgE sensitization (IgE containing media is removed after 4 h and replaced with culture media containing omalizumab and kept for 48 h) and for the following 48 h before degranulation induction. Pre-treatment (Day 2)

[0383] Test compounds and vehicles are added 48 h post IgE sensitization / omalizumab treatment for 30 min. at Day 2 of culture. Degranulation (Day 2 + 30 mins)

[0384] The CTMCs are stimulated with Substance P, Compound 48 / 80, anti-IgE, or Tyrode’s buffer on Day 2 of culture. β-Hexosaminidase Assay to Assess Mast-Cell Degranulation

[0385] For the β-hexosaminidase assay, 50 µL of cell supernatant is collected in each well 45 min. after degranulation treatment. Supernatant is collected on n=3 wells per condition. β- Hexosaminidase is a potent inflammatory mediator stored in mast cells and is released by activated mast cells. The determination of β-hexosaminidase is used to evaluate the level of mast cell degranulation. The assay is a colorimetric assay measuring the 4-nitrophenol production using a multimode plate reader. See J. Karhausen, et al., J. Clin. Invest., 2016, 126(10), 3981-98. Cytokine Release Assay

[0386] For the cytokine release assay, 60 µL of cell supernatant is collected in each well 8 h after degranulation treatment, an anti-protease cocktail added, and frozen at −80 °C until used. Supernatant is collected on n=3 wells per condition. Cytokine release into the culture medium is measured using a custom V-PLEX Plus Human Cytokine Kit (MesoScale Discovery): TNF-α, IL- 13, GM-CSF, VEGF-A, MCP-1, IL-6, IL-4, IL-5, IL-10, and IL-8. Culture media is diluted as follows: Plate 1: Chemokine Panel 1 (human) kit–ref K15047 (panel MCP-1)–1:10; Plate 2: Proinflammatory Panel 1 (human) kit–ref K15049 (panel IL-4, IL-6, IL-8, IL-10, IL-13, TNF-α)–1:5; Plate 3: Cytokine Panel 1 (human) kit–ref K15050 (panel GM-CSF, IL-5, VEGF)–1:5. EXAMPLE 39 Determining the Effect of Example Compounds on Cytokine / Chemokine Release from HypoSkin Models After Subcutaneous Injection of Cetrorelix or Cortistatin-14

[0387] This assay evaluates the effect of the test compounds on cytokine / chemokine release (potentially from mast cells) upon systematic pre-treatment and treatment of HypoSkin models prior to subcutaneous injection of drugs known to degranulate mast cells and cause injection site reactions (namely, Cortistatin-14 and Cetrorelix).

[0388] 74 HypoSkin models of 20 mm in diameter and 10 mm total thickness with 15 / 20 mm diameter silicon rings are produced from 2 donors (37 models per donor) according to standard procedures and cultured with 2 mL standard HypoSkin medium. Models are maintained in standard cell culture conditions for the whole culture duration at 37 °C, 5% CO2 and water saturation, with culture medium renewed every day except during weekends. Systematic Treatment

[0389] Vehicle control and test compounds are added to the culture media daily, from Day 0 to Day 2. The compounds remain in the culture media upon subcutaneous injections. Subcutaneous Injection

[0390] 100 µL of Cetrorelix, Cortistatin-14, or PBS are subcutaneously injected in to the models on Day 2. End of Culture and Sampling

[0391] Culture media is collected on Days 2 + 8 h and Day 3 (24 h post-injection) and frozen at −80 °C. Sampling of HypoSkin models is performed on Day 0 and Day 3 (24 h post- injection) and processed as follows:

[0392] 1 / 2 are fixed in 10% buffered formalin and processed for paraffin wax embedding; and

[0393] 1 / 2 are snap frozen and stored at −80 °C. Hematoxylin and Eosin staining

[0394] Hematoxylin and Eosin staining is performed on one 5 µm thick skin cross section for each sample. Representative images of both the epidermis / dermis and hypodermis are taken at 40× magnification to analyze skin structure integrity and viability. MSD Immunoassay

[0395] Cytokine release in the culture medium is measuring using the V-PLEX Plus Human Cytokine 36-Plex Kit (K15089G, MesoScale Discovery): Eotaxin, Eotaxin-3, GM-CSF, IFN-γ, IL- 1α, IL-1β, Il-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL12 / IL-23p40, IL-23p70, IL-13, IL-15, IL-16, IL-17α, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, MIP-3α, TARC, TNF-α, TNF-β, and VEGF-A. EXAMPLE 40 Characterization of JAK inhibitors MRGPRX2 antagonists on mast cell activation

[0396] The effect of the janus kinase inhibitors Povorcitinib, Ruxolitinib, and MRGPRX2 antagonists disclosed herein on the activation of mast cells in vitro is compared and characterized under different activating conditions, mimicking the in vivo disease situation. This assay determines the effect of JAK inhibition and MRGPRX2 antagonism on interference different mast cell activation pathways; the effect of JAK inhibition and MRGPRX2 antagonism in mast cells to prevent the release of mediators involved in the activation of primary human blood eosinophils and T cells.

[0397] Primary human skin mast cells (hsMC) are used to study how Povorcitinib, Ruxolitinib, and MRGPRX2 antagonists interfere with different prototype mast cell activators. The cells are obtained from individuals undergoing circumcision or breast reduction surgery by isolation from skin explants in a multi-step protocol. In vitro dose response studies using different concentration of the compounds to identify IC50 values are conducted. For these studies, hsMCs are pre-incubated in the presence or absence of the compounds for 20 min., followed by stimulation with anti-IgE (Fc ^RI stimulation) or cortistatin-14 (MRGPRX2 agonist). Degranulation responses are measured by determination of β-hexosaminidase after 1 h at 37 °C.

[0398] Next, three different concentrations of the compounds according to the determined IC50 are employed to assess the spectrum of mast cell activating pathways inhibited by each compound. Therefore, hsMCs are pre-incubated in the presence or absence of the individual compounds for 20 min., followed by stimulation with five distinct activators: anti-IgE, corstatin- 14 (CST), stem cell factor (SCF), complement peptides C3a, and C5a. In a parallel setup, hsMCs are pre-treated with various concentrations of cyclosporine A (CSA), to assess difference in efficacy to the test compounds. CSA, inhibiting the translocation of the transcription factor NFAT into the nucleus in MCs and other immune cells, is widely used to treat urticaria. As an alternative to CSA, another JAK or BTK inhibitor can be used. Degranulation responses are measured by determination of the β-hexosaminidase after 1 h at 37 °C. In addition, cell viability and surface expression of Fc ^RI, MRGPRX2, cKitm C3aR / C5aR are measured by flow cytometry. Mast cells from three individual mast cell preparations are used.

[0399] To assess if treatment of mast cells with Povorcitinib, Ruxolitinib, or MRGPRX2 antagonists alters their mediator release profile and thereby their ability to activate eosinophils or T cells, hsMCs are pre-treated with the compounds for 20 min., followed by stimulation with anti- IgE, CST, SCF, C3a, or C5a for 1 h, 4 h, 8 h, and 24 h. Culture supernatants are collected and added to freshly isolated human peripheral blood eosinophils and total T cells. To achieve complete T cell activation, simultaneous activation of the TCR and costimulatory receptor with antibodies targeting CD3 and CD28 together with the mast cell supernatant is performed.

[0400] Cell activation is assessed using flow cytometry by measuring upregulation of CD69 and CD63 on eosinophils, as well as level of CD69, CD154, CD25, or CD62L on T cells. In addition, cytokines secreted by the mast cells are measured using bead-based cytokine multiplex assays (45 plex). Three individual experiments are performed using mast cells and eosinophils from three individual donors.

[0401] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, including U.S. Patent Application No. 63 / 588,638, filed on October 6, 2023, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0402] These and other changes can be made to the embodiments in light of the above- detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS 1. A compound having the structure of Formula (I):or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: L1is –(CR′R′′)q−, –(CR′R′′)u−CR′=CR′−(CR′R′′)v−, –(CR′R′′)u−C≡C−(CR′R′′)v−, −(CR′R′′)u−O−(CR′R′′)v−, −(CR′R′′)u−NR′−(CR′R′′)v−, −(CR′R′′)u−C(O)−(CR′R′′)v−; L2is –(CRaRb)w−; R1is C1-6 alkyl, carbocycle or heterocycle, wherein R1is substituted with –(R5)n; R2is halo, C1-6 alkyl, carbocycle or heterocycle, wherein R2is substituted with –(R6)p; R3is H or C1-6 alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −C(O)N(R8)2, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NHC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z;R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl; m is 0–5; n is 0–5; p is 0–5 q is 1–3; u is, at each occurrence, independently 0–3; v is, at each occurrence, independently 0–3; w is 0–3; x is 0–3; y is 0–3; and z is 0–3; wherein R2is carbocycle or heterocycle when L1is −C(R′R′′)q−.

2. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is carbocycle or heterocycle.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is heterocycle.

4. The compound of any one of claims 1–3, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is heterocycloalkyl.

5. The compound of any one of claims 1–4, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is aziridinyl, oziranyl, thiranyl, azetidinyl, 1,2-dihydroazotyl, oxetanyl, 2H-oxetyl, thietanyl, 2H-thietyl, pyrrolidinyl,4,5-dihydro-1H-imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, 2H-pyranyl, 3,4-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, morpholinyl, thianyl, 1,4-dithianyl, 2H-thiopyranyl, azepanyl, 1,4-diazepanyl, oxepanyl, or thiepanyl.

6. The compound of any one of claims 1–3, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is heteroaryl.

7. The compound of any one of claims 1–3 or 6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,3,4-thiatriazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, [1,2,3]triazolo[4,5-b]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-purinyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-c]pyriminyl, pyrrolo[1,2-b]pyrdazinyl, imidazo[4,5-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, pyrido[3,4-d]pyridazinyl, 1,5-naphtyridinyl, 1,8-natphyridinyl, 9H-carbazolyl, benzoxazolyl, dibenzofuranyl, benzothiophenyl, or dibenzothiophenyl.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is carbocycle.

9. The compound of any one of claims 1, 2, or 8, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is cycloalkyl.

10. The compound of any one of claims 1, 2, 8, or 9, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

11. The compound of any one of claims 1, 2, or 8, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is aryl.

12. The compound of any one of claims 1, 2, 8, or 11, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1is naphthyl or phenyl.

13. The compound of any one of claims 1, 2, 8, 11, or 12, having the structure of Formula (II):or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: L1is –(CR′R′′)q−, –(CR′R′′)u−CR′=CR′−(CR′R′′)v−, –(CR′R′′)u−C≡C−(CR′R′′)v−, −(CR′R′′)u−O−(CR′R′′)v−, −(CR′R′′)u−NR′−(CR′R′′)v−, −(CR′R′′)u−C(O)−(CR′R′′)v−; L2is –(CRaRb)w−; R2is carbocycle or heterocycle, wherein R2is substituted with –(R6)p; R3is H or C1-6 alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle;R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl; m is 0–5; n is 0–5; p is 0–5 q is 1–3; u is, at each occurrence, independently 0–3; v is, at each occurrence, independently 0–3; w is 0–3; x is 0–3; y is 0–3; and z is 0–3; wherein R2is carbocycle or heterocycle when L1is −C(R′R′′)q−.

14. The compound of any one of claims 1–13, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is carbocycle or heterocycle.

15. The compound of any one of claims 1–14, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is heterocycle.

16. The compound of any one of claims 1–15, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is heterocycloalkyl.

17. The compound of any one of claims 1–16, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is aziridinyl, oziranyl, thiranyl, azetidinyl, 1,2-dihydroazotyl, oxetanyl, 2H-oxetyl, thietanyl, 2H-thietyl, pyrrolidinyl, 4,5-dihydro-1H-imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, 2H-pyranyl, 3,4-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, morpholinyl, thianyl, 1,4-dithianyl, 2H-thiopyranyl, azepanyl, 1,4-diazepanyl, oxepanyl, thiepanyl, or 2,3-dihydrobenzo[1,4]dioxine, benzo[1,3]dioxolyl.

18. The compound of any one of claims 1–15, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is heteroaryl.

19. The compound of any one of claims 1–15 or 18, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,3,4-thiatriazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, [1,2,3]triazolo[4,5-b]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-purinyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-c]pyriminyl, pyrrolo[1,2-b]pyrdazinyl, imidazo[4,5-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,pyrido[2,3-b]pyrazinyl, pteridinyl, pyrido[3,4-d]pyridazinyl, 1,5-naphtyridinyl, 1,8-natphyridinyl, 9H-carbazolyl, benzoxazolyl, dibenzofuranyl, benzothiophenyl, or dibenzothiphenyl.

20. The compound of any one of claims 1–14, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is carbocycle.

21. The compound of any one of claims 1–14 or 20, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is cycloalkyl.

22. The compound of any one of claims 1–14, 20, or 21, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

23. The compound of any one of claims 1–14 or 20, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is aryl.

24. The compound of any one of claims 1–14, 20, or 23, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R2is naphthyl or phenyl.

25. The compound of any one of claims 1–20, 23, or 24, having the structure of Formula (III):or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:L1is –(CR′R′′)q−, –(CR′R′′)u−CR′=CR′−(CR′R′′)v−, –(CR′R′′)u−C≡C−(CR′R′′)v−, −(CR′R′′)u−O−(CR′R′′)v−, −(CR′R′′)u−NR′−(CR′R′′)v−, −(CR′R′′)u−C(O)−(CR′R′′)v−; L2is –(CRaRb)w−; Q1, Q2, and Q3are, at each occurrence, independently CR6or N; R3is H or C1-6 alkyl, or R3and one R6, together with the atoms to which they are attached, form a ring; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl m is 0–5; n is 0–5; p is 0–5 q is 1–3; u is, at each occurrence, independently 0–3; v is, at each occurrence, independently 0–3;w is 0–3; x is 0–3; y is 0–3; and z is 0–3.

26. The compound of claim 25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1, Q2, and Q3are each CR6.

27. The compound of claim 25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1is N and Q2and Q3are each CR6.

28. The compound of claim 25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q2is N and Q1and Q3are each CR6.

29. The compound of claim 25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q3is N and Q1and Q2are each CR6.

30. The compound of any one of claims 1–29, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein w is 1.

31. The compound of any one of claims 1–30, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais H.

32. The compound of any one of claims 1–30, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais C1-6 alkyl.

33. The compound of any one of claims 1–30 or 32, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais methyl.

34. The compound of any one of claims 1–33, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis H.

35. The compound of any one of claims 1–33, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis C1-6 alkyl.

36. The compound of any one of claims 1–33 or 35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis methyl.

37. The compound of any one of claims 1–30, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Raand Rb, together with the carbon atom to which they are attached, form a cycloalkyl.

38. The compound of any one of claims 1–30 or 37, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Raand Rb, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, or cyclopentyl.

39. The compound of any one of claims 1–29, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein w is 0.

40. The compound of any one of claims 1–39, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is –(CR′R′′)q−.

41. The compound of any one of claims 1–40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein q is 1.

42. The compound of any one of claims 1–40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein q is 2.

43. The compound of any one of claims 1–42, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein each R′ is H.

44. The compound of any one of claims 1–42, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′ is C1-6 alkyl.

45. The compound of any one of claims 1–42 or 44, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′ is methyl.

46. The compound of any one of claims 1–45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein each R′′ is H.

47. The compound of any one of claims 1–45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′′ is C1-6 alkyl.

48. The compound of any one of claims 1–45 or 47, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′′ is methyl.

49. The compound of any one of claims 1–45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′′ is C1-6 alkenyl.

50. The compound of any one of claims 1–45 or 49, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′′ is vinyl.

51. The compound of any one of claims 1–42, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one occurrence of R′ and R′′ attached to the same carbon atom form a cycloalkyl together with the carbon to which they are attached.

52. The compound of claim 51, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one occurrence of R′ and R′′ attached to the same carbon atom form a cyclopropyl or a cyclobutyl together with the carbon to which they are attached.

53. The compound of any one of claims 1–52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−CR′=CR′−(CR′R′′)v−.

54. The compound of any one of claims 1–52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −CR′=CR′−.

55. The compound of claim 53 or 54, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein each R′ is H.

56. The compound of claims 53 or 54, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′ is C1-6 alkyl.

57. The compound of any one of claims 53, 54, or 56, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R′ is methyl.

58. The compound of any one of claims 1–52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−C≡C−(CR′R′′)v−.

59. The compound of claim 58, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −C≡C−.

60. The compound of any one of claims 1–52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−O−(CR′R′′)v−.

61. The compound of claim 60, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein u is 0 or 1.

62. The compound of claim 60 or 61, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein v is 0 or 1.

63. The compound of any one of claims 60–62, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −O−.

64. The compound of any one of claims 1–52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−NR′−(CR′R′′)v−.

65. The compound of claim 64, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein u is 0 or 1.

66. The compound of claim 64 or 65, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein v is 0 or 1.

67. The compound of any one of claims 60–62, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −NR′−.

68. The compound of claim 67, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R′ is H.

69. The compound of claim 67, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R′ is C1-6 alkyl.

70. The compound of any one of claims 1–52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −(CR′R′′)u−C(O)−(CR′R′′)v−.

71. The compound of claim 70, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein u is 0 or 1.

72. The compound of claim 70 or 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein v is 0 or 1.

73. The compound of any one of claims 70–72, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L1is −C(O)−.

74. A compound having the structure of Formula (III-A) or Formula (III-B):or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q1, Q2, and Q3are, at each occurrence, independently CR6or N; R3is H or C1-6 alkyl; R4is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, C1-6 alkyl, C1-6 haloalkyl; R5is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −S(O)2−R7, C1-6 alkyl, C1-6 haloalkyl, carbocycle, or heterocycle; R6is, at each occurrence, independently halo, −CN, −OR7, −N(R7)2, −SR7, −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, −S(O)2−R7, −C1-6 alkyl−R7, C1-6 haloalkyl, carbocycle substituted with −(R7)x, or heterocycle substituted with −(R7)x; R7is, at each occurrence, independently H, −OR8, −N(R8)2, −C(O)OR8, −NRC(O)OR8, −C1-6 alkyl−R8, C1-6 haloalkyl, carbocycle substituted with –(R8)y, or heterocycle substituted with –(R8)y; R8is, at each occurrence, independently H, −OR, −NR2, −C1-6 alkyl−R, carbocycle substituted with –(R)z, or heterocycle substituted with –(R)z; R′ and R′′ are, at each occurrence, independently H, halo, cyano, hydroxy, amino, C1-6 alkyl, or C1-6 alkenyl, or, independently, at each occurrence of R′ and R′′ attached to the same carbon atom, R′ and R′′, together with the carbon to which they are attached, form a cycloalkyl; Raand Rbare, at each occurrence, independently H, halo, cyano, hydroxy, amino, or C1-6 alkyl or, independently, at each occurrence of Raand Rbattached to the same carbon atom, Raand Rb, together with the carbon to which they are attached, form a cycloalkyl; R is, at each occurrence, independently H, halo, −CN, −OH, −NH2, or C1-6 alkyl m is 0–5; n is 0–5;p is 0–5 x is 0–3; y is 0–3; and z is 0–3.

75. The compound of claim 74, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1, Q2, and Q3are each CR6.

76. The compound of claim 74, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q1is N and Q2and Q3are each CR6.

77. The compound of claim 74, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q2is N and Q1and Q3are each CR6.

78. The compound of claim 74, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q3is N and Q1and Q2are each CR6.

79. The compound of any one of claims 74–78, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais H.

80. The compound of any one of claims 74–78, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais C1-6 alkyl.

81. The compound of any one of claims 74–78 or 80, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rais methyl.

82. The compound of any one of claims 74–81, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis H.

83. The compound of any one of claims 74–81, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis C1-6 alkyl.

84. The compound of any one of claims 74–81 or 83, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Rbis methyl.

85. The compound of any one of claims 74–78, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Raand Rb, together with the carbon atom to which they are attached, form a cycloalkyl.

86. The compound of any one of claims 84–78 or 85, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Raand Rb, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, or cyclopentyl.

87. The compound of any one of claims 1–86, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0.

88. The compound of any one of claims 1–86, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1 or 2.

89. The compound of any one of claims 1–86 or 88, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is C1-6 alkyl.

90. The compound of any one of claims 1–86, 88, or 89, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is methyl.

91. The compound of any one of claims 1–86 or 88, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is halo.

92. The compound of any one of claims 1–86, 88 or 91, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is Cl or F.

93. The compound of any one of claims 1–86 or 88, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is −CN.

94. The compound of any one of claims 1–86 or 88, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is C1-6 alkoxy.

95. The compound of any one of claims 1–86, 88, or 94, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R4is −OCH3.

96. The compound of any one of claims 1–95, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0.

97. The compound of any one of claims 1–95, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1, 2, or 3.

98. The compound of any one of claims 1–95 or 97, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is C1-6 alkyl.

99. The compound of any one of claims 1–95, 97, or 98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is methyl, ethyl, propyl, or butyl.

100. The compound of any one of claims 1–95 or 97, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is halo.

101. The compound of any one of claims 1–95, 97, or 100, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is Cl or F.

102. The compound of any one of claims 1–95 or 97, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is −CN.

103. The compound of any one of claims 1–95 or 97, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is C1-6 alkoxy.

104. The compound of any one of claims 1–95, 97, or 103, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is methoxy.

105. The compound of any one of claims 1–95 or 97, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is carbocycle.

106. The compound of any one of claims 1–95, 97, or 105, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R5is phenyl.

107. The compound of any one of claims 1–106, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein p is 0.

108. The compound of any one of claims 1–106, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein p is 1, 2, or 3.

109. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is halo.

110. The compound of any one of claims 1–106, 108, or 109, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is Cl of F.

111. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −CN.

112. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −OR7.

113. The compound of claim 112, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R7is H, −C1-6 alkyl−R8, or C1-6 haloalkyl.

114. The compound of any one of claims 1–106, 108, 112, or 113, or a pharmaceutically115. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −N(R7)2.

116. The compound of claim 115, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R7is H or −C1-6 alkyl−R8.

117. The compound of any one of claims 1–106, 108, 115, or 116, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is:

118. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −SR7or −S(O)2R7.

119. The compound of claim 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R7is −N(R8)2, −C1-6 alkyl−R8, or carbocycle substituted with –(R8)y.

120. The compound of any one of claims 1–106, 108, 118, or 119, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is:

121. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −C(O)OR7, −N(R8)C(O)R7, −N(R8)C(O)OR7, or −C(O)N(R8)2.

122. The compound of claim 121, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R7is H or −C1-6 alkyl−R8.

123. The compound of claim 121 or 122, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R8is H, −C1-6 alkyl−R8, or carbocycle.

124. The compound of any one of claims 1–106, 108, or 121–123, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is:

125. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −C1-6 alkyl−R7.

126. The compound of claim 125, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R7is H.

127. The compound of claim 125 or 126, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is methyl, ethyl, propyl, or butyl.

128. The compound of claim 125, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R7is −OR8, −N(R8)2, −C(O)OR8, −NHC(O)OR8, or heterocycle substituted with –(R8)y.

129. The compound of any one of claims 1–106, 108, or 125–128, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is:

130. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −C1-6 haloalkyl.

131. The compound of claim 130, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is −CHF2 or −CF3.

132. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is carbocycle substituted with −(R7)x.

133. The compound of claim 132, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x is 0.

134. The compound of claim 132, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x is 1, 2, or 3.

135. The compound of any one of claims 1–106, 108, or 132–134, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is phenyl substituted with −(R7)x.

136. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is heterocycle substituted with −(R7)x.

137. The compound of claim 136, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x is 0.

138. The compound of claim 136, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein x is 1, 2, or 3.

139. The compound of any one of claims 1–106, 108, or 136–138, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R6is pyrazolyl, thiophenyl, or tetrazolyl substituted with −(R7)x.

140. The compound of any one of claims 1–106 or 108, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R3and one R6, together with the atoms to which they are attached, form a ring.

141. The compound of claim 140, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R3and one R6, together with the atoms to which they are attached, form a 6-membered ring fused with R2.

142. A compound having the structure of a compound of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

143. An isotope of a compound of any one of claims 1–142, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, or salt thereof.

144. The isotope of claim 143 comprising at least one deuterium atom.

145. A pharmaceutical composition comprising the compound of any one of claims 1– 144, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, or salt thereof and at least one pharmaceutically acceptable excipient.

146. A method of modulating a Mas-Related G-Protein Receptor (MRGPR) X2 or a MRGPRX2 ortholog by contacting MRGPRX2 or MRGPRX2 ortholog with an effective amount of the pharmaceutical composition of claim 145.

147. A method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 145.

148. A method of treating a pseudo-allergic reaction, an itch associated condition, a pain associated condition, a cancer associated condition, an inflammatory or autoimmune disorder by administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 145.

149. The method of claim 148, wherein the pseudo-allergic reaction is caused by secretagogues, cationic peptidergic drugs, anionic peptidergic drugs, neutral peptidergic drugs, non-steroidal antagonist drugs, neuropeptides, antimicrobial peptides, MCD peptide, Substance P, VIP, PACAP, dynorphin, somatostatin, Compound 48 / 80, cortistatin-14, mastoparan, melettin, cathelicidin peptides, ciprofloxacin, vancomycin, leuprolide, goserelin, histrelin, triptorelin, cetrorelix, ganirelix, degarelix, octreotide, lanreotide, pasireotide, sermorelin, tesamorelin, icatibant, glatiramer acetate, teriparatide, pramlintide, bleomycin, exenatide, glucagon, liraglutide, enfuvirtide, colistimethate, succinylcholine, tubocurarine, atracurium, mivacurium, and rocuronium.

150. The method of claim 148, wherein the itch associated condition is chronic itch; contact dermatitis; Allergic blepharitis; Anemia; Atopic dermatitis; Bullous pemphigoid; Candidiasis; Chicken pox; end-stage renal failure; hemodialysis; Chronic urticaria; Contact dermatitis, Atopic Dermatitis; Dermatitis herpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis; Ectopic eczema; Eosinophilic fasciitis; Epidermolysis bullosa; Erythrasma; Food allergy; Folliculitis; Fungal skin infection; Hemorrhoids; Herpes; HIV infection; Hodgkin's disease; Hyperthyroidism; Iodinated contrast dye allergy; Iron deficiency anemia; Kidney disease; Leukemia, porphyrias; Lymphoma; Malignancy; Mastocystosis; Multiple myeloma; Neurodermatitis; Onchocerciasis; Paget's disease; Pediculosis; Polycythemia rubra vera; Prurigo nodularis; Lichen Planus; Lichen Sclerosis; Pruritus ani; Pseudorabies; Psoriasis; Rectal prolapse; Sarcoidosis granulomas; Scabies; Schistosomiasis; Scleroderma, Severe stress, Stasia dermatitis; Swimmer's itch; Thyroid disease; Tinea cruris; Rosacea; Cutaneous amyloidosis; Scleroderma; Acne; wound healing; burn healing; ocular itch; or Urticaria.

151. The method of claim 148, wherein the itch associated condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.

152. The method of claim 148, wherein the pain associated condition is Acute Pain, Advanced Prostate Cancer, AIDS-Related Pain, Ankylosing Spondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic Cerebral Palsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain, Behcet’s Disease (Syndrome), Burning Mouth Syndrome, Bursitis, Cancer Pain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome, Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease, Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain (CFAP), Chronic Pain, Chronic Pancreatitis, Chronic Pelvic Pain Syndrome, Collapsed Lung (Pneumothorax), Complex Regional Pain Syndrome (RSD), Corneal Neuropathic Pain, Crohn’s Disease, Degenerative Disc Disease, Dental Pain, Dercum’s Disease, Dermatomyositis, Diabetic Peripheral Neuropathy (DPN), Dystonia, Ehlers-Danlos Syndrome (EDS), Endometriosis, Eosinophilia-Myalgia Syndrome (EMS), Erythromelalgia, Fibromyalgia, Gout, Headaches, Herniated disc, Hydrocephalus, Intercostal Neuraligia, Interstitial Cystitis, Irritable Bowel syndrome (IBS), Juvenile Dermatositis (Dermatomyositis), Knee Injury, Leg Pain, Loin Pain-Haematuria Syndrome, Lupus, Lyme Disease, Medullary Sponge Kidney (MSK),Meralgia Paresthetica, Mesothelioma, Migraine, Musculoskeletal pain, Myofascial Pain, Myositis, Neck Pain, Neuropathic Pain, Occipital Neuralgia, Osteoarthritis, Paget’s Disease, Parsonage Turner Syndrome, Pelvic Pain, Periodontitis Pain, Peripheral Neuropathy, Phantom Limb Pain, Pinched Nerve, Polycystic Kidney Disease, Polymyalgia Rhuematica, Polymyositis, Porphyria, Post Herniorraphy Pain Syndrome, Post Mastectomy, Postoperative Pain, Pain Syndrome, Post Stroke Pain, Post Thorocotomy Pain Syndrome, Postherpetic Neuralgia (Shingles), Post-Polio Syndrome, Primary Lateral Sclerosis, Psoriatic Arthritis, Pudendal Neuralgia, Radiculopathy, Raynaud’s Disease, Rheumatoid Arthritis (RA), Sacroiliac Joint Dysfunction, Sarcoidosi, Scheuemann’s Kyphosis Disease, Sciatica, Scoliosis, Shingles (Herpes Zoster), Sjogren’s Syndrome, Spasmodic Torticollis, Sphincter of Oddi Dysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal Cord Injury, Spinal Stenosis, Syringomyelia, Tarlov Cysts, Transverse Myelitis, Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis, Vascular Pain or Vulvodynia.

153. The method of claim 148, wherein the inflammatory or autoimmune disorder is chronic inflammation, mast cell activation syndrome, Multiple Sclerosis, Steven Johnson’s Syndrome, Toxic Epidermal Necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy / complex regional pain syndrome (rsd / crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, allergic rhinitis, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, Crohn’s Disease, ulcerative colitis, lupus erythematous, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, permanent sputum eosiniophilia, eosinophilic leukemia, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, eosinophilic gastroenteritis, mast cell gastrointestinal disease, hypereosinophilic syndrome, aspirin-exacerbated respiratory disease, nasal polyposis, chronic rhinosinusitis, antibody-dependent cell-mediated cytotoxicity, neurofibromatosis, swannamatoisis, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, amyloidosis, renovascular ischemia, reflux nephropathy, polycystic kidney disease, liver fibrosis / cirrhosis, autoimmune liver disease, Biliary atresia, acuteand chronic Hepatitis B and C virus, Liver tumors and cancer, Alcoholic liver disease, Polycystic liver disease, Liver cholangiocarcinoma, neuromyelitis optica spectum disorder, cardiovascular disease, inflammation induced by bacterial or viral infection, inflammation associated with SARS- CoV-2 infection or its variants and Coronavirus Disease 2019 (COVID-19), acute respiratory distress syndrome, pneumonia, Long / Long-Term / Chronic COVID, Post-Acute Sequelae of COVID-19 (PASC), myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS “Brain Fog”) and vasculitis.

154. The method of claim 148, wherein the cancer associated condition is adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia- telangiectasia, beckwith-wiedemann syndrome, cholangiocarcinoma, birt-hogg-dube syndrome, bone cancer, brain stem glioma, brain tumor, breast cancer (inflammatory, metastatic, male), prostrate, basal cell, melanoma, colon, colorectal, bladder, kidney cancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lung cancer (non-small cell, small cell), leukemia (acute lymphoblastic, acute lymphocytic, acute myeloid, B cell prolymphocytic, chronic lymphocytic, chronic myeloid, chronic T cell lymphocytic, eosinophilic), Liver Cancer, Li-Fraumei syndrome, lymphoma (Hodgkin and non-hodgkin), lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma, multiple endocrine neoplasia, multiple myeloma, MUTYH-associated polyposis, myelodyspastic syndrome, nasal cavity and paranasal sinus cancer, neurobastoma, neuroendocrine tyymors, neurofibromatosis, penile cancer, parathyroid cancer, ovarian fallopian tube and peritoneal cancer, osteosarcoma, pituitary gland tumor, pleupulmonary blastoma, oral and oropharyngeal, thyroid, uterine, pancreatic, carney complex, brain and spinal cord cancer, cervical cancer, cowden syndrome, craniopharyngioma, desmoid tumor, desmoplatic infantile ganglioglioma, ependymoma, esophageal cancer, ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary, leiomyomastosis and renal cell cancer, hereditary pancreatitis, herediatary papillary renal carcinoma, hereditary mixed polyposis syndrome, HIV / AIDS related cancers, retinoblastoma, rhabdomyosarcoma, salivary glanc cancer, Kaposi sarcoma, small bowelcancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, vaginal cancer, culver cancer, werner syndrome and Xeroderma pigmentosum.

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