3-amino-4h-benzo [e] [1, 2, 4] thiadiazine 1, 1-dioxide derivatives as MRGX2 inhibitors

Abstract

The present disclosure relates to 3-amino-4H-benzo [E] [1, 2, 4] thiadiazine 1, 1-dioxide derivatives that are MRGX2 inhibitors. Compounds of Formula (1): wherein L, R1, R2, R3, R4 and R5 are defined in the specification, tautomers thereof, and pharmaceutically acceptable salts of the compounds or tautomers are disclosed. The present disclosure also relates to materials and methods for preparing the compounds of Formula (1), pharmaceutical compositions comprising them, and their use for the treatment of diseases, disorders or conditions associated with MRGX2. # imgabs0 #

Description

This application is a divisional application of the invention patent application with the application date of April 28, 2020, application number 202080047972.X, and name “3-Amino-4H-benzo[E][1,2,4]thiadiazine 1,1-dioxide derivatives as MRGX2 inhibitors”. Technical Field

[0001] The present invention relates to 3-amino-5-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as Mas-related gene X2 (MRGX2) inhibitors, to pharmaceutical compositions containing them, and to their use for treating diseases, disorders or conditions associated with MRGX2. Background Art

[0002] Mas-related gene X2 (MRGX2, MRGPRX2, TGR12) is a member of the X subfamily of the Mas family of G protein-coupled receptors (GPCRs). This subfamily is specific to humans, macaques, and rhesus monkeys, and MRGX2 is specifically expressed in mast cells (H. Subramanian et al., J Allergy Clin Immunol, 138(3):700-10(2016); K. Tatemoto et al., BiochemBiophys Res Commun, 349(4):1322-8(2006)). Activators of MRGX2 include numerous basal secretagogues, including neuropeptides (substance P, PAMPs, cortistatin, VIP, PACAP, SST), eosinophil granule proteins (MBP, EPO), antimicrobial peptides (LL-37, β-defensins), and others, such as anaphylatoxins and various venom peptides (H. Subramanian et al., Mol Pharmacol, 79(6):1005-13 (2011); K. Tatemoto et al., Biochem Biophys Res Commun, 349(4):1322-8; N. Robas et al., J Biol Chem, 278(45):44400-4 (2003); S. Kashem et al., Eur J Pharmacol, 668(1-2):299-304 (2011)). MRGX2 has been shown to activate basal secretagogues in LAD2 human mast cell lines and CD34 +MRGX2 ligands have been studied in primary human mast cells derived from cells, both of which endogenously express MRGX2. These ligands induce mast cell degranulation through MRGX2 in an IgE-independent manner and induce the release of mediators such as histamine and tryptase (K. Tatemoto et al., Biochem Biophys Res Commun, 349(4):1322-8(2006)). In addition to degranulation, activation of MRGX2 also leads to the release of cytokines (TNF-α, IL-6, IL-1α, IL-1β, GM-CSF, M-CSF, etc.) and chemokines (MCP-1, MIP-1α / β, RANTES, IL-8, etc.), leading to acute and chronic inflammatory responses.

[0003] MRGX2 is Gq-coupled and induces intracellular Ca2+ upon ligand activation. 2 Mobilization. MRGX2 is a non-canonical GPCR because it does not internalize and desensitize after agonist-induced activation (H. Subramanian et al., J Biol Chem, 286(52):44739-49(2011)). In addition, MRGX2 is expressed intracellularly in the cytoplasm of LAD2 cells and in cultured mast cells derived from adult peripheral blood (D. Fujisawa et al., J Allergy Clin Immunol, 134(3):622-33.e9(2014)). Mrg receptors are not so conserved between species, with humans and mice sharing only 45-65% amino acid sequence homology. It is reported that the mouse ortholog of the human MRGX2 receptor is Mrgprb2 (BD McNeil et al., Nature, 519(7542):237-41(2015)).

[0004] MRGX2 may be involved in host defense, drug-induced anaphylactoid reactions, neurogenic inflammation, pain, pruritus, and chronic inflammatory diseases (H. Subramanian et al., J Allergy Clin Immunol, 138(3):700-10 (2016)). MRGX2 and its ligands are associated with human disease states involving mast cells, including atopic dermatitis, chronic urticaria, and asthma (H. Subramanian et al., J Allergy Clin Immunol, 138(3):700-10 (2016); D. Fujisawa et al., J Allergy Clin Immunol, 134(3):622-33.e9 (2014)). Selective inhibition of MRGX2, resulting in reduced mast cell activation and subsequent prevention of degranulation, is a therapeutic strategy for conditions driven by mast cell pathophysiology. Summary of the Invention

[0005] The present invention provides 3-amino-5-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives and pharmaceutical compositions containing the same. 3-Amino-5-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide is an inhibitor of Mas-related gene X2 (MRGX2) and can be used to treat diseases, disorders, or conditions associated with MRGX2, including atopic dermatitis, chronic urticaria, and asthma.

[0006] One aspect of the present invention provides a compound of formula 1: or a tautomer thereof, or a pharmaceutically acceptable salt of a compound of formula 1 or a tautomer thereof, wherein: L is selected from the group consisting of a bond and C 1-4 Alkanediyl; R 1 Selected from (a) substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 1-4 Alkyl, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted with an alkyl substituent; and (b) Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; R 2 Selected from (a) substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 The C substituted with alkoxy and amino optional substituents 1-4alkyl; and (b) Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; R 3 、R 4 and R 5 are independently selected from hydrogen, halo, cyano and C 1-3 alkyl; wherein each of the above heterocyclyl and heteroaryl moieties independently has 1 to 4 heteroatoms each independently selected from N, O and S as ring members.

[0007] Another aspect of the present invention provides a compound selected from the group consisting of the compounds described in the Examples, tautomers thereof, and pharmaceutically acceptable salts of the compounds in the Examples and tautomers thereof.

[0008] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any compound, tautomer or pharmaceutically acceptable salt defined in the preceding paragraphs; and a pharmaceutically acceptable excipient.

[0009] Another aspect of the present invention provides a compound of formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of formula 1 or a tautomer thereof, or any compound, tautomer or pharmaceutically acceptable salt defined in the preceding paragraphs, for use as a medicament.

[0010] Another aspect of the present invention provides a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any one of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraphs, for use in treating a disease, disorder or condition associated with MRGX2.

[0011] Another aspect of the present invention provides a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any compound, tautomer or pharmaceutically acceptable salt defined in the preceding paragraphs, for use in the preparation of a medicament for treating a disease, disorder or condition associated with MRGX2.

[0012] Another aspect of the present invention provides a method for treating a disease, disorder or condition associated with MRGX2, comprising administering to a subject an effective amount of a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any one of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraphs.

[0013] Another aspect of the present invention provides a method of inhibiting MRGX2 in a subject, comprising administering to the subject an effective amount of a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any one of the compounds, tautomers, or pharmaceutically acceptable salts defined in the preceding paragraphs.

[0014] Another aspect of the present invention provides a method of treating a disease, disorder or condition in a subject, comprising administering to the subject an effective amount of a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any one of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraphs, wherein the disease, disorder or condition is selected from systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis, rosacea, chronic urticaria, atopic dermatitis, rheumatoid arthritis, bronchial asthma, irritable bowel syndrome (IBS), systemic mastocytosis, cutaneous mastocytosis, mast cell enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

[0015] Another aspect of the present invention provides an effective amount of a compound of Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt of a compound of Formula 1 or a tautomer thereof, or any compound, tautomer or pharmaceutically acceptable salt defined in the preceding paragraphs; and at least one additional pharmacologically active agent. DETAILED DESCRIPTION

[0016] Unless otherwise stated, this disclosure uses the definitions provided below.

[0017] "Substituted" refers to a chemical substituent or moiety (e.g., C 1-6 alkyl) means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that the valence requirements are met and that a chemically stable compound results from the substitution.

[0018] "About" or "approximately," when used in connection with a measurable numerical variable, refers to the indicated value of that variable and all values ​​of that variable that are within the experimental error range of the indicated value or within ±10% of the indicated value, whichever is greater.

[0019] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, etc.). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentan-1-yl, pentan-2-yl, pentan-3-yl, 3-methylbutan-1-yl, 3-methylbutan-2-yl, 2-methylbutan-2-yl, 2,2,2-trimethylethan-1-yl, n-hexyl, and the like.

[0020] "Alkanediyl" refers to a divalent alkyl group where alkyl is as defined above and typically has the specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (ie, 1, 2, 3 or 4) carbon atoms, C 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, etc.). Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0021] "Alkenyl" refers to straight and branched hydrocarbon groups having one or more carbon-carbon double bonds and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0022] "Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and typically having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0023] "Alkoxy" refers to straight-chain and branched saturated hydrocarbon groups attached through an oxygen atom, typically having a specified number of carbon atoms (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (ie, 1, 2, 3 or 4) carbon atoms, C 1-6 Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, etc.). Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexyloxy, and the like.

[0024] "Amino" refers to -NH2, which, when indicated, may optionally include one or two non-hydrogen substituents which may be the same or different.

[0025] "Aminocarbonyl" refers to -C(O)NH2 which, when specified, may optionally include one or two non-hydrogen substituents which may be the same or different.

[0026] "Halo," "halogen," and "halo" are used interchangeably to refer to fluoro, chloro, bromo, and iodo.

[0027] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups, respectively, substituted with one, two, three, or more halogen atoms, wherein alkyl, alkenyl, and alkynyl are as defined above and typically have the indicated number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0028] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, typically having a specified number of carbon atoms constituting one or more rings (e.g., C 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms as ring members, C 3-8 Cycloalkyl refers to a cycloalkyl group having 3-8 carbon atoms as ring members, etc.). Bicyclic hydrocarbon groups can include isolated rings (two rings share no carbon atoms), spiro rings (two rings share one carbon atom), fused rings (two rings share two carbon atoms and a bond between the two shared carbon atoms), and bridged rings (two rings share two carbon atoms but no shared bond). Cycloalkyl groups may be attached via any ring atom unless such attachment would violate valence requirements and, where indicated, may optionally include one or more non-hydrogen substituents unless such substitution would violate valence requirements.

[0029] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, etc. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, etc. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, etc. Examples of isolated bicyclic cycloalkyl groups include those derived from bis(cyclobutane), cyclobutanecyclopentane, bis(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bis(cyclohexane), and the like.

[0030] "Cycloalkylene" refers to a divalent monocyclic cycloalkyl group, where cycloalkyl is as defined above, attached through a single carbon atom of the group, and generally having the specified number of carbon atoms constituting the ring (e.g., C 3-6 Cycloalkylene refers to a cycloalkylene group having 3 to 6 carbon atoms as ring members, C 3-8Cycloalkylene refers to a cycloalkylene group having 3 to 8 carbon atoms as ring members, etc.) Examples include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0031] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon radicals, typically having a specified number of carbon atoms constituting one or more rings. Like cycloalkyl, bicyclic cycloalkenyl can include isolated rings, spirocycles, condensed rings or bridged rings. Similarly, cycloalkenyl can be connected by any ring atom, and when specified, can optionally include one or more non-hydrogen substituents, unless such connection or replacement would violate valence requirements. Examples of cycloalkenyl include partially unsaturated analogs of the above-mentioned cycloalkyls, such as cyclobutenyl (i.e., cyclobutene-1-yl and cyclobutene-3-yl), cyclopentenyl, cyclohexenyl, bicyclo [2.2.1] hept-2-enyl etc.

[0032] "Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic aromatic hydrocarbons having at least one aromatic ring. Monocyclic and polycyclic aromatic groups generally have a specified number of carbon atoms constituting their ring members (e.g., C 6-10 Aryl refers to an aromatic group having 6 to 10 carbon atoms as ring members, C 6-14 Aryl refers to an aromatic group having 6 to 14 carbon atoms as ring members, etc.). The group may be attached via any ring atom and, where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutylphenyl, indenyl, naphthyl, benzocycloheptanyl, biphenylene, fluorenyl, groups derived from cycloheptatrienyl cations, and the like.

[0033] "Arylene" refers to a divalent aromatic radical, wherein aryl is as defined above. Examples of arylene radicals include phenylene (ie, benzene-1,2-diyl).

[0034] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group whose ring atoms consist of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Monocyclic and bicyclic groups typically have a specified number of carbon atoms in one or more of their rings (e.g., C 2-6 A heterocyclic group is a group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members. 2-9Heterocyclyl refers to a heterocyclyl having 2 to 9 carbon atoms and 1 to 4 heteroatoms as ring members, etc.). As with bicyclic cycloalkyl, bicyclic heterocyclyls may include isolated, spiro, fused, and bridged rings. The heterocyclyl group may be attached via any ring atom and, where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heterocyclic groups include oxiranyl, thiirane, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thiirane, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl alkyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl and 1,2-dihydropyrazolo[1,5-d][1,2,4]triazinyl.

[0035] "Heterocycle-diyl" refers to a heterocycle group linked through two ring atoms of the group, wherein heterocycle is as defined above. They typically have a specified number of carbon atoms in one or more of their rings (e.g., C 2-6 Heterocyclic-diyl refers to a heterocyclic diyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members, C 2-9 Heterocycle-diyl refers to a heterocycle-diyl group having 2 to 9 carbon atoms and 1 to 4 heteroatoms as ring members. Examples of heterocycle-diyl groups include polyvalent analogs of the above-mentioned heterocyclic groups, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, -(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

[0036] "Heteroaromatic" and "heteroaryl" are used interchangeably to refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, the ring atoms of which consist of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C 1-5Heteroaryl refers to a heteroaryl group having 1 to 5 carbon atoms and 1 to 4 heteroatoms as ring members, 1-9 Heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members, etc.), and may include any bicyclic group in which any of the monocyclic heterocycles listed above is fused to a benzene ring. The heteroaryl group may be attached via any ring atom (or ring atoms of a fused ring) and, where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. For purposes of this disclosure, 2-pyridones and 4-pyridones, 2-quinolones and 4-quinolones, etc. are considered to be 2-oxo- and 4-oxo-substituted derivatives of the corresponding heteroaromatic groups (pyridine, quinoline, etc.).

[0037] Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0038] Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindololinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl , 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[ 4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxane, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[3,4-d]pyrimidinyl, [2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0039] Other examples of heteroaryl groups include bicyclic groups 2,3-dihydrobenzofuranyl, 2-oxo-1,2,5,6,7,8-hexahydroquinolinyl, 4-oxo-4H-pyrido[1,2-a]pyrimidinyl, 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine, yl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 5-oxo-5H-thiazolyl[3,2-a]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl and pyrrolo[1,2-c]pyrimidinyl.

[0040] "Heteroarylene" refers to a heteroaryl group linked through two ring atoms of a group, wherein heteroaryl is as defined above. They typically have a specified number of carbon atoms in one or more of their rings (e.g., C 3-5 Heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members. Examples of heteroarylene groups include polyvalent analogs of the above-mentioned heteroaryl groups, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0041] "Oxo" refers to a double-bonded oxygen (=0).

[0042] "Leaving group" refers to any group that leaves a molecule during a cleavage process including substitution reactions, elimination reactions, and addition-elimination reactions. A leaving group can be nuclear-free, in which the group leaves with a pair of electrons that previously served as a bond between the leaving group and the molecule, or can be electrofugal, in which the group leaves without an electron pair. The ability of a nuclear-free leaving group to leave depends on the strength of its base, with the strongest base being the worst leaving group. Common nuclear-free leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., methanesulfonates), fluoroalkyl sulfonates (e.g., trifluoromethanesulfonates, hexafluoromethanesulfonates, perfluoromethanesulfonates, and trifluoroethanesulfonates (tresylate)), and aryl sulfonates (e.g., toluenesulfonates, bromobenzenesulfonates, hypochlorobenzenesulfonates, and nosylate). Others include carbonates, halides, carboxylate anions, phenolates, and alkoxides. Some stronger bases such as NH2 - and OH - Can be made into a better leaving group by treatment with an acid. Common electron-leaving leaving groups include protons, CO2, and metals.

[0043] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by inverting all stereocenters of the reference molecule. For example, if the reference molecule has an absolute stereochemistry of S, the opposite enantiomer has an absolute stereochemistry of R. Similarly, if the reference molecule has an absolute stereochemistry of S,S, the opposite enantiomer has an R,R stereochemistry, and so on.

[0044] A "stereoisomer" of a compound having a given stereochemical configuration refers to the opposite enantiomer and any diastereomers of the compound, including geometric isomers (Z / E) of the compound. For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having an R,S,Z configuration, as well as its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration. If the stereochemical configuration of a compound is not specified, "stereoisomer" refers to any possible stereochemical configuration of the compound.

[0045] "Substantially pure stereoisomer" and variations thereof refers to a sample containing a compound having a particular stereochemical configuration, which constitutes at least about 95% of the sample.

[0046] "Pure stereoisomers" and variations thereof refer to a sample containing a compound having a specific stereochemical configuration, which constitutes at least about 99.5% of the sample.

[0047] "Subject" refers to mammals, including humans.

[0048] "Pharmaceutically acceptable" substances refer to those substances that are suitable for administration to a subject.

[0049] "Treat," "treat," or "treat" means to reverse, alleviate, prevent, or inhibit the progress of the disease, disorder, or condition to which such term applies, or to reverse, alleviate, prevent, or inhibit the progress of one or more symptoms of such disease, disorder, or condition.

[0050] “Treatment” means the act of “treating” as defined in the preceding paragraph.

[0051] "Drug," "drug substance," "active pharmaceutical ingredient," etc., refers to a compound (e.g., a compound of Formula 1, including subclasses of compounds and compounds specifically named in the specification) that can be used to treat a subject in need of treatment.

[0052] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like refer to the amount of a drug that can be used to treat a subject and may depend, among other things, on the weight and age of the subject, the route of administration, and the like.

[0053] "Excipient" refers to any diluent or vehicle for a drug.

[0054] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0055] "Drug product," "drug dosage form," "dosage form," "final dosage form," and the like refer to a pharmaceutical composition suitable for treating a subject in need of treatment, and typically can be in the form of a tablet, capsule, sachet containing powder or granules, liquid solution or suspension, patch, film, and the like.

[0056] "A disease, disorder, or condition associated with MRGX2" and similar phrases relate to a disease, disorder, or condition in a subject for which inhibition of MRGX2 may provide a therapeutic or prophylactic benefit.

[0057] The following abbreviations may be used in this specification: Ac (acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); Boc (tert-butyloxycarbonyl); Cbz (benzyloxycarbonyl); dba (dibenzylideneacetone); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1- dichloroethane); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine, Hünig's base); DMA (N,N-dimethylacetamide); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); dppf (1,1′-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC 50 (effective concentration at half maximum response); EDA (ethoxylated dodecyl alcohol, 35); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq (equivalent); Et (ethyl); Et3N (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V)); HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); AcOH (acetic acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC 50 (50% inhibition concentration); IPA (isopropyl alcohol); IPAc (isopropyl acetate); IPE (isopropyl ether); K d(dissociation constant); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperbenzoic acid); Me (methyl); MeOH (methanol); MTBE (methyl tert-butyl ether); mp (melting point); NaOt-Bu (sodium tert-butoxide); NMM (N-methylmorpholine); NMP (N-methyl-pyrrolidone); OTf (trifluoromethanesulfonate); Pd(amphos)Cl2 (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)); PE (petroleum ether); Ph (phenyl); pEC 50 (-log 10 (EC 50 ), where EC 50 Given in molar (M) units); pIC 50 (-log 10 (IC 50 ), where IC 50 Given in molar (M) units); pKd (-log 10 (K d ), where K d given in molar (M) units); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); RT (room temperature, approximately 20°C to 25°C); T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide); TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMEDA (N 1 ,N 1 ,N 2 ,N 2 -tetramethylethylene-1,2-diamine); TMS (trimethylsilyl); and Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer).

[0058] As described below, the present disclosure relates to compounds of Formula 1, their tautomers, and pharmaceutically acceptable salts of the compounds and their tautomers, and pharmaceutically acceptable salts of compounds of Formula 1 and their tautomers. The present disclosure also relates to materials and methods for preparing compounds of Formula 1, pharmaceutical compositions containing them, and the use of compounds of Formula 1, their tautomers, and pharmaceutically acceptable salts of compounds of Formula 1 and their tautomers (optionally in combination with other pharmacologically active agents) for treating diseases, disorders, or conditions associated with MRGX2.

[0059] In addition to the specific compounds in the examples, the compounds of formula 1, Its tautomers, or pharmaceutically acceptable salts of the compound of formula 1 or its tautomers, also include the following compounds, wherein: (1) L is selected from a bond and C 1-4 Alkanediyl; R 1 Selected from (a) substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 1-4 Alkyl, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino and amino Each of the optional substituents of the carbonyl group is independently substituted with 0 to 2 independently selected from C 1-4 substituted with an alkyl substituent; and (b) Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 The optional substituents of the alkoxy, amino and aminocarbonyl groups are Generation, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 independently selected from C 1-4 substituted by an alkyl substituent; R 2 Selected from (a) substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 The C substituted with alkoxy and amino optional substituents 1-4 alkyl base; and (b) Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C3-5 The heterocyclic group may be substituted with an optional substituent, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; R 3 、R 4 and R 5 are independently selected from hydrogen, halo, cyano and C 1-3 wherein each of the above heterocyclyl and heteroaryl moieties independently has 1 to 4 heteroatoms each independently selected from N, O and S as ring members.

[0060] In addition to the embodiment (1) in the preceding paragraph, the compounds of formula 1 also include the following compounds, wherein: (2)R 1 is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 1-4 Alkyl, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0061] In addition to or as an alternative to embodiment (2) in the preceding paragraph, compounds of Formula 1 include compounds wherein: (3) R 1 C 1-4 Alkyl is selected from methyl, ethyl, propyl and isopropyl, each of which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (4) R 1 C1-4 Alkyl is selected from methyl or ethyl, each of which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (5) R 1 C 1-4 Alkyl is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkoxy, amino and aminocarbonyl optionally substituted methyl, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0062] In addition to or as an alternative to any one of embodiments (2) to (5) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (6) R 1 C 1-4 Alkyl is substituted with 0 to 3 independently selected halo, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (7) R 1 C 1-4 Alkyl is substituted with 0 to 3 independently selected halo, C 1-4 Alkoxy and aminocarbonyl are optionally substituted, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (8) R 1 C 1-4 The alkyl group is substituted with 0 to 3 groups independently selected from halo and C 1-4Alkoxy is optionally substituted with a substituent wherein the C 1-4 Each of the optional substituents of alkoxy is independently substituted with 0 to 3 substituents independently selected from halo; (9) R 1 C 1-4 Alkyl is substituted with 0 to 3 optional substituents independently selected from halo; (10) R 1 C 1-4 Alkyl is substituted with 0 to 3 optional substituents independently selected from fluoro and chloro; (11) R 1 C 1-4 The alkyl group is substituted with 0 to 3 fluorinated substituents; (12) R 1 C 1-4 Alkyl is composed of 0 to 3 independently selected C 1-4 Alkoxy is optionally substituted with a substituent wherein the C 1-4 Each of the optional substituents of alkoxy is independently substituted with 0 to 3 substituents independently selected from halo; (13) R 1 C 1-4 Alkyl is C 1-4 Alkoxy substituted, wherein the C 1-4 The alkoxy substituent is substituted with 0 to 3 substituents independently selected from halo; (14) R 1 C 1-4 Alkyl is C 1-4 Alkoxy substituted, wherein the C 1-4 The alkoxy substituent is substituted with 0 to 3 fluoro substituents; (15) R 1 C 1-4 Alkyl is C 1-4 Alkoxy substituted, wherein the C 1-4 The alkoxy substituent is unsubstituted; (16) R 1 C 1-4 The alkyl group is substituted with an unsubstituted methoxy group; or (17) R 1 C 1-4 The alkyl group is unsubstituted.

[0063] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (18)R 1 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0064] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (19)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 3-8 Cycloalkyl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (20)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 3-6 Cycloalkyl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (21)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Cyclopropyl substituted by an optional substituent of alkoxy, amino and aminocarbonyl, wherein the C 1-4 Alkyl and C 1-4Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (22)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Cyclobutyl substituted by an optional substituent of alkoxy, amino and aminocarbonyl, wherein said C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0065] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (23)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 2-9 Heterocyclic group, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (24)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 2-6 Heterocyclic group, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (25)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 3-5 Heterocyclic group, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0066] In addition to or as an alternative to any one of embodiments (23) to (25) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (26) R 1 The cyclic group has 1 or 2 heteroatoms each independently selected from N, O and S as ring members; (27) R 1 The cyclic group has 1 or 2 heteroatoms each independently selected from N and O as ring members; or (28) R 1 The cyclic group has 1 heteroatom selected from N and O as a ring member.

[0067] In addition to or as an alternative to any one of embodiments (23) to (28) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (29) R 1 Cyclic groups are monocyclic.

[0068] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (30)R 1 is a cyclic group selected from tetrahydrofuranyl and morpholinyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0069] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (31)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 6-14 Aryl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (32)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 6-10 Aryl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (33)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Phenyl substituted by an optional substituent of alkoxy, amino and aminocarbonyl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0070] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (34)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 1-9 Heteroaryl, wherein the C 1-4 Alkyl and C 1-4Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (35)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 1-5 Heteroaryl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (36)R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 3-5 Heteroaryl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0071] In addition to or as an alternative to any one of embodiments (34) to (36) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (37)R 1 The cyclic group has 1 or 2 heteroatoms each independently selected from N, O and S as ring members.

[0072] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein: (38)R 1is a cyclic group selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is substituted by 0 to 3 independently selected groups selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (39)R 1 is a cyclic group selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (40)R 1 is a cyclic group selected from furyl, pyrazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl and pyrimidinyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0073] In addition to or in lieu of any one of embodiments (18) to (40) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (41)R 1 The cyclic group is composed of 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is optionally substituted with a substituent wherein the C 1-4 Alkyl and C 1-4 Each of the optional substituents of alkoxy is independently substituted with 0 to 3 substituents independently selected from halo; or (42)R 1 The cyclic group is composed of 0 to 3 independently selected fluoro, chloro, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is optionally substituted with a substituent wherein the alkyl and C 1-4 Each of the optional substituents of the alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo.

[0074] In addition to or in lieu of any of embodiments (41) and (42) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (43)R 1 C on the cyclic group 1-4 Alkyl and C 1-4 each of the optional substituents of the alkoxy group is independently substituted with 0 to 3 substituents independently selected from fluoro and chloro; (44)R 1 C on the cyclic group 1-4 Alkyl and C 1-4 Each of the optional substituents of alkoxy is independently substituted with 0 to 3 substituents selected from fluoro; or (45)R 1 C on the cyclic group 1-4 Alkyl and C 1-4 Each of the optional substituents of the alkoxy group is unsubstituted.

[0075] In addition to or as an alternative to any one of embodiments (41) to (45) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (46)R 1 C on the cyclic group 1-4 each of the optional substituents of the alkyl group is independently selected from methyl, ethyl and isopropyl; or (47)R 1 C on the cyclic group 1-4 Each of the optional substituents of the alkoxy group is independently selected from methoxy and ethoxy.

[0076] In addition to or as an alternative to any one of embodiments (18) to (47) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (48) R 1 The cyclic group is substituted with 0 to 2 optional substituents; or (49) R 1 The cyclic group is substituted with 0 or 1 optional substituents.

[0077] In addition to or in lieu of any one of embodiments (18) to (40) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (50) R 1 The cyclic group is unsubstituted.

[0078] In addition to or as an alternative to any one of embodiments (1) to (50) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (51) L is selected from a bond, -CH2-, -CH2CH2-, and -CH(CH3)-; (52) L is selected from a bond, -CH2- and -CH2CH2-; (53) L is selected from a bond and -CH2-; (54) L is –CH2–; or (55)L is a bond.

[0079] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (56)R 2 is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 The C substituted with alkoxy and amino optional substituents 1-4 alkyl.

[0080] In addition to embodiment (56) in the preceding paragraph, compounds of Formula 1 also include compounds wherein: (57) R 2 C 1-4 Alkyl is selected from methyl, ethyl, propyl and isopropyl, each of which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 substituted with optional substituents of alkoxy and amino; (58) R 2 C 1-4 Alkyl is selected from methyl, ethyl and isopropyl, each of which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 substituted with optional substituents of alkoxy and amino; (59) R 2 C 1-4 Alkyl is selected from methyl and ethyl, each of which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 substituted with optional substituents of alkoxy and amino; (60) R 2 C 1-4 Alkyl is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 methyl substituted with optional substituents of alkoxy and amino; or (61) R 2 C 1-4 Alkyl is substituted by 0 to 3 groups independently selected from halo, hydroxy and C 1-4 The alkoxy group may be optionally substituted with a methyl group.

[0081] In addition to or as an alternative to any one of embodiments (56) to (61) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (62) R 2 C 1-4 The alkyl group is substituted with 0 to 3 groups independently selected from halo and C 1-4 substituted by an optional substituent of the alkoxy group; (63) R 2 C 1-4 Alkyl is substituted with 0 to 3 optional substituents independently selected from fluoro, chloro, methoxy and ethoxy; (64) R 2 C 1-4 Alkyl is substituted with 0 to 3 optional substituents independently selected from fluoro and methoxy; or (65) R 2 C 1-4 The alkyl group is unsubstituted.

[0082] In addition to or as an alternative to any one of embodiments (56) to (61) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (66) R 2 C 1-4 Alkyl is C 1-4 substituted with alkoxy; (67) R 2 C 1-4 the alkyl group is substituted with a methoxy or ethoxy group; or (68) R 2 C 1-4 The alkyl group is substituted with a methoxy group.

[0083] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (69)R 2 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (70)R 2 Selected from C 3-8 Cycloalkyl, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0084] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (71)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 3-8 Cycloalkyl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (72)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 3-6 Cycloalkyl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (73)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The cyclopropyl group substituted by the optional substituents of the heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (74)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The cyclobutyl group substituted by the optional substituents of the heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0085] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (75)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 2-9 heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (76)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 2-6 heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (77)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 3-5 heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0086] In addition to or in lieu of any of embodiments (75) to (77) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (78) R 2 The cyclic group has 1 or 2 heteroatoms each independently selected from N, O and S as ring members; (79) R 2 The cyclic group has 1 or 2 heteroatoms each independently selected from N and O as ring members; or (80) R 2 The cyclic group has 1 heteroatom selected from N and O as a ring member.

[0087] In addition to or as an alternative to any one of embodiments (75) to (80) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (81) R 2 Cyclic groups are monocyclic.

[0088] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (82)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 6-14 Aryl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (83)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 6-10 Aryl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (84)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The phenyl group substituted by the optional substituents of the heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0089] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (85)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 1-9 heteroaryl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (86)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 1-5 heteroaryl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (87)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The C substituted by the optional substituent of the heterocyclic group 3-5 heteroaryl, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0090] In addition to or in lieu of any of embodiments (85) to (87) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (88) R 2 The cyclic group has 1 or 2 heteroatoms each independently selected from N, O and S as ring members; or (89) R 2 Cyclic groups have 1 or 2 heteroatoms, each of which is N, as ring members.

[0091] In addition to or in lieu of any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (90)R 2is a cyclic group selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is substituted by 0 to 3 independently selected groups selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (91)R 2 is a cyclic group selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (92)R 2 is a cyclic group selected from pyrazolyl, pyridinyl and pyrimidinyl, each of which is independently selected from 0 to 3 halo, hydroxy, cyano, C1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; (93)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 pyrazolyl substituted by an optional substituent of a heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; or (94)R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The pyridyl group substituted by the optional substituents of the heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

[0092] In addition to or as an alternative to any one of embodiments (69) to (94) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (95) R 2 The cyclic group is composed of 0 to 3 independently selected halo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of heterocyclyl is independently substituted with 0 to 3 substituents independently selected from halo; or (96) R 2 The cyclic group is composed of 0 to 3 independently selected fluoro, chloro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of the heterocyclyl group is independently substituted with 0 to 3 substituents independently selected from halo.

[0093] In addition to or in lieu of any of embodiments (95) and (96) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (97)R 2 C on the cyclic group 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 each of the optional substituents of the heterocyclyl group is independently substituted with 0 to 3 substituents independently selected from fluoro and chloro; (98)R 2 C on the cyclic group 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of heterocyclyl is independently substituted with 0 to 3 substituents independently selected from fluoro; or (99)R 2 C on the cyclic group 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of the heterocyclyl group is unsubstituted.

[0094] In addition to or in lieu of any of embodiments (95) to (99) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (100)R 2 C on the cyclic group 1-4 Each of the optional substituents of the alkyl group is independently selected from methyl, ethyl, and isopropyl; (101)R 2 C on the cyclic group 1-4 Each of the optional substituents of the alkoxy group is independently selected from methoxy and ethoxy; (102)R 2 C on the cyclic group 3-8 The cycloalkyl group may optionally be substituted by a cyclopropyl group and a cyclobutyl group; (103)R 2 C on the cyclic group 3-5 The optional substituents of the heterocyclyl group have 1 or 2 heteroatoms independently selected from N, O and S as ring members; or (104)R 2 C on the cyclic group 3-5 The optional substituents of the heterocyclyl group have 1 heteroatom selected from N and O as a ring member.

[0095] In addition to or as an alternative to any one of embodiments (95) to (99), (103) and (104) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (105)R 2 C on the cyclic group 3-5 An optional substituent of a heterocyclyl group is monocyclic.

[0096] In addition to or in lieu of any of embodiments (95) to (99) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (106)R 2C on the cyclic group 3-5 An optional substituent for the heterocyclic group is oxetanyl.

[0097] In addition to or as an alternative to any one of embodiments (1) to (106) in the preceding paragraphs, compounds of Formula 1 include compounds wherein: (107)R 3 、R 4 and R 5 are independently selected from hydrogen, halo and C 1-3 alkyl; (108)R 3 、R 4 and R 5 are independently selected from hydrogen, fluoro and C 1-3 alkyl; (109)R 3 、R 4 and R 5 are each independently selected from hydrogen, fluoro and methyl; (110)R 3 and R 4 are each independently selected from hydrogen, fluoro and methyl, and R 5 is hydrogen; (111)R 4 is selected from hydrogen and fluoro, and R 3 and R 5 are each hydrogen; or (112)R 3 、R 4 and R 5 Each is hydrogen.

[0098] The compounds of formula 1 include all compounds specifically named in the embodiments (1) to (112) described in the preceding paragraphs and in the examples above, and may exist in the form of salts, complexes, solvates, hydrates, and liquid crystals. Similarly, the compounds of formula 1 as salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0099] The compound of formula 1 can form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including diacids) and basic salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid and phosphorous acid, and non-toxic salts derived from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0100] Pharmaceutically acceptable base salts include salts derived from bases including metal cations such as alkali or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, ethanolamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see SM Berge et al., J. Pharm. Sci. (1977) 66: 1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0101] Various methods can be used to prepare pharmaceutically acceptable salts. For example, the compound of formula 1 can be reacted with a suitable acid or base to obtain the desired salt. Alternatively, the precursor of the compound of formula 1 can be reacted with an acid or base to remove an acid-unstable or base-unstable protecting group or to open the lactone or lactam group of the precursor. In addition, the salt of the compound of formula 1 can be converted into another salt (or free form) by treating with a suitable acid or base or by contacting with an ion exchange resin. After the reaction, if the salt precipitates from the solution, it can be separated by filtration, or by evaporation to reclaim the salt. The degree of ionization of the salt can vary from completely ionized to almost unionized.

[0102] The compound of formula 1 can exist in a continuous solid state from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or liquid depending on the temperature. Typically, such materials do not provide a unique X-ray diffraction pattern and, although exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change in properties from solid to liquid occurs, characterized by a change in state, typically second order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and provides a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid when fully heated, but the change from solid to liquid is characterized by a phase transition, typically first order ("melting point").

[0103] The compound of formula 1 can also exist in non-solvated and solvated forms. The term "solvate" describes a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those compounds in which the solvent can be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0104] The currently recognized classification system for organic compound solvates and hydrates is a system that distinguishes isolated sites, channels and metal ion coordination solvates and hydrates.See, for example, KR Morris (HG Rittain compiles) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are solvates and hydrates in which solvent (for example, water) molecules are isolated by the organic compound molecules in between and do not directly contact each other. In channel solvates, solvent molecules are located in lattice channels, where they are adjacent to other solvent molecules. In metal ion coordination solvates, solvent molecules are bonded to metal ions.

[0105] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In these cases, nonstoichiometry is often observed.

[0106] Formula 1 compound can also exist as a multi-component complex (except salt and solvate), wherein the compound (drug) and at least one other component are present in a stoichiometric or non-stoichiometric amount. This type of complex includes clathrate (drug-host inclusion compound) and eutectic. The latter is generally defined as a crystalline complex of neutral molecular components combined together by non-covalent interactions, but can also be a complex of neutral molecules and salts. Eutectic can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. See, for example, O.Almarsson and MJZaworotko, Chem.Commun. (2004) 17: 1889-1896. For a general review of multi-component complexes, see JKHaleblian, J.Pharm.Sci. (1975) 64 (8): 1269-88.

[0107] When subjected to appropriate conditions, the compound of Formula 1 can exist in a mesomorphic state (mesophase or liquid crystal). The mesomorphic state is between a true crystalline state and a true liquid state (melt or solution). Mesomorphism that occurs due to temperature changes is described as "thermotropic", while mesomorphism caused by the addition of a second component such as water or another solvent is described as "lyotropic". Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and include compounds with polar ionic moieties (e.g., -COOˉNa + 、-COOˉK + 、-SO3ˉNa + ) or polar nonionic part (such as -NˉN + (CH3)3) molecules. See, for example, NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0108] Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0109] "Prodrug" refers to a compound with little or no pharmacological activity that can be converted into a compound with the desired pharmacological activity when metabolized in the body. Prodrugs can be prepared by replacing appropriate functional groups present in pharmacologically active compounds with "promoles", such as those described in H.Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or amide derivatives of compounds of formula 1 having carboxylic acid, hydroxyl or amino functional groups, respectively. For further discussion of prodrugs, see, for example, T.Higuchi and V.Stella "Pro-drugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and E.B.Roche, ed., Bioreversible Carriers in Drug Design (1987).

[0110] "Metabolites" refer to compounds formed in vivo after administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

[0111] The compounds of Formula 1 may exist as stereoisomers resulting from the presence of one or more stereogenic centers, one or more double bonds, or both. Stereoisomers may be pure, substantially pure, or mixtures. Such stereoisomers may also be produced by acid addition salts or base salts where the counterion is optically active, such as when the counterion is D-lactic acid or L-lysine.

[0112] The compounds of Formula 1 may exist as tautomers, which are isomers produced by tautomerization. Tautomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0113] Compounds of Formula 1 may exhibit more than one type of isomerism.

[0114] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

[0115] Conventional techniques for preparing or separating compounds with specific stereochemical configurations include synthesizing or splitting racemates (or racemates of salts or derivatives) from suitable optically pure precursor chirality, for example, using chiral high pressure liquid chromatography (HPLC). Alternatively, racemates (or racemic precursors) can react with suitable optically active compounds, such as alcohols, or when Formula 1 compound contains acidic or basic moieties, acid or alkali, such as tartaric acid or 1-phenylethylamine. The diastereomeric mixtures gained can be separated by chromatography, fractional crystallization, etc., and suitable diastereomers can be converted into compounds with required stereochemical configurations. For further discussion of the technology for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0116] The compounds of Formula 1 may have isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Suitable isotopes for inclusion in the compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; nitrogen isotopes, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; isotopes of chlorine, such as 36 Cl, and isotopes of iodine, such as 123 I and 125 I. Isotopic variations (e.g., deuterium, 2 The use of H) may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations of the disclosed compounds may contain radioactive isotopes (e.g., tritium, 3 H or 14 C), which can be used for drug and / or substrate tissue distribution studies. 11 C. 18 F. 15 O and 13N substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.Isotopically labeled compounds can be prepared by methods analogous to those described elsewhere in this disclosure using an appropriate isotopically labeled reagent in place of the unlabeled reagent.

[0117] Formula 1 compound can be prepared using the technology described below. Some schemes and embodiments may omit the details including common reactions such as oxidation and reduction, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, grinding, crystallization, etc.) and analytical procedures, which are known to those of ordinary skill in the field of organic chemistry. The detailed information of such reactions and techniques can be seen in many papers, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B.Smith et al., Compendium of Organic Synthetic Methods (1974 and later versions, etc.). Starting materials and reagents can be obtained from commercial sources, or can be prepared using literature methods. Some reaction schemes may omit the minor products (for example, the alcohol produced by ester hydrolysis, the CO produced by diacid decarboxylation, etc.) produced by chemical transformation. In addition, in some cases, the reaction intermediates can be used for subsequent steps without separation or purification (that is, in situ).

[0118] In some following reaction processes and embodiments, some compound can be prepared using protecting group, and protecting group prevents undesirable chemical reaction from occurring in other reactive sites. Protecting group can also be used for improving solubility or otherwise changing the physical property of compound. About the discussion of protecting group strategy, for installing and removing the description of the materials and methods of protecting group, and the compilation of the useful protecting group of common functional groups (including amine, carboxylic acid, alcohol, ketone, aldehyde etc.), referring to TW Greene and PGWuts, Protecting Groups in Organic Chemistry (1999), and P.Kocienski, Protective Groups (2000).

[0119] In general, the chemical transformations described throughout the specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions may benefit from using an excess of one or more reactants. In addition, many reactions disclosed throughout the specification can be carried out at approximately room temperature (RT) and ambient pressure, but some reactions may be carried out at elevated pressure or using higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C) depending on reaction kinetics, yield, etc. Any reference to stoichiometric ranges, temperature ranges, pH ranges, etc. in the present disclosure and claims, whether or not the word "range" is explicitly used, also includes the indicated endpoints.

[0120] Many chemical transformations may also utilize one or more compatible solvents, which can affect reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylene); halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy) -ethanol); ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydrothiophene-1,1,-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphorus triamide).

[0121] In the following schemes, the substituent identifiers (e.g., L, R 1 、R 2 、R 3etc.) are as defined above for Formula 1. However, as previously mentioned, some starting materials and intermediates may contain protecting groups that are removed prior to the final product. In such cases, the substituent identifiers refer to the moieties defined in Formula 1 as well as those moieties with appropriate protecting groups. For example, a starting material or intermediate in the scheme may include R having a potentially reactive amine. 2 In this case, R 2 Moieties with or without, for example, a Boc or Cbz group attached to an amine will be included.

[0122] Scheme A shows a general method for preparing compounds of Formula 1. According to this method, a 2-halogenated aniline (A-1, X = bromine, iodine) is reacted with a boronic acid or ester (A-2, wherein, for example, each R is substituted with 2-halogenated aniline) in the presence of a palladium catalyst (e.g., PdCl2(dppf), PdCl2(dppf)·CH2Cl2, Pd(PPh3)4, Pd(amphos)Cl2, etc.), a base (e.g., K2CO3, KHCO3, Na2CO3, NaHCO3, CsF, KF, etc.) and one or more polar solvents (e.g., dioxane, DMF, water, etc.). 6 H or C 1-4 alkyl) at elevated temperature (e.g., 75-130° C.) to give R 2 -substituted aniline (A-3). In the presence of a polar solvent (nitromethane), R 2 -substituted aniline is reacted with isocyanate sulfonyl chloride at a reduced temperature (e.g., -40 to 0°C) to give a urea intermediate (not shown), which is subsequently treated with aluminum trichloride at a reduced temperature (e.g., -20 to 0°C) and then at an elevated temperature (e.g., 100 to 120°C) to give the 3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide intermediate (A-4), which may exist as the corresponding tautomer, i.e., 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide derivative. After ring closure, the 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide derivative (A-4) is reacted with POCl3 in a compatible solvent at elevated temperature (e.g., 120°C) to give the 3-chloro-4H-benzo[e][1,2,4]thiadiazin-1,1-dioxide intermediate (A-5), which is subsequently reacted with R 1-L-substituted amine (A-6) is reacted in the presence of a non-nucleophilic base (e.g., DIPEA, Et3N, K2CO3, Cs2CO3, etc.) and a polar solvent (e.g., ACN, DMA, DMSO, MeOH, EtOH, i-PrOH, i-BuOH, etc.) at elevated temperature (e.g., 60-150° C.). This reaction directly or indirectly affords the compound of Formula 1, for example, after removal of protecting groups, further elaboration of functional groups, salt formation, etc. Plan A

[0123] Scheme B shows a general method for preparing compounds of Formula 1. As with Scheme A, the method starts with a 2-halogenated aniline (A-1, X = bromine, iodine), but reacts with isocyanate sulfonyl chloride in the presence of a polar solvent (nitromethane) at a reduced temperature (e.g., -40 to 0°C) to give a urea intermediate (not shown), which is then treated with AlCl3 at a reduced temperature (e.g., -20 to 0°C) and then at an elevated temperature (e.g., 100 to 120°C) to give the 3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide intermediate (B-1) or its corresponding tautomer, i.e., a 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide derivative. After ring closure, the 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide derivative (B-1) is reacted with POCl3 in a compatible solvent at elevated temperature (e.g., 120°C) to give the 3-chloro-4H-benzo[e][1,2,4]thiadiazin-1,1-dioxide intermediate (B-2), which is subsequently reacted with R 1 -L-substituted amine (A-6) is reacted in the presence of a non-nucleophilic base (e.g., DIPEA, Et3N, K2CO3, Cs2CO3, etc.) and a polar solvent (e.g., ACN, DMA, DMSO, MeOH, EtOH, i-PrOH, i-BuOH, etc.) at an elevated temperature (e.g., 60-150°C). The resulting R 1 The -L-substituted intermediate (B-3) is then reacted with a boronic acid or ester (A-2, wherein, for example, each R 6 H or C 1-4alkyl) in the presence of a palladium catalyst (e.g., PdCl2(dppf), PdCl2(dppf)·CH2Cl2, Pd(PPh3)4, Pd(amphos)Cl2, etc.), a base (e.g., K2CO3, KHCO3, Na2CO3, NaHCO3, CsF, KF, etc.) and one or more polar solvents (e.g., dioxane, DMF, water, etc.). The palladium-catalyzed cross-coupling reaction is typically carried out at an elevated temperature (e.g., 75-130° C.) and produces a compound of Formula 1 directly or indirectly, for example, after removal of protecting groups, further elaboration of functional groups, salt formation, etc. Alternatively, R 2 -Substituents can be coupled by Negishi coupling (e.g., B-3 with R 2 ZnX in a compatible solvent and a catalytic amount of S-Phos and Pd(OAc)2) or Ullman reaction (e.g., reacting B-3 with R 2 -H is installed by reaction in the presence of a non-nucleophilic base, a Cu(I) iodide catalyst, and a compatible solvent). Plan B

[0124] The methods described in these schemes can be varied as desired. For example, protecting groups can be added or removed, and the products (including intermediates) can be further processed by, for example, alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkylation, etc. to obtain the desired final product. In addition, any intermediate or final product comprising a mixture of stereoisomers can optionally be purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with an optically pure reagent as described above to obtain the desired stereoisomer.

[0125] The biopharmaceutical properties of the compound of Formula 1 (including the compounds named in the specification and pharmaceutically acceptable complexes, salts, solvates and hydrates thereof), such as solubility and stability of the solution in the pH range, permeability, etc., should be evaluated to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use can be administered as crystalline or amorphous products and can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying or radio frequency drying.

[0126] The compound of formula 1 can be administered alone or in combination with another or with one or more pharmacologically active compounds different from the compound of formula 1. Typically, one or more of these compounds are administered as a pharmaceutical composition (formulation) together with one or more pharmaceutically acceptable excipients. The choice of excipient depends on the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and methods for their preparation can be found in, for example, A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th edition, 2000).

[0127] The compound of Formula 1 can be administered orally. Oral administration may involve swallowing, in which case the compound enters the bloodstream through the gastrointestinal tract. Alternatively, or in addition, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration), such that the compound enters the bloodstream through the oral mucosa.

[0128] Formulations suitable for oral administration include solid, semisolid and liquid systems such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids or powders; lozenges that can be filled with liquids; chewables; gels; fast-dispersing dosage forms; films; ovules; sprays; and buccal or mucosal adhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose) and typically contain a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil) and one or more emulsifiers, suspending agents, or both. Liquid formulations can also be prepared by reconstitution of a solid (e.g., from a capsule).

[0129] The compounds of Formula 1 may also be used in fast dissolving, fast disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0130] For tablet dosage forms, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% of the dosage form, or more typically from about 5 wt% to about 60 wt% of the dosage form, depending on the dose. In addition to the API, the tablet may also contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorings, preservatives, and taste masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6Alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant comprises from about 1 wt % to about 25 wt % or from about 5 wt % to about 20 wt % of the dosage form.

[0131] Binders are generally used to impart cohesive quality to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0132] The tablets may also contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the surfactant may comprise from about 0.2 wt % to about 5 wt % of the tablet, and the glidant may comprise from about 0.2 wt % to about 1 wt % of the tablet.

[0133] The tablet may also contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant may comprise from about 0.25 wt % to about 10 wt % or from about 0.5 wt % to about 3 wt % of the tablet.

[0134] Tablet blends can be directly compressed or formed into tablets by rolling. Alternatively, the tablet blend or a portion of the blend can be wet, dry, or melt granulated, melt solidified, or extruded before tableting. If desired, one or more components can be size-graded by screening or grinding, or both, before blending. The final dosage form can comprise one or more layers and can be coated, uncoated, or encapsulated. An exemplary tablet can contain up to about 80 wt% of the API, about 10 wt% to about 90 wt% of a binder, about 0 wt% to about 85 wt% of a diluent, about 2 wt% to about 10 wt% of a disintegrant, and about 0.25 wt% to about 10 wt% of a lubricant. For a discussion of blending, granulation, milling, sieving, tableting, coating, and description of alternative techniques for preparing drug products, see A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H.A. Lieberman et al. (eds.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0135] The oral film that can be used for people or animals is a flexible water-soluble or water-swellable film formulation that can dissolve quickly or adhere to the mucous membrane. In addition to API, typical film also includes one or more film-forming polymers, adhesives, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Other film components may include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, fillers, defoamers, surfactants and taste masking agents. Some components of preparations may exercise more than a function.

[0136] In addition to dosing requirements, the amount of API in the film can also depend on its solubility. If it is water-soluble, the API will generally account for about 1 wt% to about 80 wt% of the non-solvent component (solute) in the film, or about 20 wt% to about 50 wt% of the solute in the film. APIs with poor solubility can account for a larger proportion of the composition, typically up to about 88 wt% of the non-solvent component in the film.

[0137] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and typically comprises from about 0.01 wt % to about 99 wt % or from about 30 wt % to about 80 wt % of the film.

[0138] Thin-film dosage forms are typically prepared by evaporative drying of an aqueous film coated onto a peelable backing support or paper, which can be performed in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in a lyophilizing apparatus, or in a vacuum oven.

[0139] Useful solid formulations for oral administration may include immediate release formulations and modified release formulations. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. For a general description of suitable modified release formulations, see U.S. Patent 6,106,864. For detailed information on other useful release technologies such as high-energy dispersion and osmotic and coated particles, see RK Verma and S. Garg, Pharmaceutical Technology On-line (2001) 25 (2): 1-14.

[0140] The compound of formula 1 can also be administered directly into the bloodstream, muscle or internal organs of a subject. Suitable parenteral administration techniques include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration. Applicable devices for parenteral administration include needle syringes, including microneedle syringes, needle-free syringes and infusion devices.

[0141] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (e.g., pH about 3 to about 9). However, for some applications, the compound of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dry form to be used with a suitable vehicle such as sterile pyrogen-free water. Preparation of parenteral formulations under aseptic conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques.

[0142] The solubility of the compound for preparing parenteral solution can be improved by appropriate formulation technology, for example, by introducing solubility enhancer.Preparations for parenteral administration can be formulated to release immediately or improve release.Improved release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.Therefore, Formula 1 compound can be formulated into suspension, solid, semisolid or thixotropic liquid, to be used as an implant reservoir for providing improved release of active compound.The example of such preparation includes drug-coated stent and semisolid and suspension comprising drug-loaded poly (DL-lactic acid-co-glycolic acid) (PGLA) microspheres.

[0143] Formula 1 compound can also be applied topically, intradermally or transdermally to the skin or mucous membrane. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, membranes, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers can include alcohol, water, mineral oil, liquid petrolatum, white vaseline, glycerol, polyethylene glycol and propylene glycol. Topical formulations can also include penetration enhancers. See, for example, B.C. Finnin and T.M. Morgan, J. Pharm. Sci. 88 (10): 955-958 (1999).

[0144] Other local delivery methods include electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject TM and Bioject TM ) injection. Formulations for topical administration may be formulated to be immediate release or modified release as described above.

[0145] The compound of formula 1 can also be administered intranasally or by inhalation, typically in the form of a dry powder, aerosol spray, or nasal drops. An inhaler can be used to administer a dry powder comprising a separate API, a powder blend of an API and a diluent such as lactose, or mixed component particles comprising an API and a phospholipid such as phosphatidylcholine. For intranasal use, the powder can comprise a bioadhesive, such as chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer can be used to produce an aerosol spray from a solution or suspension comprising the API, one or more agents for dispersing, dissolving, or prolonging the release of the API (e.g., EtOH with or without water), one or more solvents acting as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligomeric lactic acid. An electrohydrodynamic atomizer can be used to produce a fine mist.

[0146] Prior to use in a dry powder or suspension formulation, the drug product is typically comminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles are less than 5 microns in their largest dimension, based on volume). This can be achieved by any suitable size reduction method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0147] Capsules, blisters, and cartridges (made, for example, of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator may be formulated containing a powder mix of the active compound, a suitable powder base such as lactose or starch, and a modifier such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0148] Suitable solution formulations for atomizers that use electrohydrodynamics to generate a fine mist can contain about 1 μg to about 20 mg of API per actuation, and the actuation volume can vary from about 1 μL to about 100 μL. Typical formulations can include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0149] Formulations for inhaled administration, intranasal administration, or both can be formulated for immediate release or modified release using, for example, PGLA. Suitable flavorings, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, can be added to formulations intended for inhaled / intranasal administration.

[0150] In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. The unit is typically arranged to administer a metered dose or "puff" containing from about 10 μg to about 1000 μg of API. The total daily dose is generally in the range of from about 100 μg to about 10 mg, which can be administered in a single dose or, more typically, in divided doses throughout the day.

[0151] The active compound can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration may be formulated to be immediate release or modified release as described above.

[0152] Formula 1 compound can also be directly applied to eyes or ears, usually in the form of drops of micronized suspension or solution in isotonic, pH-regulated sterile saline.Other preparations suitable for eye and ear administration include ointment, gel, biodegradable implant (such as absorbable gel sponge, collagen), non-biodegradable implant (such as silicone resin), film tablet, lens and microparticle or vesicle system, such as vesicle (niosome) or liposome.The preparation can include one or more polymers and preservatives, such as benzalkonium chloride.Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer (such as, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose) and heteropolysaccharide polymer (such as, gellan gum (gelan gum)).Such preparations can also be delivered by iontophoresis.Preparations for eye or ear administration can be formulated into immediate release or improved release as described above.

[0153] In order to improve their solubility, dissolution rate, taste masking, bioavailability or stability, the compounds of Formula 1 can be combined with soluble macromolecular entities including cyclodextrins and their derivatives and polyethylene glycol-containing polymers. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct compounding with the API, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents or solubilizers. α-, β- and γ-cyclodextrins are commonly used for these purposes. See, for example, WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0154] As described above, one or more compounds of Formula 1, including the compounds specifically named above, and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof, can be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions, or disorders. In such cases, the active compounds can be combined in a single dosage form as described above, or can be provided in the form of a kit suitable for co-administration of the composition. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device for separately storing the two pharmaceutical compositions, such as a separate bottle or a separate foil packet. An example of such a kit is a common blister package for packaging tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or for administering different pharmaceutical compositions at different dosing intervals, or for titrating different pharmaceutical compositions against each other. To aid patient compliance, the kit typically includes instructions for administration and may be provided with a memory aid.

[0155] For use to human patients, according to the route of administration, the total daily dose of the compound claimed and disclosed is generally in the range of about 0.1 mg to about 3000 mg. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may only require a total daily dose of about 0.1 mg to about 300 mg. The total daily dose can be used in a single dose or divided dose, and according to the doctor's judgment, it is possible to exceed the typical range given above. Although these dosages are based on the average human subjects of about 60 kg to about 70 kg body weight, the doctor can determine appropriate dosage for the patient (for example, pediatric patient) whose body weight falls outside the weight range.

[0156] The compounds of Formula 1 can be used to treat diseases, disorders or conditions for which inhibition of MRGX2 is indicated. These diseases, disorders or conditions include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis, rosacea, chronic urticaria, atopic dermatitis, rheumatoid arthritis, bronchial asthma, irritable bowel syndrome (IBS), systemic mastocytosis, cutaneous mastocytosis, mast cell enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergies, pruritus, allergic rhinitis, microbial infections, eosinophilic esophagitis (EOE) and chronic pain.

[0157] The claimed and disclosed compounds can be combined with one or more other pharmacologically active compounds or therapies to treat one or more diseases, disorders or conditions associated with MRGX2. Such combinations can provide significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity. For example, a compound of Formula 1 or a tautomer thereof, including compounds specifically named in the specification, and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof, can be administered simultaneously, sequentially, or separately in combination with one or more anti-inflammatory agents, analgesics, biological response modifiers, disease-modifying antirheumatic drugs (DMARDs), antihistamines, mast cell stabilizers, prokinetics, antidiarrheals, secretagogues, antibiotics, antidepressants, anxiolytics, antipsychotics, and anticonvulsants.

[0158] Formula 1 compound can be combined with anti-inflammatory agent, and anti-inflammatory agent includes non-steroidal anti-inflammatory drug (NSAID) and corticosteroid.Representational non-steroidal anti-inflammatory drug includes azapropazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate and sulindac.Representational corticosteroid includes betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and prednisone.

[0159] Alternatively or additionally, the compound of Formula 1 can be combined with an analgesic, a biological response modifier, a DMARD or some combination thereof. Representative analgesics include acetaminophen and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene and tramadol, all with or without acetaminophen. Representative biological response modifiers include TNF-α inhibitors, such as adalimumab, etanercept and infliximab; selective B cell inhibitors, such as rituximab; IL-1 inhibitors, such as anakinra, and selective costimulatory modulators, such as abatacept. Representative DMARDs include auranofin (oral gold), azathioprine, chlorambucil, cyclophosphamide, cyclosporine, sodium thiomalate (gold for injection), hydroxychloroquine, leflunomide, methotrexate, minocycline, mycophenolate mofetil, penicillamine, sulfasalazine and JAK3 inhibitors (e.g., tofacitinib).

[0160] Useful combinations include a compound of Formula 1 and methotrexate; a compound of Formula 1 and one or more biologic response modifiers, such as leflunomide, etanercept, adalimumab, and infliximab; or a compound of Formula 1, methotrexate, and one or more biologic response modifiers, such as leflunomide, etanercept, adalimumab, and infliximab.

[0161] Additionally or alternatively, Formula 1 compound can be combined with antihistamines, mast cell stabilizers, prokinetics, antidiarrheals, secretagogues, antibiotics or some of their combinations. Representational antihistamines include H1-antihistamines (e.g., acrivastine, azelastine, bilastine, brompheniramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethylindane, diphenhydramine, doxylamine, ebastine, embramin, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, ol These include pheniramine, phenazone, orphenadrine, phenindrine, pheniramine, phenyltoloxamine, promethazine, rupatadine, tripeliramine, and triprolidine), H1 inverse agonists (e.g., cimetidine, famotidine, lafutidine, nizatidine, ranitidine, and roxatidine), H3-antihistamines (e.g., clobenpropit, ciproxifan, conessine, and thioperamide), and H4-antihistamines (e.g., thioperamide).

[0162] Representative mast cell stabilizers include azelastine, β2 adrenergic receptor agonists (e.g., abediterol, arformoterol, bambuterol, bitolterol, carmoterol, clenbuterol, fenoterol, formoterol, indacaterol, isoproterenol, isoxazolamide, levalbuterol, mabuterol, olodaterol, metaproterenol, pirbuterol, procaterol, ritodrine, albuterol, terbutaline, vilanterol, and zilpaterol), cromolyn, ketotifen, mepolizumab, nedocromil, olopatadine, omalizumab, palmitoylethanolamide, pemirolast, quercetin, rupatadine, tranilast, and vitamin D.

[0163] Representative prokinetic agents include cinipride, cisapride, domperidone, itopride, levosulpride, linaclotide, metoclopramide, mitecina, mosapride, prucalopride, renzapride, and tegaserod. Representative antidiarrheal drugs include bismuth subsalicylate, crofelemer, diphenoxin hydrochloride / atropine, diphenoxylate hydrochloride / atropine, loperamide, loperamide / simethicone, octreotide, and paregoric. Representative secretagogues include lubiprostone, linaclotide, plecanatide, and elobixibat. Representative antibiotics include tetracycline, amoxicillin clavulanate, metronidazole, fluoroquinolones (e.g., norfloxacin), and rifaximin.

[0164] In addition or alternatively, Formula 1 compound can be with antidepressant, antipsychotic, antianxiety drug, anticonvulsant or other drug combinations for the treatment of neurological or psychiatric disorders.For example, Formula 1 compound can be with antidepressant combination including tricyclic antidepressants, selective serotonin reuptake inhibitor (SSRI) or selective serotonin and norepinephrine reuptake inhibitor (SNRI), or with antipsychotic combination including atypical antipsychotic or some combination thereof.Representational antidepressant includes amitriptyline, amoxapine, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, imipramine, isocarboxazid, levmilnacipran, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone and vortioxetine. Representative antipsychotics include aripiprazole, asenapine, chlorpromazine, clozapine, desipramine, fluphenazine, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, perphenazine, quetiapine, risperidone, and ziprasidone.

[0165] Likewise, Formula 1 compound can be combined with one or more medicaments (anxiolytics) for the treatment of anxiety disorders or medicaments (antiepileptics or anticonvulsants) for the treatment of epilepsy or some of its combinations. Representative anxiolytics include benzodiazepines (e.g., alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepam, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), non-benzodiazepines (e.g., eszopiclone, zaleplon, zolpidem, and zopiclone) and buspirone. Representative anticonvulsants include acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0166] Biological activity

[0167] The activity of exemplified compounds can be determined by a variety of methods, including in vitro and in vivo methods.

[0168] In vitro inhibition of intracellular calcium flux (EC 50 )

[0169] Using FLIPR The system measures the release of intracellular calcium after stimulation of cells with substance P in the presence or absence of inhibitor compounds. CHO-K1 cells overexpressing MRGX2 were seeded into 384-well plates (black clear bottom, TC treated, Fisher #07-200-655) and incubated overnight to allow cell attachment. The culture medium was removed and 1X loading buffer ( Calcium 5 assay solution, Molecular Devices, according to the manufacturer's instructions). The plate was incubated at 37°C for 30 minutes. Test compounds were added to the cells (11-point dose response, 10 μM maximum concentration) and analyzed using FLIPR The system measures fluorescence (120 seconds, real time). Immediately thereafter, the MRGX2 ligand substance P was added at a final concentration of 1 μM and the fluorescence was measured using the FLIPR The system measures fluorescence (120 seconds, real time). The data in the examples are reported as pEC 50 .

[0170] In vitro radioligand binding assay (K d )

[0171] The equilibrium dissociation constants K for a number of compounds described in the Examples section ("test compounds") were determined in the presence of cell membranes prepared from the SF9 cell line overexpressing the human MRGX2 receptor. d The assay was performed in a 96-well plate (Greiner V-Bottom #651201). A fixed amount of cell membrane preparation (75 μg / well, final concentration) and 3H-labeled ligand, 3-(((furan-2-yl-4,5-t2)methyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Quotient Bioresearch, 40 μM final concentration), and a series of (unlabeled) test compounds (8-point dose response curve, 10 μM maximum concentration, 4-fold serial dilution) in 50 mM HEPES buffer containing 10 mM MgCl2, 0.01% Triton X-100, 200 μM EDTA, pH 7.4. The assay mixture containing MRGX2 receptor, radiolabeled ligand, and test compound was incubated at room temperature (~22°C) for 60 minutes to reach equilibrium. After incubation, the assay mixture was collected onto a filter mat (Filtermat A, PerkinElmer) using a cell harvester (Harvester 96, TOMTEC). The filter mat was completely dried. Solid scintillant (Meltilex, Perkin Elmer) was added to each filter membrane, and the level of radioactivity ("signal") from each well (assay mixture) was recorded using a scintillation counter (Trilux Microbeta, Perkin Elmer). K was determined by curve fitting the dose response data ([I], signal) for each set of samples to the following equation: d , where [I] is the concentration of the test compound. Data are reported as pK d . Example

[0172] The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the invention.

[0173] Many of the compounds in the following examples were obtained 1 H nuclear magnetic resonance (NMR) spectra. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, and the main peaks are assigned using conventional abbreviations, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad peak). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), CD3OD (deuterated methanol), CD3CN (deuterated acetonitrile), and THF-d8 (deuterated tetrahydrofuran). Mass spectra (for [M+H]) were recorded using electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry. + m / z).

[0174] Where indicated, products of certain preparations and examples were analyzed by mass-triggered HPLC (e.g., pump: Waters TM 2525;MS:ZQ TM Software: MassLynx TM ), flash chromatography, or preparative thin layer chromatography (TLC). Reverse phase chromatography is typically performed under acidic conditions ("acid mode") on a column (e.g., Phenomenex Gemini TM 5μ, C18, 30mm x 150mm; Axia TM , 5μ, 30mm x 75mm), eluted with CH3CN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or eluted under basic conditions ("base mode") with water and 20 / 80 (v / v) water / acetonitrile mobile phases, both containing 10mM NH4HCO3. Preparative TLC is usually carried out on silica gel 60F 254 After chromatography, the solvent is removed and the mixture is evaporated in a centrifugal evaporator (e.g., GeneVac TM ), a rotary evaporator, a vacuum flask, etc. to obtain the product. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H2) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0175] Preparation 1: 3-Chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0176] To a suspension of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (3 g, 8.76 mmol) and (2-chloro-3-fluorophenyl)boronic acid (1.833 g, 10.51 mmol) in dioxane (20 mL) and saturated (aq) NaHCO3 (20 mL) was added PdCl2(dppf) (0.641 g, 0.876 mmol). The mixture was heated at 75 ° C in a microwave reactor for 30 minutes. The residue was diluted with EtOAc and washed with saturated (aq) NH4Cl (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (Teledyne ISCO CombiFlash TM , 120 g column) eluting with a gradient of 30-100% EtOAc in hexanes. The title compound was isolated as a brown solid (1.00 g, 33%).

[0177] Preparation 2: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0178] Step A: 2'-Chloro-3',5-difluoro-[1,1'-biphenyl]-2-amine

[0179] To a 300 mL thick-walled flask was added (2-chloro-3-fluorophenyl)boric acid (5.51 g, 31.6 mmol), 2-bromo-4-fluoroaniline (5 g, 26.3 mmol) and PdCl (dppf) (1.925 g, 2.63 mmol) in dioxane (60 mL) and saturated (aq) NaHCO (60.0 mL) to give an orange solution. The flask was sealed, heated to 100° C. and stirred for 18 hours. The reaction mixture was partially concentrated, then diluted with EtOAc and washed with saturated (aq) NH Cl (3 x 100 mL). The combined organic layers were dried over MgSO , filtered, and concentrated in vacuo. The product was purified by column chromatography (Teledyne ISCO CombiFlash TM , 120 g column) using a gradient of 10-90% EtOAc in hexanes. The title compound was isolated as a red oil (3.75 g, 60%); ESI-MS m / z [M+H] + 239.4.

[0180] Step B: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0181] Isocyanate sulfonyl chloride (1.907mL, 21.91mmol) and nitromethane (10mL) were added to a 200mL round-bottom flask. The mixture was cooled to 0°C. Next, 2'-chloro-3',5-difluoro-[1,1'-biphenyl]-2-amine (3.75g, 15.7mmol) in nitromethane (40mL) was added dropwise to give a yellow solution. The reaction mixture was stirred at 0°C for 30 minutes. Aluminum chloride (3.13g, 23.47mmol) was added and the reaction mixture was heated to 120°C for 1.5 hours. After the reaction, the mixture was concentrated, diluted with EtOAc, and washed with saturated (aq) NH4Cl (3x 80mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a brown solid. The product was purified by column chromatography (Teledyne ISCO CombiFlashTM , 120 g column) eluting with a gradient of 30-100% EtOAc in hexanes. The title compound was isolated as a tan solid (2.57 g, 48%). 1 HNMR (400MHz, DMSO-d6), δppm 7.27 (d, J=7.07Hz, 1H), 7.42-7.63 (m, 3H), 7.79 (dd, J=7.07, 2.53Hz, 1H), 10.20 (br s, 1H).

[0182] Step C: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0183] To a 200mL round-bottom flask was added 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (2.57g, 7.46mmol) in POCl3 (50mL, 536mmol) and N,N-diethylaniline (1.716mL, 10.73mmol) to give a black solution. The reaction mixture was heated to 120°C and stirred for 5 hours, then cooled to ambient temperature and stirred overnight. The reaction mixture was poured into ice water and stirred for 2 hours. The black oil eventually formed a brown precipitate, which was collected by vacuum filtration and dried in vacuo to give the title compound (2.55g, 65%) as a brown solid. The product was used without further purification.

[0184] Preparation 3: (3-Fluoropyridin-2-yl)methanamine

[0185] 3-Fluorocyanopyridine (500mg, 4.10mmol) in EtOH (25mL) and hydrochloric acid (12M, 1.02mL) stirred solution and H2 in the presence of catalyst (10% Pd / C, 200mg) under 50psi reaction for 16 hours. The progress of hydrogenation reaction was monitored by TLC. After the reaction was completed, the mixture was filtered to remove the catalyst. The solvent was removed under reduced pressure, and the gained solid was suspended in acetonitrile and filtered to obtain the HCl salt of the title compound (700mg), which was used without further purification. 1 H NMR (400MHz, CDCl3) δppm 8.54 (br s, 2H), 8.49 (d, J = 4.8Hz, 1H), 7.83 (dt, J = 1.1, 9.2Hz, 1H), 7.54 (td, J = 4.4, 8.4Hz, 1H), 4.40-4.12 (m, 2H).

[0186] Preparation 4: 3-(((3-fluoropyridin-2-yl)methyl)amino)-5-iodo-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0187] Under stirring at 80 ° C, to a solution of (3-fluoropyridin-2-yl)methylamine (1.06 g, 3.08 mmol) and 3-chloro-5-iodo-4H-benzo [e] [1,2,4] thiadiazine 1,1-dioxide (500 mg, 3.08 mmol) in 10 mL of isopropanol was added Et3N (1.28 mL, 9.24 mmol). The reaction mixture was stirred at 80 ° C for 30 minutes, at which time TLC monitoring (DCM / MeOH = 10: 1 mobile phase) showed that the reaction was complete. The volatiles were removed in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with a gradient of 50-80% EtOAc in petroleum ether to give the title compound (1.20 g) as a light yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.62(s,1H),8.84(t,J=4.8Hz,1H),8.46(d,J=4.8Hz,1H),8.09(dd,J=1.2,7.8Hz,1H),7.78(t,J=9.2Hz,1H),7 .71(d,J=7.8Hz,1H),7.48(td,J=4.4,8.4Hz,1H),7.08(t,J=7.8Hz,1H),4.68(d,J=3.6Hz,2H); ESI-MSm / z[M+H] + 433.0.

[0188] Preparation 5: 3-Chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0189] Step A: 2'-Chloro-5-fluoro-[1,1'-biphenyl]-2-amine

[0190] To a solution of 2-bromo-4-fluoro-aniline (5.00 g, 26.31 mmol) and (2-chlorophenyl)boronic acid (4.53 g, 28.94 mmol) in dioxane (50.00 mL) was added Pd(dppf)Cl (962.56 mg, 1.32 mmol) and NaHCO (4.42 g, 52.62 mmol) in H O (10.00 mL). The mixture was purged with N (3x) and heated to 120 ° C for 2 hours. The solvent was removed in vacuo, and residue was distributed between H O (80 mL) and EtOAc (50 mL). The water layer was extracted with EtOAc (3x 30 mL). The organic layers were merged, washed with salt water (50 mL) and dried over Na SO. The crude product was purified by column chromatography (ISCO 80 g column) eluting with a gradient of EtOAc / petroleum ether (1:50-1:8) to give the title compound (5.18 g, 89%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δppm 3.44(br s,2H),6.73(dd,J=4.9,8.8Hz,1H),6.81(dd,J=2.9,9.0Hz,1H),6.94(dt,J=2.9,8.5Hz,1H),7.42-7.29(m,3H),7.57-7.48(m,1H).

[0191] Step B: 5-(2-Chlorophenyl)-7-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0192] At -5 ℃ to 0 ℃, to isocyanic acid sulfonyl chloride (4.96g, 35.06mmol) in nitromethane (60.00mL) solution, add 2 '-chloro-5-fluoro-[1,1 '-biphenyl] -2-amine (5.18g, 23.37mmol). The resulting mixture was stirred at -5 ℃ to 0 ℃ for 30 minutes, then AlCl3 (6.23g, 46.74mmol, 2.55mL) was added. The reaction mixture was heated to 120 ℃ and kept for 1.5 hours, then cooled to 25 ℃, poured into ice water (200mL) and stirred for 30 minutes. The precipitate was collected by filtration. The collected solid was dissolved in EtOAc (50mL) and washed with saturated (aq) NaHCO3 solution (3x 50mL). The combined aqueous layers were adjusted to pH 1 with concentrated (aq) HCl and extracted with EtOAc (3x 30mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the title compound (3.80 g, 50%) as a dark solid. 1H NMR (400MHz, DMSO-d6) δppm 7.55-7.39 (m, 4H), 7.65-7.57 (m, 1H), 7.79 (dd, J = 2.8, 7.1Hz, 1H), 10.32 (s, 1H).

[0193] Step C: 3-Chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0194] To a solution of 5-(2-chlorophenyl)-7-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.00 g, 3.06 mmol) in POCl3 (15.00 mL) was added N,N-diethylaniline (456.74 mg, 3.06 mmol, 491.12 μL). The solution was heated to 120 ° C for 20 hours, then cooled to 25 ° C, poured into ice water (100 mL), and stirred for 1 hour. The mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (900 mg, 85%) as a dark solid. The product was used without further purification.

[0195] Preparation 6: 3-Chloro-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0196] To a 20 mL microwave vial equipped with a stirrer was added (2,3-difluorophenyl)boronic acid (0.507 g, 3.21 mmol), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.00 g, 2.92 mmol), CsCO (2 M, 3.65 mL, 7.30 mmol), and Pd(dppf) CHCl adduct (0.238 g, 0.292 mmol) dissolved in dioxane (14.60 mL). The reaction mixture was heated at 120°C in a microwave reactor for 30 minutes and then diluted in deionized water (~100 mL). 1N (aq) HCl was then added dropwise until a precipitate formed. The solid was collected by vacuum filtration through a Kiriyama Rohto SB-40 glass filter funnel and washed with copious amounts of deionized water followed by hexanes. The filter cake was dried in a vacuum oven to give the title compound as a (crude) solid (1.164 g).

[0197] Preparation 7: 3-Chloro-5-(2-chloro-3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0198] The title compound was prepared in a manner similar to that of Preparation 6 using (2-chloro-3,5-difluorophenyl)boronic acid (90 mg, 0.467 mmol), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (80 mg, 0.234 mmol), Cs2CO3 (2 M, 0.292 mL, 0.584 mmol) and Pd(dppf)2·CH2Cl2 adduct (19.07 mg, 0.023 mmol) dissolved in dioxane (1168 μL) and isolated as a (crude) solid (56.2 mg). ESI-MS m / z [M+H] + 362.9.

[0199] Preparation 8: 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0200] To a flask containing 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (2 g, 5.84 mmol) and a solution of K2CO3 (0.807 g, 5.84 mmol) in DMA (11.68 mL) was added 2-methoxyethylamine (0.554 mL, 6.42 mmol). The reaction mixture was heated at 100 ° C for 2 hours, then cooled and diluted with water (300 mL). The organic phase (oil) was collected at the bottom of the flask. The aqueous phase was decanted and extracted with DCM (3 x 50 mL). The organic layer was merged with oil and concentrated to give the title compound (1.8 g, 81%) as an orange-brown solid.

[0201] Preparation 9: 3-Chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0202] Under nitrogen, a stirring vessel equipped with 3-chloro-5-iodo-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide (1.000 g, 2.92 mmol), (2-chlorophenyl)boronic acid (0.479 g, 3.07 mmol), Cs2CO3 (5.84 mL, 11.68 mmol) and dioxane (14.60 mL) were added to a 20 mL microwave vial with Pd(dppf)2·CH2Cl2 adduct (0.238 g, 0.292 mmol). The reaction mixture was heated to 120°C in a microwave reactor for 15 minutes and then poured into water (200 mL). 1N HCl(aq) was added until a tan solid began to form. The solid was filtered and washed with plenty of water followed by hexanes to give the title compound (0.95 g, 99%). ESI-MS m / z[M+H] + 326.9.

[0203] Preparation 10: 3-Chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0204] To a 20 mL pressurized microwave vial equipped with a stir bar was added 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (750 mg, 2.91 mmol), 3-chloro-5-iodo-4H-benzo[iota]-pyridine (750 mg, 2.91 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (750 mg, 2.91 mmol). [e][1,2,4]thiadiazine 1,1-dioxide (907 mg, 2.65 mmol), cesium fluoride (aq) (1.006 g, 6.62 mmol) and Pd(dppf)2·CH2Cl2 adduct (216 mg, 0.265 mmol). The reaction mixture was heated at 120 ° C for 30 minutes in a microwave reactor. 1N (aq) HCl was then added to precipitate the solid from the solution. The solid was collected by vacuum filtration through a Kiriyama Rohto SB-21 glass filter funnel and washed with plenty of deionized water and then with hexane. The filter cake was dried in a vacuum oven to give the title compound (933.8 mg, 2.70 mmol) as a (crude) solid, which was used to prepare Examples 48, 49, 50 and 51.

[0205] To reduce the Pd content, a portion of the crude product (400 mg) was dispersed in EtOH (5 mL), 1,4-diazabicyclo[2,2,2]octane activated carbon (10% by weight, 40 mg) was added, and the mixture was heated at 60° C. for 2.5 h. The mixture was then washed with MeOH. Filtration through a prepacked plug and concentration in vacuo afforded the title compound used to prepare Examples 52, 53, 54 and 55 (296.3 mg).

[0206] Preparation 11: 3-chloro-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0207] A 20 mL microwave vial equipped for stirring was charged with 1,3-dimethyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (421 mg, 1.898 mmol), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (500 mg, 1.460 mmol), Cs2CO3 (2.919 mL, 5.84 mmol) and Pd(dppf)2·CH2Cl2 adduct (119 mg, 0.146 mmol) and dioxane (7.298 mL). The reaction mixture was heated at 120 ° C for 30 minutes in a microwave reactor, then diluted in deionized water (75 mL) and extracted with DCM / IPA (4x). Only the nominal amount of product entered the organic phase. The aqueous phase was concentrated with 60 Å silica gel and the residue was purified by normal phase column chromatography ( The product was purified by HPLC (1 / 2 column) eluting with 80 / 20 DCM / MeOH. The fractions containing the product were collected, concentrated, and dried under vacuum to give the title compound (549.8 mg) as the major product. ESI-MS m / z [M+H] + 311.0.

[0208] Preparation 12: 3-Chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0209] A 20 mL pressurized microwave vial equipped for stirring was charged with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (700 mg, 2.044 mmol), (3,5-difluorophenyl)boronic acid (355 mg, 2.248 mmol), CsCO (2.55 mL, 5.11 mmol) and Pd(dppf) CHCl adduct (167 mg, 0.204 mmol) dissolved in dioxane (10.2 mL). The reaction mixture was heated at 120 ° C for 30 minutes in a microwave reactor and then diluted in approximately 100 mL of deionized water. 1N HCl (approximately 3 mL) was added dropwise to the mixture until a precipitate formed. The solid was collected by vacuum filtration through a Kiriyama Rohto SB-40 glass funnel and washed with plenty of deionized water, followed by washing with hexane to give the title compound (779.6 mg) as a pale pink solid. The crude product was dried in a vacuum oven before use.

[0210] Preparation 13: 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0211] To a 20 mL vial was added 3-chloro-5-iodo-4H-benzo[theta] in DMA (7 mL). [e][1,2,4]thiadiazine 1,1-dioxide (800 mg, 2.34 mmol), methylamine (2 M in MeOH, 1.518 mL, 3.04 mmol) and DIPEA (0.408 mL, 2.335 mmol) gave a yellow solution. The reaction mixture was heated to 80 ° C and stirred overnight. LC / MS indicated that the reaction was complete. The reaction mixture was then diluted with EtOAc and washed with saturated (aq) NH4Cl (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 40g column) eluting with a gradient of 30-100% EtOAc in hexane to give the title compound (356 mg, 45%) as a brown oil. ESI-MSm / z [M + H] + 338.

[0212] Preparation 14: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0213] Step A: 5-Bromo-3-hydroxy-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0214] 2-Bromo-4-methylaniline (700mg, 3.76mmol) in nitromethane (5mL) was added to a 25mL round-bottom flask, and the reaction mixture was cooled to -40°C. Isocyanate sulfonyl chloride (0.425mL, 4.89mmol) was added, and the reaction mixture was slowly warmed to 25°C and stirred for another 30 minutes. Next, aluminum chloride (602mg, 4.51mmol) was added. The reaction mixture was heated at 100°C for 1.5 hours, cooled to 25°C, poured into ice water, and ultrasonicated to obtain a tan precipitate. Solids were collected by vacuum filtration and vacuum dried to obtain the title compound (685mg, 63%). 1 H NMR (400MHz, DMSO-d6), δppm 2.4 (s, 3H), 4.4 (s, 1H), 7.6 (s, 1H), 7.8 (s, 1H), 10.3 (s, 1H).

[0215] Step B: 5-Bromo-3-chloro-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0216] To a 50 mL round-bottom flask was added 5-bromo-3-hydroxy-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (685 mg, 2.353 mmol) in nitromethane (12 mL). To the resulting brown solution was added separate POCl3 (1.382 mL, 14.82 mmol) and N,N-diethylaniline (0.151 mL, 0.941 mmol). The reaction mixture was heated to 100 ° C for 16 hours, then cooled to 0 ° C, quenched with water and sonicated to obtain a precipitate. The solid was collected by vacuum filtration to give the title compound (160 mg, 22%) as a tan solid. The product was used without purification. 1 H NMR (400MHz, DMSO-d6), δppm2.4(s,3H),7.5(s,1H),7.7(s,1H).

[0217] Step C: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0218] 5-Bromo-3-chloro-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (160 mg, 0.517 mmol), Pd2Cl2(dppf) (3.78 mg, 5.17 μmol), (2-chloro-3-fluorophenyl)boronic acid (108 mg, 0.620 mmol) and saturated (aq) NaHCO3 (3.0 mL) were added to a 5 mL microwave vial. The reaction mixture was heated at 75 ° C for 1 hour in a microwave reactor, then diluted in EtOAc and washed with saturated (aq) NH4Cl (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (ISCO 4 g column) eluting with a gradient of 30-100% EtOAc in hexane to give the title compound (44 mg, 24%) as a yellow oil. ESI-MS m / z [M+H] + 359.0.

[0219] Preparation 15: 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0220] A 100 mL round-bottom flask was charged with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (750 mg, 2.190 mmol), 4-isopropylaniline (0.449 mL, 3.28 mmol), Et3N (0.916 mL, 6.57 mmol) and EtOH (20 mL). The resulting brown solution was heated to 65 ° C and stirred overnight. LC / MS showed that the reaction was not yet complete. The reaction mixture was stirred again overnight, after which LC / MS showed that the reaction was essentially complete. The reaction mixture was then concentrated, absorbed in EtOAc, and washed with saturated (aq) NH4Cl (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 40g column) eluting with a gradient of 30-100% EtOAc in hexane to give the title compound as a purple solid. ESI-MSm / z [M + H] + 442.

[0221] Preparation 16: 5-iodo-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0222] To a solution of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol) in EtOH (mL) was added 3-isopropylaniline (74.0 mg, 0.547 mmol) followed by Et3N (0.102 mL, 0.730 mmol). The reaction mixture was heated at 80°C for 2 days and allowed to stand (first reaction mixture). To a 10 mL vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol), 3-isopropylaniline (64.1 mg, 0.474 mmol) and DIPEA (0.127 mL, 0.730 mmol) in DMA (3.5 mL). The second reaction mixture was heated to 100°C and stirred for 18 hours. The second reaction mixture was combined with the first reaction mixture, diluted with EtOAc, and washed with saturated (aq) NH4Cl (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO) eluting with a gradient of 20-70% EtOAc in hexanes to give the title compound (118 mg, 37%). ESI-MS m / z [M+H] + 442.1.

[0223] Preparation 17: 5-iodo-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0224] To a solution of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol) in EtOH (3.5 mL) was added 6-isopropylpyridin-3-amine (74.5 mg, 0.547 mmol) followed by Et3N (0.102 mL, 0.730 mmol). The reaction mixture was heated at 80°C for 3 days to yield the first crop of product (~50% conversion of starting material). To a 10 mL vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol), 6-isopropylpyridin-3-amine (64.6 mg, 0.474 mmol), and DIPEA (0.127 mL, 0.730 mmol) in DMA (3.5 mL). The reaction mixture was heated to 100° C. and stirred for 2 days to give a second batch of product (approximately 50% conversion). The first and second batches were combined, diluted with EtOAc and washed with saturated (aq) NH 4 Cl (3x). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated. The product was purified by column chromatography (ISCO) eluting with a gradient of 40-95% EtOAc in hexane to give the title compound (87 mg) as a mixture with the starting material. ESI-MS m / z [M+H] + 443.0.

[0225] Preparation 18: 5-iodo-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0226] To a 10 mL vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (250 mg, 0.730 mmol), (6-methoxypyridin-2-yl)methanamine (131 mg, 0.949 mmol) and DIPEA (0.255 mL, 1.460 mmol) in DMA (3.5 mL). The reaction mixture was heated to 100 ° C and stirred for 5 hours. The reaction mixture was then diluted with EtOAc and washed with saturated (aq) NH4Cl (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO NH column) eluting with a gradient of 0-10% MeOH in DCM. The title compound was isolated as a light yellow solid (167 mg, 52%). ESI-MS m / z [M+H] + 445.0.

[0227] Preparation 19: 3-(((3-fluoropyridin-2-yl)methyl)amino)-5-iodo-4H-benzo[alpha] [e][1,2,4]thiadiazine 1,1-dioxide

[0228] The title compound was prepared in a manner similar to that of Preparation 18 using 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (175 mg, 0.511 mmol), (3-fluoropyridin-2-yl)methanamine (97 mg, 0.766 mmol) and DIPEA (0.178 mL, 1.022 mmol) in DMA (2 mL) and isolated as a light yellow solid (53 mg, 24%). ESI-MS m / z [M+H] + 433.0.

[0229] Preparation 20: 5-iodo-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0230] The title compound was prepared in a manner similar to that of Preparation 18 using 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.200 g, 0.584 mmol) and aniline (0.800 mL, 8.76 mmol) and isolated as a light pink solid (35 mg, 15%). ESI-MS m / z [M+H] + 400.0.

[0231] Preparation 21: 5-iodo-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0232] To a 2-5 mL microwave vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (200 mg, 0.584 mmol), thiazol-2-ylmethylamine (120 mg, 0.796 mmol) and K2CO3 (81 mg, 0.584 mmol) in DMA (1.168 mL). The reaction mixture was heated at 100 ° C for 2 hours, then poured into water and extracted with EtOAc (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give the title compound as a light brown oil, which was used without further purification. ESI-MS m / z [M + H] + 421.2.

[0233] Preparation 22: 5-iodo-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0234] To a 2-5 mL microwave vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (200 mg, 0.584 mmol), 2-methoxypropan-1-amine hydrochloride (81 mg, 0.642 mmol) and K2CO3 (81 mg, 0.584 mmol) in DMA (1.168 mL). The reaction mixture was heated at 100 ° C for 2 hours, then poured into water and extracted with EtOAc (3x). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give the title compound as a light brown oil, which was used without further purification. ESI-MS m / z [M+H] + 396.0.

[0235] Preparation 23: 3-((cyclobutylmethyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0236] The title compound was prepared in a manner similar to that of 22 using 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (200 mg, 0.584 mmol), cyclobutylmethylamine hydrochloride (78 mg, 0.642 mmol) and K2CO3 (81 mg, 0.584 mmol) in DMA (1.168 mL) and isolated as an oil. ESI-MS m / z [M+H] + 391.9.

[0237] Preparation 24: 5-iodo-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0238] To a stirred solution of pyridin-2-ylmethylamine (0.020 mL, 0.200 mmol) in MeOH (0.125 mL) was added 3-chloro-5-iodo-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.034 g, 0.1 mmol). During the addition of benzo[e][1,2,4]thiadiazine 1,1-dioxide, the mixture was cooled in an ice bath. After the addition, the reaction mixture was stirred at room temperature overnight. One drop of Et3N was added, and the reaction mixture was stirred at room temperature for 1 hour, then at 65°C for another hour. Additional pyridin-2-ylmethylamine (0.020 mL, 0.200 mmol) was added, and the mixture was stirred at 65°C for 6 hours. This first reaction mixture was allowed to stand. To a stirred solution of pyridin-2-ylmethylamine (40.9 μL, 0.400 mmol) in 2-propanol (250 μL) was added Et3N (84 μL, 0.600 mmol) followed by 3-chloro-5-iodo-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (68.5 mg, 0.2 mmol). The reaction mixture was cooled in an ice bath during the addition of base and benzo[e][1,2,4]thiadiazine 1,1-dioxide and then stirred at room temperature for 96 hours. The first and second reaction mixtures were combined and purified by preparative HPLC using a gradient elution of 5-95% aqueous ACN (formic acid conditions). The title compound was isolated as an off-white solid (42 mg, 51%). ESI-MS m / z [M+H] + 415.0.

[0239] Preparation 25: 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0240] To a stirred solution of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.250 g, 3.65 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.139 g, 5.47 mmol) in water (10 mL) and dioxane (30 mL) was added PdCl2(dppf)·CHCl2 adduct (298 mg, 0.365 mmol) and K2CO3 (1.110 g, 8.03 mmol). The reaction mixture was heated at 100°C for 1.5 hours, then cooled to room temperature and poured into water (50 mL). A tan precipitate formed. 1N HCl(aq) solution was added to adjust the pH from 8 to 5, thereby precipitating more solid. The mixture was filtered, but only trace material was recovered. The filtrate was extracted with EtOAc (3x) to form an emulsion, which was separated and extracted with DCM. The product was only in the aqueous layer, which was concentrated. The solid was rinsed with ACN and the salt was filtered out. The filtrate was concentrated and dried in a vacuum oven to give the title compound as a tan solid, which was used without further purification (1.16 g, 95% purity according to LC / MS). ESI-MSm / z[M+H] + 297.0.

[0241] Preparation 26: 3-Chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0242] To a solution of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1 g, 2.92 mmol) and (2,5-difluorophenyl)boronic acid (2 g, 12.67 mmol) in dioxane (30 mL) was added PdCl2(dppf) (50 mg, 0.068 mmol). The mixture was sparged with nitrogen. Saturated (aq) NaHCO3 (5 mL) was added and the reaction mixture was stirred and heated in a microwave reactor at 140 ° C. The solvent was removed under high vacuum. The crude material was suspended in DMA (30 mL) and the residual solid was removed by filtration. The filtrate was used as a stock solution of the title compound (3 mmol / mL). ESI-MS m / z [M+H] + 329.0.

[0243] Preparation 27: 2-(3-chloro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0244] To a mixture of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.461 g, 1.34 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.28 g, 1.2 mmol), CsCO (2.445 mL, 4.89 mmol) and dioxane (6.11 mL) in a 20 mL microwave vial equipped for stirring was added Pd(dppf) CHCl adduct (0.100 g, 0.122 mmol) under nitrogen. The reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes, then cooled, poured into water (150 mL) and acidified with 1N HCl(aq) until a brown precipitate formed. The solid was filtered and washed with plenty of water, followed by washing with hexane to give the (crude) title compound (0.42 g). ESI-MS m / z [M+H] + 318.0.

[0245] Preparation 28: 2-(3-chloro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile

[0246] A 20 mL microwave vial equipped for stirring was charged with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.55 g, 1.606 mmol), 2-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.436 g, 1.766 mmol), Cs2CO3 (3.21 mL, 6.42 mmol) and dioxane (8.03 mL). Next, Pd(dppf)2·CH2Cl2 adduct (0.131 g, 0.161 mmol) was added under nitrogen. The reaction mixture was heated to 120°C in a microwave reactor for 20 minutes, then cooled, poured into water (150 mL) and acidified with 1N HCl(aq) until a brown precipitate formed. The solid was filtered and washed with plenty of water, followed by washing with hexane to give the title compound, which was used without further purification (0.42 g, 78%).

[0247] Preparation 29: 3-Chloro-5-(2-cyclopropyl-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0248] Under nitrogen, a stirring vessel equipped with 3-chloro-5-iodo-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide (0.297 g, 0.867 mmol), 2-(2-cyclopropyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 g, 0.954 mmol), Cs2CO3 (1.734 mL, 3.47 mmol) and dioxane (4.34 mL) were added to a 20 mL microwave vial with Pd(dppf)2·CH2Cl2 adduct (0.071 g, 0.087 mmol). The reaction mixture was heated to 120°C in a microwave reactor for 20 minutes, then cooled, poured into water (150 mL) and acidified with 1N HCl(aq) until a brown precipitate formed. The solid was filtered and washed with plenty of water followed by hexanes to give the title compound (0.2 g, 66%).

[0249] Example 1: 5-(2-chloro-3-fluorophenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0250] To a mixture of 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (300 mg, 0.869 mmol) and Et3N (0.363 mL, 2.61 mmol) in EtOH (7.00 mL) was added methylamine (2M in MeOH, 0.869 mL, 1.74 mmol). The mixture was heated at 65 °C for 12 hours. The solvent was then removed in vacuo and the residue was suspended in DCM and washed with saturated (aq) NH4Cl (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (Teledyne ISCO CombiFlash TM , 24g column) was purified with a gradient elution of 40-100% EtOAc in hexane. The fractions containing the product were combined and the solvent was removed to give a white solid, which was dissolved in EtOAc and IPA after heating and ultrasonic treatment. The solution was cooled in an ice bath and allowed to equilibrate at room temperature for 12 hours, during which time white crystals were formed. The solution was decanted and the crystals were collected by vacuum filtration while washing with IPA. The crystalline solid was dried at 35 ° C under vacuum for several hours to give the title compound (85.0 mg, 29.1%) as a white crystalline solid. 1H NMR (400MHz, DMSO-d6) δppm 2.74 (d, J = 4.55Hz, 3H), 7.21 (br s,1H),7.28-7.45(m,3H),7.52-7.66(m,2H),7.78(dd,J=7.71,1.14Hz,1H),9.05(s,1H); ESI-MSm / z[M+H] + 340.0.

[0251] Example 2: 5-(2-chloro-3-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0252] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120 mg, 0.348 mmol), DIPEA (0.121 mL, 0.695 mmol) and methoxyethylamine (31.3 mg, 0.417 mmol) in DMA (0.695 mL) and isolated as a light beige solid (76.8 mg, 57.6%). 1 HNMR(400MHz,DMSO-d6)δppm 3.27(s,3H),3.39(dd,J=10.99,4.67Hz,2H),3.44(d,J=4.55Hz,2H),3.98(s,1H),7.33-7.40(m,2H) ,7.42-7.49(m,2H),7.58-7.65(m,2H),7.80(dd,J=7.58,1.26Hz,1H),9.09(s,1H); ESI-MSm / z[M+H] + 384.0.

[0253] Example 3: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0254] To a 20 mL vial was added 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (300 mg, 0.826 mmol) in EtOH (9 mL) along with methylamine (33% in MeOH, 0.134 mL, 1.074 mmol) and Et3N (0.345 mL, 2.48 mmol). The resulting yellow solution was heated to 65 ° C and stirred for 4 hours. The mixture was then concentrated, diluted with EtOAc, and washed with saturated (aq) NH4Cl (3x20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (Teledyne ISCO CombiFlash TM , 12 g column) eluting with a gradient of 20-100% EtOAc in hexanes. The title compound was isolated as an off-white solid (44 mg, 15%). 1 H NMR (400MHz, DMSO-d6), δppm 2.73 (d, J = 4.55Hz, 3H), 7.22 (br s,1H),7.34(d,J=7.07Hz,1H),7.44(dd,J=8.84,2.78Hz,1H),7.52-7.70(m,3H),9.01-9.24(m,1H); ESI-MSm / z[M+H] + 358.0; mp 241-243℃.

[0255] Example 4: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0256] The title compound was prepared in a manner similar to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol), 2-methoxyethylamine (26.9 mg, 0.358 mmol) and Et3N (0.115 mL, 0.826 mmol) in EtOH (3 mL) and isolated as a yellow film (19 mg, 17%); ESI-MS m / z [M+H] + 402.2.

[0257] Example 5: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0258] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol), thiazol-2-ylmethylamine hydrochloride (53.9 mg, 0.358 mmol) and Et3N (0.115 mL, 0.826 mmol) in EtOH (3 mL) and isolated as a yellow film (15 mg, 12%). 1 H NMR (400MHz, CD3OD) δppm 4.61(s,1H),4.82(br s,2H),7.25-7.36(m,2H),7.39-7.58(m,3H),7.61-7.68(m,1H),7.71(br s,1H); ESI-MSm / z[M+H] + 441.2.

[0259] Example 6: 5-(2-chloro-3-fluorophenyl)-3-(ethylamino)-7-fluoro-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0260] The title compound was prepared in a manner similar to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol), ethylamine (2 M in THF, 0.179 mL, 0.358 mmol) and Et3N (0.115 mL, 0.826 mmol) in EtOH (3 mL) and isolated as a brown oil (10 mg, 10%); ESI-MS m / z [M+H] + 371.9.

[0261] Example 7: 5-(2-chloro-3-fluorophenyl)-3-((cyclopropylmethyl)amino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0262] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol), cyclopropylmethylamine (25.5 mg, 0.358 mmol) and Et3N (0.115 mL, 0.826 mmol) in EtOH (3 mL) and isolated as a yellow oil (25 mg, 23%). 1 HNMR(400MHz,CD3OD)δppm 0.23(q,J=4.55Hz,2H),0.46-0.56(m,2H),0.94-1.08(m,1H),3.16(d,J=7.33Hz,2H),7.23-7.32(m,2 H),7.42-7.49(m,1H),7.50-7.58(m,1H),7.61(dd,J=7.07,3.03Hz,1H),7.87(s,1H); ESI-MSm / z[M+H] + 398.1.

[0263] Example 8: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((1-(thiazol-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0264] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol), 1-(thiazol-2-yl)ethanamine hydrochloride (58.9 mg, 0.358 mmol) and Et3N (0.115 mL, 0.826 mmol) in EtOH (3 mL) and isolated as a brown film (8.0 mg, 6%). 1 H NMR (400MHz, CD3OD) δppm 1.61 (t, J=6.69Hz, 3H), 5.40 (m, 1H), 7.17-7.37 (m, 2H), 7.41-7.60 (m, 3H), 7.63 (dd, J=6.95, 2.91Hz, 1H), 7.71 (br s,1H);ESI-MSm / z[M+H] + 455.0.

[0265] Example 9: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((1-(thiazol-4-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0266] The title compound was prepared in a manner similar to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol), 1-(thiazol-4-yl)ethanamine (45.9 mg, 0.358 mmol) and Et3N (0.115 mL, 0.826 mmol) in EtOH (3 mL) and isolated as a brown film (4 mg, 3%); ESI-MS m / z [M+H] + 454.9.

[0267] Example 10: 5-(2-chloro-3-fluorophenyl)-3-((2,2-difluoroethyl)amino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0268] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.138 mmol), 2,2-difluoroethylamine HCl (24.27 mg, 0.207 mmol) and Et3N (57.6 μL, 0.413 mmol) in EtOH (0.688 mL) and isolated as a light beige solid (19.1 mg, 34%). 1 H NMR (400MHz, DMSO-d6), δppm 3.72(d,J=3.28Hz,2H),5.98-6.33(m,1H),7.36-7.43(m,1H),7.52(dd,J=8.84,2.78Hz,1H),7.58-7.75(m,4H),9.30(s,1H); ESI-MSm / z[M+H] + 408.0.

[0269] Example 11: 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0270] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.138 mmol), 2-fluoroethylamine HCl (20.56 mg, 0.207 mmol) and Et3N (57.6 μL, 0.413 mmol) in EtOH (0.688 mL) and isolated as a yellow film (10.8 mg, 20.6%). 1 H NMR(400MHz,DMSO-d6)δppm 3.50-3.61(m,2H),4.47-4.63(m,2H),7.37-7.41(m,1H),7.50(dd,J=8.84,3.03Hz,1H),7.59-7.72(m,4H),9.19(s,1H); ESI-MSm / z[M+H] + 390.0.

[0271] Example 12: 5-(2-chloro-3-fluorophenyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0272] To a solution of 3-(((3-fluoropyridin-2-yl)methyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (500 mg, 1.16 mmol) and 2-chloro-3-fluorophenyl)boronic acid (202 mg, 1.16 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl (84.9 mg, 116 μmol) and NaHCO (244 mg, 2.90 mmol) under N2. The reaction mixture was stirred at 110 °C for 2 hours, then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (3 x 20 mL), then with brine (1 x 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC to give the title compound (225 mg, 44.3%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.40(br s,1H),8.41(br s,1H),8.00(br s,1H),7.86-7.72(m,2H),7.67-7.53(m,2H),7.48-7.27(m,4H),4.72-4.54(m,2H); ESI-MSm / z[M+H] +435.0.

[0273] Example 13: 5-(2-chlorophenyl)-7-fluoro-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0274] The title compound was prepared in a manner similar to Example 3 using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (500 mg, 1.45 mmol) and methylamine (2M in THF, 10.0 mL, 20.0 mmol), except that the reaction mixture was heated to 80° C. for 1 hour. The solvent was removed under vacuum and the crude product was analyzed by preparative HPLC (Phenomenex C18, 10 μm, ID 50 x 250 mm column) using a gradient of 30-55% ACN in water (0.1% TFA). The title compound was isolated as a brown solid (323.87 mg, 63%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.07(s,1H),7.74-7.27(m,7H),2.73(d,J=4.6Hz,3H)ESI-MSm / z[M+H] + 340.1

[0275] Example 14: 5-(2-chlorophenyl)-7-fluoro-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0276] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), methoxyethylamine (34.81 mg, 0.463 mmol) and Et3N (115 μL, 0.826 mmol) in EtOH (3 mL) and isolated as a white solid (30.14 mg, 34%). 1 H NMR (400MHz, CD3CN) δppm 2.96-3.70 (m, 7H), 6.24 (br s, 1H), 7.26 (dd, J=2.4, 8.8Hz, 1H), 7.40-7.69 (m, 7H), 8.02 (br s, 1H); ESI-MSm / z[M+H] + 384.0.

[0277] Example 15: 5-(2-chlorophenyl)-3-(ethylamino)-7-fluoro-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0278] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), ethylamine (52.24 mg, 1.16 mmol) and Et3N (151 μL, 0.826 mmol) in EtOH (3 mL) and isolated as a white solid (17 mg, 20%). 1 H NMR (400MHz, CD3CN) δppm 1.11 (t, J=7.2Hz, 3H), 3.28 (dd, J=5.4, 7.2Hz, 2H), 5.93 (br s,1H),7.22(dd,J=2.9,8.8Hz,1H),7.39-7.44(m,1H),7.46-7.60(m,3H),7.63(dd,J=1.3,7.8Hz,1H),7.84(br s,1H); ESI-MSm / z[M+H] + 354.0.

[0279] Example 16: 5-(2-chlorophenyl)-7-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0280] The title compound was prepared in a manner analogous to Example 3 using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), (3-fluoropyridin-2-yl)methanamine (61.39 mg, 486.70 μmol) and Et3N (151 μL, 0.826 mmol) in EtOH (3 mL) and isolated as a white solid (24.87 mg, 14%). 1 H NMR(400MHz,DMSO-d6)δppm 4.61(br s,2H),7.17-7.83(m,9H),8.21–8.57(m,1H); ESI-MSm / z[M+H] + 435.0.

[0281] Example 17: 5-(2-chloro-3-fluorophenyl)-3-((cyclobutylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0282] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and cyclobutylmethylamine HCl (16.91 mg, 0.139 mmol) in DMA (0.232 mL) and isolated as a brown-orange solid (22.8 mg, 50%). 1 HNMR(400MHz,DMSO-d6)δppm 1.60-1.73(m,2H),1.81-1.91(m,2H),1.95-2.05(m,2H),2.40-2.49(m,1H),3.22-3.31(m,2H),7.27-7.39 (m,3H),7.41-7.45(m,1H),7.57-7.67(m,2H),7.80(dd,J=7.83,1.26Hz,1H),8.98(s,1H); ESI-MSm / z[M+H] + 394.0.

[0283] Example 18: 5-(2-chloro-3-fluorophenyl)-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0284] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), DIPEA (30.4 μL, 0.174 mmol) and (6-methoxypyridin-2-yl)methanamine (14.41 mg, 0.104 mmol) in DMA (0.174 mL) and isolated as a light yellow oil (24.5 mg, 63%). 1H NMR(400MHz,DMSO-d6)δppm 3.84(s,3H),4.46(d,J=5.81Hz,2H),6.73(d,J=8.34Hz,1H),6.92(d,J=7.33Hz,1H),7.35-7.41(m,2H),7.45-7 .48(m,1H),7.58-7.67(m,2H),7.70(dd,J=8.08,7.33Hz,1H),7.78-7.83(m,2H),9.28(s,1H); ESI-MSm / z[M+H] + 447.0.

[0285] Example 19: 5-(2,3-difluorophenyl)-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0286] To a 2 mL conical microwave vial equipped with a stirrer was added 3-chloro-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.122 mmol), DIPEA (42.5 μL, 0.243 mmol) and (6-methoxypyridin-2-yl)methanamine (20.18 mg, 0.146 mmol) dissolved in DMA (243 μL). The reaction mixture was heated at 90° C. for 4 hours and then analyzed by mass-triggered preparative-LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column) using a 35-60% ACN in water gradient (acid mode). Product-containing fractions were collected, concentrated, and dried in vacuo to give the title compound (27.4 mg, 52%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.85(s,3H),4.47(d,J=5.56Hz,2H),6.73(d,J=8.08Hz,1H),6.94(d,J=7.07Hz,1H),7.31-7.36(m,1H),7.38-7.47(m,2H),7.5 4(dd,J=7.58,1.26Hz,1H),7.61-7.68(m,1H),7.71(dd,J=8.08,7.33Hz,1H),7.81-7.87(m,2H),9.46(s,1H); ESI-MSm / z[M+H] + 431.0.

[0287] Example 20: 3-(((5-(2,3-difluorophenyl)-1,1-dioxo-4H-benzo [e][1,2,4]thiadiazin-3-yl)amino)methyl)-1-methylpyridin-2(1H)-one

[0288] In a manner similar to Example 19, 3-chloro-5- The title compound was prepared from (2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.122 mmol), DIPEA (42.5 μL, 0.243 mmol) and 3-(aminomethyl)-1-methylpyridin-2(1H)-one (20.18 mg, 0.146 mmol) and isolated as a light yellow solid (1.2 mg, 2%). 1 H NMR(400MHz,DMSO-d6)δppm 3.47(s,3H),4.20(br s,2H),6.25(t,J=6.69Hz,1H),7.31(d,J=7.07Hz,1H),7.40(dd,J=15.41,7.07Hz,3H),7.51(d,J=6.32 Hz,1H),7.64(d,J=9.35Hz,1H),7.70(d,J=6.82Hz,1H),7.81(d,J=6.82Hz,2H),9.32(s,1H); ESI-MSm / z [M+H] + 431.1.

[0289] Example 21: 5-(2,3-difluorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0290] In a manner similar to Example 19, 3-chloro-5- The title compound was prepared from (2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), DIPEA (31.9 μL, 0.183 mmol) and 2-fluoroethylamine HCl (23.6 mg, 0.237 mmol) and isolated as a tan solid (25 mg, 39%). 1H NMR(400MHz,CD3OD)δppm 3.47-3.54(m,1H),3.58(d,J=2.02Hz,1H),4.48(s,1H),4.60(s,1H),7.27-7.33(m,1H),7.39 (d,J=7.83Hz,2H),7.51(d,J=1.52Hz,1H),7.60-7.69(m,2H),7.79-7.84(m,1H),9.26(s,1H).

[0291] Example 22: 3-((Cyclobutylmethyl)amino)-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0292] In a manner similar to Example 19, 3-chloro-5- The title compound was prepared from (2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), DIPEA (31.9 μL, 0.183 mmol) and cyclobutylmethylamine HCl (28.9 mg, 0.237 mmol) and isolated as a tan solid (14.2 mg, 20.6%). 1 H NMR(400MHz,CD3OD)δppm 2.09(s,4H),3.22-3.26(m,3H),3.37-3.39(m,5H),3.41-3.45(m,4H),3.44(br s,1H),7.31-7.39(m,2H),7.42-7.51(m,1H),7.61-7.68(m,1H),7.73-7.82(m,2H),7.88-7.93(m,1H),8.94-9.00(m,1H).

[0293] Example 23: 5-(2,3-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0294] In a manner similar to Example 19, 3-chloro-5- The title compound was prepared from (2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), DIPEA (31.9 μL, 0.183 mmol) and 2-methoxypropan-1-amine HCl (29.8 mg, 0.237 mmol) and isolated as an orange-brown oil (25.7 mg, 36.9%). 1 H NMR(400MHz,CD3OD)δppm 2.09(s,4H),3.22-3.26(m,3H),3.37-3.39(m,5H),3.41-3.45(m,4H),3.44(br s,1H),7.31-7.39(m,2H),7.42-7.51(m,1H),7.61-7.68(m,1H),7.73-7.82(m,2H),7.88-7.93(m,1H),8.94-9.00(m,1H).

[0295] Example 24: (R)-5-(2,3-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0296] Example 25: (S)-5-(2,3-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0297] The racemates prepared in Example 23 were separated by chiral chromatography using a SFC / UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20 x 150 mm, flow rate 75 mL / min) eluting with 25% MeOH. The first eluting peak was arbitrarily assigned as the R-stereochemical configuration (Example 24), and the second eluting peak was assigned as the S-stereochemical configuration (Example 25). Each title compound was isolated as a white solid (7 mg).

[0298] Example 26: 5-(2,3-difluorophenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0299] In a manner similar to Example 19, 3-chloro-5- The title compound was prepared from (2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), DIPEA (31.9 μL, 0.183 mmol) and methylamine (2M solution in MeOH, 0.119 mL, 0.237 mmol) and isolated as a tan solid (13 mg, 22%). 1 H NMR(400MHz,CD3OD)δppm 2.75(d,J=4.80Hz,3H),7.24-7.33(m,2H),7.33-7.39(m,1H),7.39-7.46(m ,1H),7.46-7.53(m,1H),7.54-7.69(m,1H),7.74-7.83(m,1H),9.23(s,1H).

[0300] Example 27: 5-(2,3-difluorophenyl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0301] In a manner similar to Example 19, 3-chloro-5- The title compound was prepared from (2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.122 mmol), DIPEA (42.5 μL, 0.243 mmol) and oxazol-2-ylmethanamine (14.3 mg, 0.146 mmol) and isolated as a colorless oil (5 mg, 10%). 1 H NMR(400MHz,DMSO-d6)δppm 4.61(d,J=4.55Hz,2H),7.20(d,J=1.01Hz,1H),7.33(t,J=6.82Hz,1H),7.42(d,J=7.58Hz,2H),7.55(dd,J=7.58,1.26Hz,1H ),7.61-7.69(m,1H),7.84(dd,J=7.96,1.14Hz,1H),7.95(t,J=5.68Hz,1H),8.12(d,J=0.76Hz,1H),9.49(s,1H); ESI-MSm / z [M+H] + 391.1.

[0302] Example 28: 5-(2-chloro-3-fluorophenyl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0303] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and oxazol-2-ylmethanamine HCl (18.71 mg, 0.139 mmol) in DMA (0.232 mL) and isolated as a light beige solid (13.0 mg, 28%). 1 H NMR(400MHz,DMSO-d6)δppm 3.98(s,1H),4.60(dd,J=5.68,1.89Hz,2H),7.20(d,J=0.76Hz,1H),7.34-7.43(m,2H),7.45-7.49(m,1H),7.57-7.66 (m,2H),7.82(dd,J=7.71,1.14Hz,1H),7.89(t,J=5.56Hz,1H),8.11(d,J=0.76Hz,1H),9.31(s,1H); ESI-MSm / z[M+H] + 407.0.

[0304] Example 29: 5-(2-chloro-3-fluorophenyl)-3-((cyclopropylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0305] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and cyclopropylmethylamine (9.89 mg, 0.139 mmol) in DMA (0.232 mL) and isolated as a brown-orange solid (13.6 mg, 31%). 1 HNMR(400MHz,DMSO-d6)δppm 0.22(d,J=3.79Hz,2H),0.46(dd,J=7.96,1.64Hz,2H),0.90-1.04(m,1H),3.03-3.12(m,2H),7. 32-7.44(m,4H),7.56-7.68(m,2H),7.78(dd,J=7.71,1.39Hz,1H),9.00(s,1H); ESI-MSm / z[M+H] + 380.0.

[0306] Example 30: 5-(2-chloro-3-fluorophenyl)-3-(((4-methyloxazol-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0307] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.174 mmol), DIPEA (60.7 μL, 0.348 mmol) and (4-methyloxazol-2-yl)methanamine HCl (31.0 mg, 0.209 mmol) in DMA (0.348 mL) and isolated as a light yellow solid (33.7 mg, 46%). 1 H NMR(400MHz,DMSO-d6)δppm 2.07(d,J=1.26Hz,3H),4.54(dd,J=5.43,2.40Hz,2H),7.34-7.37(m,1H),7.38-7.42(m,1 H),7.45-7.49(m,1H),7.58-7.66(m,2H),7.78-7.89(m,3H),9.30(s,1H); ESI-MSm / z[M+H] + 421.0.

[0308] Example 31: 5-(2-chloro-3-fluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0309] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and pyridin-2-ylmethanamine (15.04 mg, 0.139 mmol) in DMA (232 μL) and isolated as a light green solid (30.4 mg, 63%). 1HNMR(400MHz,DMSO-d6)δppm 3.98(s,1H),4.59(br s,2H),7.36-7.42(m,3H),7.44-7.48(m,2H),7.59-7.66(m,2H),7.82(dd,J=7.83,1.26Hz,1H) ,7.90(t,J=7.07Hz,1H),7.98(brs,1H),8.60(d,J=4.55Hz,1H),9.41(s,1H); ESI-MSm / z[M+H] + 417.0.

[0310] Example 32: 5-(2-chloro-3,5-difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0311] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (56.2 mg, 0.155 mmol), DIPEA (54.1 μL, 0.309 mmol) and 2-methoxyethylamine (13.95 mg, 0.186 mmol) in DMA (500 μL) and isolated as a clear film (7.1 mg, 11%). 1 HNMR(400MHz,CD3OD)δppm 3.35(s,3H),3.49(br s,4H),7.15(d,J=7.33Hz,1H),7.32-7.48(m,3H),7.89(dd,J=7.58,1.77Hz,1H); ESI-MSm / z[M+H] + 402.0.

[0312] Example 33: 5-(2-chloro-3-fluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0313] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and 2-methoxypropan-1-amine HCl (17.47 mg, 0.139 mmol) in DMA (232 μL) and isolated as a light beige solid (21.6 mg, 47%). 1 H NMR(400MHz,DMSO-d6)δppm 1.06(dd,J=6.06,3.28Hz,3H),3.14-3.22(m,1H),3.24(d,J=3.28Hz,3H),3.35-3.50(m,2H),7.32-7.38(m,2H) ,7.39-7.46(m,2H),7.56-7.65(m,2H),7.79(dd,J=7.58,1.26Hz,1H),9.09(d,J=2.27Hz,1H); ESI-MSm / z[M+H] + 398.0.

[0314] Example 34: 5-(2-chloro-3-fluorophenyl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0315] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and 2,2-difluoroethylamine HCl (16.34 mg, 0.139 mmol) in DMA (232 μL) and isolated as a brown-orange solid (13.5 mg, 30%). 1 HNMR(400MHz,DMSO-d6)δppm 3.63-3.78(m,2H),5.99-6.30(m,1H),7.33-7.47(m,3H),7.56-7.67(m,3H),7.82(dd,J=7.71,1.14Hz,1H),9.19(s,1H); ESI-MSm / z[M+H] + 390.0.

[0316] Example 35: 5-(2-chlorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0317] To a 10 mL microwave vial equipped for stirring was charged 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.04 g, 0.105 mmol), (2-chlorophenyl)boronic acid (0.016 g, 0.105 mmol), CsCO (2 M, 0.210 mL, 0.420 mmol) and dioxane (0.525 mL). To the mixture was added Pd(dppf)CHCl adduct (4.28 mg, 5.25 μmol) under nitrogen. The reaction mixture was heated to 100 °C in a microwave reactor for 2 h, then cooled, diluted with MeOH (1 mL) and filtered. The residue was purified by preparative LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column) using a 25-90% ACN in water gradient (acid mode). Product-containing fractions were collected, concentrated, and dried in vacuo to give the title compound (2 mg, 5%) as a tan solid. 1 HNMR(400MHz,CD3OD)δppm 3.48(br s,4H) 7.35-7.43(m,3H),7.46-7.55(m,2H),7.58-7.65(m,1H),7.81-7.89(m,1H); ESI-MSm / z[M+H] + 366.0.

[0318] Example 36: 5-(3-chloro-2-fluoropyridin-4-yl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0319] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.157 mmol), 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (81 mg, 0.315 mmol), cesium fluoride (aq) (59.8 mg, 0.394 mmol) and Pd(dppf)2·CH2Cl2 adduct (12.85 mg, 0.016 mmol) in dioxane (525 μL) and isolated as a white solid (49.7 mg, 82%). 1H NMR(400MHz,DMSO-d6)δppm 3.27(s,3H),3.37-3.47(m,4H),7.27(br s,1H),7.38-7.45(m,1H),7.49-7.55(m,1H),7.58(d,J=4.80Hz,1H),7.8 6(d,J=7.83Hz,1H),8.40(d,J=5.05Hz,1H),9.20(s,1H); ESI-MSm / z[M+H] + 385.0.

[0320] Example 37: 5-(2,3-difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0321] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.105 mmol), (2,3-difluorophenyl)boronic acid (22 mg, 0.136 mmol), Cs2CO3 (2M, 0.210 mL, 0.420 mmol) and Pd(dppf)2·CH2Cl2 adduct (8.57 mg, 10.49 μmol) in dioxane (525 μL) and isolated as a tan solid (19 mg, 49%). 1 H NMR(400MHz,CD3OD)δppm 3.26(s,3H),3.36-3.41(m,2H),3.42-3.47(m,2H),7.26-7.32(m,1H),7.34-7.39(m,1H),7 .40-7.46(m,1H),7.47-7.55(m,2H),7.60-7.68(m,1H),7.77-7.83(m,1H); ESI-MSm / z[M+H] + 368.0.

[0322] Example 38: 5-(2-chloro-3-fluorophenyl)-3-(((5-methyloxazol-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0323] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (50.6 μL, 0.290 mmol) and (5-methyloxazol-2-yl)methanamine (19.49 mg, 0.174 mmol) in DMA (290 μL) and isolated as a yellow-orange solid (18.6 mg, 31%). 1 H NMR(400MHz,DMSO-d6)δppm 2.28(d,J=1.26Hz,3H),4.53(dd,J=5.56,2.27Hz,2H),6.80(d,J=1.01Hz,1H),7.35(dd,J=6.44,1.14Hz,1H), 7.41(d,J=7.58Hz,1H),7.45-7.48(m,1H),7.59-7.68(m,2H),7.81-7.89(m,2H),9.29(s,1H); ESI-MSm / z[M+H] + 421.0.

[0324] Example 39: 5-(2-chloro-3-fluorophenyl)-3-(ethylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0325] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and ethylamine HCl (11.34 mg, 0.139 mmol) in DMA (232 μL) and isolated as a light beige solid (15.6 mg, 38%). 1 H NMR(400MHz,DMSO-d6)δppm 1.10(t,J=7.20Hz,3H),3.18-3.28(m,2H),7.26-7.39(m,3H),7.41-7.45(m,1H) ,7.56-7.68(m,2H),7.80(dd,J=7.58,1.26Hz,1H),8.98(s,1H);ESI-MSm / z[M+H] + 354.1.

[0326] Example 40: 5-(2-chlorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0327] To a solution of 2-methoxypropan-1-amine HCl (34.9 mg, 0.278 mmol) and DIPEA (37.4 μL, 0.214 mmol) in DMA (428 μL) was added 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (70 mg, 0.214 mmol). The reaction mixture was heated at 70° C. for 24 hours, then diluted with MeOH (1 mL) and filtered. The residue was analyzed by preparative LC / MS (Waters C18,5 The 5-mercaptoethanol was purified on a 1.5 μm, ID 30 x 75 mm column) using a 25-90% gradient of aqueous ACN (acid mode). The product-containing fractions were collected, concentrated, and dried under vacuum to give the title compound as a brown solid (16 mg, 20% yield). ESI-MS m / z [M+H] + 380.0.

[0328] Example 41: 5-(2-chlorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0329] The title compound was prepared in a manner analogous to Example 40 using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.153 mmol), pyridin-2-ylmethanamine (16.53 mg, 0.153 mmol) and DIPEA (26.7 μL, 0.153 mmol) in DMA (306 μL) and isolated as a black oil (34 mg, 56%). 1 HNMR(400MHz,CD3OD)δppm 1.10(t,J=7.20Hz,3H),3.22(dd,J=7.33,5.31Hz,2H),7.31-7.55(m,6H),7.78(dd,J=7.83,1.01Hz,1H),9.12(s,1H); ESI-MSm / z[M+H] + 399.8.

[0330] Example 42: 5-(2-chlorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0331] The title compound was prepared in a manner analogous to Example 40 using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), ethylamine HCl (19.44 mg, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL) and isolated as a light beige solid (14.9 mg, 24%). 1 H NMR(400MHz,DMSO-d6)δppm 1.10(t,J=7.33Hz,3H),3.18-3.24(m,2H),7.30-7.43(m,3H),7.44-7.49(m,1H),7.5 0-7.63(m,2H),7.70(dd,J=7.96,1.14Hz,1H),7.77(dd,J=7.45,1.89Hz,1H),8.93(br s,1H);ESI-MSm / z [M+H] + 336.0.

[0332] Example 43: 5-(2-chlorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0333] The title compound was prepared in a manner analogous to Example 40 using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), methylamine (2 M in MeOH) (119 μL, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL) and isolated as a light beige solid (10.6 mg, 18%). 1 H NMR (400MHz, DMSO-d6) δppm 2.73 (d, J = 4.80Hz, 3H), 7.12 (br s,1H),7.32-7.39(m,3H),7.43-7.47(m,1H),7.51-7.59(m,2H),7.67(dd,J=7.83,1.26Hz,1H),7.75(dd,J=7.45,1.89Hz,1H),9.00(br s,1H);ESI-MSm / z[M+H] + 322.0.

[0334] Example 44: 5-(2-chlorophenyl)-3-((2,2-difluoroethyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0335] The title compound was prepared in a manner analogous to Example 40 using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), 2,2-difluoroethylamine HCl (28.0 mg, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL) and isolated as a light beige solid (9.0 mg, 13%). 1 H NMR(400MHz,DMSO-d6)δppm 0.97-1.38(m,2H),3.66-3.79(m,2H),5.98-6.33(m,1H),7.37-7.44(m ,2H),7.46-7.50(m,1H),7.54-7.63(m,2H),7.70-7.83(m,3H),9.18(br s,1H);ESI-MSm / z[M+H] + 372.0.

[0336] Example 45: 5-(2-chlorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0337] The title compound was prepared in a manner analogous to Example 40 using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), 2-fluoroethylamine HCl (23.73 mg, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL) and isolated as a brown-orange solid (26.8 mg, 41%). 1 H NMR(400MHz,DMSO-d6)δppm 3.48-3.59(m,3H),4.48(t,J=5.05Hz,1H),4.60(t,J=4.80Hz,1H),7.34-7.43(m,2H),7.46-7.50(m,1H),7. 53-7.63(m,2H),7.71(dd,J=7.71,1.39Hz,2H),7.79(dd,J=7.58,1.77Hz,1H),9.07(s,1H); ESI-MSm / z[M+H] + 354.0.

[0338] Example 46: 3-(((5-(2-chloro-3-fluorophenyl)-1,1-dioxo-4H-benzo [e][1,2,4]thiadiazin-3-yl)amino)methyl)-1-methylpyridin-2(1H)-one

[0339] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and 3-(aminomethyl)-1-methylpyridin-2(1H)-one (16.01 mg, 0.116 mmol) in DMA (232 μL) and isolated as a light beige solid (16.7 mg, 32%). 1 H NMR(400MHz,DMSO-d6)δppm 3.47(s,3H),4.14-4.25(m,2H),6.25(t,J=6.82Hz,1H),7.31-7.40(m,2H),7.40-7.45(m,2H),7. 56-7.65(m,2H),7.70(dd,J=6.69,1.64Hz,1H),7.73-7.82(m,2H),9.16(s,1H); ESI-MSm / z[M+H] + 447.0.

[0340] Example 47: (R)-5-(2-chloro-3-fluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0341] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), DIPEA (30.4 μL, 0.174 mmol) and (R)-2-methoxypropan-1-amine HCl (13.10 mg, 0.104 mmol) in DMA (217 μL) and isolated as a clear film (2.6 mg, 8%). 1H NMR (400MHz, CD3OD) δppm 1.14 (br s, 3H), 3.50 (d, J = 16.67Hz, 3H), 7.25 (br s, 1H), 7.36-7.55 (m, 4H), 7.88 (d, J = 8.08Hz, 1H); ESI-MSm / z [M+H] + 398.0.

[0342] Example 48: 5-(3-chloro-2-fluoropyridin-4-yl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0343] To a 2 mL scintillation vial equipped with a stirrer was added 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.4 μL, 0.231 mmol) and oxazol-2-ylmethanamine HCl (18.66 mg, 0.139 mmol) dissolved in DMA (385 μL). The reaction mixture was heated at 60° C. overnight and then passed through a 0.5 in. The syringe was rinsed with methanol and the sample was analyzed by mass-triggered preparative LC / MS ( The filtrate was purified using an XSelect CSH Prep C18, 5 μm, ID 30 x 75 mm column) eluting with a gradient of 20-50% ACN in water (acid mode). The collected fractions were concentrated and dried in vacuo to give the title compound (6.5 mg, 14%) as a brown-orange film. 1 H NMR (400MHz, CD3OD) δppm4.69 (br s, 2H), 7.29 (br s, 1H), 7.47-7.59 (m, 3H), 7.98 (d, J = 6.57Hz, 2H), 8.35 (d, J = 4.80Hz, 1H); ESI-MSm / z [M+H] + 408.0.

[0344] Example 49: 5-(3-chloro-2-fluoropyridin-4-yl)-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0345] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), DIPEA (30.3 μL, 0.173 mmol) and thiazol-2-ylmethanamine HCl (15.66 mg, 0.104 mmol) dissolved in DMA (433 μL) and isolated as a clear film (1.46 mg, 4%). 1 H NMR (400MHz, CD3OD) δppm 4.84 (s, 2H), 7.42-7.53 (m, 3H), 7.54 (d, J = 3.28Hz, 1H), 7.72 (br s,1H),7.95(dd,J=7.71,1.64Hz,1H),8.30(d,J=4.80Hz,1H); ESI-MSm / z[M+H] + 424.0.

[0346] Example 50: 5-(3-chloro-2-fluoropyridin-4-yl)-3-((cyclopropylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0347] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.4 μL, 0.231 mmol) and cyclopropylmethylamine (9.86 mg, 0.139 mmol) dissolved in DMA (385 μL) and isolated as a brown-orange solid (6.4 mg, 15%). 1 H NMR (400MHz, DMSO-d6) δppm 0.22 (d, J = 3.79Hz, 2H), 0.44-0.47 (m, 2H), 1.23 (br s,3H),3.03-3.10(m,2H),7.21(d,J=8.59Hz,1H),7.49-7.52(m,1H),7.57(s,1H),7.79(br s,1H),7.85(s,1H),8.22(d,J=5.05Hz,1H),8.39(d,J=5.05Hz,1H),9.15(s,1H); ESI-MSm / z[M+H] + 381.0.

[0348] Example 51: 5-(3-chloro-2-fluoropyridin-4-yl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0349] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.4 μL, 0.231 mmol) and (3-fluoropyridin-2-yl)methanamine HCl (22.55 mg, 0.139 mmol) dissolved in DMA (385 μL) and isolated as a beige solid (3.3 mg, 7%). 1 H NMR (400MHz, CD3OD) δppm 1.34 (s, 4H), 4.75 (br s, 2H), 7.36-7.57 (m, 4H), 7.65 (t, J = 9.09Hz, 1H), 7.99 (dd, J = 7.58, 1.52Hz, 1H), 8.28-8.44 (m, 2H); ESI-MS m / z [M+H] + 436.0.

[0350] Example 52: 5-(3-chloro-2-fluoropyridin-4-yl)-3-(ethylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0351] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), Et3N (24.16 μL, 0.231 mmol) and ethylamine (70% in water, 7.01 μL, 0.087 mmol) dissolved in EtOH (500 μL) and isolated as a clear film (3.3 mg, 11%). 1 H NMR(400MHz,CD3OD)δppm 1.17(t,J=7.20Hz,3H),3.33-3.38(m,2H),7.38-7.51(m,3H),7.93(dd,J=7.71,1.64Hz,1H),8.29(d,J=5.05Hz,1H); ESI-MSm / z [M+H] + 355.0.

[0352] Example 53: 5-(3-chloro-2-fluoropyridin-4-yl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0353] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), Et3N (32.2 μL, 0.231 mmol) and 2,2-difluoroethylamine HCl (16.30 mg, 0.139 mmol) dissolved in EtOH (500 μL) and isolated as a clear film (6.9 mg, 15%). 1 H NMR(400MHz,CD3OD)δppm 3.69-3.78(m,2H),5.85-6.18(m,1H),7.41(d,J=5.05Hz,1H),7.44-7.53(m, 2H),7.95(dd,J=7.58,1.77Hz,1H),8.30(d,J=5.05Hz,1H); ESI-MSm / z[M+H] + 391.1.

[0354] Example 54: 5-(3-chloro-2-fluoropyridin-4-yl)-3-((4-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0355] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), Et3N (32.2 μL, 0.231 mmol) and (4-fluorophenyl)methanamine (17.35 mg, 0.139 mmol) dissolved in EtOH (500 μL) and isolated as an orange solid (12.5 mg, 25%). 1H NMR(400MHz,DMSO-d6)δppm 4.39-4.48(m,2H),7.17-7.23(m,2H),7.38(dd,J=8.59,5.56Hz,2H),7.41-7.46(m,1H),7.51-7.55(m,2H), 7.58(d,J=4.80Hz,1H),7.87(dd,J=7.71,1.14Hz,1H),8.38(d,J=4.80Hz,1H),9.27(s,1H); ESI-MSm / z[M+H] + 435.3.

[0356] Example 55: 2-(((5-(3-chloro-2-fluoropyridin-4-yl)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)thiazole-5-carbonitrile

[0357] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), Et3N (32.2 μL, 0.231 mmol) and 2-(aminomethyl)thiazole-5-carbonitrile HCl (24.35 mg, 0.139 mmol) dissolved in EtOH (500 μL) and isolated as a yellow solid (16.1 mg, 31%). 1 H NMR(400MHz,DMSO-d6)δppm 4.85(br s,2H),7.47(d,J=7.58Hz,1H),7.55-7.66(m,2H),7.89(d,J=7.83Hz,2H),8.40(d,J=4.80Hz,1H),8.63(s,1H),9.73(br s,1H); ESI-MSm / z[M+H] + 449.3.

[0358] Example 56: 5-(3-chloro-2-fluoropyridin-4-yl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0359] The title compound was prepared in a manner analogous to Example 48 using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (19.25 mg, 0.056 mmol), Et3N (23.25 μL, 0.167 mmol) and methylamine (33% in EtOH) (10.38 μL, 0.083 mmol) dissolved in EtOH (479 μL) and isolated as a light beige film (2.2 mg, 12%). 1 H NMR (400MHz, CD3OD) δppm 2.92 (s, 3H), 7.45-7.50 (m, 2H), 7.52-7.55 (m, 1H), 7.98 (d, J = 7.58Hz, 1H), 8.34 (d, J = 4.80Hz, 1H); ESI-MSm / z [M+H] + 341.0.

[0360] Example 57: 5-(2-chloro-3-fluorophenyl)-3-(((4-methylmorpholin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0361] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and 4-methylmorpholin-2-yl)methanamine HCl (23.17 mg, 0.139 mmol) in DMA (232 μL) and isolated as a light beige solid (24.8 mg, 49%). 1 H NMR(400MHz,DMSO-d6)δppm 2.83(br s,3H),3.01(br s,1H),3.22-3.40(m,2H),3.46-3.57(m,2H),3.63-3.72(m,1H),3.78(br s,1H),3.98(s,1H),4.06(d,J=10.61Hz,1H),7.32-7.36(m,1H),7.38-7.42(m,1H),7.4 5-7.48(m,1H),7.56-7.68(m,3H),7.82(d,J=7.83Hz,1H),9.19(s,1H); ESI-MSm / z[M+H] + 439.0.

[0362] Example 58: 5-(2-chloro-3-fluorophenyl)-3-((2-ethoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0363] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and 2-ethoxypropan-1-amine HCl (19.42 mg, 0.139 mmol) in DMA (232 μL) and isolated as a light yellow film (15.4 mg, 32%). 1 H NMR(400MHz,DMSO-d6)δppm 1.06-1.14(m,6H),3.18-3.26(m,1H),3.43(dt,J=6.76,3.32Hz,1H),3.51(ddd,J=9.85,6.82,3.28Hz,1H),3.54-3.61 (m,1H),7.33-7.44(m,4H),7.58-7.67(m,2H),7.80(dd,J=7.71,1.39Hz,1H),9.12(d,J=4.04Hz,1H); ESI-MSm / z[M+H] + 412.0.

[0364] Example 59: 3-(((5-chloropyridin-2-yl)methyl)amino)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0365] To a 5 mL microwave vial equipped for stirring was charged 3-chloro-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.193 mmol), (5-chloropyridin-2-yl)methanamine (35.8 mg, 0.251 mmol), DIPEA (67.4 μL, 0.386 mmol) and DMA (386 μL). The reaction mixture was heated at 70° C. for 21 h, then diluted in MeOH and passed through a 0.5 in. The product was purified by column chromatography and filtered through a 12 mL sintered syringe with a pad of 1% celite. The precipitate was dried over 400 nmol / L (water bath set at 60° C.) to give the title compound (17.9 mg, 22%) as a pale yellow solid.1 H NMR(400MHz,DMSO-d6)δppm 2.07(s,3H),3.87(s,3H),4.57(d,J=5.31Hz,2H),7.26-7.34(m,1H),7.40(dd,J=7.58,1.52Hz,1H),7.47(d,J=8.84Hz,1H),7.67(dd,J=7. 83,1.26Hz,1H),7.86(s,1H),7.96(dd,J=8.59,2.53Hz,1H),8.22(t,J=5.43Hz,1H),8.62(d,J=2.02Hz,1H),9.44(s,1H); ESI-MSm / z[M+H] + 417.0.

[0366] Example 60: 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0367] To a 5 mL microwave vial equipped for stirring was charged 3-chloro-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.193 mmol), 2-methoxypropan-1-amine HCl (29.1 mg, 0.232 mmol), DIPEA (67.4 μL, 0.386 mmol) and DMA (386 μL). The reaction mixture was heated at 70° C. for 15 h, then diluted in MeOH and passed through a 0.5 in. The product was filtered through a 12 mL sintered syringe with a pad of 1 mL. The product was analyzed by mass-triggered preparative LC / MS (Waters C18, 5 μm, ID 30x75 mm column) eluting with a 20-45% gradient of aqueous ACN (acid mode). Product-containing fractions were collected, concentrated, and dried in vacuo to give the title compound (17.9 mg, 26%) as an orange solid. 1H NMR(400MHz,DMSO-d6)δppm 1.09(d,J=6.06Hz,3H),2.05(s,3H),3.14-3.21(m,1H),3.27(s,3H),3.38-3.50(m,2H),3.87(s,3H),7.26 -7.31(m,1H),7.37(dd,J=7.58,1.52Hz,1H),7.64-7.71(m,2H),7.85(s,1H),9.23(s,1H); ESI-MSm / z[M+H] + 364.0.

[0368] Example 61: 3-((Cyclobutylmethyl)amino)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0369] In a manner similar to Example 60, 3-chloro-5- The title compound was prepared from (1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.161 mmol), cyclobutylmethylamine HCl (25.4 mg, 0.209 mmol) and DIPEA (28.1 μL, 0.161 mmol) and isolated as a colorless oil (34 mg, 56%). 1 H NMR(400MHz,CD3OD)δppm 1.60-1.74(m,2H),1.78-1.90(m,2H),1.94-2.02(m,2H),2.03(s,3H),2.40-2.47(m,1H),3.24(dd,J=7.20,5.43Hz,2H ),3.85(s,3H),7.26(s,1H),7.33-7.37(m,1H),7.52-7.58(m,1H),7.62-7.68(m,1H),7.83(s,1H),9.02-9.06(m,1H).

[0370] Example 62: 2-((5-(2-chloro-3-fluorophenyl)-1,1-dioxo-4H-benzo [e][1,2,4]thiadiazin-3-yl)amino)-N,N-dimethylacetamide

[0371] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.5 μL, 0.232 mmol) and 2-amino-N,N-dimethylacetamide (14.20 mg, 0.139 mmol) in DMA (232 μL) and isolated as a light beige solid (12.2 mg, 26%). 1 H NMR(400MHz,DMSO-d6)δppm 2.88(s,3H),2.97(s,3H),4.11(d,J=4.29Hz,2H),7.33-7.46(m,3H),7.57-7.66(m,2H ),7.76(t,J=4.29Hz,1H),7.81(dd,J=7.71,1.39Hz,1H),9.53(s,1H); ESI-MSm / z[M+H] + 411.0.

[0372] Example 63: 5-(2-cyclopropylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0373] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.157 mmol), (2-cyclopropylphenyl)boronic acid (28.0 mg, 0.173 mmol), Cs2CO3 (2M, 197 μL, 0.394 mmol) and Pd(dppf)2·CH2Cl2 adduct (12.85 mg, 0.016 mmol) in dioxane (787 μL) and isolated as a light yellow solid (21.2 mg, 36.3%). 1 H NMR(400MHz,DMSO-d6)δppm 0.66-0.78(m,4H),1.37-1.46(m,1H),3.26(s,3H),3.36-3.45(m,4H),7.08(d,J=7.58Hz,1H),7.22(dd,J= 7.45,1.14Hz,1H),7.32-7.37(m,2H),7.39-7.47(m,2H),7.68-7.76(m,2H),8.93(s,1H); ESI-MSm / z[M+H] + 372.0.

[0374] Example 64: 5-(2-chloro-3-fluorophenyl)-3-((isothiazol-3-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0375] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and isothiazol-3-ylmethylamine (10.75 mg, 0.094 mmol) in EtOH (2 mL) and isolated as a white solid (2 mg, 7%). 1 H NMR(400MHz,DMSO-d6)δppm 4.54-4.66(m,2H)7.28-7.49(m,4H),7.53-7.67(m,2H),7.75-7.84(m,1H),7.92(s,1H),9.06(d,J=4.55Hz,1H),9.29(s,1H); ESI-MSm / z[M+H] + 423.0.

[0376] Example 65: 5-(2-chloro-3-fluorophenyl)-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0377] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (75.0 mg, 0.217 mmol), Et3N (91 μL, 0.652 mmol) and thiazol-2-ylmethanamine hydrochloride (120 mg, 0.796 mmol) in EtOH (3.0 mL) and isolated as a white solid (115 mg, 46%). 1 HNMR(400MHz,DMSO-d6)δppm 9.32(br s,1H),8.00(br s,1H),7.85-7.79(m,1H),7.76(d,J=3.2Hz,1H),7.67(d,J=3.2Hz,1H),7.65-7.53(m,2H),7.48 -7.43(m,1H),7.40(d,J=7.8Hz,1H),7.38-7.32(m,1H),4.75(d,J=6.0Hz,2H); ESI-MSm / z[M+H] + 423.0.

[0378] Example 66: 5-(2-chloro-3-fluorophenyl)-3-((pyrimidin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0379] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and pyrimidin-2-ylmethanamine (15.8 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a yellow oil (12 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δppm 4.66(br s,2H),7.30-7.49(m,4H),7.55-7.68(m,2H),7.79(dd,J=7.96,1.39Hz,1H),8.01(s,1H),8.81(d,J=4.80Hz,2H),9.47(s,1H); ESI-MS m / z[M+H] + 418.0.

[0380] Example 67: 5-(2-chloro-3-fluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0381] The title compound was prepared as a TFA salt in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), Et3N (61 μL, 0.435 mmol) and 2-(pyridin-2-yl)ethanamine (26.5 mg, 0.217 mmol) in EtOH (2 mL) and isolated as an off-white solid (30 mg, 48%). 1HNMR(400MHz,DMSO-d6)δppm 3.09(t,J=6.69Hz,2H),3.60-3.69(t,J=6.69Hz,2H),7.26-7.48(m,4H),7.49-7.66(m,4H),7.78(dd,J=7.71,1.39Hz,1H),8.07(br s,1H),8.66(d,J=4.55Hz,1H),9.08(s,1H); ESI-MS m / z[M+H] + 431.1.

[0382] Example 68: 5-(2-chloro-3-fluorophenyl)-3-((2-(pyridin-4-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0383] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 2-(pyridin-4-yl)ethanamine (13.3 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a white solid (9 mg, 29%). 1 H NMR(400MHz,DMSO-d6)δppm 2.94-3.07(m,2H),3.51-3.63(m,2H),7.26-7.50(m,4H),7.52-7.64(m,2H),7.67(d,J=5.31 Hz,2H),7.78(dd,J=7.83,1.26Hz,1H),8.69(d,J=6.32Hz,2H),9.07(s,1H); ESI-MSm / z[M+H] + 431.1.

[0384] Example 69: 5-(2-chloro-3-fluorophenyl)-3-((2-(pyridin-3-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0385] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 2-(pyridin-3-yl)ethanamine (13 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a white solid (10 mg, 32%); ESI-MS m / z [M+H] + 431.1.

[0386] Example 70: 5-(2-chloro-3-fluorophenyl)-3-((3-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0387] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 2-(3-methoxyphenyl)ethanamine (16.4 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a white solid (5 mg, 14%); ESI-MS m / z [M+H] + 460.1.

[0388] Example 71: 5-(2-chloro-3-fluorophenyl)-3-((2-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0389] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 2-(2-methoxyphenyl)ethanamine (16.4 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a white solid (4 mg, 12%); ESI-MS m / z [M+H] + 460.1.

[0390] Example 72: 5-(2-chloro-3-fluorophenyl)-3-((4-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0391] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 2-(4-methoxyphenyl)ethanamine (16.4 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a white solid (3.0 mg, 9%); ESI-MS m / z [M+H] + 460.1.

[0392] Example 73: 5-(2-chloro-3-fluorophenyl)-3-((2-(tetrahydrofuran-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0393] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 2-(tetrahydrofuran-2-yl)ethanamine (12.5 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a brown film (2.0 mg, 7%); ESI-MS m / z [M+H] + 424.1.

[0394] Example 74: 5-(2-chloro-3-fluorophenyl)-3-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0395] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et3N (30 μL, 0.217 mmol) and 1-isopropyl-5-methyl-1H-pyrazol-3-amine (15 mg, 0.109 mmol) in EtOH (2 mL) and isolated as a white solid (1 mg, 3%); ESI-MS m / z [M+H] + 448.1.

[0396] Example 75: 5-(3,5-difluorophenyl)-3-((4-fluorobenzyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0397] 3-Chloro-5-(3,5-difluorophenyl)-4H-benzo[alpha] [e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.076 mmol), (4-fluorophenyl)methanamine (19.03 mg, 0.152 mmol), Et3N (0.032 mL, 0.228 mmol) and EtOH (2 mL). The reaction mixture was heated to 65 ° C and stirred overnight. LC / MS indicated that the reaction was complete. The solvent was removed and the product was taken up in DMF (1 mL), filtered, and purified by supercritical fluid chromatography. The purified fractions were evaporated above Celite® to give the title compound (6.7 mg, 21%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 4.42(d,J=5.56Hz,2H),7.13-7.23(m,2H),7.23-7.31(m,2H),7.31-7.45(m,4H),7.48(dd,J=7.58 ,1.52Hz,1H),7.77(dd,J=7.83,1.01Hz,1H),7.84(t,J=5.56Hz,1H),9.19(s,1H); ESI-MSm / z[M+H] + 418.1.

[0398] Example 76: 3-((2,5-difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0399] In a manner similar to Example 75, 3-chloro-5- The title compound was prepared from (3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.076 mmol), (2,5-difluorophenyl)methanamine (21.8 mg, 0.152 mmol) and Et3N (0.032 mL, 0.228 mmol) and isolated as a white solid (2.7 mg, 8%). 1H NMR(400MHz,DMSO-d6)δppm 4.47(d,J=5.31Hz,2H),7.13-7.23(m,1H),7.23-7.33(m,4H),7.33-7.39(m,1H),7.39-7.46(m,1H),7.49(d d,J=7.58,1.52Hz,1H),7.77(dd,J=7.83,1.01Hz,1H),7.89(t,J=5.68Hz,1H),9.29(s,1H); ESI-MSm / z[M+H] + 436.0.

[0400] Example 77: 5-(3,5-difluorophenyl)-3-((2-fluorobenzyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0401] In a manner similar to Example 75, 3-chloro-5- The title compound was prepared from (3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.076 mmol), (2-fluorophenyl)methanamine (19 mg, 0.152 mmol) and Et3N (0.032 mL, 0.228 mmol) and isolated as a white solid (3.5 mg, 11%). 1 H NMR(400MHz,DMSO-d6)δppm 4.47(d,J=5.31Hz,2H),7.14-7.24(m,2H),7.24-7.31(m,2H),7.31-7.46(m,4H),7.48(dd,J =7.45,1.39Hz,1H),7.77(d,J=6.82Hz,1H),7.83-7.91(m,1H),9.19(s,1H); ESI-MSm / z[M+H] + 418.1.

[0402] Example 78: 3-((2,6-difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0403] In a manner similar to Example 75, 3-chloro-5- The title compound was prepared from (3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.076 mmol), (2,6-difluorophenyl)methanamine (22 mg, 0.152 mmol) and Et3N (0.032 mL, 0.228 mmol) and isolated as a white solid (2 mg, 6%). ESI-MS m / z [M+H] + 436.0.

[0404] Example 79: 5-(3,5-difluorophenyl)-3-(((6-methylpyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0405] In a manner similar to Example 75, 3-chloro-5- The title compound was prepared from (3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.076 mmol), (6-methylpyridin-2-yl)methanamine (19 mg, 0.152 mmol) and Et3N (0.032 mL, 0.228 mmol) and isolated as a white solid (10 mg, 32%). ESI-MS m / z [M+H] + 415.0.

[0406] Example 80: 5-(3,5-difluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0407] In a manner similar to Example 75, 3-chloro-5- The title compound was prepared as a TFA salt from (3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (75 mg, 0.228 mmol), 2-(pyridin-2-yl)ethanamine (42.0 mg, 0.342 mmol) and Et3N (0.095 mL, 0.684 mmol) and isolated as an orange oil (21 mg, 23%). 1H NMR(400MHz,DMSO-d6)δppm 3.07(t,J=6.82Hz,2H),3.59-3.70(m,2H),7.24(d,J=6.06Hz,2H),7.30-7.37(m,1H ),7.41(t,J=9.60Hz,1H),7.44-7.65(m,4H),7.75(dd,J=7.83,1.26Hz,1H),8.00(br s,1H),8.62(br s,1H),9.18(s,1H);ESI-MSm / z[M+H] + 415.5.

[0408] Example 81: 3-((Cyclobutylmethyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0409] The title compound was prepared in a manner analogous to Example 75 using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.152 mmol), cyclobutylmethylamine HCl (37.0 mg, 0.304 mmol) and Et3N (0.0636 mL, 0.456 mmol) in EtOH (3.5 mL) and isolated as a white semisolid (33.0 mg, 58%). 1 H NMR(400MHz,CD3OD)δppm 1.68-1.80(m,2H),1.83-1.99(m,2H),2.07(d,J=8.08Hz,2H),2.53(dt,J=15.22,7.67Hz,1H),3.33(d,J=7.33 Hz,2H),7.01-7.17(m,3H),7.30-7.40(m,1H),7.47(d,J=7.33Hz,1H),7.83(d,J=7.58Hz,1H); ESI-MSm / z[M+H] + 378.1.

[0410] Example 82: 5-(3,5-difluorophenyl)-3-((pyridin-4-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0411] The formate salt of the title compound was prepared in a manner analogous to Example 75 using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.076 mmol), pyridin-4-ylmethanamine (32.90 mg, 0.304 mmol) and Et3N (0.032 mL, 0.228 mmol) in EtOH (2.0 mL) and isolated as a yellow solid (23.92 mg, 35%). 1 H NMR(400MHz,DMSO-d4)δppm 4.48(d,J=5.2Hz,2H),7.42-7.28(m,6H),7.48(d,J=8.4Hz,1H),7.75(d,J=7.6Hz,1H),7.99(s,1H),8.51(d,J=5.6Hz,2H); ESI-MSm / z[M+H] + 401.1.

[0412] Example 83: 5-(3,5-difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0413] The title compound was prepared in a manner analogous to Example 75 using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.152 mmol), pyridin-2-ylmethanamine (21.4 mg, 0.198 mmol) and DIPEA (26.6 μL, 0.152 mmol) in DMA (304 μL) and isolated as a white solid (31 mg, 51%). 1 H NMR(400MHz,CD3OD)δppm 4.67-4.82(m,2H),7.05-7.22(m,3H),7.35-7.43(m,1H),7.46-7.57(m,1H)7.57-7.69(m,1H) ,7.73-7.82(m,1H),7.80-7.88(m,1H),8.12-8.27(m,1H),8.54-8.66(m,1H); ESI-MSm / z[M+H] + 401.0.

[0414] Example 84: 5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0415] The title compound was prepared in a manner analogous to Example 75 using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol), 2-methoxypropan-1-amine HCl (45.8 mg, 0.365 mmol) and DIPEA (106 μL, 0.608 mmol) in DMA (608 μL) and isolated as a white solid (56.1 mg, 48%). 1 H NMR(400MHz,DMSO-d6)δppm 1.10(d,J=6.32Hz,3H),3.15-3.21(m,1H),3.26(s,3H),3.38-3.50(m,2H),7.28(d,J=6.32Hz,2H),7.33-7.37( m,1H),7.42-7.49(m,2H),7.59(t,J=5.05Hz,1H),7.77(dd,J=7.71,1.14Hz,1H),9.22(s,1H); ESI-MSm / z[M+H] + 382.1.

[0416] Example 85: (R)-5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0417] The racemate prepared in Example 84 was resolved by 2D separation using an SFC / UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20 x 150 mm, flow rate 100 mL / min) eluting with 30% IPA. The title compound, which was arbitrarily assigned the R-stereochemistry as the first eluting peak, was isolated as a white solid (15.4 mg, 27.5%). 1 HNMR(400MHz,DMSO-d6)δppm 1.10(d,J=6.32Hz,3H),3.15-3.21(m,1H),3.26(s,3H),3.38-3.50(m,2H),7.28(d,J=6.32Hz,2H),7.33-7.37( m,1H),7.42-7.49(m,2H),7.59(t,J=5.05Hz,1H),7.77(dd,J=7.71,1.14Hz,1H),9.22(s,1H); ESI-MSm / z[M+H] + 382.1.

[0418] Example 86: (S)-5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0419] The racemate prepared in Example 84 was resolved by 2D separation using an SFC / UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20 x 150 mm, flow rate 100 mL / min) eluting with 30% IPA. The title compound, arbitrarily assigned to the S-stereochemistry, was isolated as a white solid (21.2 mg, 37.8%) as the second eluting peak. 1 HNMR(400MHz,DMSO-d6)δppm 1.10(d,J=6.32Hz,3H),3.14-3.22(m,1H),3.26(s,3H),3.37-3.51(m,2H),7.29(d,J=6.06Hz,2H),7.32-7.37( m,1H),7.41-7.50(m,2H),7.59(t,J=5.18Hz,1H),7.77(dd,J=7.83,1.26Hz,1H),9.22(s,1H); ESI-MSm / z[M+H] + 382.1.

[0420] Example 87: 5-(3,5-difluorophenyl)-3-((2-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0421] The title compound was prepared in a manner analogous to Example 75 using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.152 mmol), 2-methoxybutan-1-amine HCl (27.6 mg, 0.198 mmol) and DIPEA (26.6 μL, 0.152 mmol) in DMA (304 μL) and isolated as a tan solid (12 mg, 20%). 1H NMR(400MHz,CD3OD)δppm 0.93(td,J=7.39,1.64Hz,3H),1.43-1.64(m,2H),3.35(d,J=2.27Hz,2H),3.53-3.62(m,1H), 7.07-7.17(m,3H),7.33-7.40(m,1H),7.45-7.50(m,1H),7.82-7.86(m,1H); ESI-MSm / z[M+H] + 396.0.

[0422] Example 88: 3-(Benzylamino)-5-(3,5-difluorophenyl)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0423] The title compound was prepared in a manner analogous to Example 75 using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.076 mmol), benzylamine (32.60 mg, 0.304 mmol) and Et3N (32.0 μL, 0.028 mmol) in EtOH (2.0 mL) and isolated as a white solid (32.00 mg, 54%). 1 H NMR (400MHz, CDCl3) δppm 4.40(d,J=5.6Hz,2H),6.06(t,J=5.6Hz,1H),6.74(d,J=5.2Hz,2H),6.82(t,J=8.8Hz,1H),7.20-7.18 (m,2H),7.28-7.26(m,3H),7.35-7.34(m,2H),7.88-7.86(dd,J=6.4Hz,J=3.2Hz,2H); ESI-MSm / z[M+H] + 400.0.

[0424] Example 89: 2-Fluoro-6-(3-(methylamino)-1,1-dioxo-4H-benzo [e][1,2,4]thiadiazin-5-yl)benzonitrile

[0425] To a 10 mL vial was added 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19 mg, 0.077 mmol), saturated (aq) aqueous NaHCO3 (2 mL) and PdCl2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL). The reaction mixture was heated to 80°C and stirred overnight. LC / MS indicated the reaction was complete. The solvent was boiled off with gentle heating. The crude product was taken up in MeOH, filtered using a 0.45 μm PTFE syringe filter, and analyzed by preparative LC / MS (Waters C18, 5 μm, ID 4 x 50 mm column) with gradient elution using aqueous ACN (acid mode). Pure fractions were combined and lyophilized to give the TFA salt of the title compound as a white solid (1 mg, 5%). ESI-MS m / z [M+H] + 331.0.

[0426] Example 90: 4-chloro-2-(3-(methylamino)-1,1-dioxo-4H-benzo [e][1,2,4]thiadiazin-5-yl)benzonitrile

[0427] The title compound was prepared as a TFA salt in a manner similar to Example 89 using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (5-chloro-2-cyanophenyl)boronic acid (14 mg, 0.077 mmol), saturated (aq) aqueous NaHCO3 solution (2 mL) and PdCl2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL) and isolated as a white solid (1.0 mg, 5%). ESI-MS m / z [M+H] + 347.0.

[0428] Example 91: 5-(2-ethylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0429] The title compound was prepared as a TFA salt in a manner similar to Example 89 using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-ethylphenyl)boronic acid (12 mg, 0.077 mmol), saturated (aq) aqueous NaHCO3 solution (2 mL) and PdCl2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL) and isolated as a white solid (1 mg, 5%). ESI-MS m / z [M+H] + 316.1.

[0430] Example 92: 5-(2-chloro-4-methylphenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0431] The title compound was prepared as a TFA salt in a manner similar to Example 89 using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-chloro-4-methylphenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) aqueous NaHCO3 solution (2 mL) and PdCl2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL) and isolated as a white solid (2 mg, 8%). ESI-MS m / z [M+H] + 336.0.

[0432] Example 93: 5-(2-chloro-5-fluorophenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0433] The title compound was prepared as a TFA salt in a manner similar to Example 89 using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-chloro-5-fluorophenylboronic acid (13 mg, 0.077 mmol), saturated (aq) aqueous NaHCO solution (2 mL) and PdCl(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL) and isolated as a white solid (1 mg, 5%); ESI-MS m / z [M+H] + 340.0.

[0434] Example 94: 5-(2-chloro-4-fluorophenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0435] The title compound was prepared as a TFA salt in a manner similar to Example 89 using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-chloro-4-fluorophenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) aqueous NaHCO3 solution (2 mL) and PdCl2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL) and isolated as a white solid (2 mg, 10%). ESI-MS m / z [M+H] + 340.0.

[0436] Example 95: 5-(3-Fluoro-2-methylphenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0437] The title compound was prepared as a TFA salt in a manner similar to Example 89 using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (3-fluoro-2-methylphenyl)boronic acid (12 mg, 0.077 mmol), saturated (aq) aqueous NaHCO3 solution (2 mL) and PdCl2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL) and isolated as a white solid (1 mg, 5%). ESI-MS m / z [M+H] + 320.1.

[0438] Example 96: 3-(Methylamino)-5-(2,3,5-trifluorophenyl)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0439] To a 2-5 mL microwave vial was added 5-iodo-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.445 mmol), (2,3,5-trifluorophenyl)boronic acid (82 mg, 0.467 mmol) and dioxane (2.225 mL) were added, followed by Cs2CO3 (2 M, 890 μL, 1.780 mmol) and Pd(dppf)2·CH2Cl2 adduct (36.3 mg, 0.044 mmol). The mixture was purged with nitrogen and then heated in a microwave reactor at 120 ° C for 45 minutes. The reaction mixture was then poured into water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting brown oil was dissolved in MeOH (2 mL), filtered, and analyzed by preparative LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column) using a gradient of 30-50% ACN in water (acid mode). The title compound was isolated as a white solid (23.6 mg, 16%). 1 H NMR (400MHz, DMSO-d6) δppm 2.69 (d, J = 4.55Hz, 3H), 7.14 (br s,1H),7.22-7.36(m,2H),7.46(dd,J=7.58,1.52Hz,1H),7.64-7.81(m,2H),9.24(s,1H); ESI-MSm / z[M+H] + 342.0.

[0440] Example 97: 5-(2-chloro-3-fluorophenyl)-7-methyl-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0441] To a 10 mL vial was added 3-chloro-5-(2-chloro-3-fluorophenyl)-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (44 mg, 0.122 mmol) in EtOH (9 mL) along with methylamine (2 M in MeOH, 0.122 mL, 0.245 mmol) and Et3N (0.051 mL, 0.367 mmol). The resulting yellow solution was heated to 65 ° C and stirred for 16 hours. The mixture was then concentrated and analyzed by preparative HPLC (Waters C18, 5 μm, ID 30 x 75 mm column) using a gradient of ACN (0.1% TFA) in water (0.1% TFA). The title compound was isolated as a white solid (26 mg, 60%). 1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),2.73(d,J=4.55Hz,3H),7.13(d,J=4.29Hz,1H),7.24(d,J=1.52 Hz,1H),7.27-7.33(m,1H),7.52-7.64(m,3H),8.99(s,1H); ESI-MSm / z[M+H] + 354.5.

[0442] Example 98: 3-((4-Isopropylphenyl)amino)-5-(5-methyl-1H-pyrazol-3-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0443] An 8 mL vial was charged with 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), (5-methyl-1H-pyrazol-3-yl)boronic acid (10.7 mg, 0.085 mmol), saturated (aq) NaHCO3 (1.5 mL), PdCl2(dppf) (2.073 mg, 2.83 μmol) and dioxane (1.5 mL). The reaction mixture was heated to 80 ° C and stirred overnight. LC / MS indicated that the reaction was complete. The reaction mixture was diluted with EtOAc, and the organic layer was separated and introduced into a 4 mL vial. The solvent was boiled off. The residue was diluted with MeOH, filtered and purified to give the title compound (1.0 mg, 5%) as a white solid; ESI-MS m / z [M + H] + 396.5.

[0444] Example 99: 5-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0445] The title compound was prepared in a manner analogous to Example 98 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.74 mg, 0.085 mmol), saturated (aq) NaHCO (1.5 mL) and PdCl(dppf) (2.073 mg, 2.83 μmol) in dioxane (1.5 mL) and was isolated as a white solid (1.0 mg, 5%); ESI-MS m / z [M+H] + 432.0.

[0446] Example 100: 3-((4-Isopropylphenyl)amino)-5-(1H-pyrazol-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0447] To an oven-dried 8 mL vial was charged 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), 1H-pyrazole (7.71 mg, 0.113 mmol), K2CO3 (15.66 mg, 0.113 mmol), copper(I) iodide (1.079 mg, 5.67 μmol) and DMF (2 mL). The reaction mixture was degassed with N2 and then heated to 125°C and stirred for 18 hours. The reaction mixture was then diluted with DMF (1 mL), filtered through a 0.45 μm PTFE syringe filter, and analyzed by preparative HPLC (Phenomenex C18, 10 μm, ID 50 x 250 mm column) using a gradient of 40-55% ACN in water (acid mode). Pure fractions were combined and lyophilized to afford the TFA salt of the title compound as a white solid (6 mg, 28%). 1H NMR(400MHz,DMSO-d6)δppm 1.22(d,J=6.82Hz,6H),2.91(quin,J=6.88Hz,1H),6.54(s,1H),6.70(s,1H),7.25-7.42(m,4H),7.45(t, J=8.08Hz,1H),7.72-7.81(m,1H),7.95(d,J=8.08Hz,1H),8.55(d,J=2.53Hz,1H),10.25(s,1H),11.21(br s,1H);ESI-MSm / z[M+H] + 382.1.

[0448] Example 101: 3-((4-isopropylphenyl)amino)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0449] To the mixture were added 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.091 mmol) and 1-(oxetan-3-yl)-4- To a stirred solution of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34.0 mg, 0.136 mmol) in water (1 mL) and dioxane (3 mL) was added PdCl2(dppf)·CH2Cl2 adduct (7.40 mg, 9.06 μmol) and K2CO3 (27.6 mg, 0.199 mmol). The reaction mixture was heated at 100°C for 18 hours, then washed with brine (2x) and extracted with EtOAc. The organic layers were combined, dried over MgSO4, concentrated, filtered, and analyzed by reverse phase preparative LC / MS (Phenomenex C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 35-60% 10 mM NH 4 HCO 3 (aq) in water / ACN (20 / 80 v / v containing 10 mM NH 4 HCO 3 ) to give the title compound (3.2 mg, 8%) as a white solid. 1H NMR(400MHz,CD3OD)δppm 1.21-1.26(m,6H),2.89(spt,J=6.82Hz,1H),5.06-5.16(m,4H),5.62-5.70(m,1H),7.21(d,J=8.59Hz,2H),7.35(t,J=7 .71Hz,1H),7.40(d,J=8.59Hz,2H),7.52-7.55(m,1H),7.78(dd,J=7.96,1.39Hz,1H),7.86(s,1H),8.08(s,1H); ESI-MS m / z[M+H] + 438.3.

[0450] Example 102: 5-(1-ethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0451] The title compound was prepared as a TFA salt in a manner analogous to Example 101 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.091 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30.20 mg, 0.13 mmol), K2CO3 (27.6 mg, 0.199 mmol) and PdCl2(dppf)·CH2Cl2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL) and isolated as a tan solid (14.7 mg, 31%). 1 H NMR(400MHz,CD3OD)δppm 1.24(d,J=6.82Hz,6H),1.54(t,J=7.33Hz,3H),2.89(spt,J=6.86Hz,1H),4.29(q,J=7.33Hz,2H),7.22(d,J=8.34Hz,2H),7.32-7.37(m ,1H),7.40(d,J=8.34Hz,2H),7.53(dd,J=7.58,1.52Hz,1H),7.73(s,1H),7.77(dd,J=7.96,1.39Hz,1H),7.96(s,1H); ESI-MSm / z[M+H] + 410.2.

[0452] Example 103: 5-(1,3-dimethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0453] The title compound was prepared in a manner analogous to Example 101 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (45 mg, 0.102 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27.2 mg, 0.122 mmol), K2CO3 (31 mg, 0.224 mmol) and PdCl2(dppf)·CH2Cl2 adduct (8.33 mg, 10.20 μmol) in water (1 mL) and dioxane (3 mL) and isolated as an off-white solid (7.0 mg, 17%). 1 HNMR(400MHz,DMSO-d6)δppm 1.14-1.22(m,6H),2.09(s,3H),2.86(dt,J=13.58,6.98Hz,1H),3.28-3.36(m,3H),7.18-7.34(m,3H),7.41( d,J=7.83Hz,3H),7.68(d,J=6.32Hz,1H),7.90(s,1H),9.08-9.44(m,1H),9.47-9.83(m,1H); ESI-MSm / z[M+H] + 410.2.

[0454] Example 104: 5-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0455] In a manner similar to Example 101, 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (55 mg, 0.125 mmol), 1-(3,3-difluorocyclobutyl)-4- The title compound was prepared as a TFA salt from (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53.10 mg, 0.187 mmol), K2CO3 (37.9 mg, 0.274 mmol) and PdCl2(dppf)·CH2Cl2 adduct (10.18 mg, 0.012 mmol) and isolated as an off-white solid (15.9 mg, 22%). 1 H NMR(400MHz,DMSO-d6)δppm 1.20(d,J=7.07Hz,6H),2.81-2.95(m,1H),3.19-3.30(m,4H),4.97-5. 08(m,1H),7.26(d,J=8.34Hz,2H),7.34(t,J=7.71Hz,1H),7.40(d,J=8. 59Hz,2H),7.53(dd,J=7.71,1.39Hz,1H),7.69(dd,J=7.83,1.01Hz,1H),7.93(s,1H),8.32(s,1H),9.43(s,1H),9.72(s,1H); ESI-MSm / z[M+H] + 472.2.

[0456] Example 105: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0457] The title compound was prepared as a TFA salt in a manner analogous to Example 101 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.091 mmol), 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (33.70 mg, 0.136 mmol), K2CO3 (27.6 mg, 0.199 mmol) and PdCl2(dppf)·CH2Cl2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL) and isolated as a white solid (7.2 mg, 14%). 1H NMR(400MHz,CD3OD)δppm 1.24(d,J=6.82Hz,6H),1.89-1.98(m,2H),2.48-2.57(m,2H),2.59-2. 71(m,2H),2.89(dt,J=13.77,7.01Hz,1H),4.91-4.98(m,1H),7.22(d,J =8.34Hz,2H),7.35(t,J=7.71Hz,1H),7.41(d,J=8.59Hz,2H),7.53(dd,J=7.58,1.52Hz,1H),7.75-7.79(m,2H),8.01(s,1H); ESI-MSm / z[M+H] + 436.3.

[0458] Example 106: 3-((4-Isopropylphenyl)amino)-5-(3-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0459] To a solution of 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.240 mmol) in dioxane (3 mL) was added PdCl2(dppf) (5 mg, 6.83 μmol) and saturated (aq)NaHCO3 (1 mL). The mixture was sparged with nitrogen for 30 seconds. The stirred reaction mixture was heated at 135 ° C for 60 minutes in a microwave reactor and then cooled to room temperature. The solution was decanted from the salt and the product was purified by preparative HPLC (Waters C18, 5 μm, ID 30 x 75 mm column) using a gradient of ACN (0.1% formic acid) in water (0.1% formic acid). Product-containing fractions were combined and dried to give the title compound (7.2 mg, 32%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 1.26-1.32(m,6H),2.87-3.03(m,1H),3.18(s,1H),3.38-3.42(m,1H),4.88(s,1H),7. 25-7.32(m,2H),7.41-7.47(m,3H),7.50-7.55(m,1H),7.87(dd,J=8.08,1.52Hz,1H); ESI-MS m / z [M+H] + 396.2.

[0460] Example 107: 3-((4-Isopropylphenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0461] The title compound was prepared in a manner analogous to Example 106 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.240 mmol), PdCl2(dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO3 (1 mL) in dioxane (3 mL) and isolated as a white solid (10 mg, 45%). 1 H NMR(400MHz,CD3OD)δppm 1.22-1.26(m,6H),2.89(dt,J=13.83,6.85Hz,1H),4.00(s,3H),7.22(d,J=8.34Hz,2H),7.32-7.44(m,3H) ,7.53(dd,J=7.58,1.26Hz,1H),7.70(s,1H),7.77(dd,J=7.83,1.52Hz,1H),7.92(s,1H); ESI-MSm / z[M+H] + 396.2.

[0462] Example 108: 3-((4-Isopropylphenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0463] The title compound was prepared in a manner analogous to Example 106 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.240 mmol), PdCl2(dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO3 (1 mL) in dioxane (3 mL) and isolated as a white solid (6.4 mg, 29%). 1 H NMR(400MHz,DMSO-d6)δppm 1.21(d,J=7.07Hz,6H),2.89(dt,J=13.77,7.01Hz,1H),3.72(s,3H),6.58(d,J=1.52Hz,1H),7.27(d,J=8.59Hz,2H),7.37-7. 46(m,3H),7.61(d,J=6.57Hz,1H),7.69(d,J=1.77Hz,1H),7.88(d,J=7.83Hz,1H),9.28(s,1H),9.71(s,1H); ESI-MSm / z[M+H] + 396.2.

[0464] Example 109: 5-cyclopropyl-3-((4-isopropylphenyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0465] The title compound was prepared in a manner analogous to Example 106 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.057 mmol), cyclopropylboronic acid (16.35 mg, 0.190 mmol), PdCl2(dppf) (10.92 mg, 0.013 μmol) and saturated (aq) NaHCO3 (1.5 mL mL) in dioxane (1.5 mL) and isolated as an off-white solid (11.19 mg, 19%). 1H NMR (400MHz, CDCl3) δppm 0.42-0.46(m,2H),0.72-0.74(m,2H),1.25(d,J=6.9Hz,6H),1.43~1.58(m,1H),2.88 -2.98(m,1H),7.17~7.25(m,6H),7.79(d,J=7.6Hz,1H),8.49(s,1H); ESI-MSm / z[M+H] + 356.0.

[0466] Example 110: 5-Isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0467] Step A: 3-((4-Isopropylphenyl)amino)-5-(prop-1-en-2-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0468] The title compound was prepared in a manner analogous to Example 106 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (113.5 mg, 259 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74.25 mg, 441.88 μmol), PdCl2(dppf) (49.58 mg, 0.059 μmol) and saturated (aq) NaHCO3 (7.0 mL) in dioxane (7.0 mL) and isolated as a (crude) brown solid (120 mg); ESI-MS m / z [M+H] + 356.1.

[0469] Step B: 5-isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0470] To a solution of 5-isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120.00 mg, 337.60 μmol) in MeOH (40 mL) was added Pd / C (50 mg, 5%). The reaction mixture was stirred under a hydrogen atmosphere (balloon filled with H2) at 15 psi and 25 ° C for 20 hours. Additional Pd / C (100.00 mg, 5%) was added to the reaction mixture, which was stirred under H2 at 15 psi and 25 ° C for another 20 hours. After hydrogenation, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi TM C18, 4 μm, ID 30 x 150 mm column) eluting with a gradient of 50-80% water (0.225% formic acid) in ACN. Product-containing fractions were combined and dried to give the title compound (15.67 mg, 13%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 1.22(d,J=6.8Hz,6H),1.28(d,J=6.4Hz,6H),2.85-2.90(m,1H),3.23-3.29(m,1H),7.25-7.27( m,3H),7.49(d,J=7.6Hz,2H),7.57(d,J=5.8Hz,2H),9.43(s,1H),9.83(s,1H); ESI-MSm / z[M+H] + 358.2.

[0471] Example 111: 5-cyclobutyl-3-((4-isopropylphenyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0472] To a mixture of 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (160 mg, 0.362 mmol), bromo(cyclobutyl)zinc (0.5 M, 725.14 μL), S-Phos (29.77 mg, 0.073 mmol) in THF (2.00 mL) was added Pd(OAc) (16.28 mg, 0.073 mmol). The resulting mixture was heated to 65° C. for 16 hours. The reaction mixture was then poured into saturated (aq) NH4Cl (40 mL) and extracted with EtOAc (2 x 30 mL). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The crude product was purified by preparative HPLC (Welch Ultimate AQ-C18, 5 μm, ID 30 x 150 mm column) eluting with a gradient of 50-80% water in ACN (acid mode).The title compound was isolated as a white solid (3.83 mg, 3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.21(d,J=6.8Hz,6H),1.85-1.88(m,1H),2.03-2.17(m,3H),2.41-2.55(m,2H),2.85-2.90(m,1H),3.77-3.79(m ,1H),7.24-7.27(m,3H),7.47(d,J=7.6Hz,2H),7.56(d,J=7.6Hz,2H),9.39(s,1H),9.56(s,1H); ESI-MSm / z[M+H] + 370.1.

[0473] Example 112: 5-(2-chlorophenyl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0474] The title compound was prepared in a manner analogous to Example 101 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.113 mmol), (2-chlorophenyl)boronic acid (21.26 mg, 0.136 mmol), K2CO3 (34.5 mg, 0.249 mmol) and PdCl2(dppf)·CH2Cl2 adduct (9.25 mg, 0.011 mmol) in water (1 mL) and dioxane (3 mL) and isolated as a white solid (28 mg, 59%). 1H NMR (400MHz, DMSO-d6) δppm 1.19 (d, J=6.82Hz, 6H), 2.86 (dt, J=13.71, 6.92Hz, 1H), 7.23 (br s,2H),7.33-7.46(m,4H),7.49-7.64(m,3H),7.72(d,J=7.33Hz,1H),7.81(d,J=7.07Hz,1H),9.12(br s,1H),9.50(br s,1H); ESI-MSm / z[M+H] + 426.1.

[0475] Example 113: 3-((4-Isopropylphenyl)amino)-5-(3-methylpyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0476] The title compound was prepared in a manner analogous to Example 101 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.113 mmol), (3-methylpyridin-4-yl)boronic acid (23.27 mg, 0.170 mmol), K2CO3 (34.5 mg, 0.249 mmol) and PdCl2(dppf)·CH2Cl2 adduct (9.25 mg, 0.011 mmol) in water (1 mL) and dioxane (3 mL) and isolated as a tan solid (10.8 mg, 23%). 1 H NMR(400MHz,CD3OD)δppm 1.23(d,J=7.07Hz,6H),2.18(s,3H),2.88(spt,J=6.99Hz,1H),7.20(d,J=8.59Hz,2H),7. 33-7.41(m,3H),7.44-7.49(m,2H),7.89-7.94(m,1H),8.49-8.71(m,2H); ESI-MSm / z[M+H] + 407.2.

[0477] Example 114: 5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0478] The title compound was prepared as a TFA salt in a manner analogous to Example 101 using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.091 mmol), (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (19.03 mg, 0.136 mmol), K2CO3 (27.6 mg, 0.199 mmol) and PdCl2(dppf)·CH2Cl2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL) and isolated as a tan solid (4.7 mg, 9%). 1 H NMR(400MHz,CD3OD)δppm 1.24(d,J=7.07Hz,6H),2.20(s,3H),2.89(spt,J=6.99Hz,1H),3.90(s,3 H),7.22(d,J=8.59Hz,2H),7.34-7.42(m,3H),7.42-7.47(m,1H),7.57(br s,1H),7.81(dd,J=7.83,1.52Hz,1H);ESI-MSm / z[M+H] + 410.2.

[0479] Example 115: 5-(1,3-dimethyl-1H-pyrazol-4-yl)-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0480] To a stirred solution of 5-iodo-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (59 mg, 0.134 mmol) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35.6 mg, 0.160 mmol) in water (1 mL) and dioxane (3 mL) was added PdCl(dppf)-CHCl adduct (10.92 mg, 0.013 mmol) and KCO (40.7 mg, 0.294 mmol). The reaction mixture was heated at 100°C for 6 hours. The mixture was neutralized with 1N (aq) HCl and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO, and concentrated in vacuo. The product was analyzed by reverse phase LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column) eluting with a gradient of 30-55% (aq) formic acid in ACN (containing 1% formic acid) to give the title compound (16 mg, 29%) as an off-white solid. 1 H NMR(400MHz,CD3OD)δppm 1.24(d,J=6.82Hz,6H),2.14(s,3H),2.88(dt,J=13.83,6.85Hz,1H),3.92(s,3H),7.03(d,J=7.33Hz,1H),7.22-7.28 (m,1H),7.29-7.34(m,1H),7.36(s,2H),7.45(d,J=7.33Hz,1H),7.71(s,1H),7.80(d,J=7.83Hz,1H); ESI-MSm / z[M+H] + 410.2.

[0481] Example 116: 5-cyclopropyl-3-((3-isopropylphenyl)amino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0482] The title compound was prepared in a manner analogous to Example 115 using 5-iodo-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (59 mg, 0.134 mmol), cyclopropylboronic acid (13.78 mg, 0.160 mmol), K2CO3 (40.7 mg, 0.294 mmol) and PdCl2(dppf)·CH2Cl2 adduct (10.92 mg, 0.013 mmol) in water (1 mL) and dioxane (3 mL) and isolated as a tan solid (11.3 mg, 24%). 1 H NMR (400MHz, CD3OD) δppm 0.74 (br s, 2H), 1.09 (d, J = 6.06Hz, 2H), 1.27 (d, J = 6.57Hz, 6H), 1.89 (br s,1H),2.85-3.00(m,1H),7.05(d,J=7.07Hz,1H),7.22-7.33(m,2H),7.37-7.50(m,3H),7.66(d,J=7.58Hz,1H); ESI-MSm / z[M+H] + 356.2.

[0483] Example 117: 5-(2-chlorophenyl)-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0484] To a stirred solution of 5-iodo-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (43 mg, 0.097 mmol) and (2-chlorophenyl)boronic acid (18.24 mg, 0.117 mmol) in water (1 mL) and dioxane (3 mL) were added PdCl2(dppf)·CHCl2 adduct (7.94 mg, 9.72 μmol) and K2CO3 (29.6 mg, 0.214 mmol). The reaction mixture was heated at 100°C for 3 hours. The reaction mixture was then neutralized with 1N HCl(aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. The product was purified by reverse phase chromatography (Waters C18, 5 μm, ID 30 x 75 mm column) eluting with a gradient of 20-45% water (1% formic acid) in ACN (1% formic acid). The title compound was isolated as a white solid (8 mg, 19%). 1 HNMR(400MHz,DMSO-d6)δppm 1.20(d,J=6.82Hz,6H),2.96(br s,1H),7.40(br s,3H),7.45-7.62(m,3H),7.69(d,J=6.57Hz,1H),7.78(br s,1H),7.90(dd,J=8.59,2.27Hz,1H),8.41(br s,1H);ESI-MSm / z[M+H] + 427.1.

[0485] Example 118: 5-Cyclopropyl-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0486] The title compound was prepared in a manner analogous to Example 117 using 5-iodo-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (63 mg, 0.142 mmol), cyclopropylboronic acid (18.35 mg, 0.21 mmol), PdCl2(dppf)·CH2Cl2 adduct (11.63 mg, 0.014 mmol) and K2CO3 (43.3 mg, 0.313 mmol) in water (1 mL) and dioxane (3 mL) and isolated as a light yellow solid (6.0 mg, 12%). 1 H NMR(400MHz,CD3OD)δppm 0.73-0.79(m,2H),1.10-1.16(m,2H),1.30(d,J=7.07Hz,6H),1.88-1.97(m,1H),3.00-3.12(m,1H),7.23-7.29(m,1H),7.35(d,J=8.59Hz, 1H),7.43(dt,J=7.64,1.11Hz,1H),7.66(dd,J=7.83,0.76Hz,1H),8.10(dd,J=8.59,2.53Hz,1H),8.56(d,J=2.27Hz,1H); ESI-MSm / z[M+H] + 357.2.

[0487] Example 119: 5-Cyclopropyl-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0488] To a stirred solution of 3-(((3-fluoropyridin-2-yl)methyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (53 mg, 0.123 mmol) and cyclopropylboronic acid (13.69 mg, 0.159 mmol) in water (1 mL) and dioxane (3 mL) was added PdCl2(dppf)·CHCl2 adduct (10.01 mg, 0.012 mmol) and K2CO3 (37.3 mg, 0.270 mmol). The reaction mixture was heated at 100°C for 29 hours, then neutralized with 1N HCl(aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. The product was purified by reverse phase column chromatography (Phenomenex C18, 5 μm, ID 30 x 75 mm column) eluting with a gradient of 25-50% water in ACN (basic mode). The title compound was isolated as a light yellow solid (4.5 mg, 11%). 1 H NMR(400MHz,CD3OD)δppm 0.71-0.77(m,2H),1.06-1.15(m,2H),1.85-1.96(m,1H),4.78(d,J=1.52Hz,2H),7.19-7. 24(m,1H),7.37-7.44(m,2H),7.59-7.66(m,2H),8.41(d,J=4.55Hz,1H); ESI-MSm / z[M+H] + 347.1.

[0489] Example 120: 5-Cyclopropyl-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0490] In a manner similar to Example 119, 5-iodo-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[alpha]-[ ... The title compound was prepared from [e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.056 mmol), cyclopropylboronic acid (5.80 mg, 0.068 mmol), PdCl2(dppf)·CH2Cl2 adduct (4.60 mg, 5.63 μmol) and K2CO3 (17.11 mg, 0.124 mmol) and isolated as a tan semisolid (2.6 mg, 13%). 1 H NMR(400MHz,CD3OD)δppm 0.69-0.75(m,2H),1.05-1.14(m,2H),1.83-1.92(m,1H),3.93(s,3H),4.60(s,2H),6.69(d,J=8.08Hz,1H),6 .99(d,J=7.33Hz,1H),7.19-7.25(m,1H),7.39(dt,J=7.58,1.14Hz,1H),7.61-7.68(m,2H); ESI-MSm / z[M+H] + 359.1.

[0491] Example 121: 5-Cyclopropyl-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0492] The title compound was prepared in a manner analogous to Example 119 using 5-iodo-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (35 mg, 0.088 mmol), cyclopropylboronic acid (11.30 mg, 0.132 mmol), PdCl2(dppf)·CH2Cl2 adduct (7.16 mg, 8.77 μmol) and K2CO3 (26.7 mg, 0.193 mmol) in water (1 mL) and dioxane (3 mL) and isolated as a light yellow solid (5.7 mg, 21%). 1 HNMR(400MHz,CD3OD)δppm 0.73-0.78(m,2H),1.08-1.14(m,2H),1.87-1.95(m,1H),7.14-7.20(m,1H),7.26(t,J=7.71Hz,1H),7.35-7.41 (m,2H),7.44(d,J=7.58Hz,1H),7.59(dd,J=8.59,1.01Hz,2H),7.67(dd,J=7.96,0.88Hz,1H); ESI-MSm / z[M+H] + 314.1.

[0493] Example 122: 5-(2-chloro-3-fluorophenyl)-3-(((3-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0494] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50.0 mg, 0.014 mmol), Et3N (56 μL, 0.760 mmol) and (3-methoxypyridin-2-yl)methanamine hydrochloride (50.60 mg, 0.29 mmol) in EtOH (2.0 mL) and isolated as an off-white solid (29.8 mg, 46%). 1H NMR(400MHz,DMSO-d6)δppm 3.86-3.95(m,4H),4.54(dd,J=7.58,4.80Hz,2H),7.30-7.45(m,4H),7.51(dd,J=8.34,1.01Hz,1H),7.54-7.67(m ,2H),7.80(dd,J=7.83,1.52Hz,1H),8.03(t,J=4.42Hz,1H),8.13(d,J=4.29Hz,1H),9.54(s,1H); ESI-MSm / z[M+H] + 447.1.

[0495] Example 123: 5-(2-chloro-3-fluorophenyl)-3-(((tetrahydrofuran-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0496] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), DIPEA (16.7 μL, 0.096 mmol) and (tetrahydrofuran-2-yl)methanamine (8.79 mg, 0.087 mmol) in DMA (435 μL) and isolated as a light beige solid (8.3 mg, 23%). 1 H NMR(400MHz,DMSO-d6)δppm 1.44-1.56(m,1H),1.77-1.86(m,2H),1.89-2.00(m,1H),3.06-3.19(m,1H),3.36-3.49(m,1H),3.89(td,J=7.20,3.54Hz,1H),7.30-7 .39(m,2H),7.39-7.45(m,1H),7.51(q,J=5.98Hz,1H),7.54-7.65(m,2H),7.78(dd,J=7.83,1.26Hz,1H),9.05(s,1H); ESI-MSm / z[M+H] + 410.0.

[0497] Example 124: 3-((2-methoxyethyl)amino)-5-(2-(trifluoromethyl)phenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0498] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.262 mmol), (2-(trifluoromethyl)phenyl)boronic acid (52.3 mg, 0.275 mmol), calcium carbonate (2M 525 μL, 1.049 mmol) and Pd(dppf)2·CH2Cl2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL) and isolated as a light brown solid (34.3 mg, 33%). 1 H NMR(400MHz,DMSO-d6)δppm 3.26(s,3H),3.39-3.48(m,3H),7.30-7.41(m,3H),7.43-7.55(m,2H),7.74-7.89(m,3H),7.98(d,J=7.33Hz,1H),8.96(s,1H); ESI-MSm / z[M+H] + 400.1.

[0499] Example 125: 2-Fluoro-6-(3-((2-methoxyethyl)amino)-1,1-dioxo- 4H-Benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0500] To a 20 mL microwave vial equipped for stirring was charged 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.03 g, 0.079 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.025 g, 0.102 mmol), Cs2CO3 (0.157 mL, 0.315 mmol) and dioxane (0.394 mL). Next, Pd(dppf)2·CH2Cl2 adduct (6.43 mg, 7.87 μmol) was added under nitrogen and the reaction mixture was heated to 90°C for 12 hours. The mixture was then cooled, diluted with MeOH (1 mL) and heated to 40°C for 12 hours. The residue was filtered on (Waters Purify by preparative LC / MS on a C18, 5 μm, ID 30 x 75 mm column) eluting with a gradient of 25-90% ACN in water (acid mode).Collected fractions were concentrated and dried in vacuo to give the title compound (5 mg, 17%) as a tan solid. 1HNMR(400MHz,DMSO-d6)δppm 3.26(s,3H),3.43(d,J=4.29Hz,4H),7.40(s,4H),7.50-7.57(m,2H),7.69-7.80( m,1H),7.82-7.88(m,1H),7.92-8.01(m,1H),9.23-9.33(m,1H); ESI-MSm / z[M+H] + 375.0.

[0501] Example 126: 2-(1,1-dioxo-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile

[0502] To a 2-5 mL microwave vial was added 5-iodo-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.357 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (211.65 mg, 0.856 mmol), CsCO (0.759 mL, 1.518 mmol), and Pd(dppf) CHCl adduct (31.0 mg, 0.038 mmol) in dioxane (1.898 mL). The reaction mixture was heated at 120° C. in a microwave reactor for 30 minutes, then poured into water and extracted with EtOAc (3×). The organic layers were combined, dried over MgSO, filtered, and concentrated to a light brown oil. The oil was dissolved in MeOH (2 mL), filtered, and purified by supercritical fluid chromatography (SFC) to give, after removal of the solvent, the formate salt of the title compound as a white solid (10.37 mg, 4%). 1 H NMR (400MHz, DMSO-d6) δppm 4.58 (s, 2H), 7.02 (t, J = 7.6Hz, 1H), 7.24-7.49 (m, 4H), 7.56-7.76 (m, 3H), 8.28 (s, 1H); ESI-MSm / z [M+H] + 414.0.

[0503] Example 127: 3-((2-methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0504] To a 2-5 mL microwave vial was added (crude) 5-iodo-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.380 mmol), (2,3,5-trifluorophenyl)boronic acid (70.1 mg, 0.399 mmol) and dioxane (1.898 mL), followed by CsCO (759 μL, 1.518 mmol) and Pd(dppf) CHCl adduct (31.0 mg, 0.038 mmol). The mixture was purged with nitrogen and then heated in a microwave reactor at 120 ° C for 45 minutes. The reaction mixture was poured into water and then extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over MgSO, filtered, and concentrated to give a brown oil. The oil was dissolved in MeOH (2 mL), filtered, and purified by supercritical fluid chromatography (SFC) to give the title compound (8.5 mg, 6%) as a clear oil after removal of the solvent. 1 H NMR (400MHz, CD3OD) δppm 1.07-1.21(m,3H),3.11-3.24(m,1H),3.31(dt,J=3.28,1.64Hz,3H),3.46-3.62(m,2H),7.09(br s,1H),7.32-7.44(m,2H),7.51(d,J=7.33Hz,1H),7.89(dd,J=7.96,1.39Hz,1H); ESI-MS m / z [M+H] + 400.0.

[0505] Example 128: (S)-3-((2-methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide and

[0506] Example 129: (R)-3-((2-methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0507] To a 10-20 mL microwave vial was added 5-iodo-3-((2-methoxypropyl)amino)- 4H-Benzo[e][1,2,4]thiadiazine 1,1-dioxide (400 mg, 1.012 mmol), (2,3,5-trifluorophenyl)boronic acid (214 mg, 1.215 mmol) and dioxane (5.061 mL) were added, followed by Cs2CO3 (2.024 mL, 4.05 mmol) and Pd(dppf)2·CH2Cl2 adduct (83 mg, 0.101 mmol). The mixture was purged with nitrogen and then heated at 120°C for 80 minutes. The reaction mixture was poured into water and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting brown oil was purified by The mixture was filtered through a pad of Celite® and purified by supercritical fluid chromatography (SFC) to afford the racemate of the title compound as a clear oil after removal of the solvent. The racemate was resolved by chiral chromatography using a SFC / UV 04 system (Chiral Technology AS-H column, 5 μm, ID 2.1 x 150 mm, flow rate 1.25 mL / min) eluting with 30% EtOH.

[0508] Example 128, which was the first eluting peak and arbitrarily assigned the S-stereochemistry, was isolated as a clear oil (15.7 mg, 3.9%). 1 H NMR (400MHz, CD3OD) δppm 1.14(s,3H),3.13-3.23(m,1H),3.32-3.36(m,2H),3.46-3.56(m,2H),7.10(br s,1H),7.31-7.46(m,2H),7.51(d,J=7.33Hz,1H),7.90(dd,J=7.83,1.52Hz,1H); ESI-MS m / z [M+H] + 400.1.

[0509] Example 129, which was arbitrarily assigned the R-stereochemistry, was isolated as a clear oil (17.3 mg, 4.3%) as the second eluting peak. 1 H NMR (400MHz, CD3OD) δppm 1.14(s,3H),3.08-3.24(m,1H),3.32-3.35(m,3H),3.45-3.57(m,2H),7.10(br s,1H),7.32-7.45(m,2H),7.51(d,J=7.07Hz,1H),7.90(dd,J=7.83,1.52Hz,1H); ESI-MS m / z [M+H] + 400.1.

[0510] Example 130: 3-((Cyclobutylmethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0511] The title compound was prepared in a manner analogous to Example 127 using 3-((cyclobutylmethyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.383 mmol), (2,3,5-trifluorophenyl)boronic acid (70.8 mg, 0.403 mmol), Pd(dppf)2·CH2Cl2 adduct (31.3 mg, 0.038 mmol) and Cs2CO3 (767 μL, 1.534 mmol) in dioxane (1.917 mL) and isolated as a tan solid (5.1 mg, 3%). 1 H NMR(400MHz,DMSO-d6)δppm 1.61-1.74(m,2H),1.78-1.89(m,2H),1.93-2.06(m,2H),3.22-3.30(m,2H),7.27-7.40 (m,3H),7.52(dd,J=7.58,1.52Hz,1H),7.71-7.86(m,2H),9.21(s,1H); ESI-MSm / z[M+H] + 396.1.

[0512] Example 131: 3-((Pyridin-2-ylmethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0513] The title compound was prepared in a manner analogous to Example 127 using 5-iodo-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120 mg, 0.290 mmol), (2,3,5-trifluorophenyl)boronic acid (53.5 mg, 0.304 mmol), Pd(dppf)2·CH2Cl2 adduct (23.66 mg, 0.029 mmol) and Cs2CO3 (579 μL, 1.159 mmol) in dioxane (1.449 mL) and isolated as a white solid (3.4 mg, 3%). 1H NMR (400MHz, DMSO-d6) δppm 4.60 (br s, 2H), 7.34-7.44 (m, 3H), 7.46 (d, J = 7.58Hz, 1H), 7.57 (d, J = 6.57Hz, 1H), 7.73-7.93 (m, 3H), 7.99 (br s,1H),8.59(d,J=4.55Hz,1H),9.54-9.66(m,1H); ESI-MSm / z[M+H] + 419.0.

[0514] Example 132: 5-(2-chloro-3-(trifluoromethyl)phenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0515] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.262 mmol), (2-chloro-3-(trifluoromethyl)phenyl)boronic acid (61.8 mg, 0.275 mmol), Cs2CO3 (2M, 525 μL, 1.049 mmol) and Pd(dppf)2·CH2Cl2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL) and isolated as a white solid (1.0 mg, 1%). 1 H NMR (400MHz, CD3OD) δppm 3.49-3.58(m,4H),7.46(br s,2H),7.72(d,J=4.80Hz,2H),7.92-7.97(m,1H),8.02(t,J=4.67Hz,1H); ESI-MSm / z[M+H] + 434.0.

[0516] Example 133: 5-(2-chloro-4-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0517] Step A: 3-Chloro-5-(2-chloro-4-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0518] To a 2-5 mL microwave vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120 mg, 0.350 mmol), (2-chloro-4-fluorophenyl)boronic acid (64.1 mg, 0.368 mmol), Pd(dppf)2·CHCl2 adduct (28.6 mg, 0.035 mmol), Cs2CO3 (0.701 mL, 1.401 mmol) and dioxane (1.7 mL). The mixture was purged with nitrogen and heated in a microwave reactor at 120°C for 30 minutes, then cooled. The reaction mixture was poured into water (10 mL) and acidified with 1N HCl(aq) (5 mL), forming a difficult-to-filter precipitate. The filtrate was extracted with EtOAc (2 x 20 mL), and the organic layers were combined, dried over MgSO4, and filtered. The solvent was removed to give the title compound as a reddish brown oil which was used without further purification. ESI-MS m / z [M+H] + 344.9.

[0519] Step B: 5-(2-chloro-4-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0520] To (crude) 3-chloro-5-(2-chloro-4-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.058 mmol) was added DMA (290 μL), followed by DIPEA (11.13 μL, 0.064 mmol) and 2-methoxyethylamine (5.49 μL, 0.064 mmol). The reaction mixture was heated at 70° C. overnight, then filtered and analyzed by preparative LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column) using a gradient of 30-50% ACN in water (acid mode). Product-containing fractions were collected and the solvent removed to give the title compound (13 mg, 59%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 3.26 (s, 3H), 3.35–3.40 (m, 2H), 3.42 (d, J = 5.31Hz, 2H), 7.31–7.46 (m, 3H), 7.48 (br s,1H),7.54(dd,J=8.46,6.19Hz,1H),7.70–7.79(m,2H),9.03(s,1H); ESI-MSm / z[M+H] + 384.0.

[0521] Example 134: 5-(2-chloro-5-(trifluoromethyl)phenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0522] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.262 mmol), (2-chloro-5-(trifluoromethyl)phenyl)boronic acid (61.8 mg, 0.275 mmol), Cs2CO3 (2M, 525 μL, 1.049 mmol) and Pd(dppf)2·CH2Cl2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL) and isolated as a brown solid (5.5 mg, 5%). 1 H NMR(400MHz,DMSO-d6)δppm 3.26(br s,3H),3.43(br s,2H),7.19-7.56(m,3H),7.66-8.13(m,5H),9.15(br s,1H); ESI-MSm / z[M+H] + 434.0.

[0523] Example 135: 5-(3-chloro-2-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0524] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.262 mmol), 2-(3-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70.7 mg, 0.276 mmol), Cs2CO3 (2M, 328 μL, 0.656 mmol) and Pd(dppf)2·CH2Cl2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL) and isolated as a white film (5.0 mg, 5%). 1H NMR(400MHz,CD3OD)δppm 3.33(br s,2H),3.49(br s,4H),7.30-7.43(m,3H),7.47(d,J=7.07Hz,1H),7.61-7.73(m,1H),7.87(dd,J=7.83,1.52Hz,1H); ESI-MSm / z[M+H] + 384.0.

[0525] Example 136: 3-((4-ethylphenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0526] To a solution of 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.169 mmol) in DMA (1 mL) was added 4-ethylaniline (0.063 mL, 0.506 mmol). The reaction mixture was heated at 120 °C for 15 hours. The reaction mixture was cooled to room temperature, extracted with EtOAc, and washed with brine (3x). The organic layers were combined, concentrated, filtered, and analyzed by preparative LC / MS (Waters C18, 5 μm, ID 30x75 mm column) eluting with a gradient of 20-70% water in ACN (base mode). Product-containing fractions were collected and concentrated to give the title compound (3.2 mg, 5%) as a brown solid. 1 H NMR(400MHz,CD3OD)δppm 1.22-1.26(m,3H),2.64(qd,J=7.62,3.41Hz,2H),3.98(s,3H),7.16-7.23(m,2H),7.2 9-7.34(m,1H),7.42(d,J=8.34Hz,2H),7.53-7.57(m,1H),7.72-7.76(m,1H),7.98(br s,1H),8.55(br s,1H);ESI-MSm / z[M+H] + 382.1.

[0527] Example 137: 3-((Furan-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0528] Step A: 3-Chloro-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0529] To a stirred solution of 3-chloro-5-iodo-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.034 g, 0.1 mmol) and o-tolylboronic acid (0.014 g, 0.1 mmol) in water (0.5 mL) and dioxane (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5 μmol) and Na2CO3 (0.089 g, 0.837 mmol). The (first) reaction mixture was heated at 100°C for 1 hour, then cooled to room temperature and allowed to stand. To a (second) stirred solution of 3-chloro-5-iodo-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (68.5 mg, 0.2 mmol) and o-tolylboronic acid (27.2 mg, 0.2 mmol) in water (1 mL) and dioxane (1 mL) was added tetrakis(triphenylphosphine)palladium(0) (11.56 mg, 10 μmol) and Na2CO3 (177 mg, 1.674 mmol). The reaction mixture was heated at 70°C for 0.5 hours and at 80°C for 1 hour, then cooled to room temperature and combined with the first reaction mixture. The combined mixture was neutralized with 1N HCl(aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous NaSO4, and concentrated in vacuo. The crude product was purified on a silica gel column eluted with 50% EtOAc in hexane. The product-containing fractions were collected and concentrated in vacuo to give the title compound as an off-white solid (49 mg, 53%). ESI-MS m / z [M+H] + 307.0.

[0530] Step B: 3-((Furan-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0531] To a mixture of 3-chloro-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.163 mmol) and furan-2-ylmethylamine (200 mg, 2.059 mmol) dissolved in n-butanol (5 mL) was added Cs2CO3 (100 mg, 0.307 mmol). The reaction mixture was stirred at 150°C for 2 hours in a microwave reactor, then cooled and analyzed by preparative LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column). The title compound was isolated as a white solid (50 mg, 44%). 1 H NMR (400MHz, CD3OD) δppm 2.08(s,3H),4.46(s,2H),6.29-6.35(m,2H),7.17-7.23(m,1H),7.32-7.44(m,6H),7.79-7.87(m,1H); ESI-MSm / z[M+H] + 368.1.

[0532] Example 138: 5-(2-chlorophenyl)-6-fluoro-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0533] Step A: 2'-Chloro-6-fluoro-[1,1'-biphenyl]-2-amine

[0534] To a solution of 2-bromo-3-fluoroaniline (1.00 g, 5.26 mmol) and (2-chlorophenyl)boronic acid (1.23 g, 7.89 mmol) in dioxane (10 mL) and water (1 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (171.50 mg, 263.00 To the mixture was added 4-[ ... 1 H NMR(400MHz,DMSO-d6)δppm 5.07-4.62(m,2H),6.44-6.36(m,1H),6.61-6.56(m,1H),7.13-7.05(m,1H) ,7.35-7.29(m,1H),7.47-7.40(m,2H),7.64-7.56(m,1H); ESI-MSm / z[M+H] + 222.1.

[0535] Step B: 5-(2-Chlorophenyl)-6-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide

[0536] To a solution of isocyanate sulfonyl chloride (536.96 mg, 3.79 mmol) in nitromethane (9.00 mL) was added 2'-chloro-6-fluoro-[1,1'-biphenyl]-2-amine (6 mL). The reaction mixture was stirred at a temperature of -20 ° C to 0 ° C for 30 minutes. AlCl (433.62 mg, 3.25 mmol) was slowly added, and the temperature of the mixture was gradually increased to 100 ° C to 110 ° C. The reaction mixture was stirred for another hour at this temperature under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then poured into water (30.00 mL) and extracted with EtOAc (2 x 30 mL). The combined organic fractions were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness under vacuum, and the remaining residue was purified by preparative TLC (DCM / MeOH) to give the title compound (300 mg, 34% yield) as a white solid.

[0537] Step C: 3-Chloro-5-(2-chlorophenyl)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0538] A solution of 5-(2-chlorophenyl)-6-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (300 mg, 0.918 mmol), N,N-diethylaniline (137.02 mg, 0.918 mmol) and POCl3 (5.00 mL) was stirred at 120°C for 3 hours and then allowed to cool to room temperature. The volatiles were removed in vacuo to give the title compound (crude) as a brown oil, which was used without additional purification (300 mg). ESI-MS m / z [M+H] + 345.1.

[0539] Step D: 5-(2-chlorophenyl)-6-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0540] To a solution of 3-chloro-5-(2-chlorophenyl)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (320.00 mg, 0.927 mmol) and methylamine HCl (93.89 mg, 1.39 mmol) in IPA (5.00 mL) was added Et3N (469.04 mg, 4.64 mmol). The resulting mixture was stirred at 70°C for 2 hours. The solvent was removed and the crude material was purified by preparative HPLC (Phenomenex Synergi TMC18, 10 μm, ID 25 x 150 mm) eluting with a gradient of water (0.225% formic acid) in ACN. Product-containing fractions were combined and dried to give the title compound (36 mg, 11%) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δppm 2.71(s,3H),7.32-7.20(m,2H),7.59-7.47(m,4H),7.71-7.69(m,1H),7.81-7.78(m,1H); ESI-MSm / z[M+H] + 340.0.

[0541] Example 139: 5-(2,5-difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0542] To a solution of 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol) and pyridin-2-ylmethylamine (33.2 mg, 0.307 mmol) in DMA (5 mL) was added CsCO (100 mg, 0.307 mmol). The reaction mixture was stirred and heated in a microwave reactor at 150 ° C for 2 hours. The product was analyzed by preparative HPLC (Waters C18, 5 μm, ID 30 x 75 mm column) using a gradient of ACN (0.1% formic acid) in water (0.1% formic acid). The title compound was isolated as a white solid (18 mg, 15%). 1 H NMR (400MHz, CD3OD) δppm 4.62 (br s, 2H), 7.19-7.56 (m, 1H), 7.88 (dd, J = 7.96, 1.64Hz, 1H), 8.36-8.56 (m, 1H); ESI-MSm / z [M+H] + 401.0.

[0543] Example 140: 3-((Cyclopropylmethyl)amino)-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0544] In a manner similar to Example 139, 3-chloro-5- The title compound was prepared from (2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol), cyclopropylmethylamine (200 mg, 2.81 mmol) and Cs2CO3 (100 mg, 0.307 mmol) and isolated as a white solid (22 mg, 20%). 1 HNMR(400MHz,CD3OD)δppm 0.21-0.30(m,2H),0.46-0.58(m,2H),1.03(qt,J=7.64,7.64,7.64,7.64,4.80,4.80Hz,1H),3.17(d,J =7.33Hz,2H),7.19-7.43(m,3H),7.48(dd,J=7.58,1.52Hz,1H),7.86(dd,J=7.83,1.52Hz,1H); ESI-MS m / z[M+H] + 364.1.

[0545] Example 141: 5-(2,5-difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0546] In a manner similar to Example 139, 3-chloro-5- The title compound was prepared from (2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol), methoxyethylamine (400 mg, 5.33 mmol) and Cs2CO3 (100 mg, 0.307 mmol) and isolated as a white solid (65 mg, 58%). 1 HNMR (400MHz, CD3OD) δppm 3.49 (br s, 4H) 7.22 (br s, 1H) 7.26-7.44 (m, 3H) 7.48 (d, J = 6.57Hz, 1H) 7.87 (dd, J = 7.83, 1.52Hz, 1H); ESI-MSm / z [M+H] + 368.1.

[0547] Example 142: 5-(2,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0548] The title compound was prepared in a manner analogous to Example 139 using 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (70 mg, 0.213 mmol), 2-methoxypropan-1-amine HCl (34.8 mg, 0.277 mmol) and DIPEA (37.2 μL, 0.213 mmol) in DMA (426 μL) and isolated as a white solid (31 mg, 38%). 1 H NMR (400MHz, CD3OD) δppm 1.07 (d, J=6.06Hz, 3H), 3.10-3.21 (m, 1H), 3.24 (s, 3H), 3.38 (br s,2H),3.40-3.43(m,1H),7.30-7.39(m,1H),7.40-7.56(m,5H),7.74-7.82(m,1H),9.26(s,1H); ESI-MSm / z[M+H] + 401.4.

[0549] Example 143: 5-(2,5-difluorophenyl)-3-(ethylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0550] The title compound was prepared in a manner analogous to Example 139 using 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (70 mg, 0.213 mmol), ethylamine HCl (22.57 mg, 0.277 mmol) and DIPEA (37.2 μL, 0.213 mmol) in DMA (426 μL) and isolated as a tan solid (14 mg, 20%). 1 HNMR(400MHz,CD3OD)δppm 1.10(t,J=7.20Hz,3H),3.22(dd,J=7.33,5.31Hz,2H),7.31-7.55(m,6H),7.78(dd,J=7.83,1.01Hz,1H),9.12(s,1H); ESI-MSm / z[M+H] + 338.0.

[0551] Example 144: 5-(2-chloro-5-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0552] The title compound was prepared in a manner analogous to Example 35 using 5-iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.262 mmol), (2-chloro-5-fluorophenyl)boronic acid (46 mg, 0.262 mmol), Cs2CO2 (2 M, 525 μL, 1.049 mmol) and Pd(dppf)2.CH2Cl2 adduct (32 mg, 0.039 mmol) in dioxane (1312 μL) and isolated as a light yellow oil (5 mg, 5%); ESI-MS m / z [M+H] + 384.0.

[0553] Example 145: 2-(3-((2-methoxypropyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0554] To a solution of 2-methoxypropane-1-amine HCl (36.0 mg, 0.286 mmol) and DIPEA (38.5 μL, 0.220 mmol) in DMA (441 μL) was added 2-(3-chloro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile (70 mg, 0.220 mmol). The reaction mixture was heated at 70 ° C for 24 hours, then diluted with MeOH (1 mL) and filtered. The residue was purified by preparative LC / MS on (ZQ3) using a gradient elution of 25-90% ACN aqueous solution (acid mode). The fractions containing the product were collected, concentrated, and dried in vacuo to give the title compound (3 mg, 4%) as a tan solid. 1 H NMR(400MHz,CD3OD)δppm 1.05-1.10(m,3H),3.24(s,3H),3.43(s,3H),7.33-7.40(m,1H),7.43-7.53(m,2H),7.63- 7.68(m,1H),7.71-7.85(m,2H),7.87-7.93(m,1H),8.05-8.13(m,1H),9.20-9.29(m,1H).

[0555] Example 146: 2-(3-((cyclobutylmethyl)amino)-1,1-dioxo-4H-benzo [e][1,2,4]thiadiazin-5-yl)benzonitrile

[0556] The title compound was prepared in a manner analogous to Example 145 using 2-(3-chloro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile (70 mg, 0.220 mmol), cyclobutylmethylamine HCl (34.8 mg, 0.286 mmol) and DIPEA (38.5 μL, 0.220 mmol) in DMA (441 μL) and isolated as a tan solid (32 mg, 40%). 1 HNMR(400MHz,CD3OD)δppm 1.61-1.72(m,2H),1.83(s,2H),1.94-2.03(m,2H),2.40-2.46(m,1H),3.24(br s,2H),7.30-7.41(m,2H),7.45-7.51(m,1H),7.46-7.50(m,1H),7.63-7.67(m,1H),7.71 -7.77(m,1H),7.79-7.83(m,1H),7.86-7.93(m,1H),8.05-8.11(m,1H),ESI-MSm / z[M+H] + 367.1.

[0557] Example 147: 5-(2-chloro-3-fluorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0558] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (20.24 μL, 0.116 mmol) and 2-fluoroethylamine HCl (15 mg, 0.151 mmol) in DMA (232 μL) and isolated as a tan solid (11 mg, 26%). 1 HNMR(400MHz,CD3OD)δppm 3.47-3.52(m,1H),3.53-3.60(m,1H),4.44-4.50(m,1H),4.56-4.62(m,1H),7.30-7.36(m,1H),7.37 -7.41(m,1H),7.42-7.46(m,1H),7.54-7.66(m,3H),7.77-7.83(m,1H),9.07-9.11(m,1H).

[0559] Example 148: 5-(2-chloro-3-fluorophenyl)-3-(((6-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0560] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol) and (6-fluoropyridin-2-yl)methanamine (23.8 mg, 0.188 mmol) in DMA (290 μL) and isolated as a tan solid (1.2 mg, 2%). 1 HNMR(400MHz,CD3OD)δppm 4.48-4.55(m,2H),7.06-7.14(m,1H),7.30-7.40(m,4H),7.43-7.47(m,1H),7.56-7.6 6(m,2H),7.77-7.82(m,1H),7.86-7.92(m,1H),7.95-8.04(m,1H),9.29-9.40(m,1H).

[0561] Example 149: 2-Fluoro-6-(3-((2-fluoroethyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0562] To a solution of 2-fluoroethylamine HCl (16.31 mg, 0.164 mmol) and DIPEA (26.0 μL, 0.149 mmol) in DMA (298 μL) was added 2-(3-chloro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile (50 mg, 0.149 mmol). The reaction mixture was heated at 70° C. for 24 h, then diluted with MeOH (1 mL) and filtered. The residue was purified by preparative LC / MS (Waters C18, 5 μm, ID 30x75 mm column) eluting with a gradient of 25-90% ACN in water (acid mode). Collected fractions were concentrated and dried in vacuo to give the title compound (5 mg, 9%) as a tan solid. 1H NMR(400MHz,CD3OD)δppm 3.49-3.60(m,2H),4.45-4.50(m,1H),4.59(s,1H),7.39-7.46(m,1H),7.51-7.61(m,3H),7 .70-7.78(m,1H),7.83-7.88(m,1H),7.94-8.01(m,1H),9.25-9.38(m,1H); ESI-MSm / z[M+H] + 363.0.

[0563] Example 150: 2-Fluoro-6-(3-((2-methoxypropyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0564] The title compound was prepared in a manner similar to Example 149 using 2-(3-chloro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile (50 mg, 0.149 mmol), 2-methoxypropan-1-amine HCl (20.57 mg, 0.164 mmol) and DIPEA (26.0 μL, 0.149 mmol) in DMA (298 μL) and isolated as a brown oil (17 mg, 29%); ESI-MS m / z [M+H] + 389.1.

[0565] Example 151: 5-(2-chloro-3-fluorophenyl)-3-((3-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0566] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol) and 3-methoxypropan-1-amine HCl (24 mg, 0.188 mmol) in DMA (290 μL) and isolated as a tan solid (20 mg, 35%). 1HNMR(400MHz,CD3OD)δppm 4.48-4.55(m,2H),7.06-7.14(m,1H),7.30-7.40(m,4H),7.43-7.47(m,1H),7.56-7.66(m, 2H),7.77-7.82(m,1H),7.86-7.92(m,1H),7.95-8.04(m,1H),9.29-9.40(m,1H); ESI-MSm / z [M+H] + 398.0.

[0567] Example 152: 5-(2-chloro-3-fluorophenyl)-3-((3-fluoropropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0568] The title compound was prepared in a manner analogous to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol) and 3-fluoropropan-1-amine HCl (18.1 mg, 0.159 mmol) in DMA (290 μL) and isolated as a tan solid (37 mg, 66%); ESI-MS m / z [M+H] + 386.0.

[0569] Example 153: 5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0570] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol) and 3-methoxybutan-1-amine HCl (26.3 mg, 0.188 mmol) in DMA (290 μL) and isolated as a colorless oil (19 mg, 32%); ESI-MS m / z [M+H] + 412.1.

[0571] Example 154: (R)-5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0572] Example 155: (S)-5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0573] The racemate prepared in Example 153 was resolved by chiral chromatography. The first eluting peak was arbitrarily assigned to the R-stereochemistry (Example 154), and the second eluting peak was assigned to the S-stereochemistry (Example 155). Each title compound was isolated as a colorless semisolid.

[0574] Example 156: 5-(2-cyclopropyl-3-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0575] To a solution of 2-methoxyethyl-1-amine (13.92 mg, 0.185 mmol) and DIPEA (24.89 μL, 0.143 mmol) in DMA (285 μL) was added 3-chloro-5-(2-cyclopropyl-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.143 mmol). The reaction mixture was heated at 70°C for 24 hours, then diluted with MeOH (1 mL) and filtered. The product was analyzed by preparative LC / MS (Waters The product was purified using a C18, 5 μm, ID 30 x 75 mm column) eluting with a gradient of 25-90% aqueous ACN (acid mode). Fractions containing the product were collected, concentrated, and dried under vacuum to afford the title compound (14 mg, 25% yield) as a tan glassy solid. ESI-MS m / z [M+H] + 390.1

[0576] Example 157: 5-(2-cyclopropyl-3-fluorophenyl)-3-(methylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0577] The title compound was prepared in a manner similar to Example 156 using 3-chloro-5-(2-cyclopropyl-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.143 mmol), methylamine (93 μL, 0.185 mmol) and DIPEA (24.89 μL, 0.143 mmol) in DMA (285 μL) and isolated as a tan glassy solid (10 mg, 20%). ESI-MS m / z [M+H] + 346.3.

[0578] Example 158: 5-(2-chloro-3-fluorophenyl)-3-(isopropylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0579] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), DIPEA (15.2 μL, 0.087 mmol) and propan-2-amine HCl (10.8 mg, 0.113 mmol) in DMA (174 μL) and isolated as a yellow film (32 mg, 95%); ESI-MS m / z [M+H] + 368.8.

[0580] Example 159: 5-(2-chloro-3-fluorophenyl)-3-(cyclopropylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0581] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), cyclopropylamine HCl (10.6 mg, 0.113 mmol) and DIPEA (15.2 μL, 0.087 mmol) in DMA (174 μL) and isolated as a clear film (32 mg, 95%); ESI-MS m / z [M+H] + 366.8.

[0582] Example 160: 5-(2-chloro-3-fluorophenyl)-3-((2-(2,2-difluoroethoxy)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0583] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), 2-(2,2-difluoroethoxy)ethanamine HCl (18.3 mg, 0.113 mmol) and DIPEA (15.2 μL, 0.087 mmol) in DMA (174 μL) and isolated as a yellow film (32 mg, 85%); ESI-MS m / z [M+H] + 434.8.

[0584] Each compound shown in the following Examples 161 to 170 was prepared in the same manner as the above compound.

[0585] Example 161: 2-Fluoro-6-(3-((oxazol-2-ylmethyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0586] ESI-MS m / z [M+H] + 402.1.

[0587] Example 162: 3-((Pyridin-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0588] 1 H NMR(400MHz,DMSO-d6)δppm 2.05(s,3H),4.52(t,J=5.31Hz,2H),7.23(d,J=7.58Hz,1H),7.30-7.44(m,7H),7.71-7. 75(m,1H),7.79(td,J=7.71,1.77Hz,1H),8.17(brs,1H),8.53(d,J=4.04Hz,1H),9.16(br s,1H);ESI-MSm / z[M+H] + 379.2.

[0589] Example 163: 5-(2-ethylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0590] 1H NMR (400MHz, CD3OD) δppm 1.03 (t, J=7.58Hz, 3H), 2.29-2.41 (m, 1H), 2.42-2.54 (m, 1H), 3.46 (br s,4H),7.18(d,J=7.33Hz,1H),7.32-7.40(m,3H),7.45(d,J=1.52Hz,2H),7.82(dd,J=6.82,2.78Hz,1H); ESI-MSm / z[M+H] + 360.1.

[0591] Example 164: 5-(3,5-difluorophenyl)-3-((furan-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0592] 1 H NMR(400MHz,DMSO-d6)δppm 4.44(d,J=5.31Hz,2H)6.33-6.52(m,1H)7.25-7.30(m,2H)7.34-7.34(m,1H)7.36(s,1H)7.39-7.47(m,1 H)7.48-7.51(m,1H)7.64-7.67(m,1H)7.75-7.81(m,1H)7.83-7.89(m,1H)9.14(s,1H); ESI-MSm / z[M+H] + 390.4

[0593] Example 165: 5-(2,3-difluorophenyl)-3-(ethylamino)-4H-benzo [e][1,2,4]thiadiazine 1,1-dioxide

[0594] 1 H NMR(400MHz,DMSO-d6)δppm 1.10(t,J=7.20Hz,3H)3.19-3.28(m,2H)7.24-7.34(m,2H)7.34-7.37(m,1H)7.39-7.45(m,1H) 7.49(dd,J=7.58,1.52Hz,1H)7.59-7.69(m,1H)7.76-7.82(m,1H)9.14(s,1H); ESI-MSm / z[M+H] + 338.0.

[0595] Example 166: 5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0596] ESI-MS m / z [M+H] + 382.4

[0597] Example 167: 5-(2-chloro-3-fluorophenyl)-3-((3-methoxycyclobutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0598] ESI-MS m / z [M+H] + 410.6

[0599] Example 168: 3-((2-methoxyethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0600] 1 H NMR (400MHz, CD3OD) δppm 3.32-3.38(m,3H),3.50(br s,4H),7.07-7.14(m,1H),7.40(s,2H),7.47-7.55(m,1H),7.87-7.92(m,1H); ESI-MSm / z[M+H] + 386.4

[0601] Example 169: 3-((4-Isopropylphenyl)amino)-5-(methoxymethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0602] 1 H NMR (400MHz, DMSO-d6) δ9.81(s,1H),9.66(s,1H),7.72(d,J=7.6Hz,1H),7.70(d,J=8.0Hz,1H),7.43(d,J=8.4H z,2H),7.33-7.28(m,3H),4.64(s,2H),3.32(s,3H),2.92-2.86(m,1H),1.21(d,J=6.8Hz,6H); ESI-MSm / z[M+H] + 360.1.

[0603] Example 170: 5-(3,4-Difluoro-2-methylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0604] 1 H NMR(400MHz,CD3OD)δppm 2.10(d,J=2.78Hz,3H),3.36(td,J=3.47,1.89Hz,5H),3.53(d,J=3.28Hz,2H),4.90-4.91(m ,1H),7.07-7.15(m,1H),7.26-7.37(m,1H),7.40-7.46(m,2H),7.87-7.92(m,1H); ESI-MSm / z [M+H] + 382.1.

[0605] Table 1 lists the hMRGX2 cell potency (pEC 50 ) and binding affinity (pK d ), among which the larger pEC 50 A higher value indicates higher activity or potency, while a larger pK d A value of 0.001 represents a higher binding affinity. Methods for measuring cellular potency and binding affinity are described above in the section entitled "Biological Activity."

[0606] Table 1: hMRGX2 cell potency (pEC 50 ) and binding affinity (pK d ) Table 1: hMRGX2 cell potency (pEC 50 ) and binding affinity (pK d )—Continued

[0607] As used in this specification and the appended claims, singular articles such as "a", "an" and "the" may refer to a single object or a plurality of objects, unless the context clearly indicates otherwise. Thus, for example, a reference to a composition comprising "a compound" may include a single compound or two or more compounds. The above description is intended to be illustrative and not restrictive. After reading the above description, many embodiments will be apparent to those skilled in the art. Therefore, the scope of the present invention should be determined with reference to the appended claims, and includes the full scope of equivalents to which these claims are entitled. The disclosures of all articles and references (including patents, patent applications and publications) cited in this disclosure are incorporated herein by reference in their entirety for all purposes.

Claims

1. a compound of formula 1, or a tautomer thereof, or a pharmaceutically acceptable salt of a compound of formula 1 or a tautomer thereof, wherein: L is selected from the group consisting of a bond and C 1-4 Alkanediyl; R 1 Selected from (a) substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkoxy, The amino group and the aminocarbonyl group are optionally substituted with C 1-4 Alkyl, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted with an alkyl substituent; and (b) Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; R 2 Selected from (a) substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 The C substituted with alkoxy and amino optional substituents 1-4 alkyl; and (b) Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy Base, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent; R 3 、R 4 and R 5 are independently selected from hydrogen, halo, cyano and C 1-3 alkyl; wherein each of the above heterocyclyl and heteroaryl moieties independently has 1 to 4 heteroatoms each independently selected from N, O and S as ring members.

2. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R 1 is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 C substituted by alkoxy, amino and aminocarbonyl optional substituents 1-4 Alkyl, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

3. The compound, tautomer or pharmaceutically acceptable salt according to claim 2, wherein R 1 C 1-4 Alkyl is methyl or ethyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

4. The compound, tautomer or pharmaceutically acceptable salt according to any one of claims 2 and 3, wherein said R 1 C 1-4 Alkyl is substituted with 0 to 3 independently selected halo, C 1-4 Alkoxy and aminocarbonyl are optionally substituted, wherein the C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

5. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R 1 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

6. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R 1 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Phenyl substituted by an optional substituent of alkoxy, amino and aminocarbonyl, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

7. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R 1 is a cyclic group selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino and aminocarbonyl optional substituents, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

8. The compound, tautomer or pharmaceutically acceptable salt according to any one of claims 5 to 7, wherein R 1 The cyclic group is composed of 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is optionally substituted with a substituent wherein the C 1-4 Alkyl and C 1-4 Each of the optional substituents of the alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo.

9. The compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein L is selected from a bond, -CH2-, -CH2CH2- and -CH(CH3)-.

10. The compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein L is -CH2-.

11. The compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein L is a bond.

12. The compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R 2 is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 The C substituted with alkoxy and amino optional substituents 1-4 alkyl.

13. The compound, tautomer or pharmaceutically acceptable salt according to claim 12, wherein R 2 C 1-4 The alkyl group is substituted with 0 to 3 groups independently selected from halo and C 1-4 The alkoxy group is optionally substituted with a substituent.

14. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R 2 Selected from C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-14 Aryl and C 1-9 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

15. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R 2 is a cyclic group, which is substituted by 0 to 3 independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The phenyl group substituted by the optional substituents of the heterocyclic group, provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

16. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R 2 is a cyclic group selected from pyrazolyl, pyridinyl and pyrimidinyl, each of which is substituted by 0 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the heterocyclyl optional substituents is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the amino optional substituents are independently substituted with 0 to 2 substituents independently selected from C 1-4 substituted by an alkyl substituent.

17. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 14 to 16, wherein R 2 The cyclic group is composed of 0 to 3 independently selected halo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 The heterocyclic group may be optionally substituted with substituents provided that the cyclic group has not more than one selected from C 3-8 Cycloalkyl and C 3-5 The optional substituents of the heterocyclic group, and wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of the heterocyclyl group is independently substituted with 0 to 3 substituents independently selected from halo.

18. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein R 3 、R 4 and R 5 are each independently selected from hydrogen, halo and C 1-3 alkyl.

19. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein R 3 、R 4 and R 5 Each is hydrogen.

20. The compound according to claim 1, which is selected from the following compounds and their tautomers: 5-(2-chloro-3-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(ethylamino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((cyclopropylmethyl)amino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((1-(thiazol-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((1-(thiazol-4-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2,2-difluoroethyl)amino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-fluoro-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-7-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-7-fluoro-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-(ethylamino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-7-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((cyclobutylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-(((5-(2,3-difluorophenyl)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)-1-methylpyridin-2(1H)-one; 5-(2,3-Difluorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((cyclobutylmethyl)amino)-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (R)-5-(2,3-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (S)-5-(2,3-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((cyclopropylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((4-methyloxazol-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3,5-difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((5-methyloxazol-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-(((5-(2-chloro-3-fluorophenyl)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)-1-methylpyridin-2(1H)-one; (R)-5-(2-chloro-3-fluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-((cyclopropylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluoropyridin-4-yl)-3-((4-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-(((5-(3-chloro-2-fluoropyridin-4-yl)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)thiazole-5-carbonitrile; 5-(3-chloro-2-fluoropyridin-4-yl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((4-methylmorpholin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-ethoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-(((5-chloropyridin-2-yl)methyl)amino)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((Cyclobutylmethyl)amino)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-((5-(2-chloro-3-fluorophenyl)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)-N,N-dimethylacetamide; 5-(2-cyclopropylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((isothiazol-3-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((pyrimidin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-(pyridin-4-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-(pyridin-3-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((3-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((4-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-(tetrahydrofuran-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((4-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((2,5-difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((2,6-difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-(((6-methylpyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((cyclobutylmethyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((pyridin-4-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (R)-5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (S)-5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-(Benzylamino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-Fluoro-6-(3-(methylamino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 4-chloro-2-(3-(methylamino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 5-(2-ethylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-4-methylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-5-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-4-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-Fluoro-2-methylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-(Methylamino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-7-methyl-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(5-methyl-1H-pyrazol-3-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(1H-pyrazol-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1-ethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1-cyclobutyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(3-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-Cyclopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-Isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-cyclobutyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(3-methylpyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-cyclopropyl-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-cyclopropyl-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-Cyclopropyl-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-cyclopropyl-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-Cyclopropyl-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((3-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((tetrahydrofuran-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((2-methoxyethyl)amino)-5-(2-(trifluoromethyl)phenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-Fluoro-6-(3-((2-methoxyethyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 2-(1,1-dioxo-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile; 3-((2-methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (S)-3-((2-methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (R)-3-((2-methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((cyclobutylmethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((pyridin-2-ylmethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-(trifluoromethyl)phenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-4-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-5-(trifluoromethyl)phenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3-chloro-2-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-ethylphenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((Furan-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chlorophenyl)-6-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,5-difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((Cyclopropylmethyl)amino)-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,5-difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,5-difluorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-5-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-(3-((2-methoxypropyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 2-(3-((cyclobutylmethyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 5-(2-chloro-3-fluorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(((6-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-Fluoro-6-(3-((2-fluoroethyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 2-Fluoro-6-(3-((2-methoxypropyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 5-(2-chloro-3-fluorophenyl)-3-((3-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((3-fluoropropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (R)-5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (S)-5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-cyclopropyl-3-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-cyclopropyl-3-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(isopropylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-(cyclopropylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-(2,2-difluoroethoxy)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-Fluoro-6-(3-((oxazol-2-ylmethyl)amino)-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 3-((pyridin-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-ethylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((furan-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((3-methoxycyclobutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((2-methoxyethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((4-Isopropylphenyl)amino)-5-(methoxymethyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,4-difluoro-2-methylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; and Pharmaceutically acceptable salts of any of the above compounds and tautomers.

21. A pharmaceutical composition comprising: A compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1 to 20; and Pharmaceutically acceptable excipients.

22. A compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1 to 20 for use as a medicament.

23. A compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1 to 20 for use in treating a disease, disorder or condition selected from systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis, rosacea, chronic urticaria, atopic dermatitis, rheumatoid arthritis, bronchial asthma, irritable bowel syndrome (IBS), systemic mastocytosis, cutaneous mastocytosis, mast cell enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

24. A method of inhibiting MRGX2 in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1 to 20.

25. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1 to 20, wherein the disease, disorder or condition is selected from systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis, rosacea, chronic urticaria, atopic dermatitis, rheumatoid arthritis, bronchial asthma, irritable bowel syndrome (IBS), systemic mastocytosis, cutaneous mastocytosis, mast cell enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

26. A combination comprising a compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1 to 20, and at least one additional pharmacologically active agent.

27. The combination of claim 25, wherein the additional pharmacologically active agent is selected from anti-inflammatory agents, analgesics, biologic response modifiers, disease-modifying antirheumatic drugs (DMARDs), antihistamines, mast cell stabilizers, prokinetics, antidiarrheals, secretagogues, antibiotics, antidepressants, anxiolytics, antipsychotics, and anticonvulsants.

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