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

Abstract

Disclosed are compounds of formula (1), their tautomers, and pharmaceutically acceptable salts of said compounds or tautomers, wherein L, R 1 , R 2 , R 3 , R 4 and R 5 are defined in the specification. The present disclosure also relates to materials and methods for preparing compounds of formula (1), pharmaceutical compositions comprising them, and their use for treating diseases, disorders or conditions associated with MRGX2.

Description

Technical Field

[0001] The present invention relates to 3-amino-5-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as inhibitors of Mas-related gene X2 (MRGX2), 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., Biochem Biophys Res Commun, 349(4):1322-8 (2006)). Activators of MRGX2 include numerous basic secretagogues, including: neuropeptides (substance P, PAMP, cortistatin, VIP, PACAP, SST), eosinophil granule proteins (MBP, EPO), antimicrobial peptides (LL-37, β-defensin), 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)). It has been shown in the LAD2 human mast cell line and CD34 +The study of MRGX2 ligands was conducted in cell-derived human primary mast cells, both of which endogenously express MRGX2. These ligands induce mast cell degranulation via 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.), resulting in acute and chronic inflammatory responses.

[0003] MRGX2 is Gq-coupled and induces intracellular Ca 2 mobilization upon ligand activation. MRGX2 is a non-canonical GPCR as it does not internalize and desensitize after agonist-induced activation (H. Subramanian et al., J Biol Chem, 286(52):44739-49 (2011)). Additionally, MRGX2 is intracellularly expressed 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 as conserved across species, with humans and mice sharing only 45-65% amino acid sequence homology. The mouse ortholog of the human MRGX2 receptor has been reported to be Mrgprb2 (B. D. 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, leading to 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 them. 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 related to MRGX2, including atopic dermatitis, chronic urticaria and asthma, etc.

[0006] One aspect of the present invention provides a compound of formula 1:

[0007]

[0008] or a tautomer thereof, or a pharmaceutically acceptable salt of the compound of formula 1 or a tautomer thereof, wherein:

[0009] L is selected from a bond and C 1-4 alkanediyl;

[0010] R 1 is selected from

[0011] (a) C 1-4 alkyl optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; and

[0012] (b) cyclic groups selected from C 3-8 cycloalkyl, C 2-9 heterocyclic group, C 6-14 aryl and C 1-9 heteroaryl, wherein the cyclic group is substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0013] R2 Selected from

[0014] (a) C alkyl optionally substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy and amino; and 1-4 and

[0015] (b) a cyclic group selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 6-14 aryl and C 1-9 heteroaryl, wherein the cyclic group is optionally substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 heterocycloalkyl, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocycloalkyl, and wherein each of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocycloalkyl optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein said amino optional substituent is independently substituted with from 0 to 2 substituents independently selected from C 1-4 alkyl;

[0016] R 3 、R 4 and R 5 are each independently selected from hydrogen, halo, cyano and C 1-3 alkyl;

[0017] wherein each of said heterocycloalkyl and heteroaryl moieties independently has from 1 to 4 heteroatoms independently selected from N, O and S as ring members.

[0018] Another aspect of the invention provides a compound selected from the compounds described in the examples, its tautomers, and pharmaceutically acceptable salts of the compounds in the examples and their tautomers.

[0019] Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of a compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph; and a pharmaceutically acceptable excipient.

[0020] Another aspect of the present invention provides a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph, which is used as a medicine.

[0021] Another aspect of the present invention provides a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph, which is used for the treatment of diseases, disorders or conditions related to MRGX2.

[0022] Another aspect of the present invention provides a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph, which is used for the preparation of a medicine for the treatment of diseases, disorders or conditions related to MRGX2.

[0023] Another aspect of the present invention provides a method for treating a disease, disorder or condition related to MRGX2, which method comprises administering to a subject an effective amount of a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph.

[0024] Another aspect of the present invention provides a method for inhibiting MRGX2 in a subject, which method comprises administering to the subject an effective amount of a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph.

[0025] Another aspect of the present invention provides a method for treating a disease, disorder or condition of a subject, which method comprises administering to the subject an effective amount of a compound of formula 1, its tautomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its tautomer, or any of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraph, 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, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

[0026] 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 of the compounds, tautomers or pharmaceutically acceptable salts defined in the preceding paragraphs; and at least one additional pharmacologically active agent. Detailed Description

[0027] Unless otherwise specified, the present disclosure uses the definitions provided below.

[0028] "Substituted", when used in connection with 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 a chemically stable compound is produced by the substitution.

[0029] "About" or "approximately", when used in connection with a measurable numerical variable, means the indicated value of the variable, and all values of the variable within the experimental error of the indicated value or within ±10% of the indicated value, whichever is greater.

[0030] "Alkyl" means a straight-chain and branched-chain saturated hydrocarbon group, typically having a specified number of carbon atoms (e.g., C 1-4 alkyl means an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 alkyl means an alkyl group having 1 to 6 carbon atoms, and so on). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

[0031] "Alkylene" means a divalent alkyl group, where the alkyl group is as defined above, and typically has a specified number of carbon atoms (e.g., C 1-4 alkylene means an alkylene group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 alkylene means an alkylene group having 1 to 6 carbon atoms, and so on). Examples of alkylene 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.

[0032] "Alkenyl" refers to straight-chain and branched-chain hydrocarbon groups having one or more carbon-carbon double bonds and usually having a specified number of carbon atoms. Examples of alkenyl groups include vinyl, 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.

[0033] "Alkynyl" refers to straight-chain or branched-chain hydrocarbon groups having one or more carbon-carbon triple bonds and usually 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.

[0034] "Alkoxy" refers to straight-chain and branched-chain saturated hydrocarbon groups connected through an oxygen atom and usually having a specified number of carbon atoms (e.g., C 1-4 Alkoxy having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 Alkoxy having 1 - 6 carbon atoms, etc.). Examples of alkoxy groups 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.

[0035] "Amino" refers to -NH 2 which, when specified, may optionally include one or two non-hydrogen substituents which may be the same or different.

[0036] "Aminocarbonyl" refers to -C(O)NH 2 which, when specified, may optionally include one or two non-hydrogen substituents which may be the same or different.

[0037] "Halogenated", "halogen", and "halo" are used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0038] "Halogenoalkyl", "halogenoalkenyl" and "halogenoalkynyl" respectively refer to an alkyl, alkenyl and alkynyl group substituted by one, two, three or more halogen atoms, wherein the alkyl, alkenyl and alkynyl groups are as defined above and generally have a specified number of carbon atoms. Examples of halogenoalkyl 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, etc.

[0039] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms constituting one or more rings (e.g., C 3-6 Cycloalkyl refers to a cycloalkyl having 3-6 carbon atoms as ring members, C 3-8 Cycloalkyl refers to a cycloalkyl having 3-8 carbon atoms as ring members, etc.). Bicyclic hydrocarbon groups can include isolated rings (the two rings do not share carbon atoms), spiro rings (the two rings share one carbon atom), fused rings (the two rings share two carbon atoms and the bond between the two shared carbon atoms), and bridged rings (the two rings share two carbon atoms but have no shared bond). The cycloalkyl can be attached through any ring atom, unless such attachment would violate valence requirements, and when specified, can optionally include one or more non-hydrogen substituents, unless such substitution would violate valence requirements.

[0040] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentyl (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]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, etc. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[4.2.2]decyl, bicyclo[4.3.1]decyl, bicyclo[3.3.3]undecyl, bicyclo[4.3.2]undecyl, bicyclo[4.3.3]dodecyl, etc. Examples of spirocycloalkyl groups include spiro[3.3]heptyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[2.5]octyl, spiro[3.5]nonyl, etc. Examples of isolated bicyclic cycloalkyl groups include those groups derived from bis(cyclobutane), cyclobutane cyclopentane, bis(cyclopentane), cyclobutane cyclohexane, cyclopentane cyclohexane, bis(cyclohexane), etc.

[0041] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group, where the cycloalkyl group is as defined above, which is connected through a single carbon atom of the group and typically has a specified number of ring-forming carbon atoms (e.g., C 3-6 Cycloalkylidene refers to cycloalkylidene having 3 to 6 carbon atoms as ring members, C 3-8 Cycloalkylidene refers to cycloalkylidene having 3 to 8 carbon atoms as ring members, etc.). Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0042] "Cycloenyl" refers to a partially unsaturated monocyclic and bicyclic hydrocarbon group, typically having a specified number of carbon atoms forming one or more rings. Like cycloalkyl groups, bicyclic cycloenyl groups can include isolated rings, spiro rings, fused rings, or bridged rings. Similarly, cycloenyl groups can be connected through any ring atom and, when specified, can optionally include one or more non-hydrogen substituents, unless such connection or substitution would violate valence requirements. Examples of cycloenyl groups include partially unsaturated analogs of the above cycloalkyl groups, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, etc.

[0043] "Aryl" means a fully unsaturated monocyclic aromatic hydrocarbon and a polycyclic hydrocarbon having at least one aromatic ring. Monocyclic and polycyclic aryl groups typically have a specified number of carbon atoms that make up the ring members thereof (e.g., C 6-10 aryl means an aryl group having 6 to 10 carbon atoms as ring members, C 6-14 aryl means an aryl group having 6 to 14 carbon atoms as ring members, etc.). The group may be attached through any ring atom and, when so specified, may optionally include one or more non-hydrogen substituents, provided that such attachment or substitution does not violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutaphenyl, indenyl, naphthyl, benzocycloheptyl, biphenylene, fluorenyl, groups derived from the tropylium cation, and the like.

[0044] "Arylene" means a divalent aryl group, wherein the aryl group is as defined above. Examples of arylene groups include phenylene (i.e., benzene-1,2-diyl).

[0045] "Heterocycle" and "heterocyclic group" are used interchangeably and mean 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 heterocyclic group means a heterocyclic group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members, C 2-9A heterocyclic group refers to a heterocyclic group having 2 to 9 carbon atoms and 1 to 4 heteroatoms as ring members, etc.). Like a bicyclic cycloalkyl group, a bicyclic heterocyclic group can include an isolated ring, a spiro ring, a fused ring, and a bridged ring. The heterocyclic group can be attached through any ring atom and, when specified, can 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, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-thiazinyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 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.

[0046] "Heterocyclic-diyl" refers to a heterocyclic group attached through two ring atoms of the group, where the heterocyclic group 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 having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members, C 2-9 Heterocyclic-diyl refers to a heterocyclic-diyl having 2 - 9 carbon atoms and 1 - 4 heteroatoms as ring members). Examples of heterocyclic-diyl include polyvalent analogs of the above heterocyclic groups, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, -(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, etc.

[0047] "Heteroaromatic" and "heteroaryl" can be used interchangeably and refer to an unsaturated monocyclic aromatic group and a polycyclic group having at least one aromatic ring, the ring atoms of which are composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The monocyclic and polycyclic groups typically both have a specified number of carbon atoms as ring members (e.g., C 1-5Heteroaryl refers to a heteroaryl having 1 to 5 carbon atoms and 1 to 4 heteroatoms as ring members, C 1-9 Heteroaryl refers to a heteroaryl 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 can be attached through any ring atom (or ring atom of a fused ring), and when specified, may optionally include one or more non-hydrogen substituents, provided that such attachment or substitution does not violate valence requirements or result in a chemically unstable compound. For the purposes of this disclosure, 2-pyridone and 4-pyridone, 2-quinolone and 4-quinolone, etc. are considered 2-oxo- and 4-oxo-substituted derivatives of the corresponding heteroaromatic groups (pyridine, quinoline, etc.).

[0048] Examples of heteroaryl 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, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0049] Examples of heteroaryl also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzothiophen-2-yl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindolinyl, 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]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzothiazolyl, 2,3-dihydro-1H-pyrrolo[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.

[0050] Other examples of heteroaryl groups also include bicyclic groups such as 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]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 5-oxo-5H-thiazolo[3,2-a]pyrimidinyl, 6,7-dihydro-5H-cyclopentadieno[b]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, and pyrrolo[1,2-c]pyrimidinyl. “Subheteroaryl” refers to a heteroaryl group that is attached through two ring atoms of the group, where the heteroaryl group is as defined above. They typically have a specified number of carbon atoms in one or more of their rings (e.g., C

[0051] subheteroaryl refers to a subheteroaryl having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members). Examples of subheteroaryl groups include polyvalent analogs of the above heteroaryl groups, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like. 3-5 “Oxo” refers to double-bonded oxygen (=O).

[0052] “Leaving group” refers to any group that leaves the molecule during a cleavage process, including substitution reactions, elimination reactions, and addition-elimination reactions. A leaving group can be nucleofugal, where the group leaves with a pair of electrons that previously served as the bond between the leaving group and the molecule, or it can be electrofugal, where the group leaves without a pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, and the strongest bases are the worst leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., mesylate), fluoroalkyl sulfonates (e.g., triflate, nonaflate, perfluate, and tresylate), and aryl sulfonates (e.g., tosylate, p-bromobenzenesulfonate, hypochlorobenzenesulfonate, and nosylate). Others include carbonates, halides, carboxylate anions, phenoxide ions, and alkoxides. Some stronger bases such as NH

[0053] and OH 2 - can be made into better leaving groups by treatment with an acid. Common electrofugal leaving groups include protons, CO - and metals. 2

[0054] ​"Opposite enantiomer" refers to a molecule that is a non - superimposable mirror image of a reference molecule and can be obtained by inverting all the stereocenters of the reference molecule. For example, if the reference molecule has an S absolute stereochemical configuration, the opposite enantiomer has an R absolute stereochemical configuration. Similarly, if the reference molecule has an S,S absolute stereochemical configuration, the opposite enantiomer has an R,R stereochemical configuration, and so on.

[0055] "Stereoisomers" of a compound having a given stereochemical configuration refer to the opposite enantiomers and any diastereomers of the compound, including the geometric isomers (Z / E) of the compound. For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers will include its opposite enantiomer having an R,S,Z configuration, and 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 the compound is not specified, "stereoisomers" refers to any possible stereochemical configuration of the compound.

[0056] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound having a specific stereochemical configuration and comprising at least about 95% of the sample.

[0057] "Pure stereoisomer" and variations thereof refer to a sample containing a compound having a specific stereochemical configuration and comprising at least about 99.5% of the sample.

[0058] "Subject" refers to a mammal, including a human.

[0059] "Pharmaceutically acceptable" substances refer to those substances that are suitable for administration to a subject.

[0060] "Treat" refers to reversing, alleviating, preventing, or inhibiting the progression of a disease, disorder, or condition to which the term applies, or reversing, alleviating, preventing, or inhibiting one or more symptoms of such a disease, disorder, or condition.

[0061] "Treatment" refers to the act of "treating" as defined in the previous paragraph.

[0062] "Drug", "drug substance", "active pharmaceutical ingredient", etc. refer to a compound (e.g., a compound of formula 1, including subclasses of the compound and specifically named compounds in the specification) that can be used to treat a subject in need of treatment.

[0063] "Effective amount" of a drug, "therapeutically effective amount" of a drug, etc. refer to the amount of a drug that can be used to treat a subject and can depend on factors such as the weight and age of the subject and the route of administration.

[0064] "Excipient" refers to any diluent or vehicle for a drug.

[0065] "Drug composition" refers to a combination of one or more active pharmaceutical ingredients and one or more excipients.

[0066] "Drug product", "drug dosage form", "dosage form", "final dosage form", etc. refer to a drug composition suitable for treating a subject in need of treatment and can generally be in the form of tablets, capsules, sachets containing powders or granules, liquid solutions or suspensions, patches, films, etc.

[0067] "Diseases, disorders or conditions associated with MRGX2" and similar phrases refer to diseases, disorders or conditions of a subject in which inhibition of MRGX2 can provide a therapeutic or prophylactic benefit.

[0068] The following abbreviations may be used in this specification: Ac (acetyl); ACN (acetonitrile); AIBN (azobis(isobutyronitrile)); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); Boc (tert-butoxycarbonyl); 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-maximal response); EDA (ethoxylated dodecyl alcohol, 35); EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq (equivalent); Et (ethyl); Et 3 N (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 (concentration at 50% inhibition); IPA (isopropanol); IPAc (isopropyl acetate); IPE (isopropyl ether); K d(Dissociation constant); LDA (Lithium diisopropylamide); LiHMDS (Lithium bis(trimethylsilyl)amide); mCPBA (meta-Chloroperoxybenzoic acid); Me (Methyl); MeOH (Methanol); MTBE (Methyl tert-butyl ether); mp (Melting point); NaOt-Bu (Sodium tert-butoxide); NMM (N-Methylmorpholine); NMP (N-Methyl-2-pyrrolidone); OTf (Trifluoromethanesulfonate); Pd(amphos)Cl 2 (Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride); PE (Petroleum ether); Ph (Phenyl); pEC 50 (-log 10 (EC 50 ), where EC 50 is given in moles (M); pIC 50 (-log 10 (IC 50 ), where IC 50 is given in moles (M); pKd (-log 10 (K d ), where K d is given in moles (M); 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-trioxatriphosphinane 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 -Tetramethylethane-1,2-diamine); TMS (Trimethylsilyl); and Tris buffer (2-Amino-2-hydroxymethylpropane-1,3-diol buffer).

[0069] As described below, the present disclosure relates to compounds of formula 1, their tautomers, and pharmaceutically acceptable salts of the compounds and their tautomers, as well as 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 pharmacological active agents) for the treatment of diseases, disorders, or conditions associated with MRGX2.

[0070] In addition to the specific compounds in the examples, compounds of formula 1,

[0071]

[0072] The tautomer thereof, or a pharmaceutically acceptable salt of the compound of Formula 1 or its tautomer, further includes the following compounds, wherein:

[0073] (1) L is selected from a bond and C 1-4 alkanediyl;

[0074] R 1 is selected from

[0075] (a) C 1-4 alkyl optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, amino, and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; and

[0076] (b) a cyclic group selected from C 3-8 cycloalkyl, C 2-9 heterocyclic group, C 6-14 aryl, and C 1-9 heteroaryl, wherein the cyclic group is optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0077] R 2 is selected from

[0078] (a) C 1-4 alkyl optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, and amino; and

[0079] (b) a cyclic group selected from C 3-8 cycloalkyl, C 2-9 heterocyclic group, C 6-14 aryl, and C 1-9 heteroaryl, wherein the cyclic group is optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl, and C 3-5 optionally substituted by substituents of heterocyclic group, provided that the cyclic group has no more than one optionally substituted group selected from C 3-8 cycloalkyl and C 3-5 optionally substituted group of heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8

[0080] cycloalkyl and C 3-5 each of the optionally substituted groups of heterocyclic group is independently substituted by 0 to 3 substituents independently selected from halo, and wherein the optionally substituted group of amino is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl;

[0081] R 3 、R 4 and R 5 are each independently selected from hydrogen, halo, cyano, and C 1-3 alkyl;

[0082] wherein each of the above heterocyclic group and heteroaryl moiety independently has 1 to 4 heteroatoms each independently selected from N, O, and S as ring members.

[0083] In addition to the embodiment (1) in the foregoing paragraph, the compound of formula 1 further includes the following compounds, wherein:

[0084] (2)R 1 is C 1-4 alkyl optionally substituted by 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, amino, and aminocarbonyl, wherein each of the optionally substituted groups of said C 1-4 alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optionally substituted groups of said amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl.

[0085] In addition to the embodiment (2) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0086] (3) said R 1 C 1-4 alkyl is selected from methyl, ethyl, propyl, and isopropyl, each of which is independently substituted by 0 to 3 substituents selected from halo, hydroxy, cyano, C 1-4substituted by optional substituents of alkoxy, amino and aminocarbonyl, wherein said C 1-4 each of the optional substituents of the alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl;

[0087] (4) said R 1 C 1-4 alkyl is selected from methyl or ethyl, each of which is substituted by 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl; or 1-4 alkyl is methyl substituted by 0 to 3 substituents independently selected from halo, hydroxy, cyano, C

[0088] (5) said R 1 C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl; 1-4 1-4 1-4 alkyl.

[0089] Except for any one of embodiments (2) to (5) in the foregoing paragraphs, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0090] (6) said R 1 C 1-4 alkyl is substituted by 0 to 3 substituents independently selected from halo, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl; 1-4 alkyl;

[0091] (7) said R 1 C 1-4 alkyl is substituted by 0 to 3 substituents independently selected from halo, C1-4 substituted by optional substituents of alkoxy and aminocarbonyl, wherein said C 1-4 each of the optional substituents of the alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl;

[0092] (8) said R 1 C 1-4 alkyl is substituted by 0 to 3 substituents independently selected from halo and C 1-4 optional substituents of alkoxy, wherein each of the optional substituents of said C 1-4 alkoxy is independently substituted by 0 to 3 substituents independently selected from halo;

[0093] (9) said R 1 C 1-4 alkyl is substituted by 0 to 3 optional substituents independently selected from halo;

[0094] (10) said R 1 C 1-4 alkyl is substituted by 0 to 3 optional substituents independently selected from fluoro and chloro;

[0095] (11) said R 1 C 1-4 alkyl is substituted by 0 to 3 fluoro substituents;

[0096] (12) said R 1 C 1-4 alkyl is substituted by 0 to 3 substituents independently selected from C 1-4 optional substituents of alkoxy, wherein each of the optional substituents of said C 1-4 alkoxy is independently substituted by 0 to 3 substituents independently selected from halo;

[0097] (13) said R 1 C 1-4 alkyl is substituted by C 1-4 alkoxy, wherein the C 1-4 alkoxy substituent is substituted by 0 to 3 substituents independently selected from halo;

[0098] (14) said R 1 C 1-4 alkyl is substituted by C 1-4 alkoxy, wherein the C 1-4 alkoxy substituent is substituted by 0 to 3 fluoro substituents;

[0099] (15) said R1 C 1-4 The alkyl group is replaced by C 1-4 alkoxy, wherein the C 1-4 alkoxy substituent is unsubstituted;

[0100] (16) The R 1 C 1-4 alkyl group is replaced by an unsubstituted methoxy group; or

[0101] (17) The R 1 C 1-4 alkyl group is unsubstituted.

[0102] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein:

[0103] (18) R 1 is a cyclic group selected from C 3-8 cycloalkyl, C 2-9 heterocyclic group, C 6-14 aryl and C 1-9 heteroaryl, wherein the cyclic group is substituted by 0 to 3 optionally substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl.

[0104] In addition to the above embodiment (1), the compound of formula 1 also includes the following compounds, wherein:

[0105] (19) R 1 is a cyclic group which is a C 1-4 cycloalkyl substituted by 0 to 3 optionally substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 3-8 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted by 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl;

[0106] (20) R 1is a cyclic group, which is a C 1-4 alkyl group, C 1-4 alkoxy group, amino group or aminocarbonyl group which is optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 3-6 cycloalkyl group, wherein each of the optional substituents of the C 1-4 alkyl group and C 1-4 alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino group and the aminocarbonyl group is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl groups;

[0107] (21)R 1 is a cyclic group, which is a cyclopropyl group optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl group, C 1-4 alkoxy group, amino group or aminocarbonyl group, wherein each of the optional substituents of the C 1-4 alkyl group and C 1-4 alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino group and the aminocarbonyl group is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl groups; or

[0108] (22)R 1 is a cyclic group, which is a cyclobutyl group optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl group, C 1-4 alkoxy group, amino group or aminocarbonyl group, wherein each of the optional substituents of the C 1-4 alkyl group and C 1-4 alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino group and the aminocarbonyl group is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl groups.

[0109] In addition to the above embodiment (1), the compound of formula 1 further includes the following compounds, wherein:

[0110] (23)R 1 is a cyclic group, which is a C 1-4 alkyl group, C 1-4 alkoxy group, amino group or aminocarbonyl group which is optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 2-9 heterocyclic group, wherein each of the optional substituents of the C 1-4 alkyl group and C 1-4Each of the optional substituents of the alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl groups;

[0111] (24)R 1 is a cyclic group which is a C 1-4 alkyl group, a C 1-4 alkoxy group, an amino group or an aminocarbonyl group which is substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 2-6 heterocyclic group, wherein each of the optional substituents of the C 1-4 alkyl group and the C 1-4 alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl groups; or

[0112] (25)R 1 is a cyclic group which is a C 1-4 alkyl group, a C 1-4 alkoxy group, an amino group or an aminocarbonyl group which is substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 3-5 heterocyclic group, wherein each of the optional substituents of the C 1-4 alkyl group and the C 1-4 alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl groups.

[0113] In addition to, or as an alternative to, any one of embodiments (23) to (25) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0114] (26) the R 1 cyclic group has 1 or 2 heteroatoms each independently selected from N, O and S as ring members;

[0115] (27) the R 1 cyclic group has 1 or 2 heteroatoms each independently selected from N and O as ring members; or

[0116] (28) the R 1 cyclic group has 1 heteroatom selected from N and O as a ring member.

[0117] In addition to, or alternatively to, any one of embodiments (23) to (28) in the foregoing paragraphs, the compound of formula 1 includes the following compounds, wherein:

[0118] (29) said R 1 The cyclic group is monocyclic.

[0119] In addition to embodiment (1) above, the compound of formula 1 further includes the following compounds, wherein:

[0120] (30) R 1 is a cyclic group selected from tetrahydrofuranyl and morpholinyl, each of which is optionally substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of said C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halogen, and wherein each of the optional substituents of said amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

[0121] In addition to embodiment (1) above, the compound of formula 1 further includes the following compounds, wherein:

[0122] (31) R 1 is a cyclic group which is a C 1-4 aryl substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, C 1-4 alkyl, C 6-14 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of said C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halogen, and wherein each of the optional substituents of said amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0123] (32) R 1 is a cyclic group which is a C 1-4 aryl substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, C 1-4 alkyl, C 6-10 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of said C 1-4 alkyl and C 1-4Each of the optional substituents of the alkoxy group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0124] (33)R 1 is a cyclic group which is a phenyl group substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

[0125] In addition to the above embodiment (1), the compound of formula 1 further includes the following compounds, wherein:

[0126] (34)R 1 is a cyclic group which is a C 1-4 heteroaryl substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-9 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0127] (35)R 1 is a cyclic group which is a C 1-4 heteroaryl substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-5 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of the amino and aminocarbonyl groups is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0128] (36)R1 is a cyclic group, which is a C optionally substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and aminocarbonyl, and the C 3-5 heteroaryl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and each of the optional substituents of the amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

[0129] In addition to any one of the embodiments (34) to (36) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0130] (37) R 1 The cyclic group has 1 or 2 heteroatoms each independently selected from N, O and S as ring members.

[0131] In addition to the above embodiment (1), the compound of formula 1 further includes the following compounds, wherein:

[0132] (38) R 1 is a cyclic group selected from pyrrolyl, 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, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is independently substituted with 0 to 3 substituents selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and aminocarbonyl, wherein each of the optional substituents of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and each of the optional substituents of the amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0133] (39) R 1is a cyclic group selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is independently substituted with 0 to 3 optional substituents selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, and aminocarbonyl, wherein each of the optional substituents of said C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of said amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0134] (40)R 1 is a cyclic group selected from furyl, pyrazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, and pyrimidinyl, each of which is independently substituted with 0 to 3 optional substituents selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, and aminocarbonyl, wherein each of the optional substituents of said C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of the optional substituents of said amino and aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

[0135] In addition to, or alternatively to, any one of embodiments (18) to (40) in the preceding paragraph, the compound of formula 1 includes the following compounds, wherein:

[0136] (41)R 1 The cyclic group is independently substituted with 0 to 3 optional substituents selected from halo, hydroxy, cyano, C 1-4 alkyl, and C 1-4 alkoxy, wherein each of the optional substituents of said C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo; or

[0137] (42)R 1 The cyclic group is independently substituted with 0 to 3 optional substituents selected from fluoro, chloro, hydroxy, cyano, C 1-4 alkyl, and C 1-4 alkoxy, wherein each of the optional substituents of said alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo.

[0138] In addition to, or as an alternative to, any one of embodiments (41) and (42) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0139] (43) R 1 C on the cyclic group 1-4 alkyl and C 1-4 each of the optional substituents on the alkoxy group is independently substituted with 0 to 3 substituents independently selected from fluoro and chloro;

[0140] (44) R 1 C on the cyclic group 1-4 alkyl and C 1-4 each of the optional substituents on the alkoxy group is independently substituted with 0 to 3 substituents selected from fluoro; or

[0141] (45) R 1 C on the cyclic group 1-4 alkyl and C 1-4 each of the optional substituents on the alkoxy group is unsubstituted.

[0142] In addition to, or as an alternative to, any one of embodiments (41) to (45) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0143] (46) R 1 C on the cyclic group 1-4 each of the optional substituents on the alkyl group is independently selected from methyl, ethyl, and isopropyl; or

[0144] (47) R 1 C on the cyclic group 1-4 each of the optional substituents on the alkoxy group is independently selected from methoxy and ethoxy.

[0145] In addition to, or as an alternative to, any one of embodiments (18) to (47) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0146] (48) The R 1 cyclic group is substituted with 0 to 2 optional substituents; or

[0147] (49) The R 1 cyclic group is substituted with 0 or 1 optional substituents.

[0148] In addition to, or as an alternative to, any one of embodiments (18) to (40) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0149] (50) The R 1The cyclic group is unsubstituted.

[0150] In addition to, or as an alternative to, any one of embodiments (1) to (50) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0151] (51) L is selected from a bond, –CH 2 –, –CH 2 CH 2 –, and –CH(CH 3 )–;

[0152] (52) L is selected from a bond, –CH 2 –, and –CH 2 CH 2 –;

[0153] (53) L is selected from a bond and –CH 2 –;

[0154] (54) L is –CH 2 –; or

[0155] (55) L is a bond.

[0156] In addition to, or as an alternative to, any one of embodiments (1) to (55) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0157] (56) R 2 is C 1-4 alkyl substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, and amino.

[0158] In addition to embodiment (56) in the foregoing paragraph, the compound of formula 1 further includes the following compounds, wherein:

[0159] (57) The R 2 C 1-4 alkyl is selected from methyl, ethyl, propyl, and isopropyl, each of which is substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, and amino;

[0160] (58) The R 2 C 1-4 alkyl is selected from methyl, ethyl, and isopropyl, each of which is substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, and amino;

[0161] (59) The R 2 C 1-4The alkyl group is selected from methyl and ethyl, each of which is independently substituted with 0 to 3 optional substituents selected from halo, hydroxy, cyano, C 1-4 alkoxy, and amino;

[0162] (60) The R 2 C 1-4 alkyl group is methyl substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, and amino; or

[0163] (61) The R 2 C 1-4 alkyl group is methyl substituted with 0 to 3 optional substituents independently selected from halo, hydroxy, and C 1-4 alkoxy.

[0164] In addition to, or as an alternative to, any one of embodiments (56) to (61) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0165] (62) The R 2 C 1-4 alkyl group is substituted with 0 to 3 optional substituents independently selected from halo and C 1-4 alkoxy;

[0166] (63) The R 2 C 1-4 alkyl group is substituted with 0 to 3 optional substituents independently selected from fluoro, chloro, methoxy, and ethoxy;

[0167] (64) The R 2 C 1-4 alkyl group is substituted with 0 to 3 optional substituents independently selected from fluoro and methoxy; or

[0168] (65) The R 2 C 1-4 alkyl group is unsubstituted.

[0169] In addition to, or as an alternative to, any one of embodiments (56) to (61) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0170] (66) The R 2 C 1-4 alkyl group is substituted with C 1-4 alkoxy;

[0171] (67) The R 2 C 1-4 alkyl group is substituted with methoxy or ethoxy; or

[0172] (68) The R2 C 1-4 The alkyl group is replaced by a methoxy group.

[0173] In addition to, or as an alternative to, any one of embodiments (1) to (55) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0174] (69) R 2 is a cyclic group selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 6-14 aryl and C 1-9 heteroaryl, wherein the cyclic group is substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 heterocycloalkyl, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 heterocycloalkyl, and wherein each of the optional substituents of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocycloalkyl is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituent of said amino is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0175] (70) R 2 is a cyclic group selected from C 3-8 cycloalkyl, C 6-14 aryl and C 1-9 heteroaryl, wherein the cyclic group is substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 heterocycloalkyl, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 heterocycloalkyl, and wherein each of the optional substituents of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocycloalkyl is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituent of said amino is independently substituted with 0 to 2 substituents independently selected from C 1-4The alkyl group is substituted with an alkyl substituent.

[0176] In addition to or as an alternative to any one of embodiments (1) to (55) in the preceding paragraphs, compounds of Formula 1 include compounds wherein:

[0177] (71)R 2 is a cyclic group, 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 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 An optional substituent of a heterocyclic group, and wherein said 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;

[0178] (72)R 2 is a cyclic group, 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 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 An optional substituent of a heterocyclic group, and wherein said 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;

[0179] (73)R 2 is a cyclic group, 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 C3-5 Cyclopropyl substituted with an optional substituent of a heterocyclic group, provided that the cyclic group has no more than one selected from C 3-8 Cycloalkyl and C 3-5 Optional substituent of a heterocyclic group, and wherein said C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituent of the amino group is independently substituted with 0 to 2 substituents independently selected from C 1-4 Alkyl; or

[0180] (74)R 2 Is a cyclic group which is a cyclobutyl substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl and C 3-5 Optional substituent of a heterocyclic group, provided that the cyclic group has no more than one selected from C 3-8 Cycloalkyl and C 3-5 Optional substituent of a heterocyclic group, and wherein said C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C 3-5 Each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituent of the amino group is independently substituted with 0 to 2 substituents independently selected from C 1-4 Alkyl.

[0181] In addition to, or as an alternative to, any one of embodiments (1) to (55) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0182] (75)R 2 Is a cyclic group which is a C 1-4 Heterocyclic group substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 Alkyl, C 3-8 Alkoxy, amino, C 3-5 Cycloalkyl and C 2-9 Optional substituent of a heterocyclic group, provided that the cyclic group has no more than one selected from C 3-8 Cycloalkyl and C 3-5 Optional substituent of a heterocyclic group, and wherein said C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and C3-5 Each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl substituents;

[0183] (76)R 2 is a cyclic group which is a C 1-4 substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 3-8 alkoxy, amino, C 3-5 cycloalkyl and C 2-6 heterocyclic group, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 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 heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl substituents; or

[0184] (77)R 2 is a cyclic group which is a C 1-4 substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 3-8 alkoxy, amino, C 3-5 cycloalkyl and C 3-5 heterocyclic group, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 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 heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl substituents.

[0185] In addition to, or as an alternative to, any one of embodiments (75) to (77) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0186] (78) said R2 The cyclic group has 1 or 2 heteroatoms each independently selected from N, O, and S as ring members;

[0187] (79) Said R 2 The cyclic group has 1 or 2 heteroatoms each independently selected from N and O as ring members; or

[0188] (80) Said R 2 The cyclic group has 1 heteroatom selected from N and O as a ring member.

[0189] In addition to, or as an alternative to, any one of embodiments (75) to (80) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0190] (81) Said R 2 The cyclic group is monocyclic.

[0191] In addition to, or as an alternative to, any one of embodiments (1) to (55) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0192] (82) R 2 is a cyclic group which is an aryl group substituted by 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl, and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 6-14 cycloalkyl and C 3-8 heterocyclyl, and wherein each of the optional substituents of said C 3-5 alkyl, C 1-4 alkoxy, C 1-4 cycloalkyl, and C 3-8 heterocyclyl is independently substituted by 0 to 3 substituents independently selected from halo, and wherein the optional substituent of said amino is independently substituted by 0 to 2 substituents independently selected from C 3-5 alkyl; 1-4 alkyl;

[0193] (83) R 2 is a cyclic group which is an aryl group substituted by 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl, and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 6-10 cycloalkyl and C 3-8 cycloalkyl and C3-5 Optional substituents of the heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0194] (84)R 2 is a cyclic group, which is a phenyl group substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

[0195] In addition to any one of the embodiments (1) to (55) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0196] (85)R 2 is a cyclic group, which is a C 1-4 heteroaryl substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 3-8 alkoxy, amino, C 3-5 cycloalkyl and C 1-9 optional substituents of the heterocyclic group, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5Each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0197] (86)R 2 is a cyclic group which is a C 1-4 heteroaryl substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 3-8 alkoxy, amino, C 3-5 cycloalkyl and C 1-5 heterocyclic group, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclic group are each independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0198] (87)R 2 is a cyclic group which is a C 1-4 heteroaryl substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 3-8 alkoxy, amino, C 3-5 cycloalkyl and C 3-5 heterocyclic group, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclic group are each independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

[0199] In addition to, or as an alternative to, any one of embodiments (85) to (87) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0200] (88) said R 2The cyclic group has 1 or 2 heteroatoms each independently selected from N, O, and S as ring members; or

[0201] (89) said R 2 The cyclic group has 1 or 2 heteroatoms each being N as ring members.

[0202] In addition to, or as an alternative to, any one of embodiments (1) to (55) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0203] (90) R 2 is a cyclic group selected from pyrrolyl, 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, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted by 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl, and C 3-5 heterocyclic group, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclic group, and wherein each of the optional substituents of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and C 3-5 heterocyclic group is independently substituted by 0 to 3 substituents independently selected from halo, and wherein the optional substituent of said amino is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl;

[0204] (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 optionally substituted by 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl, and C 3-5 heterocyclic group, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5Optional substituents of the heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0205] (92)R 2 is a cyclic group selected from pyrazolyl, pyridyl and pyrimidinyl, each of which is independently substituted with 0 to 3 substituents selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl;

[0206] (93)R 2 is a cyclic group which is a pyrazolyl group substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 optional substituents of the heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo, and wherein the optional substituents of the amino group are independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; or

[0207] (94)R 2is a cyclic group, which is a pyridyl group substituted by 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, C 3-8 cycloalkyl and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclyl, and wherein each of the optional substituents of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclyl is independently substituted by 0 to 3 substituents independently selected from halo, and wherein the optional substituent of said amino is independently substituted by 0 to 2 substituents independently selected from C 1-4 alkyl.

[0208] In addition to, or alternatively to, any one of embodiments (69) to (94) in the foregoing paragraph, the compound of formula 1 includes the following compounds, wherein:

[0209] (95) said R 2 cyclic group is substituted by 0 to 3 optional substituents independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclyl, and wherein each of the optional substituents of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclyl is independently substituted by 0 to 3 substituents independently selected from halo; or

[0210] (96) said R 2 cyclic group is substituted by 0 to 3 optional substituents independently selected from fluoro, chloro, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclyl, and wherein each of the optional substituents of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C3-5 Each of the optional substituents of the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from halo.

[0211] Except for any one of the embodiments (95) and (96) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0212] (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 heterocyclic group is independently substituted with 0 to 3 substituents independently selected from fluoro and chloro;

[0213] (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 the heterocyclic group is independently substituted with 0 to 3 substituents independently selected from fluoro; or

[0214] (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 heterocyclic group is unsubstituted.

[0215] Except for any one of the embodiments (95) to (99) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0216] (100)R 2 C on the cyclic group 1-4 Each of the optional substituents of the alkyl is independently selected from methyl, ethyl and isopropyl;

[0217] (101)R 2 C on the cyclic group 1-4 Each of the optional substituents of the alkoxy is independently selected from methoxy and ethoxy;

[0218] (102)R 2 C on the cyclic group 3-8 The optional substituent of the cycloalkyl is selected from cyclopropyl and cyclobutyl;

[0219] (103)R 2 C on the cyclic group 3-5The optional substituents of the heterocyclic group have 1 or 2 heteroatoms each independently selected from N, O, and S as ring members; or

[0220] (104)R 2 C on the cyclic group 3-5 The optional substituents of the heterocyclic group have 1 heteroatom selected from N and O as a ring member.

[0221] Except for any one of embodiments (95) to (99), (103), and (104) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0222] (105)R 2 C on the cyclic group 3-5 The optional substituents of the heterocyclic group are monocyclic.

[0223] Except for any one of embodiments (95) to (99) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0224] (106)R 2 C on the cyclic group 3-5 The optional substituent of the heterocyclic group is oxetanyl.

[0225] Except for any one of embodiments (1) to (106) in the foregoing paragraph, or as an alternative thereto, the compound of formula 1 includes the following compounds, wherein:

[0226] (107)R 3 、R 4 and R 5 are each independently selected from hydrogen, halo, and C 1-3 alkyl;

[0227] (108)R 3 、R 4 and R 5 are each independently selected from hydrogen, fluoro, and C 1-3 alkyl;

[0228] (109)R 3 、R 4 and R 5 are each independently selected from hydrogen, fluoro, and methyl;

[0229] (110)R 3 and R 4 are each independently selected from hydrogen, fluoro, and methyl, and R 5 is hydrogen;

[0230] (111)R 4 is selected from hydrogen and fluoro, and R 3 and R5 each is hydrogen; or

[0231] (112)R 3 、R 4 and R 5 each is hydrogen.

[0232] The compound of Formula 1 includes the embodiments (1) to (112) described in the foregoing paragraphs and all the compounds specifically named above and in the examples, and may exist in the form of salts, complexes, solvates, hydrates and liquid crystals. Similarly, the compound of Formula 1 as a salt may exist as a complex, solvate, hydrate and liquid crystal.

[0233] The compound of Formula 1 may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including diacids) and base 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 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, cyclohexanesulfamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hippurate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate and xinofoate.

[0234] Pharmaceutically acceptable base salts include salts derived from bases, said 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 S.M. Berge et al., J. Pharm. Sci. (1977) 66:1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0235] A variety of methods can be used to prepare pharmaceutically acceptable salts. For example, a compound of Formula 1 can be reacted with a suitable acid or base to obtain the desired salt. Alternatively, a precursor of a compound of Formula 1 can be reacted with an acid or base to remove an acid-labile or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, a salt of a compound of Formula 1 can be converted to another salt (or free form) by treatment with a suitable acid or base or by contact with an ion-exchange resin. After the reaction, if the salt precipitates from the solution, it can be separated by filtration or recovered by evaporation. The degree of ionization of the salt can vary from fully ionized to hardly ionized at all.

[0236] A compound of Formula 1 can exist in a continuous solid state ranging 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 physical properties of a solid or a liquid depending on temperature. Generally, such materials do not provide a unique X-ray diffraction pattern and, while exhibiting solid properties, are more formally described as liquids. Upon heating, a change from solid to liquid properties 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 liquid properties upon sufficient heating, but the change from solid to liquid is characterized by a phase change, typically first-order ("melting point").

[0237] A compound of Formula 1 can also exist in non-solvated and solvated forms. The term "solvate" describes a molecular complex that includes the 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., D 2O, acetone-d 6 , DMSO-d 6 ).

[0238] The currently accepted classification system for organic compound solvates and hydrates is one that differentiates between isolated-site, channel, and metal-ion coordination solvates and hydrates. See, e.g., K.R. Morris (ed. H.G. Brittain), Polymorphism in Pharmaceutical Solids (1995). Isolated-site solvates and hydrates are those in which solvent (e.g., water) molecules are isolated from one another by intervening organic compound molecules and do not contact one another directly. In channel solvates, the solvent molecules are located in lattice channels where they are adjacent to other solvent molecules. In metal-ion coordination solvates, the solvent molecules are bonded to metal ions.

[0239] 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 amount of water or solvent will depend on humidity and drying conditions. In such cases, non-stoichiometry is typically observed.

[0240] The compound of Formula 1 can also exist as a multi-component complex (excluding salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrate hydrates (drug-host inclusion compounds) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular components held together by non-covalent interactions, but can also be complexes of neutral molecules with salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. See, e.g., O. Almarsson and M.J. Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a general review of multi-component complexes, see J.K. Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0241] When subjected to suitable conditions, the compound of Formula 1 can exist in a mesomorphic state (mesophase or liquid crystal). A mesomorphic state lies between a true crystalline state and a true liquid state (melt or solution). Mesomorphism that occurs due to a change in temperature 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 those with a polar ionic moiety (e.g., -COOˉNa + , -COOˉK +, -SO 3 ˉNa + ) or a polar nonionic moiety (such as -NˉN + (CH 3 ) 3 ) molecule. See, for example, N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0242] Each compound of Formula 1 can exist as a polymorph, stereoisomer, tautomer, or some combination thereof, can be isotopically labeled, can be produced by the administration of a prodrug, or can form a metabolite after administration.

[0243] "Prodrug" refers to a compound that has no or little pharmacological activity and that, when metabolized in the body, can be converted into a compound having the desired pharmacological activity. Prodrugs can be prepared by replacing a suitable functional group present in a pharmacologically active compound with a "pro-part", as described, for example, in H. Bundgaard, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of a compound of Formula 1 having a carboxylic acid, hydroxyl, or amino functional group, 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).

[0244] "Metabolite" refers to a compound formed in the body after administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxyl, secondary amino, primary amino, phenol, and carboxylic acid derivatives of a compound of Formula 1 having a methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide group, respectively.

[0245] The compounds of Formula 1 can exist as stereoisomers resulting from the presence of one or more stereocenters, one or more double bonds, or both. The stereoisomers can be pure, substantially pure, or a mixture. Such stereoisomers can also be produced from acid addition salts or base salts in which the counterion is optically active, such as when the counterion is D-lactic acid or L-lysine.

[0246] The compounds of Formula 1 can exist as tautomers, which are isomers produced by tautomerization. Tautomerization includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imino acid tautomerization.

[0247] The compounds of formula 1 can exhibit more than one type of isomerism.

[0248] Geometric (cis / trans) isomers can be separated by conventional techniques such as chromatography and fractional crystallization.

[0249] Conventional techniques for preparing or separating compounds having a specific stereochemical configuration include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative), for example using chiral high performance liquid chromatography (HPLC). Alternatively, a racemate (or a racemic precursor) can be reacted with a suitable optically active compound, which is, for example, an alcohol, or, in the case where the compound of formula 1 contains an acidic or basic moiety, an acid or a base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography, fractional crystallization, etc., and the appropriate diastereomer is converted to a compound having the desired stereochemical configuration. For further discussion of techniques for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0250] The compounds of formula 1 can have isotopic variations in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass typically found in nature. Isotopes suitable 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; isotopes of nitrogen 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. The use of isotopic variations (e.g., deuterium, 2 H) can provide certain therapeutic advantages due to higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variations of the disclosed compounds can contain radioactive isotopes (e.g., tritium, 3 H or 14 C), which can be used in drug and / or substrate tissue distribution studies. Positron emitting isotopes such as 11 C,18 F, 15 O, and 13 N substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds can be prepared by methods similar to those described elsewhere in this disclosure using appropriate isotopically labeled reagents in place of unlabeled reagents.

[0251] Compounds of Formula 1 can be prepared using the techniques described below. Details of some common reactions, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, milling, crystallization, etc.), and analytical procedures, including oxidation, reduction, etc., which are known to those of ordinary skill in the art of organic chemistry, may be omitted in some schemes and examples. Details of such reactions and techniques can be found in many treatises, 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 editions, etc.). Starting materials and reagents are commercially available or can be prepared using literature methods. Some reaction schemes may omit minor products resulting from chemical transformations (e.g., the alcohol produced by ester hydrolysis, CO 2 etc.). Additionally, in some cases, reaction intermediates can be used in subsequent steps without isolation or purification (i.e., in situ).

[0252] In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups that prevent unwanted chemical reactions at other reactive sites. Protecting groups can also be used to increase solubility or otherwise modify the physical properties of the compound. For a discussion of protecting group strategies, descriptions of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups (including amines, carboxylic acids, alcohols, ketones, aldehydes, etc.), see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999), and P. Kocienski, Protective Groups (2000).

[0253] Generally, 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. Additionally, many of the reactions disclosed throughout the specification can be carried out at approximately room temperature (RT) and ambient pressure, but depending on reaction kinetics, yield, etc., some reactions can be carried out at elevated pressures or using higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78 °C to 0 °C). Any mention in this disclosure and the claims of stoichiometric ranges, temperature ranges, pH ranges, etc., whether or not the word "range" is explicitly used, also includes the indicated endpoints.

[0254] Many chemical transformations can also be carried out using one or more compatible solvents, and such solvents can affect the reaction rate and yield. Depending on the nature of the reactants, one or more solvents can 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., hexamethylphosphoramide).

[0255] In the following schemes, substituent identifiers (e.g., L, R 1 、R 2 、R 3etc.) are defined as above for formula 1. However, as mentioned above, some starting materials and intermediates may contain protecting groups which are removed before the final product. In such cases, the substituent identifier refers to the moiety defined in formula 1 and those moieties with appropriate protecting groups. For example, the starting material or intermediate in the scheme may include an R 2 substituent. In such cases, R 2 will include the moiety with or without, for example, a Boc or Cbz group attached to the amine.

[0256] Scheme A shows a general method for preparing compounds of formula 1. According to this method, in the presence of a palladium catalyst (e.g., PdCl 2 (dppf), PdCl 2 (dppf)·CH 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(amphos)Cl 2 etc.), a base (e.g., K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , CsF, KF etc.) and one or more polar solvents (e.g., dioxane, DMF, water etc.), 2-haloaniline (A-1, X = bromine, iodine) reacts with boric acid or ester (A-2, wherein, for example, each R 6 is H or C 1-4 alkyl) at an elevated temperature (e.g., 75 - 130 °C) to give an R 2 -substituted aniline (A-3). In the presence of a polar solvent (nitromethane), the R 2 -substituted aniline reacts with isocyanatosulfonyl chloride at a reduced temperature (e.g., -40 to 0 °C) to give a urea intermediate (not shown), which is then 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 a 3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide intermediate (A-4), which may exist as the 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 (A-4) reacts with POCl 3React in a compatible solvent at an elevated temperature (e.g., 120 °C) to obtain the 3-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide intermediate (A-5), which is then reacted with R 1 -L-substituted amine (A-6) in the presence of a non-nucleophilic base (e.g., DIPEA, Et 3 N, K 2 CO 3 、Cs 2 CO 3 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 reaction directly or indirectly gives the compound of formula 1, for example, after removal of protecting groups, further processing of functional groups, formation of salts, etc.

[0257]

[0258] Scheme B shows a general method for preparing the compound of formula 1. As in Scheme A, the method starts from 2-haloaniline (A-1, X = bromine, iodine), but reacts with isocyanatosulfonyl chloride in the presence of a polar solvent (nitromethane) at a reduced temperature (e.g., -40 to 0 °C) to obtain a urea intermediate (not shown), which is then treated with AlCl 3 at a reduced temperature (e.g., -20 to 0 °C), and then at an elevated temperature (e.g., 100 to 120 °C) to obtain the 3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide intermediate (B-1) or its corresponding tautomer, i.e., the 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) reacts with POCl 3 in a compatible solvent at an elevated temperature (e.g., 120 °C) to obtain the 3-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide intermediate (B-2), which is then reacted with R 1 -L-substituted amine (A-6) in the presence of a non-nucleophilic base (e.g., DIPEA, Et 3 N, K 2 CO 3 、Cs 2 CO 3 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-L-substituted intermediate (B-3) is then reacted with boric acid or ester (A-2, where, for example, each R 6 is H or C 1-4 alkyl) in the presence of a palladium catalyst (e.g., PdCl 2 (dppf), PdCl 2 (dppf)·CH 2 Cl 2 、Pd(PPh 3 ) 4 、Pd(amphos)Cl 2 etc.), a base (e.g., K 2 CO 3 、KHCO 3 、Na 2 CO 3 、NaHCO 3 、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 directly or indirectly produces the compound of formula 1, for example, after removal of protecting groups, further processing of functional groups, salt formation, etc. Alternatively, the R 2 -substituent can be installed by a Negishi coupling (e.g., reacting B-3 with R 2 ZnX in a compatible solvent and a catalytic amount of S-Phos and Pd(OAc) 2 ) or an Ullman reaction (e.g., reacting B-3 with R 2 -H in the presence of a non-nucleophilic base, a Cu(I) iodide catalyst, and a compatible solvent).

[0259]

[0260] The methods described in these schemes can be varied as needed. For example, protecting groups can be added or removed, and the product (including intermediates) can be further processed by, for example, alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkylation, etc. to obtain the desired end product. In addition, any intermediate or end product containing 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.

[0261] The biopharmaceutical properties of the compounds of Formula 1 (including the compounds named in the specification and their pharmaceutically acceptable complexes, salts, solvates and hydrates), such as solubility and stability of the solution over a pH range, permeability, etc., should be evaluated to select a suitable dosage form and route of administration. Compounds intended for pharmaceutical use can be administered as crystalline or amorphous products and can be obtained by methods such as precipitation, crystallization, freeze-drying, spray-drying, evaporative drying, microwave drying or radiofrequency drying, for example as solid plugs, powders or films.

[0262] The compounds of Formula 1 can be administered alone or in combination with another or with one or more pharmacologically active compounds different from the compounds of Formula 1. Generally, 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 particular route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, etc. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th Edition, 2000).

[0263] The compounds of Formula 1 can be administered orally. Oral administration can involve swallowing, in which case the compound enters the bloodstream through the gastrointestinal tract. Alternatively, or in addition, oral administration can involve mucosal administration (e.g., buccal, sublingual, intragingival administration), such that the compound enters the bloodstream through the oral mucosa.

[0264] Formulations suitable for oral administration include solid, semi-solid and liquid systems, such as tablets; soft or hard capsules containing multi-particles or nanoparticles, liquid or powder; lozenges that can be filled with liquid; chewable tablets; gels; rapid-dissolution dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillings in soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose) and generally 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 reconstituting a solid (e.g., from a sachet).

[0265] The compounds of Formula 1 can also be used in rapid-dissolution, rapid-disintegration dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0266] For tablet dosage forms, depending on the dose, the active pharmaceutical ingredient (API) can account for about 1 wt% to about 80 wt% of the dosage form, or more typically about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets can also contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorants, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant accounts for about 1 wt% to about 25 wt% or about 5 wt% to about 20 wt% of the dosage form.

[0267] Binders are commonly used to impart cohesive mass to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0268] Tablets can also contain surfactants such as sodium dodecyl sulfate and polysorbate 80, as well as glidants such as silica and talc. When present, the surfactant can account for about 0.2 wt% to about 5 wt% of the tablet, and the glidant can account for about 0.2 wt% to about 1 wt% of the tablet.

[0269] Tablets can also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium dodecyl sulfate. The lubricant can account for about 0.25 wt% to about 10 wt% or about 0.5 wt% to about 3 wt% of the tablet.

[0270] Tablet blends can be directly compressed or formed into tablets by roller compaction. Alternatively, the tablet blend or a portion of the blend can be wet granulated, dry granulated, melt granulated, melt solidified, or extruded prior to tableting. If desired, one or more components can be size classified by screening or milling or both prior to blending. The final dosage form can comprise one or more layers and can be coated, uncoated, or encapsulated. Exemplary tablets can contain up to about 80 wt% API, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant. For discussion of blending, granulation, milling, screening, tableting, coating, and descriptions of alternative techniques for preparing pharmaceutical 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, Vols. 1-3 (2nd ed., 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0271] Useable oral films for human or veterinary use are flexible water-soluble or water-swellable thin film dosage forms that can rapidly dissolve or adhere to mucosal membranes. In addition to the API, typical films also contain one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film components can include antioxidants, colorants, flavoring and taste enhancing agents, preservatives, saliva stimulants, cooling agents, co-solvents (including oils), emollients, fillers, defoaming agents, surfactants, and taste masking agents. Some components of the formulation may serve more than one function.

[0272] In addition to dosing requirements, the amount of API in the film can also depend on its solubility. If water-soluble, the API will generally comprise about 1 wt% to about 80 wt% of the non-solvent components (solute) of the film, or about 20 wt% to about 50 wt% of the solute in the film. Less soluble APIs can be present in a greater proportion of the composition, typically up to about 88 wt% of the non-solvent components of the film.

[0273] Film-forming polymers can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and generally comprise about 0.01 wt% to about 99 wt% or about 30 wt% to about 80 wt% of the film.

[0274] Film dosage forms are generally prepared by evaporative drying of an aqueous film coated on a peelable backing support or paper, which can be carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in a freeze-drying apparatus, or in a vacuum oven.

[0275] Useful solid dosage forms for oral administration can include immediate release formulations and modified release formulations. Modified release formulations include delayed release, sustained release, pulsatile 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 details on other useful release technologies such as high energy dispersion and osmotic and coated particles, see R.K. Verma and S. Garg, Pharmaceutical Technology On-line (2001) 25(2):1-14.

[0276] The compound of Formula 1 can also be administered directly into the bloodstream, muscle, or viscera of a subject. Suitable parenteral administration techniques include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Devices suitable for parenteral administration include needle syringes, including micro-needle syringes, needle-free syringes, and infusion devices.

[0277] Parenteral formulations are generally aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., pH from 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 in a dry form to be used with a suitable vehicle such as sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by freeze-drying) can be readily accomplished using standard pharmaceutical techniques.

[0278] The solubility of the compound for preparing parenteral solutions can be enhanced by appropriate formulation techniques, such as by introducing solubility enhancers. Formulations for parenteral administration can be formulated for immediate release or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. Thus, the compound of Formula 1 can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implant depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions containing drug-loaded poly(DL-lactic-co-glycolic acid) (PGLA) microspheres.

[0279] The compound of Formula 1 can also be administered topically, intradermally or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers can include alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Topical formulations can also contain penetration enhancers. See, e.g., B.C. Finnin and T.M. Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0280] Other topical delivery methods include delivery by electroporation, iontophoresis, sonophoresis, sonopermation and micro-needle or needleless (e.g., Powderject TM and Bioject TM ) injection. Formulations for topical delivery can be formulated as immediate release or modified release as described above.

[0281] 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 the dry powder formulation, which contains the API alone, a powder blend of the API and a diluent such as lactose, or a mixed component particle including the API and a phospholipid such as phosphatidylcholine. For intranasal use, the powder can contain a bioadhesive, such as chitosan or cyclodextrin. A pressurized container, pump, nebulizer, atomizer or sprayer can be used to generate an aerosol spray from a solution or suspension containing the API, one or more reagents for dispersing, solubilizing or extending the release of the API (e.g., EtOH with or without water), one or more solvents serving as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and optionally a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid. An electrohydrodynamic atomizer can be used to generate a fine mist.

[0282] Prior to use in dry powder or suspension formulations, the drug product is typically comminuted to a particle size suitable for delivery by inhalation (based on volume, typically the maximum size of 90% of the particles is less than 5 microns). 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.

[0283] Capsules, blisters and cartridges for inhalers or insufflators (e.g., made of gelatin or hydroxypropyl methylcellulose) can be formulated with a powder mixture containing an active compound, a suitable powder matrix such as lactose or starch, and a modifier such as L-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0284] Suitable solution formulations for nebulizers for generating fine mists using electrohydrodynamics can contain from 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 contain one or more compounds of formula 1, propylene glycol, sterile water, EtOH and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0285] Formulations for inhaled administration, intranasal administration or both can be formulated for immediate release or modified release using, for example, PGLA. Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or sodium saccharin, can be added to formulations intended for inhaled / intranasal administration.

[0286] In the case of dry powder inhalers and aerosols, the dose 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 about 100 μg to about 10 mg, which can be administered as a single dose, or more commonly, in divided doses throughout the day.

[0287] The active compound can be administered rectally or vaginally, for example, in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. Formulations for rectal or vaginal administration can be formulated for immediate release or modified release as described above.

[0288] The compound of Formula 1 can also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in an isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable implants (e.g., absorbable gelatin sponges, collagen), non-biodegradable implants (e.g., silicone), film tablets, lenses, and particulate or vesicular systems such as niosomes or liposomes. The formulation may contain one or more polymers and preservatives such as benzalkonium chloride. Typical polymers include crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gellan gum). Such formulations can also be delivered by iontophoresis. Formulations for ocular or otic administration can be formulated as immediate release or modified release as described above.

[0289] 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 polymers containing polyethylene glycol. For example, API-cyclodextrin complexes are commonly used in most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the API, cyclodextrins can be used as adjunctive additives, i.e., as carriers, diluents, or solubilizers. α-, β-, and γ-cyclodextrins are commonly used for these purposes. See, e.g., WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0290] As described above, one or more compounds of Formula 1, including the specifically named compounds above, and their pharmaceutically acceptable complexes, salts, solvates, and hydrates, can be combined with each other or with one or more other 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 compositions. The kit contains (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) means for separately storing the two pharmaceutical compositions, such as separate bottles or separate foil packages. An example of such a kit is the common blister pack used 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 dosing instructions and can be provided with memory aids.

[0291] For administration to human patients, the total daily dose of the claimed and disclosed compounds will generally be in the range of about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require only about 0.1 mg to about 300 mg of the total daily dose. The total daily dose may be administered in a single dose or divided doses, and may, at the discretion of the physician, exceed the typical ranges given above. Although these doses are based on an average human subject weighing from about 60 kg to about 70 kg, a physician is able to determine the appropriate dose for a patient whose weight falls outside of this weight range (e.g., pediatric patients).

[0292] The compound of Formula 1 can be used to treat diseases, disorders or conditions indicative of inhibition of MRGX2. 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, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

[0293] 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, the compound of Formula 1 or its tautomer, including the compounds specifically named in the specification, and its pharmaceutically acceptable complexes, salts, solvates and hydrates, can be administered concomitantly, sequentially or separately in combination with one or more anti-inflammatory agents, analgesics, biologic response modifiers, disease-modifying antirheumatic drugs (DMARD), antihistamines, mast cell stabilizers, prokinetics, antidiarrheals, secretagogues, antibiotics, antidepressants, anxiolytics, antipsychotics and anticonvulsants, etc.

[0294] The compound of Formula 1 can be combined with anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. Representative non-steroidal anti-inflammatory drugs include azapropazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate and sulindac. Representative corticosteroids include betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and prednisone.

[0295] Alternatively or additionally, a compound of Formula 1 can be combined with an analgesic, a biologic response modifier, a DMARD, or some combination thereof. Representative analgesics include acetaminophen and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene, and tramadol, with or without acetaminophen. Representative biologic 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 costimulation modulators such as abatacept. Representative DMARDs include auranofin (oral gold), azathioprine, chlorambucil, cyclophosphamide, cyclosporine, gold sodium thiomalate (injectable gold), hydroxychloroquine, leflunomide, methotrexate, minocycline, mycophenolate mofetil, penicillamine, sulfasalazine, and JAK3 inhibitors (e.g., tofacitinib).

[0296] 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.

[0297] Additionally or alternatively, a compound of Formula 1 can be combined with an antihistamine, a mast cell stabilizer, a prokinetic, an antidiarrheal, a secretagogue, an antibiotic, or some combination thereof. Representative antihistamines include H 1 1-antihistamines (e.g., acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, rupatadine, tripelennamine, and triprolidine), H 1 2-reverse agonists (e.g., cimetidine, famotidine, lafutidine, nizatidine, ranitidine, and roxatidine), H 3 3-antihistamines (e.g., clobenpropit, ciproxifan, conessine, and thioperamide), and H 4 4-antihistamines (e.g., thioperamide).

[0298] Representative mast cell stabilizers include azelastine, β2 adrenergic receptor agonists (such as abediterol, arformoterol, bambuterol, bitolterol, carmoterol, clenbuterol, fenoterol, formoterol, indacaterol, isoprenaline, isoxsuprine, levalbuterol, mabuterol, olodaterol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, vilanterol, and zilpaterol), cromolyn acid, ketotifen, mepolizumab, nedocromil, olopatadine, omalizumab, palmitoylethanolamide, pemirolast, quercetin, rupatadine, tranilast, and vitamin D.

[0299] Representative prokinetics include cisapride, cisapride, domperidone, itopride, levosulpiride, linaclotide, metoclopramide, mitesina, mosapride, prucalopride, renzapride, and tegaserod. Representative antidiarrheals include bismuth subsalicylate, crofelemer, difenoxin hydrochloride / atropine, diphenoxylate hydrochloride / atropine, loperamide, loperamide / simethicone, octreotide, and paregoric. Representative secretagogues include lubiprostone, linaclotide, plecanatide, and elobixibat. Representative antibiotics include tetracycline, amoxicillin / clavulanic acid, metronidazole, fluoroquinolones (such as norfloxacin), and rifaximin.

[0300] Additionally or alternatively, the compound of formula 1 can be combined with antidepressants, antipsychotics, anxiolytics, anticonvulsants, or other drugs for treating neurological or mental diseases. For example, the compound of formula 1 can be combined with antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), or selective serotonin and norepinephrine reuptake inhibitors (SNRI), or with antipsychotics including atypical antipsychotics or some combinations thereof. Representative antidepressants include amitriptyline, amoxapine, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, imipramine, isocarboxazid, levomilnacipran, 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.

[0301] Similarly, the compound of Formula 1 can be combined with one or more agents for treating anxiety disorders (anxiolytics) or agents for treating epilepsy (antiepileptics or anticonvulsants) or some combinations thereof. Representative anxiolytics include benzodiazepines (such as alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), non-benzodiazepines (such as 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.

[0302] Bioactivity

[0303] The activity of the exemplary compounds can be determined by a variety of methods, including in vitro and in vivo methods.

[0304] In vitro inhibition of intracellular calcium flux (EC 50 )

[0305] Use the FLIPR system to measure the release of intracellular calcium after stimulating cells with substance P in the presence or absence of inhibitor compounds. Seed CHO-K1 cells overexpressing MRGX2 into a 384-well plate (black clear bottom, TC-treated, Fisher #07-200-655) and incubate overnight to allow cell attachment. Remove the medium and add 1X loading buffer ( Calcium 5 assay solution, Molecular Devices, according to the manufacturer's instructions). Incubate the plate at 37 °C for 30 minutes. Add the test compound to the cells (11-point dose response, 10 μM maximum concentration) and measure fluorescence using the FLIPR system (120 seconds, real-time). Immediately thereafter, add the MRGX2 ligand substance P at a final concentration of 1 μM and measure fluorescence using the FLIPR system (120 seconds, real-time). The data for the examples are reported as pEC 50 .

[0306] In vitro radioligand binding assay (K d )

[0307] The equilibrium dissociation constant K of many of the compounds (“test compounds”) described in the Examples section was determined in the presence of cell membranes prepared from an SF9 cell line overexpressing the human MRGX2 receptor. d The assay was performed in 96-well plates (Greiner V-Bottom #651201). A fixed amount of the cell membrane preparation (75 μg / well, final concentration) and 3 3-(((furan-2-yl-4,5-t 2 )methyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Quotient Bioresearch, 40 μM final concentration), an [H]-labeled ligand, 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 MgCl 2 , 0.01% Triton X-100, 200 μM EDTA, pH 7.4 were mixed in each well. The assay mixture containing the MRGX2 receptor, the radiolabeled ligand, and the test compounds was incubated for 60 minutes at room temperature (∼22 °C) to reach equilibrium. After incubation, the assay mixture was collected on a filter mat (Filtermat A, PerkinElmer) using a cell harvester (Harvester 96, TOMTEC). The filter mat was dried completely. A solid scintillant (Meltilex, PerkinElmer) was added to each filter membrane, and the radioactivity level (“signal”) from each well (assay mixture) was recorded using a scintillation counter (Trilux Microbeta, PerkinElmer). K was determined by fitting the dose-response data ([I], signal) curves for each set of samples to the following equation d ,

[0308]

[0309] where [I] is the concentration of the test compound. The data was reported as pK d .

[0310] Examples

[0311] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the invention.

[0312] Equilibrium dissociation constants were obtained for many of the compounds in the following examples 11H nuclear magnetic resonance (NMR) spectra. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, and the assignments of the major peaks are made using conventional abbreviations including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl 3 (chloroform-d), DMSO-d 6 (dimethyl sulfoxide-d), CD 3 OD (methanol-d), CD 3 CN (acetonitrile-d), and THF-d 8 (tetrahydrofuran-d). Mass spectra are recorded using electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry (for the m / z of [M+H] + ).

[0313] When indicated, the products of certain preparations and examples are purified 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 carried out under acidic conditions (“acid mode”) on columns (e.g., Phenomenex Gemini TM 5μ, C18, 30 mm x 150 mm; Axia TM , 5μ, 30 mm x 75 mm) eluted with CH 3 CN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or under basic conditions (“base mode”) with water and a 20 / 80 (v / v) water / acetonitrile mobile phase containing 10 mM NH 4 HCO 3 . Preparative TLC is typically carried out on silica gel 60F 254 plates. After chromatographic separation, the solvent is removed and the product is dried in a centrifugal evaporator (e.g., GeneVac TM ), rotary evaporator, evacuated flask, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H 2 ) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0314] Preparation 1: 3-Chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0315]

[0316] 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) NaHCO 3 (20 mL) was added PdCl 2 (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) NH 4 Cl (3x). The combined organic layers were dried over MgSO 4 4, 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%).

[0317] Preparation 2: 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0318]

[0319] Step A: 2'-Chloro-3',5-difluoro-[1,1'-biphenyl]-2-amine

[0320]

[0321] To a 300 mL thick-walled flask was added (2-chloro-3-fluorophenyl)boronic acid (5.51 g, 31.6 mmol), 2-bromo-4-fluoroaniline (5 g, 26.3 mmol), and PdCl 3 (dppf) (1.925 g, 2.63 mmol) in dioxane (60 mL) and saturated (aq) NaHCO 2 (60.0 mL) to give an orange solution. The flask was sealed, heated to 100 °C and stirred for 18 h. The reaction mixture was partially concentrated, then diluted with EtOAc and washed with saturated (aq) NH 4 Cl (3 x 100 mL). The combined organic layers were dried over MgSO 4 4, filtered, and concentrated in vacuo. The product was purified by column chromatography (Teledyne ISCO CombiFlash TM, purified by column chromatography (Teledyne ISCO CombiFlash, 120 g column), eluting with 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.

[0322] Step B: 5-(2-Chloro-3-fluorophenyl)-7-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0323]

[0324] To a 200 mL round bottom flask was added isocyanatosulfonyl chloride (1.907 mL, 21.91 mmol) and nitromethane (10 mL). The mixture was cooled to 0 °C. Next, 2'-Chloro-3',5-difluoro-[1,1'-biphenyl]-2-amine (3.75 g, 15.7 mmol) in nitromethane (40 mL) was added dropwise to give a yellow solution. The reaction mixture was stirred at 0 °C for 30 minutes. Aluminum chloride (3.13 g, 23.47 mmol) was added and the reaction mixture was heated to 120 °C for 1.5 h. After reaction, the mixture was concentrated, diluted with EtOAc, and washed with saturated (aq) NH 4 Cl (3 x 80 mL). The combined organic layers were dried over MgSO 4 4, filtered, and concentrated in vacuo to give a brown solid. The product 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 tan solid (2.57 g, 48%). 1 1H NMR (400 MHz, DMSO-d 6 6), δ ppm 7.27 (d, J = 7.07 Hz, 1H), 7.42 - 7.63 (m, 3H), 7.79 (dd, J = 7.07, 2.53 Hz, 1H), 10.20 (br s, 1H).

[0325] Step C: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0326] To a 200 mL round bottom flask was added in POCl 3(50 mL, 536 mmol) and N,N - diethylaniline (1.716 mL, 10.73 mmol) to 5 - (2 - chloro - 3 - fluorophenyl)-7 - fluoro - 3 - hydroxy - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide (2.57 g, 7.46 mmol), to obtain 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. A black oil finally formed a brown precipitate, which was collected by vacuum filtration and dried under vacuum to obtain the title compound as a brown solid (2.55 g, 65%). The product was used without further purification.

[0327] Preparation 3: (3 - fluoropyridin - 2 - yl)methanamine

[0328]

[0329] A stirred solution of 3 - fluoronicotinonitrile (500 mg, 4.10 mmol) in EtOH (25 mL) and hydrochloric acid (12 M, 1.02 mL) was reacted with H 2 in the presence of a catalyst (10% Pd / C, 200 mg) at 50 psi for 16 hours. The progress of the hydrogenation reaction was monitored by TLC. After completion of the reaction, the mixture was filtered to remove the catalyst. The solvent was removed under reduced pressure, and the resulting solid was suspended in acetonitrile and filtered to obtain the HCl salt of the title compound (700 mg), which was used without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.54 (br s, 2H), 8.49 (d, J = 4.8 Hz, 1H), 7.83 (dt, J = 1.1, 9.2 Hz, 1H), 7.54 (td, J = 4.4, 8.4 Hz, 1H), 4.40 - 4.12 (m, 2H).

[0330] Preparation 4: 3 - (((3 - fluoropyridin - 2 - yl)methyl)amino)-5 - iodo - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0331]

[0332] While stirring at 80 °C, Et was added to a solution of (3 - fluoropyridin - 2 - yl)methanamine (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 3N (1.28 mL, 9.24 mmol). The reaction mixture was stirred at 80 °C for 30 minutes, at which point TLC monitoring (mobile phase: DCM / MeOH = 10:1) showed completion of the reaction. 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 afford the title compound as a pale yellow solid (1.20 g). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.62 (s, 1H), 8.84 (t, J = 4.8 Hz, 1H), 8.46 (d, J = 4.8 Hz, 1H), 8.09 (dd, J = 1.2, 7.8 Hz, 1H), 7.78 (t, J = 9.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.48 (td, J = 4.4, 8.4 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 4.68 (d, J = 3.6 Hz, 2H); ESI-MS m / z [M+H] + 433.0.

[0333] Preparation 5: 3-Chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0334]

[0335] Step A: 2'-Chloro-5-fluoro-[1,1'-biphenyl]-2-amine

[0336]

[0337] To a solution of 2-bromo-4-fluoroaniline (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 2 in H 2 (962.56 mg, 1.32 mmol) and NaHCO 3 (4.42 g, 52.62 mmol). The mixture was purged with N 2 (3x) and heated to 120 °C for 2 hours. The solvent was removed in vacuo and the residue was partitioned between H 2 O (80 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine (50 mL) and dried over Na 2 SO 4Dry. 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 as a yellow oil (5.18 g, 89%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.44 (br s, 2H), 6.73 (dd, J = 4.9, 8.8 Hz, 1H), 6.81 (dd, J = 2.9, 9.0 Hz, 1H), 6.94 (dt, J = 2.9, 8.5 Hz, 1H), 7.42 - 7.29 (m, 3H), 7.57 - 7.48 (m, 1H).

[0338] Step B: 5-(2-Chlorophenyl)-7-fluoro-3-hydroxy-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0339]

[0340] At -5 °C to 0 °C, 2'-Chloro-5-fluoro-[1,1'-biphenyl]-2-amine (5.18 g, 23.37 mmol) was added to a solution of isocyanatosulfonyl chloride (4.96 g, 35.06 mmol) in nitromethane (60.00 mL). The resulting mixture was stirred at -5 °C to 0 °C for 30 minutes, then AlCl 3 (6.23 g, 46.74 mmol, 2.55 mL) was added. The reaction mixture was heated to 120 °C for 1.5 hours, then cooled to 25 °C, poured into ice water (200 mL) and stirred for 30 minutes. The precipitate was collected by filtration. The collected solid was dissolved in EtOAc (50 mL) and washed with saturated (aq) NaHCO 3 solution (3 x 50 mL). The aqueous layers were combined, adjusted to pH 1 with concentrated (aq) HCl and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na 2 SO 4 dried, filtered and concentrated to give the title compound as a dark solid (3.80 g, 50%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.55 - 7.39 (m, 4H), 7.65 - 7.57 (m, 1H), 7.79 (dd, J = 2.8, 7.1 Hz, 1H), 10.32 (s, 1H).

[0341] Step C: 3-Chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0342] 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 POCl 3 (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 h, then cooled to 25 °C, poured into ice water (100 mL), and stirred for 1 h. The mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the title compound as a dark solid (900 mg, 85%). The product was used without further purification.

[0343] Preparation 6: 3-Chloro-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0344]

[0345] To a 20 mL microwave vial equipped with a stirrer was added (2,3-difluorophenyl)boronic acid (0.507 g, 3.21 mmol) dissolved in dioxane (14.60 mL), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.00 g, 2.92 mmol), Cs 2 CO 3 (2 M, 3.65 mL, 7.30 mmol), and Pd(dppf) 2 ·CH 2 Cl 2 adduct (0.238 g, 0.292 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 30 min, then diluted in deionized water (∼100 mL). Next, 1 N (aq) HCl was added dropwise until a precipitate formed. The solid was collected by vacuum filtration through a Kiriyama Rohto SB-40 glass filter funnel, washed extensively with deionized water, and then with hexane. The filter cake was dried in a vacuum oven to give the title compound as a (crude) solid (1.164 g).

[0346] Preparation 7: 3-Chloro-5-(2-chloro-3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0347]

[0348] In a manner similar to the preparation of 6, using (2-chloro-3,5-difluorophenyl)boronic acid (90 mg, 0.467 mmol) dissolved in dioxane (1168 μL), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (80 mg, 0.234 mmol), Cs 2 CO 3 (2 M, 0.292 mL, 0.584 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (19.07 mg, 0.023 mmol), the title compound was prepared and isolated as a (crude) solid (56.2 mg). ESI-MS m / z [M+H] + 362.9.

[0349] Preparation 8: 5-Iodo-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0350]

[0351] To a flask containing a solution of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (2 g, 5.84 mmol) and K 2 CO 3 (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 h, then cooled and diluted with water (300 mL). The organic phase (oil) collected at the bottom of the flask. The aqueous phase was decanted and extracted with DCM (3 x 50 mL). The organic layers were combined with the oil and concentrated to give the title compound as an orange-brown solid (1.8 g, 81%).

[0352] Preparation 9: 3-Chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0353]

[0354] Under nitrogen, to a flask equipped for stirring and containing 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), Cs 2 CO 3(5.84 mL, 11.68 mmol) and dioxane (14.60 mL) were added to a 20 mL microwave vial containing Pd(dppf) 2 ·CH 2 Cl 2 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, washed with copious amounts of water and then with hexanes to afford the title compound (0.95 g, 99%). ESI-MS m / z [M+H] + 326.9.

[0355] Preparation 10: 3-Chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0356]

[0357] 3-Chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (750 mg, 2.91 mmol) dissolved in dioxane (8.826 mL), 3-chloro-5-iodo-4H-benzo[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 ·CH 2 Cl 2 adduct (216 mg, 0.265 mmol) were added to a 20 mL pressurized microwave vial equipped with a stir bar. The reaction mixture was heated at 120 °C in a microwave reactor for 30 minutes. 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 filtering funnel while washing with copious amounts of deionized water and then with hexanes. The filter cake was dried in a vacuum oven to afford the title compound as a (crude) solid (933.8 mg, 2.70 mmol) which was used in the preparation of Examples 48, 49, 50 and 51.

[0358] To reduce the Pd content, a portion of the crude product (400 mg) was dispersed in EtOH (5 mL) and 1,4-diazabicyclo[2,2,2]octane activated charcoal (10% wt, 40 mg) was added and the mixture was heated at 60 °C for 2.5 hours. The mixture was then filtered through Pre-fill the plug for filtration and concentrate under vacuum to obtain the title compound (296.3 mg) for the preparation of Examples 52, 53, 54 and 55.

[0359] Preparation 11: 3-Chloro-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0360]

[0361] Charge a 20 mL microwave vial equipped for stirring 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), Cs 2 CO 3 (2.919 mL, 5.84 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (119 mg, 0.146 mmol) and dioxane (7.298 mL). Heat the reaction mixture in a microwave reactor at 120 °C for 30 minutes, then dilute in deionized water (75 mL) and extract with DCM / IPA (4x). Only the weighed amount of the product enters the organic phase. The aqueous phase is concentrated with 60 Å silica gel and the residue is purified by normal phase column chromatography ( semi-column), eluting with 80 / 20 DCM / MeOH. Fractions containing the product are collected, concentrated and dried under vacuum to obtain the title compound (549.8 mg) as the major product. ESI-MS m / z [M+H] + 311.0.

[0362] Preparation 12: 3-Chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0363]

[0364] Charge a 20 mL pressurized microwave vial equipped for stirring with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (700 mg, 2.044 mmol) dissolved in dioxane (10.2 mL), (3,5-difluorophenyl)boronic acid (355 mg, 2.248 mmol), Cs 2 CO 3 (2.55 mL, 5.11 mmol) and Pd(dppf)2 ·CH 2 Cl 2 The adduct (167 mg, 0.204 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 30 minutes and then diluted in approximately 100 mL of deionized water. 1N HCl (approx. 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, washed with a large amount of deionized water, and then washed with hexane to give the title compound as a pale pink solid (779.6 mg). The crude product was dried in a vacuum oven before use.

[0365] Preparation 13: 5-Iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0366]

[0367] To a 20 mL vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (800 mg, 2.34 mmol) in DMA (7 mL), methylamine (2 M in MeOH, 1.518 mL, 3.04 mmol), and DIPEA (0.408 mL, 2.335 mmol) to give a yellow solution. The reaction mixture was heated to 80 °C and stirred overnight. LC / MS indicated completion of the reaction. The reaction mixture was then diluted with EtOAc and washed with saturated (aq) NH 4 Cl (3x). The organic layers were combined, dried over MgSO 4 4, filtered, and concentrated. The product was purified by column chromatography (ISCO 40 g column), eluting with a gradient of 30 - 100% EtOAc in hexane to give the title compound as a brown oil (356 mg, 45%). ESI-MS m / z [M+H] + 338.

[0368] Preparation 14: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0369]

[0370] Step A: 5-Bromo-3-hydroxy-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0371]

[0372] To a 25 mL round-bottom flask was added 2-bromo-4-methylaniline (700 mg, 3.76 mmol) in nitromethane (5 mL), and the reaction mixture was cooled to -40 °C. Isocyanatosulfonyl chloride (0.425 mL, 4.89 mmol) was added, and the reaction mixture was allowed to warm slowly to 25 °C and stirred for an additional 30 minutes. Next, aluminum chloride (602 mg, 4.51 mmol) was added. The reaction mixture was heated at 100 °C for 1.5 hours, cooled to 25 °C, poured into ice water, and sonicated to give a tan precipitate. The solid was collected by vacuum filtration and dried in vacuo to give the title compound (685 mg, 63%). 1 H NMR (400 MHz, DMSO-d 6 ), δ ppm 2.4 (s, 3H), 4.4 (s, 1H), 7.6 (s, 1H), 7.8 (s, 1H), 10.3 (s, 1H).

[0373] Step B: 5-Bromo-3-chloro-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0374]

[0375] 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 a separate solution of POCl 3 (1.382 mL, 14.82 mmol) and N,N-diethylaniline (0.151 mL, 0.941 mmol). The reaction mixture was heated at 100 °C for 16 hours, then cooled to 0 °C, quenched with water, and sonicated to give a precipitate. The solid was collected by vacuum filtration to give the title compound as a brownish solid (160 mg, 22%). The product was used without purification. 1 H NMR (400 MHz, DMSO-d 6 ), δ ppm 2.4 (s, 3H), 7.5 (s, 1H), 7.7 (s, 1H).

[0376] Step C: 3-Chloro-5-(2-chloro-3-fluorophenyl)-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0377] To a 5 mL microwave vial was added 5-bromo-3-chloro-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (160 mg, 0.517 mmol) in dioxane (3.0 mL), Pd 2Cl 2 (dppf) (3.78 mg, 5.17 μmol), (2-chloro-3-fluorophenyl)boronic acid (108 mg, 0.620 mmol), and saturated (aq) NaHCO 3 (3.0 mL). The reaction mixture was heated at 75 °C for 1 h in a microwave reactor, then diluted in EtOAc and washed with saturated (aq) NH 4 Cl (3x). The organic layers were combined, dried over MgSO 4 4, 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 hexanes to afford the title compound as a yellow oil (44 mg, 24%). ESI-MS m / z [M+H] + 359.0.

[0378] Preparation 15: 5-Iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0379]

[0380] 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), Et 3 N (0.916 mL, 6.57 mmol), and EtOH (20 mL). The resulting brown solution was heated to 65 °C and stirred overnight. LC / MS indicated that the reaction was not complete. The reaction mixture was stirred again overnight, after which LC / MS indicated that the reaction was substantially complete. The reaction mixture was then concentrated, taken up in EtOAc, and washed with saturated (aq) NH 4 Cl (3x). The organic layers were combined, dried over MgSO 4 4, filtered, and concentrated. The product was purified by column chromatography (ISCO 40 g column), eluting with a gradient of 30 - 100% EtOAc in hexanes to afford the title compound as a purple solid. ESI-MS m / z [M+H] + 442.

[0381] Preparation 16: 5-Iodo-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0382]

[0383] 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 3-isopropylaniline (74.0 mg, 0.547 mmol), followed by Et 3 N (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 h. The second reaction mixture was combined with the first reaction mixture, diluted with EtOAc, and washed with saturated (aq) NH 4 Cl (3x). The organic layers were combined, dried over MgSO 4 4, filtered, and concentrated. The product was purified by column chromatography (ISCO), eluting with a gradient of 20 - 70% EtOAc in hexanes to afford the title compound (118 mg, 37%). ESI-MS m / z [M+H] + 442.1.

[0384] Preparation 17: 5-Iodo-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0385]

[0386] 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 Et 3N (0.102 mL, 0.730 mmol). The reaction mixture was heated at 80 °C for 3 days to give the first batch of product (about 50% conversion of starting material). 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) were added to a 10 mL vial. The reaction mixture was heated to 100 °C and stirred for 2 days to give the second batch of product (about 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 hexanes to give the title compound (87 mg) as a mixture with the starting material. ESI-MS m / z [M+H] + 443.0.

[0387] Preparation 18: 5-Iodo-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0388]

[0389] 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) were added to a 10 mL vial. The reaction mixture was heated to 100 °C and stirred for 5 h. Subsequently, the reaction mixture was 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 NH column), eluting with a gradient of 0 - 10% MeOH in DCM. The title compound was isolated as a pale yellow solid (167 mg, 52%). ESI-MS m / z [M+H] + 445.0.

[0390] Preparation 19: 3-(((3-fluoropyridin-2-yl)methyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0391]

[0392] In a manner similar to the preparation of 18, the title compound was prepared 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.

[0393] Preparation 20: 5-Iodo-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0394]

[0395] In a manner similar to the preparation of 18, the title compound was prepared 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.

[0396] Preparation 21: 5-Iodo-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0397]

[0398] 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-ylmethanamine (120 mg, 0.796 mmol), and K 2 CO 3 (81 mg, 0.584 mmol) in DMA (1.168 mL). The reaction mixture was heated at 100 °C for 2 h, then poured into water and extracted with EtOAc (3x). The organic layers were combined, dried over MgSO 4 4, 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.

[0399] Preparation 22: 5-Iodo-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0400]

[0401] 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 K 2 CO 3 (81 mg, 0.584 mmol) in DMA (1.168 mL). The reaction mixture was heated at 100 °C for 2 h, then poured into water and extracted with EtOAc (3x). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated to give the title compound as a pale brown oil, which was used without further purification. ESI-MS m / z [M+H] + 396.0.

[0402] Preparation 23: 3-((Cyclobutylmethyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0403]

[0404] The title compound was prepared in a similar manner to Preparation 22, using 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (200 mg, 0.584 mmol), cyclobutylmethanamine hydrochloride (78 mg, 0.642 mmol), and K 2 CO 3 (81 mg, 0.584 mmol) in DMA (1.168 mL) and isolated as an oil. ESI-MS m / z [M+H] + 391.9.

[0405] Preparation 24: 5-Iodo-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0406]

[0407] To a stirred solution of pyridin-2-ylmethanamine (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 the benzo[e][1,2,4]thiadiazine 1,1-dioxide, the mixture was cooled in an ice bath. After addition, the reaction mixture was stirred at room temperature overnight. One drop of Et 3 N was added, and the reaction mixture was stirred at room temperature for 1 h and then at 65 °C for an additional hour. Additional pyridin-2-ylmethanamine (0.020 mL, 0.200 mmol) was added, and the mixture was stirred at 65 °C for 6 h. The first reaction mixture was allowed to stand. To a stirred solution of pyridin-2-ylmethanamine (40.9 μL, 0.400 mmol) in 2-propanol (250 μL) was added Et 3 N (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 the base and the benzo[e][1,2,4]thiadiazine 1,1-dioxide, and then stirred at room temperature for 96 h. The first and second reaction mixtures were combined and purified by preparative HPLC, eluting with a gradient 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.

[0408] Preparation 25: 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0409]

[0410] 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 PdCl 2 (dppf)·CH 2 Cl 2 adduct (298 mg, 0.365 mmol) and K 2 CO 3(1.110 g, 8.03 mmol). The reaction mixture was heated at 100 °C for 1.5 h, 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, precipitating more solid. The mixture was filtered, but only trace material was recovered. The filtrate was extracted with EtOAc (3x), forming 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 off. 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-MS m / z [M+H] + 297.0。

[0411] Preparation 26: 3-Chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0412]

[0413] 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 PdCl 2 (dppf) (50 mg, 0.068 mmol). The mixture was sparged with nitrogen. Saturated (aq) NaHCO 3 (5 mL) was added, the reaction mixture was stirred and heated at 140 °C in a microwave reactor. 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。

[0414] Preparation 27: 2-(3-Chloro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0415]

[0416] Under nitrogen, to 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), Cs 2 CO 3(2.445 mL, 4.89 mmol) and dioxane (6.11 mL) were added to a mixture in a 20 mL microwave vial equipped for stirring with Pd(dppf) 2 ·CH 2 Cl 2 adduct (0.100 g, 0.122 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 20 minutes, then cooled, poured into water (150 mL), and acidified with 1 N HCl(aq) until a brown precipitate formed. The solid was filtered and washed with a large amount of water, then with hexane, to give the (crude) title compound (0.42 g). ESI-MS m / z [M+H] + 318.0.

[0417] Preparation 28: 2-(3-Chloro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile

[0418]

[0419] 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), Cs 2 CO 3 (3.21 mL, 6.42 mmol) and dioxane (8.03 mL). Next, Pd(dppf) 2 ·CH 2 Cl 2 adduct (0.131 g, 0.161 mmol) was added under nitrogen. The reaction mixture was heated in a microwave reactor at 120 °C for 20 minutes, then cooled, poured into water (150 mL), and acidified with 1 N HCl(aq) until a brown precipitate formed. The solid was filtered and washed with a large amount of water, then with hexane, to give the title compound, which was used without further purification (0.42 g, 78%).

[0420] Preparation 29: 3-Chloro-5-(2-cyclopropyl-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0421]

[0422] Under nitrogen, to a 20 mL microwave vial equipped for stirring and containing 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), Cs 2 CO 3 (1.734 mL, 3.47 mmol) and dioxane (4.34 mL) was added Pd(dppf) 2 ·CH 2 Cl 2 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, washed with a large amount of water, and subsequently with hexane, to give the title compound (0.2 g, 66%).

[0423] Example 1: 5-(2-Chloro-3-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0424]

[0425] 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 Et 3 N (0.363 mL, 2.61 mmol) in EtOH (7.00 mL) was added methylamine (2M MeOH solution, 0.869 mL, 1.74 mmol). The mixture was heated at 65 °C for 12 hours. Subsequently, the solvent was removed in vacuo, and the residue was suspended in DCM and washed with saturated (aq) NH 4 Cl (3x). The combined organic layers were dried over MgSO 4 4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (Teledyne ISCO CombiFlash TM, purified by silica gel column chromatography (24 g column), eluted with a gradient 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 sonication. The solution was cooled in an ice bath and allowed to equilibrate at room temperature for 12 hours, during which white crystals formed. The solution was decanted and the crystals were collected by vacuum filtration, washed with IPA. The crystalline solid was dried under vacuum at 35 °C for several hours to give the title compound as a white crystalline solid (85.0 mg, 29.1%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.74 (d, J = 4.55 Hz, 3H), 7.21 (br s, 1H), 7.28 - 7.45 (m, 3H), 7.52 - 7.66 (m, 2H), 7.78 (dd, J = 7.71, 1.14 Hz, 1H), 9.05 (s, 1H); ESI-MS m / z [M+H] + 340.0.

[0426] Example 2: 5-(2-Chloro-3-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0427]

[0428] The title compound was prepared in a similar manner 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 2-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 (400 MHz, DMSO-d 6 ) δ ppm 3.27 (s, 3H), 3.39 (dd, J = 10.99, 4.67 Hz, 2H), 3.44 (d, J = 4.55 Hz, 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, 1.26 Hz, 1H), 9.09 (s, 1H); ESI-MS m / z [M+H] + 384.0.

[0429] Example 3: 5-(2-Chloro-3-fluorophenyl)-7-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0430]

[0431] 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), methylamine (33% in MeOH, 0.134 mL, 1.074 mmol), and Et 3 N (0.345 mL, 2.48 mmol). The resulting yellow solution was heated to 65 °C and stirred for 4 h. The mixture was then concentrated, diluted with EtOAc, and washed with saturated (aq) NH 4 Cl (3 x 20 mL). The combined organic layers were dried over MgSO 4 4, 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 1H NMR (400 MHz, DMSO-d 6 6), δ ppm 2.73 (d, J = 4.55 Hz, 3H), 7.22 (br s, 1H), 7.34 (d, J = 7.07 Hz, 1H), 7.44 (dd, J = 8.84, 2.78 Hz, 1H), 7.52 - 7.70 (m, 3H), 9.01 - 9.24 (m, 1H); ESI-MS m / z [M+H] + 358.0; mp 241 - 243 °C.

[0432] Example 4: 5-(2-Chloro-3-fluorophenyl)-7-fluoro-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0433]

[0434] 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) in EtOH (3 mL), 2-methoxyethylamine (26.9 mg, 0.358 mmol), and Et 3N(0.115 mL, 0.826 mmol) was used to prepare the title compound, which was isolated as a yellow film (19 mg, 17%); ESI-MS m / z [M+H] + 402.2.

[0435] Example 5: 5-(2-Chloro-3-fluorophenyl)-7-fluoro-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0436]

[0437] In a manner similar to Example 3, 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-ylmethanamine hydrochloride (53.9 mg, 0.358 mmol) and Et 3 N (0.115 mL, 0.826 mmol) were used to prepare the title compound, which was isolated as a yellow film (15 mg, 12%). 1 1H NMR (400 MHz, CD 3 3OD) δ ppm 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-MS m / z [M+H] + 441.2.

[0438] Example 6: 5-(2-Chloro-3-fluorophenyl)-3-(ethylamino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0439]

[0440] In a manner similar to Example 3, 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 Et 3 N (0.115 mL, 0.826 mmol) were used to prepare the title compound, which was isolated as a brown oil (10 mg, 10%); ESI-MS m / z [M+H] + 371.9.

[0441] Example 7: 5-(2-Chloro-3-fluorophenyl)-3-((cyclopropylmethyl)amino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0442]

[0443] In a manner similar to Example 3, 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 Et 3 N (0.115 mL, 0.826 mmol) in EtOH (3 mL) were used to prepare the title compound, which was isolated as a yellow oil (25 mg, 23%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 0.23 (q, J = 4.55 Hz, 2H), 0.46 - 0.56 (m, 2H), 0.94 - 1.08 (m, 1H), 3.16 (d, J = 7.33 Hz, 2H), 7.23 - 7.32 (m, 2H), 7.42 - 7.49 (m, 1H), 7.50 - 7.58 (m, 1H), 7.61 (dd, J = 7.07, 3.03 Hz, 1H), 7.87 (s, 1H); ESI-MS m / z [M+H] + 398.1.

[0444] 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

[0445]

[0446] In a manner similar to Example 3, 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)ethylamine hydrochloride (58.9 mg, 0.358 mmol) and Et 3 N (0.115 mL, 0.826 mmol) in EtOH (3 mL) were used to prepare the title compound, which was isolated as a brown film (8.0 mg, 6%). 1 H NMR (400 MHz, CD 3OD) δ ppm 1.61 (t, J = 6.69 Hz, 3H), 5.40 (m, 1H), 7.17 - 7.37 (m, 2H), 7.41 - 7.60 (m, 3H), 7.63 (dd, J = 6.95, 2.91 Hz, 1H), 7.71 (br s, 1H); ESI-MS m / z [M+H] + 455.0。

[0447] 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

[0448]

[0449] In a manner similar to Example 3, 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 Et 3 N (0.115 mL, 0.826 mmol) in EtOH (3 mL) were used to prepare the title compound, which was isolated as a brown film (4 mg, 3%); ESI-MS m / z [M+H] + 454.9。

[0450] Example 10: 5-(2-Chloro-3-fluorophenyl)-3-((2,2-difluoroethyl)amino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0451]

[0452] In a manner similar to Example 3, 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-difluoroethanamine HCl (24.27 mg, 0.207 mmol) and Et 3 N (57.6 μL, 0.413 mmol) in EtOH (0.688 mL) were used to prepare the title compound, which was isolated as a light beige solid (19.1 mg, 34%). 1 1H NMR (400 MHz, DMSO-d 6), δ ppm 3.72 (d, J = 3.28 Hz, 2H), 5.98 - 6.33 (m, 1H), 7.36 - 7.43 (m, 1H), 7.52 (dd, J = 8.84, 2.78 Hz, 1H), 7.58 - 7.75 (m, 4H), 9.30 (s, 1H); ESI-MS m / z [M + H] + 408.0。

[0453] Example 11: 5-(2-Chloro-3-fluorophenyl)-7-fluoro-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0454]

[0455] 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 (50 mg, 0.138 mmol), 2-fluoroethylamine HCl (20.56 mg, 0.207 mmol) and Et 3 N (57.6 μL, 0.413 mmol) in EtOH (0.688 mL), the title compound was prepared and isolated as a yellow film (10.8 mg, 20.6%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.50 - 3.61 (m, 2H), 4.47 - 4.63 (m, 2H), 7.37 - 7.41 (m, 1H), 7.50 (dd, J = 8.84, 3.03 Hz, 1H), 7.59 - 7.72 (m, 4H), 9.19 (s, 1H); ESI-MS m / z [M + H] + 390.0。

[0456] Example 12: 5-(2-Chloro-3-fluorophenyl)-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0457]

[0458] In N 2 Under nitrogen, 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 2(84.9 mg, 116 μmol) and NaHCO 3 (244 mg, 2.90 mmol). The reaction mixture was stirred at 110 °C for 2 h, 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) and then with brine (1 x 15 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The crude product was purified by preparative HPLC to give the title compound as a pale yellow solid (225 mg, 44.3%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 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-MS m / z [M + H] + 435.0.

[0459] Example 13: 5-(2-Chlorophenyl)-7-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0460]

[0461] In a manner similar to Example 3, the title compound was prepared 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 (2 M in THF, 10.0 mL, 20.0 mmol), except that the reaction mixture was heated to 80 °C for 1 h. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Phenomenex C18, 10 μm, ID 50 x 250 mm column) eluting with 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-d 6 ) δ ppm 9.07 (s, 1H), 7.74 - 7.27 (m, 7H), 2.73 (d, J = 4.6 Hz, 3H) ESI-MS m / z [M + H] + 340.1

[0462] Example 14: 5-(2-Chlorophenyl)-7-fluoro-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0463]

[0464] In a manner similar to Example 3, 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), 2-methoxyethylamine (34.81 mg, 0.463 mmol) and Et 3 N (115 μL, 0.826 mmol) in EtOH (3 mL) were used to prepare the title compound, which was isolated as a white solid (30.14 mg, 34%). 1 H NMR (400 MHz, CD 3 CN) δ ppm 2.96 - 3.70 (m, 7H), 6.24 (br s, 1H), 7.26 (dd, J = 2.4, 8.8 Hz, 1H), 7.40 - 7.69 (m, 7H), 8.02 (br s, 1H); ESI-MS m / z [M+H] + 384.0.

[0465] Example 15: 5-(2-Chlorophenyl)-3-(ethylamino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0466]

[0467] In a manner similar to Example 3, 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 Et 3 N (151 μL, 0.826 mmol) in EtOH (3 mL) were used to prepare the title compound, which was isolated as a white solid (17 mg, 20%). 1 H NMR (400 MHz, CD 3 CN) δ ppm 1.11 (t, J = 7.2 Hz, 3H), 3.28 (dd, J = 5.4, 7.2 Hz, 2H), 5.93 (br s, 1H), 7.22 (dd, J = 2.9, 8.8 Hz, 1H), 7.39 - 7.44 (m, 1H), 7.46 - 7.60 (m, 3H), 7.63 (dd, J = 1.3, 7.8 Hz, 1H), 7.84 (br s, 1H); ESI-MS m / z [M+H]+ 354.0。

[0468] Example 16: 5-(2-Chlorophenyl)-7-fluoro-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0469]

[0470] In a manner similar to Example 3, 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 Et 3 N (151 μL, 0.826 mmol) in EtOH (3 mL) were used to prepare the title compound, which was isolated as a white solid (24.87 mg, 14%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.61 (br s, 2H), 7.17 - 7.83 (m, 9H), 8.21–8.57 (m, 1H); ESI-MS m / z [M+H] + 435.0。

[0471] Example 17: 5-(2-Chloro-3-fluorophenyl)-3-((cyclobutylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0472]

[0473] In a manner similar to Example 1, 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 cyclobutylmethanamine HCl (16.91 mg, 0.139 mmol) in DMA (0.232 mL) were used to prepare the title compound, which was isolated as a brownish orange solid (22.8 mg, 50%). 1 1H NMR (400 MHz, DMSO-d 6) δ ppm 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, 1.26 Hz, 1H), 8.98 (s, 1H); ESI-MS m / z [M + H] + 394.0。

[0474] Example 18: 5-(2-Chloro-3-fluorophenyl)-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0475]

[0476] In a manner similar to Example 1, 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) were used to prepare the title compound, which was isolated as a pale yellow oil (24.5 mg, 63%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.84 (s, 3H), 4.46 (d, J = 5.81 Hz, 2H), 6.73 (d, J = 8.34 Hz, 1H), 6.92 (d, J = 7.33 Hz, 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, 7.33 Hz, 1H), 7.78 - 7.83 (m, 2H), 9.28 (s, 1H); ESI-MS m / z [M + H] + 447.0。

[0477] Example 19: 5-(2,3-Difluorophenyl)-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0478]

[0479] To a 2 mL conical microwave vial equipped with a stirring device 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 h and then purified by mass-triggered preparative-LC / MS (Waters C18, 5 μm, ID 30x75 mm column) with gradient elution using 35 - 60% aqueous ACN (acid mode). The fractions containing the product were collected, concentrated, and dried in vacuo to afford the title compound as a pale yellow solid (27.4 mg, 52%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.85 (s, 3H), 4.47 (d, J = 5.56 Hz, 2H), 6.73 (d, J = 8.08 Hz, 1H), 6.94 (d, J = 7.07 Hz, 1H), 7.31 - 7.36 (m, 1H), 7.38 - 7.47 (m, 2H), 7.54 (dd, J = 7.58, 1.26 Hz, 1H), 7.61 - 7.68 (m, 1H), 7.71 (dd, J = 8.08, 7.33 Hz, 1H), 7.81 - 7.87 (m, 2H), 9.46 (s, 1H); ESI-MS m / z [M+H] + 431.0。

[0480] Example 20: 3-(((5-(2,3-Difluorophenyl)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)-1-methylpyridin-2(1H)-one

[0481]

[0482] In a manner similar to Example 19, the title compound was prepared using 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 3-(aminomethyl)-1-methylpyridin-2(1H)-one (20.18 mg, 0.146 mmol) in DMA (243 μL) and isolated as a light yellow solid (1.2 mg, 2%). 1 H NMR (400 MHz, DMSO-d 6) δ ppm 3.47 (s, 3H), 4.20 (br s, 2H), 6.25 (t, J = 6.69 Hz, 1H), 7.31 (d, J = 7.07 Hz, 1H), 7.40 (dd, J = 15.41, 7.07 Hz, 3H), 7.51 (d, J = 6.32 Hz, 1H), 7.64 (d, J = 9.35 Hz, 1H), 7.70 (d, J = 6.82 Hz, 1H), 7.81 (d, J = 6.82 Hz, 2H), 9.32 (s, 1H); ESI-MS m / z [M+H] + 431.1。

[0483] Example 21: 5-(2,3-Difluorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0484]

[0485] In a manner similar to Example 19, the title compound was prepared using 3-chloro-5-(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) in DMA (365 μL) and isolated as a tan solid (25 mg, 39%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 3.47 - 3.54 (m, 1H), 3.58 (d, J = 2.02 Hz, 1H), 4.48 (s, 1H), 4.60 (s, 1H), 7.27 - 7.33 (m, 1H), 7.39 (d, J = 7.83 Hz, 2H), 7.51 (d, J = 1.52 Hz, 1H), 7.60 - 7.69 (m, 2H), 7.79 - 7.84 (m, 1H), 9.26 (s, 1H).

[0486] Example 22: 3-((Cyclobutylmethyl)amino)-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0487]

[0488] In a manner similar to Example 19, the title compound was prepared using 3-chloro-5-(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 cyclobutylmethanamine HCl (28.9 mg, 0.237 mmol) in DMA (365 μL) and isolated as a tan solid (14.2 mg, 20.6%). 1 H NMR(400MHz,CD 3 OD)δ ppm 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).

[0489] Example 23: 5-(2,3-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0490]

[0491] In a manner similar to Example 19, the title compound was prepared using 3-chloro-5-(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) in DMA (365 μL) and isolated as an orange-brown oil (25.7 mg, 36.9%). 1 HNMR(400MHz,CD 3 OD)δ ppm 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).

[0492] Example 24: (R)-5-(2,3-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0493] and

[0494] Example 25: (S)-5-(2,3-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0495]

[0496] Using SFC / UV, a PIC system (Chiral Technology AS-H column, 5 μm, ID 20x150 mm, flow rate 75 mL / min), eluting with 25% MeOH, the racemate prepared in Example 23 was resolved by chiral chromatography. The first eluting peak was arbitrarily assigned the R-stereochemistry (Example 24), and the second eluting peak was assigned the S-stereochemistry (Example 25). Each title compound was isolated as a white solid (7 mg).

[0497] Example 26: 5-(2,3-Difluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0498]

[0499] In a manner similar to Example 19, the title compound was prepared using 3-chloro-5-(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 MeOH solution, 0.119 mL, 0.237 mmol) in DMA (365 μL), and isolated as a tan solid (13 mg, 22%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 2.75 (d, J = 4.80 Hz, 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).

[0500] Example 27: 5-(2,3-Difluorophenyl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0501]

[0502] The title compound was prepared in a manner similar to Example 19 using 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 oxazol-2-ylmethanamine (14.3 mg, 0.146 mmol) in DMA (243 μL) and isolated as a colorless oil (5 mg, 10%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.61 (d, J = 4.55 Hz, 2H), 7.20 (d, J = 1.01 Hz, 1H), 7.33 (t, J = 6.82 Hz, 1H), 7.42 (d, J = 7.58 Hz, 2H), 7.55 (dd, J = 7.58, 1.26 Hz, 1H), 7.61 - 7.69 (m, 1H), 7.84 (dd, J = 7.96, 1.14 Hz, 1H), 7.95 (t, J = 5.68 Hz, 1H), 8.12 (d, J = 0.76 Hz, 1H), 9.49 (s, 1H); ESI-MS m / z [M+H] + 391.1。

[0503] Example 28: 5-(2-Chloro-3-fluorophenyl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0504]

[0505] 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 (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 (400 MHz, DMSO-d 6) δ ppm 3.98 (s, 1H), 4.60 (dd, J = 5.68, 1.89 Hz, 2H), 7.20 (d, J = 0.76 Hz, 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, 1.14 Hz, 1H), 7.89 (t, J = 5.56 Hz, 1H), 8.11 (d, J = 0.76 Hz, 1H), 9.31 (s, 1H); ESI-MS m / z [M + H] + 407.0。

[0506] Example 29: 5-(2-Chloro-3-fluorophenyl)-3-((cyclopropylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0507]

[0508] The title compound was prepared in a similar manner 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 brownish orange solid (13.6 mg, 31%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 0.22 (d, J = 3.79 Hz, 2H), 0.46 (dd, J = 7.96, 1.64 Hz, 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, 1.39 Hz, 1H), 9.00 (s, 1H); ESI-MS m / z [M + H] + 380.0。

[0509] Example 30: 5-(2-Chloro-3-fluorophenyl)-3-(((4-methyloxazol-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0510]

[0511] In a manner similar to Example 1, the title compound was prepared 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 pale yellow solid (33.7 mg, 46%). 1 H NMR(400MHz,DMSO-d 6 ) δ ppm 2.07 (d, J = 1.26 Hz, 3H), 4.54 (dd, J = 5.43, 2.40 Hz, 2H), 7.34 - 7.37 (m, 1H), 7.38 - 7.42 (m, 1H), 7.45 - 7.49 (m, 1H), 7.58 - 7.66 (m, 2H), 7.78 - 7.89 (m, 3H), 9.30 (s, 1H); ESI-MS m / z [M+H] + 421.0。

[0512] Example 31: 5-(2-Chloro-3-fluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0513]

[0514] In a manner similar to Example 1, the title compound was prepared 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 pale green solid (30.4 mg, 63%). 1 HNMR(400MHz,DMSO-d 6 ) δ ppm 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, 1.26 Hz, 1H), 7.90 (t, J = 7.07 Hz, 1H), 7.98 (brs, 1H), 8.60 (d, J = 4.55 Hz, 1H), 9.41 (s, 1H); ESI-MS m / z [M+H] + 417.0。

[0515] Example 32: 5-(2-Chloro-3,5-difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0516]

[0517] In a manner similar to Example 1, the title compound was prepared 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 transparent film (7.1 mg, 11%). 1 HNMR(400MHz,CD 3 OD)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-MS m / z[M+H] + 402.0。

[0518] Example 33: 5-(2-Chloro-3-fluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0519]

[0520] In a manner similar to Example 1, the title compound was prepared 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-d 6) δ ppm 1.06 (dd, J = 6.06, 3.28 Hz, 3H), 3.14 - 3.22 (m, 1H), 3.24 (d, J = 3.28 Hz, 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, 1.26 Hz, 1H), 9.09 (d, J = 2.27 Hz, 1H); ESI-MS m / z [M + H] + 398.0。

[0521] Example 34: 5-(2-Chloro-3-fluorophenyl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0522]

[0523] In a manner similar to Example 1, the title compound was prepared 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 brownish orange solid (13.5 mg, 30%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 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, 1.14 Hz, 1H), 9.19 (s, 1H); ESI-MS m / z [M + H] + 390.0。

[0524] Example 35: 5-(2-Chlorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0525]

[0526] A 10 mL microwave vial equipped for stirring was charged with 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), Cs 2 CO3 (2M, 0.210 mL, 0.420 mmol) and dioxane (0.525 mL). To the mixture was added Pd(dppf) 2 ·CH 2 Cl 2 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 30x75 mm column) eluting with a gradient of 25 - 90% aqueous ACN (acid mode). The fractions containing the product were collected, concentrated and dried in vacuo to give the title compound as a tan solid (2 mg, 5%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 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-MS m / z [M+H] + 366.0.

[0527] Example 36: 5-(3-Chloro-2-fluoropyridin-4-yl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0528]

[0529] In a similar manner 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 ·CH 2 Cl 2 adduct (12.85 mg, 0.016 mmol) in dioxane (525 μL) the title compound was prepared and isolated as a white solid (49.7 mg, 82%). 1 1H NMR (400 MHz, DMSO-d 6) δ ppm 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 = 4.80 Hz, 1H), 7.86 (d, J = 7.83 Hz, 1H), 8.40 (d, J = 5.05 Hz, 1H), 9.20 (s, 1H); ESI-MS m / z [M + H] + 385.0。

[0530] Example 37: 5-(2,3-Difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0531]

[0532] In a manner similar 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) in dioxane (525 μL), (2,3-difluorophenyl)boronic acid (22 mg, 0.136 mmol), Cs 2 CO 3 (2M, 0.210 mL, 0.420 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (8.57 mg, 10.49 μmol), the title compound was prepared and isolated as a tan solid (19 mg, 49%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 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-MS m / z [M + H] + 368.0。

[0533] Example 38: 5-(2-Chloro-3-fluorophenyl)-3-(((5-methyl-oxazol-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0534]

[0535] In a manner similar to Example 1, the title compound was prepared 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-methyl-oxazol-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-d 6 )δ ppm 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-MS m / z[M+H] + 421.0。

[0536] Example 39: 5-(2-Chloro-3-fluorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0537]

[0538] In a manner similar to Example 1, the title compound was prepared 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-d 6 )δ ppm 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-MS m / z[M+H] + 354.1。

[0539] Example 40: 5-(2-Chlorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0540]

[0541] 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 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 25 - 90% gradient of aqueous ACN (acid mode). The fractions containing the product were collected, concentrated, and dried in vacuo to give the title compound as a brown solid (16 mg, 20% yield). ESI-MS m / z [M+H] + 380.0.

[0542] Example 41: 5-(2-Chlorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0543]

[0544] The title compound was prepared in a similar manner 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 H NMR (400 MHz, CD 3 OD) δ ppm 1.10 (t, J = 7.20 Hz, 3H), 3.22 (dd, J = 7.33, 5.31 Hz, 2H), 7.31 - 7.55 (m, 6H), 7.78 (dd, J = 7.83, 1.01 Hz, 1H), 9.12 (s, 1H); ESI-MS m / z [M+H] + 399.8.

[0545] Example 42: 5-(2-Chlorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0546]

[0547] In a manner similar to Example 40, the title compound was prepared 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 (400 MHz, DMSO-d 6 ) δ ppm 1.10 (t, J = 7.33 Hz, 3H), 3.18 - 3.24 (m, 2H), 7.30 - 7.43 (m, 3H), 7.44 - 7.49 (m, 1H), 7.50 - 7.63 (m, 2H), 7.70 (dd, J = 7.96, 1.14 Hz, 1H), 7.77 (dd, J = 7.45, 1.89 Hz, 1H), 8.93 (br s, 1H); ESI-MS m / z [M+H] + 336.0。

[0548] Example 43: 5-(2-Chlorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0549]

[0550] In a manner similar to Example 40, the title compound was prepared 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 (400 MHz, DMSO-d 6) δ ppm 2.73 (d, J = 4.80 Hz, 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, 1.26 Hz, 1H), 7.75 (dd, J = 7.45, 1.89 Hz, 1H), 9.00 (br s, 1H); ESI-MS m / z [M + H] + 322.0。

[0551] Example 44: 5-(2-Chlorophenyl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0552]

[0553] In a manner similar to Example 40, the title compound was prepared 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 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 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-MS m / z [M + H] + 372.0。

[0554] Example 45: 5-(2-Chlorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0555]

[0556] In a manner similar to Example 40, the title compound was prepared 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 brownish orange solid (26.8 mg, 41%). 1 H NMR(400MHz,DMSO-d 6 )δ ppm 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-MS m / z[M+H] + 354.0。

[0557] Example 46: 3-(((5-(2-chloro-3-fluorophenyl)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)-1-methylpyridin-2(1H)-one

[0558]

[0559] In a manner similar to Example 1, the title compound was prepared 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-d 6 )δ ppm 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-MS m / z[M+H] + 447.0。

[0560] Example 47: (R)-5-(2-Chloro-3-fluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0561]

[0562] 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 (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%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.14 (br s, 3H), 3.50 (d, J = 16.67 Hz, 3H), 7.25 (br s, 1H), 7.36 - 7.55 (m, 4H), 7.88 (d, J = 8.08 Hz, 1H); ESI-MS m / z [M+H] + 398.0.

[0563] Example 48: 5-(3-Chloro-2-fluoropyridin-4-yl)-3-((oxazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0564]

[0565] To a 2 mL scintillation vial equipped with a stirring device 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 filtered through a 12 mL sintered syringe containing a 0.5 inch pad. The syringe was rinsed with methanol and purified by mass-triggered preparative LC / MS( Purify the filtrate using an XSelect CSH Prep C18, 5 μm, ID 30 x 75 mm column, and elute with a gradient of 20 - 50% ACN aqueous solution (acid mode). Collect the fractions, concentrate, and dry under vacuum to obtain the title compound as a brown - orange film (6.5 mg, 14%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 4.69 (br s, 2H), 7.29 (br s, 1H), 7.47 - 7.59 (m, 3H), 7.98 (d, J = 6.57 Hz, 2H), 8.35 (d, J = 4.80 Hz, 1H); ESI - MS m / z [M + H] + 408.0。

[0566] Example 49: 5 - (3 - chloro - 2 - fluoropyridin - 4 - yl) - 3 - ((thiazol - 2 - ylmethyl)amino) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0567]

[0568] In a manner similar to Example 48, prepare the title compound 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 - ylmethylamine HCl (15.66 mg, 0.104 mmol) dissolved in DMA (433 μL), and isolate as a transparent film (1.46 mg, 4%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 4.84 (s, 2H), 7.42 - 7.53 (m, 3H), 7.54 (d, J = 3.28 Hz, 1H), 7.72 (br s, 1H), 7.95 (dd, J = 7.71, 1.64 Hz, 1H), 8.30 (d, J = 4.80 Hz, 1H); ESI - MS m / z [M + H] + 424.0。

[0569] Example 50: 5 - (3 - chloro - 2 - fluoropyridin - 4 - yl) - 3 - ((cyclopropylmethyl)amino) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0570]

[0571] In a manner similar to Example 48, the title compound was prepared 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 cyclopropylmethanamine (9.86 mg, 0.139 mmol) dissolved in DMA (385 μL), and isolated as a brownish orange solid (6.4 mg, 15%). 1 H NMR(400MHz,DMSO-d 6 )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-MS m / z[M+H] + 381.0。

[0572] 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

[0573]

[0574] In a manner similar to Example 48, the title compound was prepared 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,CD 3 OD)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。

[0575] Example 52: 5-(3-Chloro-2-fluoropyridin-4-yl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0576]

[0577] In a manner similar to Example 48, 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol) dissolved in EtOH (500 μL), Et 3 N (24.16 μL, 0.231 mmol), and ethylamine (70% in water, 7.01 μL, 0.087 mmol) were used to prepare the title compound, which was isolated as a clear film (3.3 mg, 11%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.17 (t, J = 7.20 Hz, 3H), 3.33 - 3.38 (m, 2H), 7.38 - 7.51 (m, 3H), 7.93 (dd, J = 7.71, 1.64 Hz, 1H), 8.29 (d, J = 5.05 Hz, 1H); ESI-MS m / z [M+H] + 355.0.

[0578] Example 53: 5-(3-Chloro-2-fluoropyridin-4-yl)-3-((2,2-difluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0579]

[0580] In a manner similar to Example 48, 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol) dissolved in EtOH (500 μL), Et 3 N (32.2 μL, 0.231 mmol), and 2,2-difluoroethylamine HCl (16.30 mg, 0.139 mmol) were used to prepare the title compound, which was isolated as a clear film (6.9 mg, 15%). 1 H NMR (400 MHz, CD 3OD) δ ppm 3.69 - 3.78 (m, 2H), 5.85 - 6.18 (m, 1H), 7.41 (d, J = 5.05 Hz, 1H), 7.44 - 7.53 (m, 2H), 7.95 (dd, J = 7.58, 1.77 Hz, 1H), 8.30 (d, J = 5.05 Hz, 1H); ESI-MS m / z [M + H] + 391.1。

[0581] Example 54: 5-(3-Chloro-2-fluoropyridin-4-yl)-3-((4-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0582]

[0583] In a manner similar to Example 48, 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol) dissolved in EtOH (500 μL), Et 3 N (32.2 μL, 0.231 mmol) and (4-fluorophenyl)methanamine (17.35 mg, 0.139 mmol) were used to prepare the title compound, which was isolated as an orange solid (12.5 mg, 25%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.39 - 4.48 (m, 2H), 7.17 - 7.23 (m, 2H), 7.38 (dd, J = 8.59, 5.56 Hz, 2H), 7.41 - 7.46 (m, 1H), 7.51 - 7.55 (m, 2H), 7.58 (d, J = 4.80 Hz, 1H), 7.87 (dd, J = 7.71, 1.14 Hz, 1H), 8.38 (d, J = 4.80 Hz, 1H), 9.27 (s, 1H); ESI-MS m / z [M + H] + 435.3。

[0584] Example 55: 2-(((5-(3-Chloro-2-fluoropyridin-4-yl)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)methyl)thiazole-5-carbonitrile

[0585]

[0586] In a manner similar to Example 48, 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol) dissolved in EtOH (500 μL), Et 3 N (32.2 μL, 0.231 mmol) and 2-(aminomethyl)thiazole-5-carbonitrile HCl (24.35 mg, 0.139 mmol) were used to prepare the title compound, which was isolated as a yellow solid (16.1 mg, 31%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.85 (br s, 2H), 7.47 (d, J = 7.58 Hz, 1H), 7.55 - 7.66 (m, 2H), 7.89 (d, J = 7.83 Hz, 2H), 8.40 (d, J = 4.80 Hz, 1H), 8.63 (s, 1H), 9.73 (br s, 1H); ESI-MS m / z [M+H] + 449.3.

[0587] Example 56: 5-(3-chloro-2-fluoropyridin-4-yl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0588]

[0589] In a manner similar to Example 48, 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) dissolved in EtOH (479 μL), Et 3 N (23.25 μL, 0.167 mmol) and methylamine (33% in EtOH) (10.38 μL, 0.083 mmol) were used to prepare the title compound, which was isolated as a pale beige film (2.2 mg, 12%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 2.92 (s, 3H), 7.45 - 7.50 (m, 2H), 7.52 - 7.55 (m, 1H), 7.98 (d, J = 7.58 Hz, 1H), 8.34 (d, J = 4.80 Hz, 1H); ESI-MS m / z [M+H] + 341.0.

[0590] Example 57: 5-(2-Chloro-3-fluorophenyl)-3-(((4-methylmorpholin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0591]

[0592] 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 (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 (400 MHz, DMSO-d 6 ) δ ppm 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 = 10.61 Hz, 1H), 7.32 - 7.36 (m, 1H), 7.38 - 7.42 (m, 1H), 7.45 - 7.48 (m, 1H), 7.56 - 7.68 (m, 3H), 7.82 (d, J = 7.83 Hz, 1H), 9.19 (s, 1H); ESI-MS m / z [M+H] + 439.0。

[0593] Example 58: 5-(2-Chloro-3-fluorophenyl)-3-((2-ethoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0594]

[0595] 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 (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 (400 MHz, DMSO-d 6)δ ppm 1.06 - 1.14 (m, 6H), 3.18 - 3.26 (m, 1H), 3.43 (dt, J = 6.76, 3.32 Hz, 1H), 3.51 (ddd, J = 9.85, 6.82, 3.28 Hz, 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, 1.39 Hz, 1H), 9.12 (d, J = 4.04 Hz, 1H); ESI-MS m / z [M + H] + 412.0。

[0596] 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

[0597]

[0598] Charge 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)methylamine (35.8 mg, 0.251 mmol), DIPEA (67.4 μL, 0.386 mmol) and DMA (386 μL) into a 5 mL microwave vial equipped for stirring. Heat the reaction mixture at 70 °C for 21 h, then dilute in MeOH and filter through a 12 mL sintered syringe containing a 0.5 inch pad. Purify the product by column chromatography and dry on a Biotage Turbo II (water bath set at 60 °C) to give the title compound as a pale yellow solid (17.9 mg, 22%). 1 H NMR (400 MHz, DMSO - d 6 )δ ppm 2.07 (s, 3H), 3.87 (s, 3H), 4.57 (d, J = 5.31 Hz, 2H), 7.26 - 7.34 (m, 1H), 7.40 (dd, J = 7.58, 1.52 Hz, 1H), 7.47 (d, J = 8.84 Hz, 1H), 7.67 (dd, J = 7.83, 1.26 Hz, 1H), 7.86 (s, 1H), 7.96 (dd, J = 8.59, 2.53 Hz, 1H), 8.22 (t, J = 5.43 Hz, 1H), 8.62 (d, J = 2.02 Hz, 1H), 9.44 (s, 1H); ESI-MS m / z [M + H] + 417.0。

[0599] Example 60: 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0600]

[0601] Charge a 5 mL microwave vial equipped for stirring with 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). Heat the reaction mixture at 70 °C for 15 h, then dilute in MeOH and filter through a 12 mL sintered syringe containing a 0.5 inch pad. The product was purified 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). Fractions containing the product were collected, concentrated and dried in vacuo to afford the title compound as an orange-yellow solid (17.9 mg, 26%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.09 (d, J = 6.06 Hz, 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, 1.52 Hz, 1H), 7.64 - 7.71 (m, 2H), 7.85 (s, 1H), 9.23 (s, 1H); ESI-MS m / z [M+H] + 364.0。

[0602] Example 61: 3-((Cyclobutylmethyl)amino)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0603]

[0604] In a manner similar to Example 60, the title compound was prepared using 3-chloro-5-(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) in DMA (322 μL) and isolated as a colorless oil (34 mg, 56%). 1 HNMR(400MHz,CD 3 OD)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).

[0605] Example 62: 2-((5-(2-chloro-3-fluorophenyl)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)amino)-N,N-dimethylacetamide

[0606]

[0607] In a manner similar to Example 1, the title compound was prepared 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-d 6 )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-MS m / z[M+H] + 411.0.

[0608] Example 63: 5-(2-Cyclopropylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0609]

[0610] Prepared in a manner similar 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), Cs 2 CO 3 (2M, 197 μL, 0.394 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (12.85 mg, 0.016 mmol) in dioxane (787 μL) to prepare the title compound, which was isolated as a pale yellow solid (21.2 mg, 36.3%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 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 = 7.58 Hz, 1H), 7.22 (dd, J = 7.45, 1.14 Hz, 1H), 7.32 - 7.37 (m, 2H), 7.39 - 7.47 (m, 2H), 7.68 - 7.76 (m, 2H), 8.93 (s, 1H); ESI-MS m / z [M+H] + 372.0.

[0611] Example 64: 5-(2-Chloro-3-fluorophenyl)-3-((isothiazol-3-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0612]

[0613] 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), Et 3 N (30 μL, 0.217 mmol) and isothiazol-3-ylmethanamine (10.75 mg, 0.094 mmol) in EtOH (2 mL) to prepare the title compound, which was isolated as a white solid (2 mg, 7%). 11H NMR (400 MHz, DMSO-d 6 ) δ ppm 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 = 4.55 Hz, 1H), 9.29 (s, 1H); ESI-MS m / z [M+H] + 423.0。

[0614] Example 65: 5-(2-Chloro-3-fluorophenyl)-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0615]

[0616] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (75.0 mg, 0.217 mmol) in EtOH (3.0 mL), Et 3 N (91 μL, 0.652 mmol) and thiazol-2-ylmethanamine hydrochloride (120 mg, 0.796 mmol) were used to prepare the title compound, which was isolated as a white solid (115 mg, 46%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.32 (br s, 1H), 8.00 (br s, 1H), 7.85 - 7.79 (m, 1H), 7.76 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.48 - 7.43 (m, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 4.75 (d, J = 6.0 Hz, 2H); ESI-MS m / z [M+H] + 423.0。

[0617] Example 66: 5-(2-Chloro-3-fluorophenyl)-3-((pyrimidin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0618]

[0619] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and pyrimidin-2-ylmethanamine (15.8 mg, 0.109 mmol) were used to prepare the title compound, which was isolated as a yellow oil (12 mg, 40%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.66 (br s, 2H), 7.30 - 7.49 (m, 4H), 7.55 - 7.68 (m, 2H), 7.79 (dd, J = 7.96, 1.39 Hz, 1H), 8.01 (s, 1H), 8.81 (d, J = 4.80 Hz, 2H), 9.47 (s, 1H); ESI-MS m / z [M+H] + 418.0.

[0620] Example 67: 5-(2-Chloro-3-fluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0621]

[0622] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol) in EtOH (2 mL), Et 3 N (61 μL, 0.435 mmol) and 2-(pyridin-2-yl)ethanamine (26.5 mg, 0.217 mmol) were used to prepare the TFA salt of the title compound, which was isolated as an off-white solid (30 mg, 48%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 (t, J = 6.69 Hz, 2H), 3.60 - 3.69 (t, J = 6.69 Hz, 2H), 7.26 - 7.48 (m, 4H), 7.49 - 7.66 (m, 4H), 7.78 (dd, J = 7.71, 1.39 Hz, 1H), 8.07 (br s, 1H), 8.66 (d, J = 4.55 Hz, 1H), 9.08 (s, 1H); ESI-MS m / z [M+H] + 431.1.

[0623] Example 68: 5-(2-Chloro-3-fluorophenyl)-3-((2-(pyridin-4-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0624]

[0625] 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) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 2-(pyridin-4-yl)ethylamine (13.3 mg, 0.109 mmol) to prepare the title compound, which was isolated as a white solid (9 mg, 29%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 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, 1.26 Hz, 1H), 8.69 (d, J = 6.32 Hz, 2H), 9.07 (s, 1H); ESI-MS m / z [M+H] + 431.1.

[0626] Example 69: 5-(2-Chloro-3-fluorophenyl)-3-((2-(pyridin-3-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0627]

[0628] 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) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 2-(pyridin-3-yl)ethylamine (13 mg, 0.109 mmol) to prepare the title compound, which was isolated as a white solid (10 mg, 32%); ESI-MS m / z [M+H] + 431.1.

[0629] Example 70: 5-(2-Chloro-3-fluorophenyl)-3-((3-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0630]

[0631] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 2-(3-methoxyphenyl)ethylamine (16.4 mg, 0.109 mmol) were used to prepare the title compound, which was isolated as a white solid (5 mg, 14%); ESI-MS m / z [M+H] + 460.1.

[0632] Example 71: 5-(2-Chloro-3-fluorophenyl)-3-((2-methoxybenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0633]

[0634] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 2-(2-methoxyphenyl)ethylamine (16.4 mg, 0.109 mmol) were used to prepare the title compound, which was isolated as a white solid (4 mg, 12%); ESI-MS m / z [M+H] + 460.1.

[0635] Example 72: 5-(2-Chloro-3-fluorophenyl)-3-((4-methoxybenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0636]

[0637] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 2-(4-methoxyphenyl)ethylamine (16.4 mg, 0.109 mmol) were used to prepare the title compound, which was isolated as a white solid (3.0 mg, 9%); ESI-MS m / z [M+H] + 460.1.

[0638] Example 73: 5-(2-Chloro-3-fluorophenyl)-3-((2-(tetrahydrofuran-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0639]

[0640] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 2-(tetrahydrofuran-2-yl)ethylamine (12.5 mg, 0.109 mmol) were used to prepare the title compound, which was isolated as a brown film (2.0 mg, 7%); ESI-MS m / z [M+H] + 424.1.

[0641] 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

[0642]

[0643] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol) in EtOH (2 mL), Et 3 N (30 μL, 0.217 mmol) and 1-isopropyl-5-methyl-1H-pyrazol-3-amine (15 mg, 0.109 mmol) were used to prepare the title compound, which was isolated as a white solid (1 mg, 3%); ESI-MS m / z [M+H] + 448.1.

[0644] Example 75: 5-(3,5-Difluorophenyl)-3-((4-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0645]

[0646] An 8 mL vial was charged with 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.076 mmol), (4-fluorophenyl)methanamine (19.03 mg, 0.152 mmol), Et 3N (0.032 mL, 0.228 mmol) and EtOH (2 mL). The reaction mixture was heated to 65 °C and stirred overnight. LC / MS indicated completion of the reaction. The solvent was removed, and the product was taken up in DMF (1 mL), filtered, and purified by supercritical fluid chromatography. Evaporation of the purified fractions on Turbo gave the title compound as a white solid (6.7 mg, 21%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.42 (d, J = 5.56 Hz, 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, 1.52 Hz, 1H), 7.77 (dd, J = 7.83, 1.01 Hz, 1H), 7.84 (t, J = 5.56 Hz, 1H), 9.19 (s, 1H); ESI-MS m / z [M+H] + 418.1.

[0647] Example 76: 3-((2,5-Difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0648]

[0649] In a manner similar to Example 75, using 3-chloro-5-(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 Et 3 N (0.032 mL, 0.228 mmol) in EtOH (2 mL), the title compound was prepared and isolated as a white solid (2.7 mg, 8%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.47 (d, J = 5.31 Hz, 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 (dd, J = 7.58, 1.52 Hz, 1H), 7.77 (dd, J = 7.83, 1.01 Hz, 1H), 7.89 (t, J = 5.68 Hz, 1H), 9.29 (s, 1H); ESI-MS m / z [M+H] + 436.0.

[0650] Example 77: 5-(3,5-Difluorophenyl)-3-((2-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0651]

[0652] In a manner similar to Example 75, 3-chloro-5-(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 Et 3 N (0.032 mL, 0.228 mmol) in EtOH (2 mL) were used to prepare the title compound, which was isolated as a white solid (3.5 mg, 11%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.47 (d, J = 5.31 Hz, 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, 1.39 Hz, 1H), 7.77 (d, J = 6.82 Hz, 1H), 7.83 - 7.91 (m, 1H), 9.19 (s, 1H); ESI-MS m / z [M+H] + 418.1.

[0653] Example 78: 3-((2,6-Difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0654]

[0655] In a manner similar to Example 75, 3-chloro-5-(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 Et 3 N (0.032 mL, 0.228 mmol) in EtOH (2 mL) were used to prepare the title compound, which was isolated as a white solid (2 mg, 6%). ESI-MS m / z [M+H] + 436.0.

[0656] Example 79: 5-(3,5-Difluorophenyl)-3-(((6-methylpyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0657]

[0658] In a manner similar to Example 75, 3-chloro-5-(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 Et 3 N (0.032 mL, 0.228 mmol) in EtOH (2 mL) were used to prepare the title compound, which was isolated as a white solid (10 mg, 32%). ESI-MS m / z [M+H] + 415.0.

[0659] Example 80: 5-(3,5-Difluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0660]

[0661] In a manner similar to Example 75, 3-chloro-5-(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 Et 3 N (0.095 mL, 0.684 mmol) in EtOH (3 mL) were used to prepare the TFA salt of the title compound, which was isolated as an orange oil (21 mg, 23%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.07 (t, J = 6.82 Hz, 2H), 3.59 - 3.70 (m, 2H), 7.24 (d, J = 6.06 Hz, 2H), 7.30 - 7.37 (m, 1H), 7.41 (t, J = 9.60 Hz, 1H), 7.44 - 7.65 (m, 4H), 7.75 (dd, J = 7.83, 1.26 Hz, 1H), 8.00 (br s, 1H), 8.62 (br s, 1H), 9.18 (s, 1H); ESI-MS m / z [M+H] + 415.5.

[0662] Example 81: 3-((Cyclobutylmethyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0663]

[0664] In a manner similar to Example 75, 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 Et 3 N (0.0636 mL, 0.456 mmol) in EtOH (3.5 mL) were used to prepare the title compound, which was isolated as a white semi-solid (33.0 mg, 58%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.68 - 1.80 (m, 2H), 1.83 - 1.99 (m, 2H), 2.07 (d, J = 8.08 Hz, 2H), 2.53 (dt, J = 15.22, 7.67 Hz, 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 = 7.33 Hz, 1H), 7.83 (d, J = 7.58 Hz, 1H); ESI-MS m / z [M+H] + 378.1.

[0665] Example 82: 5-(3,5-Difluorophenyl)-3-((pyridin-4-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0666]

[0667] In a manner similar to Example 75, 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.076 mmol), pyridin-4-ylmethylamine (32.90 mg, 0.304 mmol), and Et 3 N (0.032 mL, 0.228 mmol) in EtOH (2.0 mL) were used to prepare the formate of the title compound, which was isolated as a yellow solid (23.92 mg, 35%). 1 H NMR (400 MHz, DMSO-d 4 ) δ ppm 4.48 (d, J = 5.2 Hz, 2H), 7.42 - 7.28 (m, 6H), 7.48 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 8.51 (d, J = 5.6 Hz, 2H); ESI-MS m / z [M+H] + 401.1.

[0668] Example 83: 5-(3,5-Difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0669]

[0670] In a manner similar to Example 75, the title compound was prepared 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 (400 MHz, CD 3 OD) δ ppm 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-MS m / z [M+H] + 401.0.

[0671] Example 84: 5-(3,5-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0672]

[0673] In a manner similar to Example 75, the title compound was prepared 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 (400 MHz, DMSO-d 6)δ ppm 1.10 (d, J = 6.32 Hz, 3H), 3.15 - 3.21 (m, 1H), 3.26 (s, 3H), 3.38 - 3.50 (m, 2H), 7.28 (d, J = 6.32 Hz, 2H), 7.33 - 7.37 (m, 1H), 7.42 - 7.49 (m, 2H), 7.59 (t, J = 5.05 Hz, 1H), 7.77 (dd, J = 7.71, 1.14 Hz, 1H), 9.22 (s, 1H); ESI-MS m / z [M + H] + 382.1。

[0674] Example 85: (R)-5-(3,5-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0675]

[0676] Using SFC / UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20x150 mm, flow rate 100 mL / min), eluting with 30% IPA, the racemate prepared in Example 84 was resolved by 2D separation. The title compound, eluting as the first peak and arbitrarily assigned the R-stereochemistry, was isolated as a white solid (15.4 mg, 27.5%). 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 1.10 (d, J = 6.32 Hz, 3H), 3.15 - 3.21 (m, 1H), 3.26 (s, 3H), 3.38 - 3.50 (m, 2H), 7.28 (d, J = 6.32 Hz, 2H), 7.33 - 7.37 (m, 1H), 7.42 - 7.49 (m, 2H), 7.59 (t, J = 5.05 Hz, 1H), 7.77 (dd, J = 7.71, 1.14 Hz, 1H), 9.22 (s, 1H); ESI-MS m / z [M + H] + 382.1。

[0677] Example 86: (S)-5-(3,5-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0678]

[0679] Using SFC / UV, a PIC system (Chiral Technology AS-H column, 5 μm, ID 20x150 mm, flow rate 100 mL / min), eluting with 30% IPA, the racemate prepared in Example 84 was resolved by 2D separation. The title compound, which was the second elution peak and was arbitrarily assigned the S-stereochemical configuration, was isolated as a white solid (21.2 mg, 37.8%). 1 H NMR(400MHz,DMSO-d 6 )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-MS m / z[M+H] + 382.1。

[0680] Example 87: 5-(3,5-Difluorophenyl)-3-((2-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0681]

[0682] In a manner similar to Example 75, the title compound was prepared 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 was isolated as a tan solid (12 mg, 20%). 1 H NMR(400MHz,CD 3 OD)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-MS m / z[M+H] + 396.0。

[0683] Example 88: 3-(Benzylamino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0684]

[0685] In a manner similar to Example 75, 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 Et 3 N (32.0 μL, 0.028 mmol) in EtOH (2.0 mL) were used to prepare the title compound, which was isolated as a white solid (32.00 mg, 54%). 1 1H NMR (400 MHz, CDCl 3 ) δ ppm 4.40 (d, J = 5.6 Hz, 2H), 6.06 (t, J = 5.6 Hz, 1H), 6.74 (d, J = 5.2 Hz, 2H), 6.82 (t, J = 8.8 Hz, 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 = 6.4 Hz, J = 3.2 Hz, 2H); ESI-MS m / z [M+H] + 400.0.

[0686] Example 89: 2-Fluoro-6-(3-(methylamino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0687]

[0688] To a 10 mL vial were 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) NaHCO 3 aqueous solution (2 mL) and PdCl 2 (dppf) (4.34 mg, 5.93 μmol). The reaction mixture was heated to 80 °C and stirred overnight. LC / MS indicated completion of the reaction. The solvent was boiled off under gentle heating. The crude product was taken up in MeOH, filtered using a 0.45 μPTFE syringe filter, and purified by preparative LC / MS (Waters Purified using a C18, 5 μm, ID 4 x 50 mm column and eluted with an aqueous ACN solution (acid mode) in a gradient. The 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

[0689] Example 90: 4-Chloro-2-(3-(methylamino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0690]

[0691] 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) in dioxane (2 mL), (5-chloro-2-cyanophenyl)boronic acid (14 mg, 0.077 mmol), saturated (aq) NaHCO 3 aqueous solution (2 mL) and PdCl 2 (dppf) (4.34 mg, 5.93 μmol) to prepare the TFA salt of the title compound, which was isolated as a white solid (1.0 mg, 5%). ESI-MS m / z [M+H] + 347.0

[0692] Example 91: 5-(2-Ethylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0693]

[0694] 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) in dioxane (2 mL), (2-ethylphenyl)boronic acid (12 mg, 0.077 mmol), saturated (aq) NaHCO 3 aqueous solution (2 mL) and PdCl 2 (dppf) (4.34 mg, 5.93 μmol) to prepare the TFA salt of the title compound, which was isolated as a white solid (1 mg, 5%). ESI-MS m / z [M+H] + 316.1

[0695] Example 92: 5-(2-Chloro-4-methylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0696]

[0697] In a manner similar to Example 89, 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol) in dioxane (2 mL), (2-chloro-4-methylphenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) NaHCO 3 aqueous solution (2 mL) and PdCl 2 (dppf) (4.34 mg, 5.93 μmol) were used to prepare the TFA salt of the title compound, which was isolated as a white solid (2 mg, 8%); ESI-MS m / z [M+H] + 336.0.

[0698] Example 93: 5-(2-Chloro-5-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0699]

[0700] In a manner similar to Example 89, 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol) in dioxane (2 mL), (2-chloro-5-fluorophenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) NaHCO 3 aqueous solution (2 mL) and PdCl 2 (dppf) (4.34 mg, 5.93 μmol) were used to prepare the TFA salt of the title compound, which was isolated as a white solid (1 mg, 5%); ESI-MS m / z [M+H] + 340.0.

[0701] Example 94: 5-(2-Chloro-4-fluorophenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0702]

[0703] In a manner similar to Example 89, 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol) in dioxane (2 mL), (2-chloro-4-fluorophenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) NaHCO 3 aqueous solution (2 mL) and PdCl2 (dppf) (4.34 mg, 5.93 μmol) was used to prepare the TFA salt of the title compound, which was isolated as a white solid (2 mg, 10%). ESI-MS m / z [M+H] + 340.0

[0704] Example 95: 5-(3-Fluoro-2-methylphenyl)-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0705]

[0706] In a manner similar to Example 89, 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) NaHCO 3 aqueous solution (2 mL), and PdCl 2 (dppf) (4.34 mg, 5.93 μmol) were used to prepare the TFA salt of the title compound, which was isolated as a white solid (1 mg, 5%). ESI-MS m / z [M+H] + 320.1

[0707] Example 96: 3-(methylamino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0708]

[0709] 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), followed by addition of Cs 2 CO 3 (2M, 890 μL, 1.780 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 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 and dried over MgSO 4Dry, filter, and concentrate. Dissolve the resulting brown oil in MeOH (2 mL), filter, and purify by preparative LC / MS (Waters C18, 5 μm, ID 30x75 mm column) with gradient elution using 30 - 50% aqueous ACN (acid mode). The title compound was isolated as a white solid (23.6 mg, 16%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.69 (d, J = 4.55 Hz, 3H), 7.14 (br s, 1H), 7.22 - 7.36 (m, 2H), 7.46 (dd, J = 7.58, 1.52 Hz, 1H), 7.64 - 7.81 (m, 2H), 9.24 (s, 1H); ESI-MS m / z [M+H] + 342.0。

[0710] Example 97: 5-(2-Chloro-3-fluorophenyl)-7-methyl-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0711]

[0712] 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), methylamine (2 M in MeOH, 0.122 mL, 0.245 mmol), and Et 3 N (0.051 mL, 0.367 mmol). The resulting yellow solution was heated to 65 °C and stirred for 16 h. The mixture was then concentrated and purified by preparative HPLC (Waters C18, 5 μm, ID 30x75 mm column) with gradient elution using ACN (0.1% TFA) / water (0.1% TFA) solution. The title compound was isolated as a white solid (26 mg, 60%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.36 (s, 3H), 2.73 (d, J = 4.55 Hz, 3H), 7.13 (d, J = 4.29 Hz, 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-MS m / z [M+H] + 354.5。

[0713] Example 98: 3-((4-Isopropylphenyl)amino)-5-(5-methyl-1H-pyrazol-3-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0714]

[0715] Charge an 8 mL vial 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) NaHCO 3 (1.5 mL), PdCl 2 (dppf) (2.073 mg, 2.83 μmol) and dioxane (1.5 mL). Heat the reaction mixture to 80 °C and stir overnight. LC / MS indicates completion of the reaction. Dilute the reaction mixture with EtOAc, separate the organic layer and introduce it into a 4 mL vial. Evaporate the solvent. Dilute the residue with MeOH, filter and purify to afford the title compound as a white solid (1.0 mg, 5%); ESI-MS m / z [M+H] + 396.5.

[0716] Example 99: 5-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0717]

[0718] Prepared in a manner similar 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 3 (1.5 mL) and PdCl 2 (dppf) (2.073 mg, 2.83 μmol) in dioxane (1.5 mL) to afford the title compound, isolated as a white solid (1.0 mg, 5%); ESI-MS m / z [M+H] + 432.0.

[0719] Example 100: 3-((4-Isopropylphenyl)amino)-5-(1H-pyrazol-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0720]

[0721] Charge a dried 8 mL vial with 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), K 2 CO 3 (15.66 mg, 0.113 mmol), copper(I) iodide (1.079 mg, 5.67 μmol) and DMF (2 mL). Degas the reaction mixture with N 2 then heat to 125 °C and stir for 18 h. Subsequently, dilute the reaction mixture with DMF (1 mL), filter through a 0.45 μm PTFE syringe filter, and purify by preparative HPLC (Phenomenex C18, 10 μm, ID 50x250 mm column) with a gradient elution of 40 - 55% aqueous ACN (acid mode). Combine the pure fractions and lyophilize to give the TFA salt of the title compound as a white solid (6 mg, 28%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.22 (d, J = 6.82 Hz, 6H), 2.91 (quin, J = 6.88 Hz, 1H), 6.54 (s, 1H), 6.70 (s, 1H), 7.25 - 7.42 (m, 4H), 7.45 (t, J = 8.08 Hz, 1H), 7.72 - 7.81 (m, 1H), 7.95 (d, J = 8.08 Hz, 1H), 8.55 (d, J = 2.53 Hz, 1H), 10.25 (s, 1H), 11.21 (br s, 1H); ESI-MS m / z [M+H] + 382.1。

[0722] 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

[0723]

[0724] To a stirred solution of 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-(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 PdCl 2 (dppf)·CH 2 Cl 2 adduct (7.40 mg, 9.06 μmol) and K 2 CO 3 (27.6 mg, 0.199 mmol). The reaction mixture was heated at 100 °C for 18 h, then washed with brine (2x) and extracted with EtOAc. The organic layers were combined, dried over MgSO 4 , concentrated, filtered, and purified by reverse-phase preparative LC / MS (Phenomenex C18, 5 μm, ID30x75 mm column) eluting with a gradient of 35 - 60% 10 mM NH 4 HCO 3 in water / ACN (20 / 80 v / v, containing 10 mM NH 4 HCO 3 )(aq) to give the title compound as a white solid (3.2 mg, 8%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 1.21 - 1.26 (m, 6H), 2.89 (spt, J = 6.82 Hz, 1H), 5.06 - 5.16 (m, 4H), 5.62 - 5.70 (m, 1H), 7.21 (d, J = 8.59 Hz, 2H), 7.35 (t, J = 7.71 Hz, 1H), 7.40 (d, J = 8.59 Hz, 2H), 7.52 - 7.55 (m, 1H), 7.78 (dd, J = 7.96, 1.39 Hz, 1H), 7.86 (s, 1H), 8.08 (s, 1H); ESI-MS m / z [M+H] + 438.3.

[0725] Example 102: 5-(1-Ethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0726]

[0727] In a manner similar 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), K 2 CO 3 (27.6 mg, 0.199 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL) to prepare the TFA salt of the title compound, which was isolated as a tan solid (14.7 mg, 31%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.24 (d, J = 6.82 Hz, 6H), 1.54 (t, J = 7.33 Hz, 3H), 2.89 (spt, J = 6.86 Hz, 1H), 4.29 (q, J = 7.33 Hz, 2H), 7.22 (d, J = 8.34 Hz, 2H), 7.32 - 7.37 (m, 1H), 7.40 (d, J = 8.34 Hz, 2H), 7.53 (dd, J = 7.58, 1.52 Hz, 1H), 7.73 (s, 1H), 7.77 (dd, J = 7.96, 1.39 Hz, 1H), 7.96 (s, 1H); ESI-MS m / z [M+H] + 410.2。

[0728] Example 103: 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0729]

[0730] In a manner similar 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), K 2 CO 3 (31 mg, 0.224 mmol) and PdCl2 (dppf)·CH 2 Cl 2 The adduct (8.33 mg, 10.20 μmol) was used to prepare the title compound, which was isolated as an off-white solid (7.0 mg, 17%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.14 - 1.22 (m, 6H), 2.09 (s, 3H), 2.86 (dt, J = 13.58, 6.98 Hz, 1H), 3.28 - 3.36 (m, 3H), 7.18 - 7.34 (m, 3H), 7.41 (d, J = 7.83 Hz, 3H), 7.68 (d, J = 6.32 Hz, 1H), 7.90 (s, 1H), 9.08 - 9.44 (m, 1H), 9.47 - 9.83 (m, 1H); ESI-MS m / z [M+H] + 410.2

[0731] 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

[0732]

[0733] 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53.10 mg, 0.187 mmol), K 2 CO 3 (37.9 mg, 0.274 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 The adduct (10.18 mg, 0.012 mmol) was used to prepare the TFA salt of the title compound, which was isolated as an off-white solid (15.9 mg, 22%). 1 H NMR (400 MHz, DMSO-d 6)δ ppm 1.20 (d, J = 7.07 Hz, 6H), 2.81 - 2.95 (m, 1H), 3.19 - 3.30 (m, 4H), 4.97 - 5.08 (m, 1H), 7.26 (d, J = 8.34 Hz, 2H), 7.34 (t, J = 7.71 Hz, 1H), 7.40 (d, J = 8.59 Hz, 2H), 7.53 (dd, J = 7.71, 1.39 Hz, 1H), 7.69 (dd, J = 7.83, 1.01 Hz, 1H), 7.93 (s, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 9.72 (s, 1H); ESI-MS m / z [M+H] + 472.2。

[0734] Example 105: 5-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0735]

[0736] In a manner similar 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), K 2 CO 3 (27.6 mg, 0.199 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL), the TFA salt of the title compound was prepared and isolated as a white solid (7.2 mg, 14%). 1 1H NMR (400 MHz, CD 3OD) δ ppm 1.24 (d, J = 6.82 Hz, 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, 7.01 Hz, 1H), 4.91 - 4.98 (m, 1H), 7.22 (d, J = 8.34 Hz, 2H), 7.35 (t, J = 7.71 Hz, 1H), 7.41 (d, J = 8.59 Hz, 2H), 7.53 (dd, J = 7.58, 1.52 Hz, 1H), 7.75 - 7.79 (m, 2H), 8.01 (s, 1H); ESI - MS m / z [M + H] + 436.3。

[0737] Example 106: 3 - ((4 - Isopropylphenyl)amino) - 5 - (3 - methyl - 1H - pyrazol - 4 - yl) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0738]

[0739] 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 PdCl 2 (dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO 3 (1 mL). The mixture was sparged with nitrogen for 30 seconds. The stirred reaction mixture was heated in a microwave reactor at 135 °C for 60 minutes and then cooled to room temperature. The solution was decanted from the salts and the product was purified by preparative HPLC (Waters C18, 5 μm, ID 30x75 mm column) eluting with a gradient of ACN (0.1% formic acid) in water (0.1% formic acid). The fractions containing the product were combined and dried to give the title compound as a white solid (7.2 mg, 32%). 1 HNMR (400 MHz, CD 3OD) δ ppm 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, 1.52 Hz, 1H); ESI-MS m / z [M + H] + 396.2。

[0740] Example 107: 3 - ((4 - Isopropylphenyl)amino)-5-(1 - methyl - 1H - pyrazol - 4 - yl)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0741]

[0742] In a manner similar 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), PdCl 2 (dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO 3 (1 mL), the title compound was prepared and isolated as a white solid (10 mg, 45%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.22 - 1.26 (m, 6H), 2.89 (dt, J = 13.83, 6.85 Hz, 1H), 4.00 (s, 3H), 7.22 (d, J = 8.34 Hz, 2H), 7.32 - 7.44 (m, 3H), 7.53 (dd, J = 7.58, 1.26 Hz, 1H), 7.70 (s, 1H), 7.77 (dd, J = 7.83, 1.52 Hz, 1H), 7.92 (s, 1H); ESI-MS m / z [M + H] + 396.2。

[0743] Example 108: 3 - ((4 - Isopropylphenyl)amino)-5-(1 - methyl - 1H - pyrazol - 3 - yl)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0744]

[0745] In a manner similar to Example 106, 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol) in dioxane (3 mL), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.240 mmol), PdCl 2 (dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO 3 (1 mL) were used to prepare the title compound, which was isolated as a white solid (6.4 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.21 (d, J = 7.07 Hz, 6H), 2.89 (dt, J = 13.77, 7.01 Hz, 1H), 3.72 (s, 3H), 6.58 (d, J = 1.52 Hz, 1H), 7.27 (d, J = 8.59 Hz, 2H), 7.37 - 7.46 (m, 3H), 7.61 (d, J = 6.57 Hz, 1H), 7.69 (d, J = 1.77 Hz, 1H), 7.88 (d, J = 7.83 Hz, 1H), 9.28 (s, 1H), 9.71 (s, 1H); ESI-MS m / z [M+H] + 396.2.

[0746] Example 109: 5-Cyclopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0747]

[0748] In a manner similar to Example 106, 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.057 mmol) in dioxane (1.5 mL), cyclopropylboronic acid (16.35 mg, 0.190 mmol), PdCl 2 (dppf) (10.92 mg, 0.013 μmol) and saturated (aq) NaHCO 3 (1.5 mL mL) were used to prepare the title compound, which was isolated as an off-white solid (11.19 mg, 19%). 1 H NMR (400 MHz, CDCl 3)δ ppm 0.42 - 0.46 (m, 2H), 0.72 - 0.74 (m, 2H), 1.25 (d, J = 6.9 Hz, 6H), 1.43 - 1.58 (m, 1H), 2.88 - 2.98 (m, 1H), 7.17 - 7.25 (m, 6H), 7.79 (d, J = 7.6 Hz, 1H), 8.49 (s, 1H); ESI-MS m / z [M + H] + 356.0。

[0749] Example 110: 5-Isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0750]

[0751] Step A: 3-((4-Isopropylphenyl)amino)-5-(prop-1-en-2-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0752]

[0753] In a manner similar 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) in dioxane (7.0 mL), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74.25 mg, 441.88 μmol), PdCl 2 (dppf) (49.58 mg, 0.059 μmol) and saturated (aq) NaHCO 3 (7.0 mL), the title compound was prepared and isolated as a (crude) brown solid (120 mg); ESI-MS m / z [M + H] + 356.1。

[0754] Step B: 5-Isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0755] 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 placed under a hydrogen atmosphere (filled with H 2The balloon) was stirred at 15 psi and 25 °C for 20 hours. Another portion of Pd / C (100.00 mg, 5%) was added to the reaction mixture, and it was stirred at H 2 for an additional 20 hours at 15 psi and 25 °C. 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 30x150 mm column) eluting with a gradient of 50 - 80% water in ACN (0.225% formic acid). The fractions containing the product were combined and dried to afford the title compound as a white solid (15.67 mg, 13%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.22 (d, J = 6.8 Hz, 6H), 1.28 (d, J = 6.4 Hz, 6H), 2.85 - 2.90 (m, 1H), 3.23 - 3.29 (m, 1H), 7.25 - 7.27 (m, 3H), 7.49 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 5.8 Hz, 2H), 9.43 (s, 1H), 9.83 (s, 1H); ESI-MS m / z [M+H] + 358.2.

[0756] Example 111: 5-Cyclobutyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0757]

[0758] 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), and S-Phos (29.77 mg, 0.073 mmol) in THF (2.00 mL) was added Pd(OAc) 2 (16.28 mg, 0.073 mmol). The resulting mixture was heated to 65 °C for 16 hours. Subsequently, the reaction mixture was poured into saturated (aq) NH 4 Cl (40 mL) and extracted with EtOAc (2 x 30 mL). The organic phase was dried over Na 2 SO 4Dry, then concentrate in vacuo. The crude product was purified by preparative HPLC (Welch Ultimate AQ-C18, 5 μm, ID30x150mm column) with gradient elution 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-d 6 ) δ ppm 1.21 (d, J = 6.8 Hz, 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 = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 9.39 (s, 1H), 9.56 (s, 1H); ESI-MS m / z [M+H] + 370.1。

[0759] Example 112: 5-(2-Chlorophenyl)-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0760]

[0761] In a manner similar 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), K 2 CO 3 (34.5 mg, 0.249 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 adduct (9.25 mg, 0.011 mmol) in water (1 mL) and dioxane (3 mL), the title compound was prepared and isolated as a white solid (28 mg, 59%). 1 H NMR (400 MHz, DMSO-d 6)δ ppm 1.19 (d, J = 6.82 Hz, 6H), 2.86 (dt, J = 13.71, 6.92 Hz, 1H), 7.23 (br s, 2H), 7.33 - 7.46 (m, 4H), 7.49 - 7.64 (m, 3H), 7.72 (d, J = 7.33 Hz, 1H), 7.81 (d, J = 7.07 Hz, 1H), 9.12 (br s, 1H), 9.50 (br s, 1H); ESI-MS m / z [M + H] + 426.1。

[0762] Example 113: 3 - ((4 - Isopropylphenyl)amino)-5-(3 - methylpyridin - 4 - yl)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0763]

[0764] In a manner similar 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), K 2 CO 3 (34.5 mg, 0.249 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 adduct (9.25 mg, 0.011 mmol) in water (1 mL) and dioxane (3 mL), the title compound was prepared and isolated as a tan solid (10.8 mg, 23%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 1.23 (d, J = 7.07 Hz, 6H), 2.18 (s, 3H), 2.88 (spt, J = 6.99 Hz, 1H), 7.20 (d, J = 8.59 Hz, 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-MS m / z [M + H] + 407.2。

[0765] Example 114: 5 - (1,5 - dimethyl - 1H - pyrazol - 4 - yl)-3 - ((4 - isopropylphenyl)amino)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0766]

[0767] In a manner similar to Example 101, using water (1 mL) and 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), K 2 CO 3 (27.6 mg, 0.199 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 adduct (7.40 mg, 9.06 μmol), the TFA salt of the title compound was prepared and isolated as a tan solid (4.7 mg, 9%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.24 (d, J = 7.07 Hz, 6H), 2.20 (s, 3H), 2.89 (spt, J = 6.99 Hz, 1H), 3.90 (s, 3H), 7.22 (d, J = 8.59 Hz, 2H), 7.34 - 7.42 (m, 3H), 7.42 - 7.47 (m, 1H), 7.57 (br s, 1H), 7.81 (dd, J = 7.83, 1.52 Hz, 1H); ESI-MS m / z [M+H] + 410.2.

[0768] Example 115: 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0769]

[0770] 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 2 (dppf)·CH 2 Cl 2 adduct (10.92 mg, 0.013 mmol) and K 2 CO 3(40.7 mg, 0.294 mmol). The reaction mixture was heated at 100 °C for 6 h. The mixture was neutralized with 1 N (aq) HCl and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO 4 and concentrated in vacuo. The product was purified 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 afford the title compound as an off-white solid (16 mg, 29%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 1.24 (d, J = 6.82 Hz, 6H), 2.14 (s, 3H), 2.88 (dt, J = 13.83, 6.85 Hz, 1H), 3.92 (s, 3H), 7.03 (d, J = 7.33 Hz, 1H), 7.22 - 7.28 (m, 1H), 7.29 - 7.34 (m, 1H), 7.36 (s, 2H), 7.45 (d, J = 7.33 Hz, 1H), 7.71 (s, 1H), 7.80 (d, J = 7.83 Hz, 1H); ESI-MS m / z [M+H] + 410.2.

[0771] Example 116: 5-Cyclopropyl-3-((3-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0772]

[0773] In a manner similar 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), K 2 CO 3 (40.7 mg, 0.294 mmol) and PdCl 2 (dppf)·CH 2 Cl 2 adduct (10.92 mg, 0.013 mmol) in water (1 mL) and dioxane (3 mL), the title compound was prepared and isolated as a tan solid (11.3 mg, 24%). 1 1H NMR (400 MHz, CD 3OD) δ ppm 0.74 (br s, 2H), 1.09 (d, J = 6.06 Hz, 2H), 1.27 (d, J = 6.57 Hz, 6H), 1.89 (br s, 1H), 2.85 - 3.00 (m, 1H), 7.05 (d, J = 7.07 Hz, 1H), 7.22 - 7.33 (m, 2H), 7.37 - 7.50 (m, 3H), 7.66 (d, J = 7.58 Hz, 1H); ESI-MS m / z [M + H] + 356.2。

[0774] Example 117: 5-(2-Chlorophenyl)-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0775]

[0776] 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) was added PdCl 2 (dppf)·CH 2 Cl 2 adduct (7.94 mg, 9.72 μmol) and K 2 CO 3 (29.6 mg, 0.214 mmol). The reaction mixture was heated at 100 °C for 3 h. Subsequently, the reaction mixture was neutralized with 1 N HCl(aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO 4 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 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.20 (d, J = 6.82 Hz, 6H), 2.96 (br s, 1H), 7.40 (br s, 3H), 7.45 - 7.62 (m, 3H), 7.69 (d, J = 6.57 Hz, 1H), 7.78 (br s, 1H), 7.90 (dd, J = 8.59, 2.27 Hz, 1H), 8.41 (br s, 1H); ESI-MS m / z [M + H]+ 427.1。

[0777] Example 118: 5-Cyclopropyl-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0778]

[0779] In a manner similar to Example 117, 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), PdCl 2 (dppf)·CH 2 Cl 2 adduct (11.63 mg, 0.014 mmol), and K 2 CO 3 (43.3 mg, 0.313 mmol) were used in water (1 mL) and dioxane (3 mL) to prepare the title compound, which was isolated as a pale yellow solid (6.0 mg, 12%). 1 HNMR (400 MHz, CD 3 OD) δ ppm 0.73 - 0.79 (m, 2H), 1.10 - 1.16 (m, 2H), 1.30 (d, J = 7.07 Hz, 6H), 1.88 - 1.97 (m, 1H), 3.00 - 3.12 (m, 1H), 7.23 - 7.29 (m, 1H), 7.35 (d, J = 8.59 Hz, 1H), 7.43 (dt, J = 7.64, 1.11 Hz, 1H), 7.66 (dd, J = 7.83, 0.76 Hz, 1H), 8.10 (dd, J = 8.59, 2.53 Hz, 1H), 8.56 (d, J = 2.27 Hz, 1H); ESI-MS m / z [M+H] + 357.2。

[0780] Example 119: 5-Cyclopropyl-3-(((3-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0781]

[0782] 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 PdCl 2 (dppf)·CH 2 Cl 2 adduct (10.01 mg, 0.012 mmol) and K 2 CO3 (37.3 mg, 0.270 mmol). The reaction mixture was heated at 100 °C for 29 h, then neutralized with 1 N HCl(aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO 4 and concentrated in vacuo. The product was purified by reverse-phase column chromatography (Phenomenex C18, 5 μm, ID 30x75 mm column) eluting with a gradient of 25 - 50% water in ACN (basic mode). The title compound was isolated as a pale yellow solid (4.5 mg, 11%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 0.71 - 0.77 (m, 2H), 1.06 - 1.15 (m, 2H), 1.85 - 1.96 (m, 1H), 4.78 (d, J = 1.52 Hz, 2H), 7.19 - 7.24 (m, 1H), 7.37 - 7.44 (m, 2H), 7.59 - 7.66 (m, 2H), 8.41 (d, J = 4.55 Hz, 1H); ESI-MS m / z [M+H] + 347.1.

[0783] Example 120: 5-Cyclopropyl-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0784]

[0785] In a manner similar to Example 119, using 5-iodo-3-(((6-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.056 mmol), cyclopropylboronic acid (5.80 mg, 0.068 mmol), PdCl 2 (dppf)·CH 2 Cl 2 adduct (4.60 mg, 5.63 μmol) and K2 CO 3 (17.11 mg, 0.124 mmol) was used to prepare the title compound, which was isolated as a brownish semi-solid (2.6 mg, 13%). 1 HNMR (400 MHz, CD 3 OD) δ ppm 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 = 8.08 Hz, 1H), 6.99 (d, J = 7.33 Hz, 1H), 7.19 - 7.25 (m, 1H), 7.39 (dt, J = 7.58, 1.14 Hz, 1H), 7.61 - 7.68 (m, 2H); ESI-MS m / z [M + H] + 359.1。

[0786] Example 121: 5-Cyclopropyl-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0787]

[0788] In a manner similar to Example 119, 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), PdCl 2 (dppf)·CH 2 Cl 2 adduct (7.16 mg, 8.77 μmol) and K 2 CO 3 (26.7 mg, 0.193 mmol) were used in water (1 mL) and dioxane (3 mL) to prepare the title compound, which was isolated as a pale yellow solid (5.7 mg, 21%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 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 = 7.71 Hz, 1H), 7.35 - 7.41 (m, 2H), 7.44 (d, J = 7.58 Hz, 1H), 7.59 (dd, J = 8.59, 1.01 Hz, 2H), 7.67 (dd, J = 7.96, 0.88 Hz, 1H); ESI-MS m / z [M + H] + 314.1。

[0789] Example 122: 5-(2-Chloro-3-fluorophenyl)-3-(((3-methoxypyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0790]

[0791] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50.0 mg, 0.014 mmol) in EtOH (2.0 mL), Et 3 N (56 μL, 0.760 mmol) and (3-methoxypyridin-2-yl)methanamine hydrochloride (50.60 mg, 0.29 mmol) were used to prepare the title compound, which was isolated as an off-white solid (29.8 mg, 46%). 1 HNMR (400 MHz, DMSO-d 6 ) δ ppm 3.86 - 3.95 (m, 4H), 4.54 (dd, J = 7.58, 4.80 Hz, 2H), 7.30 - 7.45 (m, 4H), 7.51 (dd, J = 8.34, 1.01 Hz, 1H), 7.54 - 7.67 (m, 2H), 7.80 (dd, J = 7.83, 1.52 Hz, 1H), 8.03 (t, J = 4.42 Hz, 1H), 8.13 (d, J = 4.29 Hz, 1H), 9.54 (s, 1H); ESI-MS m / z [M+H] + 447.1

[0792] Example 123: 5-(2-Chloro-3-fluorophenyl)-3-(((tetrahydrofuran-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0793]

[0794] In a manner similar to Example 1, 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol) in DMA (435 μL), DIPEA (16.7 μL, 0.096 mmol) and (tetrahydrofuran-2-yl)methanamine (8.79 mg, 0.087 mmol) were used to prepare the title compound, which was isolated as a light beige solid (8.3 mg, 23%). 1 H NMR (400 MHz, DMSO-d 6) δ ppm 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, 3.54 Hz, 1H), 7.30 - 7.39 (m, 2H), 7.39 - 7.45 (m, 1H), 7.51 (q, J = 5.98 Hz, 1H), 7.54 - 7.65 (m, 2H), 7.78 (dd, J = 7.83, 1.26 Hz, 1H), 9.05 (s, 1H); ESI-MS m / z [M + H] + 410.0。

[0795] Example 124: 3 - ((2 - Methoxyethyl)amino) - 5 - (2 - (trifluoromethyl)phenyl) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0796]

[0797] In a manner similar 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 ·CH 2 Cl 2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL) to prepare the title compound, which was isolated as a light brown solid (34.3 mg, 33%). 1 1H NMR (400 MHz, DMSO - d 6 ) δ ppm 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 = 7.33 Hz, 1H), 8.96 (s, 1H); ESI-MS m / z [M + H] + 400.1。

[0798] Example 125: 2 - Fluoro - 6 - (3 - ((2 - methoxyethyl)amino) - 1,1 - dioxido - 4H - benzo[e][1,2,4]thiadiazin - 5 - yl)benzonitrile

[0799]

[0800] Into 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), Cs 2 CO 3 (0.157 mL, 0.315 mmol) and dioxane (0.394 mL). Next, Pd(dppf) 2 ·CH 2 Cl 2 adduct (6.43 mg, 7.87 μmol) was added under nitrogen, and the reaction mixture was heated to 90 °C for 12 h. Subsequently, the mixture was cooled, diluted with MeOH (1 mL) and filtered on . The residue was purified by preparative LC / MS on (Waters C18, 5 μm, ID 30x75 mm column) with gradient elution using 25-90% aqueous ACN (acid mode). The fractions were collected, concentrated and dried in vacuo to give the title compound as a brown solid (5 mg, 17%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.26 (s, 3H), 3.43 (d, J = 4.29 Hz, 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-MS m / z [M+H] + 375.0.

[0801] Example 126: 2-(1,1-dioxido-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6-fluorobenzonitrile

[0802]

[0803] 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) in dioxane (1.898 mL), 2 - fluoro - 6 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzonitrile (211.65 mg, 0.856 mmol), Cs 2 CO 3 (0.759 mL, 1.518 mmol), and Pd(dppf) 2 ·CH 2 Cl 2 adduct (31.0 mg, 0.038 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 30 minutes, then poured into water and extracted with EtOAc (3x). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated to give a light brown oil. The oil was dissolved in MeOH (2 mL), filtered, and purified by supercritical fluid chromatography (SFC) to give the formate of the title compound as a white solid (10.37 mg, 4%) after removal of the solvent. 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 4.58 (s, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.24 - 7.49 (m, 4H), 7.56 - 7.76 (m, 3H), 8.28 (s, 1H); ESI - MS m / z [M + H] + 414.0.

[0804] Example 127: 3 - ((2 - methoxypropyl)amino)-5 - (2,3,5 - trifluorophenyl)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0805]

[0806] 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 Cs 2 CO 3 (759 μL, 1.518 mmol) and Pd(dppf) 2 ·CH 2 Cl 2Adduct (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 4 and 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 as a clear oil (8.5 mg, 6%) after removal of the solvent. 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.07 - 1.21 (m, 3H), 3.11 - 3.24 (m, 1H), 3.31 (dt, J = 3.28, 1.64 Hz, 3H), 3.46 - 3.62 (m, 2H), 7.09 (br s, 1H), 7.32 - 7.44 (m, 2H), 7.51 (d, J = 7.33 Hz, 1H), 7.89 (dd, J = 7.96, 1.39 Hz, 1H); ESI-MS m / z [M+H] + 400.0.

[0807] Example 128: (S)-3-((2-Methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0808] and

[0809] Example 129: (R)-3-((2-Methoxypropyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0810]

[0811] 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), followed by Cs 2 CO 3 (2.024 mL, 4.05 mmol) and Pd(dppf) 2 ·CH 2 Cl 2Adduct (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 MgSO 4 and filtered, and concentrated. The resulting brown oil was filtered through a pad and purified by supercritical fluid chromatography (SFC) to give the racemate of the title compound as a clear oil after removal of the solvent. The racemate was resolved by chiral chromatography using an 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.

[0812] Example 128, which eluted as the first peak and was arbitrarily assigned the S-stereochemistry, was isolated as a clear oil (15.7 mg, 3.9%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 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 = 7.33 Hz, 1H), 7.90 (dd, J = 7.83, 1.52 Hz, 1H); ESI-MS m / z [M+H] + 400.1.

[0813] Example 129, which eluted as the second peak and was arbitrarily assigned the R-stereochemistry, was isolated as a clear oil (17.3 mg, 4.3%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 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 = 7.07 Hz, 1H), 7.90 (dd, J = 7.83, 1.52 Hz, 1H); ESI-MS m / z [M+H] + 400.1.

[0814] Example 130: 3-((Cyclobutylmethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0815]

[0816] In a manner similar to Example 127, 3-((cyclobutylmethyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.383 mmol) in dioxane (1.917 mL), (2,3,5-trifluorophenyl)boronic acid (70.8 mg, 0.403 mmol), Pd(dppf) 2 ·CH 2 Cl 2 adduct (31.3 mg, 0.038 mmol) and Cs 2 CO 3 (767 μL, 1.534 mmol) were used to prepare the title compound, which was isolated as a tan solid (5.1 mg, 3%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 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,

[0817] 1.52 Hz, 1H), 7.71 - 7.86 (m, 2H), 9.21 (s, 1H); ESI-MS m / z [M+H] + 396.1.

[0818] Example 131: 3-((pyridin-2-ylmethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0819]

[0820] In a manner similar to Example 127, 5-iodo-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120 mg, 0.290 mmol) in dioxane (1.449 mL), (2,3,5-trifluorophenyl)boronic acid (53.5 mg, 0.304 mmol), Pd(dppf) 2 ·CH 2 Cl 2 adduct (23.66 mg, 0.029 mmol) and Cs 2 CO 3 (579 μL, 1.159 mmol) were used to prepare the title compound, which was isolated as a white solid (3.4 mg, 3%). 11H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.60 (br s, 2H), 7.34 - 7.44 (m, 3H), 7.46 (d, J = 7.58 Hz, 1H), 7.57 (d, J = 6.57 Hz, 1H), 7.73 - 7.93 (m, 3H), 7.99 (br s, 1H), 8.59 (d, J = 4.55 Hz, 1H), 9.54 - 9.66 (m, 1H); ESI-MS m / z [M + H] + 419.0。

[0821] Example 132: 5-(2-Chloro-3-(trifluoromethyl)phenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0822]

[0823] In a manner similar 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), Cs 2 CO 3 (2M, 525 μL, 1.049 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL), the title compound was prepared and isolated as a white solid (1.0 mg, 1%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 3.49 - 3.58 (m, 4H), 7.46 (br s, 2H), 7.72 (d, J = 4.80 Hz, 2H), 7.92 - 7.97 (m, 1H), 8.02 (t, J = 4.67 Hz, 1H); ESI-MS m / z [M + H] + 434.0。

[0824] Example 133: 5-(2-Chloro-4-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0825]

[0826] Step A: 3-Chloro-5-(2-chloro-4-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0827]

[0828] 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 ·CH 2 Cl 2 adduct (28.6 mg, 0.035 mmol), Cs 2 CO 3 (0.701 mL, 1.401 mmol) and dioxane (1.7 mL). The mixture was purged with nitrogen, heated in a microwave reactor at 120 °C for 30 minutes, and then cooled. The reaction mixture was poured into water (10 mL) and acidified with 1N HCl(aq) (5 mL) to form a precipitate that was difficult to filter. The filtrate was extracted with EtOAc (2 x 20 mL), and the organic layers were combined, dried over MgSO 4 and filtered. The solvent was removed to give the title compound as a slightly reddish-brown oil, which was used without further purification. ESI-MS m / z [M+H] + 344.9.

[0829] Step B: 5-(2-Chloro-4-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0830] 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 purified by preparative LC / MS (Waters C18, 5 μm, ID 30 x 75 mm column) using a gradient elution of 30 - 50% aqueous ACN (acid mode). The fractions containing the product were collected and the solvent removed to give the title compound as a white solid (13 mg, 59%). 1 H NMR (400 MHz, DMSO-d 6)δ ppm 3.26 (s, 3H), 3.35–3.40 (m, 2H), 3.42 (d, J = 5.31 Hz, 2H), 7.31–7.46 (m, 3H), 7.48 (br s, 1H), 7.54 (dd, J = 8.46, 6.19 Hz, 1H), 7.70–7.79 (m, 2H), 9.03 (s, 1H); ESI-MS m / z [M+H] + 384.0。

[0831] Example 134: 5-(2-Chloro-5-(trifluoromethyl)phenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0832]

[0833] In a manner similar 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), Cs 2 CO 3 (2M, 525 μL, 1.049 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL), the title compound was prepared and isolated as a brown solid (5.5 mg, 5%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 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-MS m / z [M+H] + 434.0。

[0834] Example 135: 5-(3-Chloro-2-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0835]

[0836] In a manner similar to Example 35, 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), Cs 2 CO 3 (2M, 328 μL, 0.656 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (21.42 mg, 0.026 mmol) were used to prepare the title compound, which was isolated as a white film (5.0 mg, 5%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 3.33 (br s, 2H), 3.49 (br s, 4H), 7.30 - 7.43 (m, 3H), 7.47 (d, J = 7.07 Hz, 1H), 7.61 - 7.73 (m, 1H), 7.87 (dd, J = 7.83, 1.52 Hz, 1H); ESI-MS m / z [M+H] + 384.0。

[0837] Example 136: 3-((4-Ethylphenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0838]

[0839] 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 h. The reaction mixture was cooled to room temperature, extracted with EtOAc, and washed with brine (3x). The organic layers were combined, concentrated, filtered, and purified by preparative LC / MS (Waters C18, 5 μm, ID30x75 mm column), eluting with a gradient of 20 - 70% water in ACN (basic mode). The fractions containing the product were collected and concentrated to give the title compound as a brown solid (3.2 mg, 5%). 1 H NMR (400 MHz, CD 3OD) δ ppm 1.22 - 1.26 (m, 3H), 2.64 (qd, J = 7.62, 3.41 Hz, 2H), 3.98 (s, 3H), 7.16 - 7.23 (m, 2H), 7.29 - 7.34 (m, 1H), 7.42 (d, J = 8.34 Hz, 2H), 7.53 - 7.57 (m, 1H), 7.72 - 7.76 (m, 1H), 7.98 (br s, 1H), 8.55 (br s, 1H); ESI-MS m / z [M + H] + 382.1。

[0840] Example 137: 3 - ((furan - 2 - ylmethyl)amino) - 5 - (o - tolyl) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0841]

[0842] Step A: 3 - chloro - 5 - (o - tolyl) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0843]

[0844] 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 Na 2 CO 3 (0.089 g, 0.837 mmol). The (first) reaction mixture was heated at 100 °C for 1 h, 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 Na 2 CO 3 (177 mg, 1.674 mmol). The reaction mixture was heated at 70 °C for 0.5 h and at 80 °C for 1 h, then cooled to room temperature and combined with the first reaction mixture. The combined mixture was neutralized with 1 N HCl(aq) and extracted with EtOAc. The organic layers were combined and dried over anhydrous NaSO 4Dry and concentrate in vacuo. Purify the crude product on a silica gel column, eluting with 50% EtOAc in hexanes. Collect the fractions containing the product and concentrate in vacuo to afford the title compound as an off-white solid (49 mg, 53%). ESI-MS m / z [M+H] + 307.0。

[0845] Step B: 3-((Furan-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0846] 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-ylmethanamine (200 mg, 2.059 mmol) dissolved in n-butanol (5 mL) was added Cs 2 CO 3 (100 mg, 0.307 mmol). The reaction mixture was stirred in a microwave reactor at 150 °C for 2 h, then cooled and purified by preparative LC / MS (Waters C18, 5 μm, ID 30x75 mm column). The title compound was isolated as a white solid (50 mg, 44%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 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-MS m / z [M+H] + 368.1。

[0847] Example 138: 5-(2-Chlorophenyl)-6-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0848]

[0849] Step A: 2'-Chloro-6-fluoro-[1,1'-biphenyl]-2-amine

[0850]

[0851] 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 μmol) and K 2 CO 3 (1.82 g, 13.15 mmol). The reaction mixture was stirred under nitrogen at 100 °C for 1 h, then poured into water (20 mL) and extracted with EtOAc (2 x 2 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated. The crude material was purified by column chromatography (SiO 2 ) eluting with petroleum ether / EtOAc (20:1) to afford the title compound as a colorless oil (800.00 mg, 69%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 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-MS m / z [M+H] + 222.1.

[0852] Step B: 5-(2-chlorophenyl)-6-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide

[0853]

[0854] To a solution of isocyanatosulfonyl 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 -20 °C to 0 °C for 30 min. AlCl 3 (433.62 mg, 3.25 mmol) was added slowly and the temperature of the mixture was gradually raised to 100 °C to 110 °C. The reaction mixture was stirred at this temperature under a nitrogen atmosphere for an additional hour. 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 Na 2 SO 4Dry and filter. The filtrate was concentrated to dryness under vacuum, and the remaining residue was purified by preparative TLC (DCM / MeOH) to give the title compound as a white solid (300 mg, 34% yield).

[0855] Step C: 3-Chloro-5-(2-chlorophenyl)-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0856]

[0857] 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 POCl 3 (5.00 mL) was stirred at 120 °C for 3 h and then cooled to room temperature. Volatiles were removed in vacuo to give the title (crude) compound as a brown oil, which was used without further purification (300 mg). ESI-MS m / z [M+H] + 345.1.

[0858] Step D: 5-(2-Chlorophenyl)-6-fluoro-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0859] 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 Et 3 N (469.04 mg, 4.64 mmol). The resulting mixture was stirred at 70 °C for 2 h. The solvent was removed and the crude material was purified by preparative HPLC (Phenomenex Synergi TM C18, 10 μm, ID 25x150 mm) using a gradient elution of water (0.225% formic acid) in ACN. The fractions containing the product were combined and dried to give the title compound as a yellow solid (36 mg, 11%). 1 HNMR (400 MHz, DMSO-d 6 ) δ ppm 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-MS m / z [M+H] + 340.0.

[0860] Example 139: 5-(2,5-Difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0861]

[0862] 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-ylmethanamine (33.2 mg, 0.307 mmol) in DMA (5 mL) was added Cs 2 CO 3 (100 mg, 0.307 mmol). The reaction mixture was stirred and heated at 150 °C for 2 h in a microwave reactor. The product was purified by preparative HPLC (Waters C18, 5 μm, ID 30x75 mm column) with gradient elution using ACN (0.1% formic acid) in water (0.1% formic acid) solution. The title compound was isolated as a white solid (18 mg, 15%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 4.62 (br s, 2H), 7.19 - 7.56 (m, 1H), 7.88 (dd, J = 7.96, 1.64 Hz, 1H), 8.36 - 8.56 (m, 1H); ESI-MS m / z [M+H] + 401.0.

[0863] Example 140: 3-((Cyclopropylmethyl)amino)-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0864]

[0865] In a manner similar to Example 139, using 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol), cyclopropylmethanamine (200 mg, 2.81 mmol) and Cs 2 CO 3 (100 mg, 0.307 mmol) in DMA (5 mL), the title compound was prepared and isolated as a white solid (22 mg, 20%). 1 1H NMR (400 MHz, CD 3OD) δ ppm 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, 4.80 Hz, 1H), 3.17 (d, J = 7.33 Hz, 2H), 7.19 - 7.43 (m, 3H), 7.48 (dd, J = 7.58, 1.52 Hz, 1H), 7.86 (dd, J = 7.83, 1.52 Hz, 1H); ESI-MS m / z [M + H] + 364.1。

[0866] Example 141: 5-(2,5-Difluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0867]

[0868] In a manner similar to Example 139, using 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol), 2-methoxyethylamine (400 mg, 5.33 mmol) and Cs 2 CO 3 (100 mg, 0.307 mmol) in DMA (5 mL), the title compound was prepared and isolated as a white solid (65 mg, 58%). 1 1H NMR (400 MHz, CD 3 OD) δ ppm 3.49 (br s, 4H) 7.22 (br s, 1H) 7.26 - 7.44 (m, 3H) 7.48 (d, J = 6.57 Hz, 1H) 7.87 (dd, J = 7.83, 1.52 Hz, 1H); ESI-MS m / z [M + H] + 368.1。

[0869] Example 142: 5-(2,5-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0870]

[0871] In a manner similar to Example 139, the title compound was prepared 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,CD 3 OD)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-MS m / z[M+H] + 401.4。

[0872] Example 143: 5-(2,5-Difluorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0873]

[0874] In a manner similar to Example 139, the title compound was prepared 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 H NMR(400MHz,CD 3 OD)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-MS m / z[M+H] + 338.0。

[0875] Example 144: 5-(2-Chloro-5-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0876]

[0877] In a manner similar to Example 35, 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), Cs 2 CO 2 (2 M, 525 μL, 1.049 mmol) and Pd(dppf) 2 ·CH 2 Cl 2 adduct (32 mg, 0.039 mmol) were used in dioxane (1312 μL) to prepare the title compound, which was isolated as a pale yellow oil (5 mg, 5%); ESI-MS m / z [M+H] + 384.0.

[0878] Example 145: 2-(3-((2-methoxypropyl)amino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0879]

[0880] To a solution of 2-methoxypropan-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-dioxido-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 h, then diluted with MeOH (1 mL) and filtered. The residue was purified by preparative LC / MS on (ZQ3) with a gradient elution of 25-90% aqueous ACN (acid mode). The fractions containing the product were collected, concentrated, and dried in vacuo to give the title compound as a tan solid (3 mg, 4%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 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).

[0881] Example 146: 2-(3-((Cyclobutylmethyl)amino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0882]

[0883] In a manner similar to Example 145, the title compound was prepared using 2-(3-chloro-1,1-dioxido-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 H NMR (400 MHz, CD 3 OD) δ ppm 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-MS m / z [M + H] + 367.1。

[0884] Example 147: 5-(2-Chloro-3-fluorophenyl)-3-((2-fluoroethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0885]

[0886] In a manner similar to Example 1, the title compound was prepared 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 H NMR (400 MHz, CD 3OD) δ ppm 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).

[0887] Example 148: 5-(2-Chloro-3-fluorophenyl)-3-(((6-fluoropyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0888]

[0889] In a manner similar to Example 1, the title compound was prepared 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,CD 3 OD) δ ppm 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).

[0890] Example 149: 2-Fluoro-6-(3-((2-fluoroethyl)amino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0891]

[0892] 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-dioxido-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% aqueous ACN (acid mode). Fractions were collected, concentrated, and dried in vacuo to afford the title compound as a tan solid (5 mg, 9%). 1 H NMR (400 MHz, CD 3 OD) δ ppm 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-MS m / z [M+H] + 363.0。

[0893] Example 150: 2-Fluoro-6-(3-((2-methoxypropyl)amino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0894]

[0895] In a manner similar to Example 149, the title compound was prepared using 2-(3-chloro-1,1-dioxido-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。

[0896] Example 151: 5-(2-Chloro-3-fluorophenyl)-3-((3-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0897]

[0898] In a manner similar to Example 1, the title compound was prepared 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-methoxypropyl-1-amine HCl (24 mg, 0.188 mmol) in DMA (290 μL), and isolated as a tan solid (20 mg, 35%). 1 HNMR(400MHz,CD 3 OD) δ ppm 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-MS m / z [M+H] + 398.0。

[0899] Example 152: 5-(2-Chloro-3-fluorophenyl)-3-((3-fluoropropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0900]

[0901] In a manner similar to Example 1, the title compound was prepared 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-fluoropropyl-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。

[0902] Example 153: 5-(2-Chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0903]

[0904] In a manner similar to Example 1, the title compound was prepared 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.

[0905] Example 154: (R)-5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0906] and

[0907] Example 155: (S)-5-(2-chloro-3-fluorophenyl)-3-((3-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0908]

[0909] The racemate prepared in Example 153 was resolved by chiral chromatography. The first eluted peak was arbitrarily assigned the R-stereochemistry (Example 154), and the second eluted peak was assigned the S-stereochemistry (Example 155). Each title compound was isolated as a colorless semi-solid.

[0910] Example 156: 5-(2-cyclopropyl-3-fluorophenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0911]

[0912] To a solution of 2-methoxyethan-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 h, then diluted with MeOH (1 mL) and filtered. The product was purified by preparative LC / MS (Waters Purified on a C18, 5μm, ID 30x75mm column), eluted with a gradient of 25 - 90% ACN aqueous solution (acid mode). The fractions containing the product were collected, concentrated, and dried under vacuum to give the title compound as a brownish - tan glassy solid (14 mg, 25% yield). ESI - MS m / z [M + H] + 390.1

[0913] Example 157: 5 - (2 - Cyclopropyl - 3 - fluorophenyl)-3-(methylamino)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0914]

[0915] 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 brownish - tan glassy solid (10 mg, 20%). ESI - MS m / z [M + H] + 346.3

[0916] Example 158: 5 - (2 - Chloro - 3 - fluorophenyl)-3-(isopropylamino)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0917]

[0918] 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

[0919] Example 159: 5 - (2 - Chloro - 3 - fluorophenyl)-3-(cyclopropylamino)-4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0920]

[0921] In a manner similar to Example 1, the title compound was prepared 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 transparent film (32 mg, 95%); ESI-MS m / z [M+H] + 366.8.

[0922] Example 160: 5-(2-Chloro-3-fluorophenyl)-3-((2-(2,2-difluoroethoxy)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0923]

[0924] In a manner similar to Example 1, the title compound was prepared 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)ethylamine 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.

[0925] Each of the compounds shown in Examples 161 to 170 below was prepared in the same manner as the above compound.

[0926] Example 161: 2-Fluoro-6-(3-((oxazol-2-ylmethyl)amino)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile

[0927]

[0928] ESI-MS m / z [M+H] + 402.1.

[0929] Example 162: 3-((Pyridin-2-ylmethyl)amino)-5-(o-tolyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0930]

[0931] 11H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3H), 4.52 (t, J = 5.31 Hz, 2H), 7.23 (d, J = 7.58 Hz, 1H), 7.30 - 7.44 (m, 7H), 7.71 - 7.75 (m, 1H), 7.79 (td, J = 7.71, 1.77 Hz, 1H), 8.17 (brs, 1H), 8.53 (d, J = 4.04 Hz, 1H), 9.16 (br s, 1H); ESI-MS m / z [M+H] + 379.2。

[0932] Example 163: 5-(2-Ethylphenyl)-3-((2-methoxyethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0933]

[0934] 1 1H NMR (400 MHz, CD 3 OD) δ ppm 1.03 (t, J = 7.58 Hz, 3H), 2.29 - 2.41 (m, 1H), 2.42 - 2.54 (m, 1H), 3.46 (br s, 4H), 7.18 (d, J = 7.33 Hz, 1H), 7.32 - 7.40 (m, 3H), 7.45 (d, J = 1.52 Hz, 2H), 7.82 (dd, J = 6.82, 2.78 Hz, 1H); ESI-MS m / z [M+H] + 360.1。

[0935] Example 164: 5-(3,5-Difluorophenyl)-3-((furan-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0936]

[0937] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.44 (d, J = 5.31 Hz, 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, 1H) 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-MS m / z [M+H] + 390.4

[0938] Example 165: 5-(2,3-Difluorophenyl)-3-(ethylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0939]

[0940] 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)

[0941] 9.14(s,1H);ESI-MS m / z[M+H] + 338.0。

[0942] Example 166: 5-(3,5-Difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0943]

[0944] ESI-MS m / z[M+H] + 382.4

[0945] Example 167: 5-(2-Chloro-3-fluorophenyl)-3-((3-methoxycyclobutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0946]

[0947] ESI-MS m / z[M+H] + 410.6

[0948] Example 168: 3-((2-Methoxyethyl)amino)-5-(2,3,5-trifluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0949]

[0950] 1 H NMR(400MHz,CD 3OD) δ ppm 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-MS m / z [M + H] + 386.4

[0951] Example 169: 3 - ((4 - Isopropylphenyl)amino) - 5 - (methoxymethyl) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0952]

[0953] 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.81 (s, 1H), 9.66 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 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 = 6.8 Hz, 6H); ESI-MS m / z [M + H] + 360.1。

[0954] Example 170: 5 - (3,4 - Difluoro - 2 - methylphenyl) - 3 - ((2 - methoxyethyl)amino) - 4H - benzo[e][1,2,4]thiadiazine 1,1 - dioxide

[0955]

[0956] 1 H NMR (400 MHz, CD 3 OD) δ ppm 2.10 (d, J = 2.78 Hz, 3H), 3.36 (td, J = 3.47, 1.89 Hz, 5H), 3.53 (d, J = 3.28 Hz, 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-MS m / z [M + H] + 382.1。

[0957] Table 1 lists the hMRGX2 cell potency (pEC 50 ) and binding affinity (pK d ) of the compounds shown in the examples, where the larger pEC50 Values represent higher activity or potency, while larger pK d values represent higher binding affinity. Methods for measuring cell potency and binding affinity are described in the section entitled "Biological Activity" in the above specification.

[0958] Table 1: hMRGX2 cell potency (pEC 50 ) and binding affinity (pK d )

[0959]

[0960] Table 1: hMRGX2 cell potency (pEC 50 ) and binding affinity (pK d ) - continued

[0961]

[0962]

[0963] As used in this specification and the appended claims, singular articles such as "a", "an", and "the" may refer to a single object or multiple objects, unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "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. Accordingly, 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 entitle. The disclosures of all articles and references (including patents, patent applications, and publications) cited in this disclosure are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein: L is selected from a bond and C 1-4 alkanediyl; (a)R 1 is a C 1-4 alkyl group substituted with 0 to 3 optional substituents independently selected from halo, C 1-4 alkoxy, and aminocarbonyl, wherein the C 1-4 alkoxy is substituted with 0 to 3 substituents independently selected from halo, and wherein the aminocarbonyl is substituted with 0 to 2 substituents independently selected from C 1-4 alkyl; and R 2 is a cyclic group selected from C 3-6 cycloalkyl, phenyl, and C 1-5 heteroaryl, wherein the cyclic group is substituted with 0 to 3 substituents independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 3-6 cycloalkyl and C 3-5 heterocyclyl, and wherein each of the C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and C 3-5 heterocyclyl is independently substituted with 0 to 3 substituents independently selected from halo; or (b)R 1 is selected from C 3-6 cycloalkyl, C 2-6 heterocyclic group, phenyl and C 1-5 heteroaryl cyclic groups, wherein the cyclic group is independently selected from 0 to 3 halo, cyano, C 1-4 alkyl, C 1-4 alkoxy optional substituents, wherein said C 1-4 alkyl and C 1-4 each of the alkoxy is independently substituted with 0 to 3 substituents independently selected from halo; and R 2 Selected from (1) C optionally substituted with from 0 to 3 substituents independently selected from C 1-4 alkoxy; and 1-4 alkyl; and (2) Selected from C 3-6 cycloalkyl, phenyl and C 1-5 a cyclic group of heteroaryl, wherein the cyclic group Optionally substituted by 0 to 3 substituents independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3-5 heterocyclic group, provided that the cyclic group has no more than one selected from C 3-6 Optional substituents of cycloalkyl and C 3-5 heterocyclic group, and wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3-5 each of the heterocyclic groups is independently substituted with 0 to 3 substituents independently selected from halo; and R 3 is hydrogen; R 4 selected from hydrogen, halogenated, and C 1-3 alkyl; and R 5 is hydrogen; wherein each of the above-mentioned heterocyclic and heteroaryl moieties independently has 1 to 3 heteroatoms each independently selected from N, O, and S as ring members.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl optionally substituted with 0 to 3 substituents independently selected from halo, C 1-4 alkoxy, and aminocarbonyl, wherein each of said C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of said aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein said R 1 C 1-4 alkyl is methyl or ethyl, each of which is optionally substituted with 0 to 3 substituents independently selected from halo, C 1-4 alkoxy, and aminocarbonyl, wherein each of said C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo, and wherein each of said aminocarbonyl is independently substituted with 0 to 2 substituents independently selected from C 1-4 alkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 3-6 Cycloalkyl, phenyl and C 1-5 heteroaryl cyclic group, wherein the cyclic group is substituted by 0 to 3 independently selected from halo, cyano, C 1-4 Alkyl, C 1-4 The alkoxy group is optionally substituted with a substituent, wherein the C 1-4 Alkyl and C 1-4 Each of the alkoxy groups is independently substituted with 0 to 3 substituents independently selected from halo.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is a cyclic group which is a phenyl group optionally substituted with 0 to 3 substituents independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, wherein each of said C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, 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 independently substituted with 0 to 3 optional substituents selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, wherein each of the C 1-4 alkyl and C 1-4 alkoxy is independently substituted with 0 to 3 substituents independently selected from halo.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond, –CH 2 –, –CH 2 CH 2 –, and –CH(CH 3 ).

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is –CH 2 –.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L is a bond.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl optionally substituted with from 0 to 3 substituents independently selected from halo, cyano, C 1-4 alkoxy.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein said R 2 C 1-4 alkyl is optionally substituted with 0 to 3 substituents independently selected from halo and C 1-4 alkoxy.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is a cyclic group selected from C 3-8 cycloalkyl, phenyl, and C 1-5 heteroaryl, wherein the cyclic group is substituted with 0 to 3 optional substituents independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and C 3-5 heterocyclyl, provided that the cyclic group has no more than one optional substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclyl, and wherein each of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and C 3-5 heterocyclyl is independently substituted with 0 to 3 substituents independently selected from halo.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is a cyclic group which is a phenyl group optionally substituted by 0 to 3 substituents independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclyl, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclyl, and wherein each of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and C 3-5 heterocyclyl is independently substituted by 0 to 3 substituents independently selected from halo.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is a cyclic group selected from pyrazolyl, pyridyl, and pyrimidinyl, each of which is independently substituted with 0 to 3 substituents selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and C 3-5 heterocyclyl, provided that the cyclic group has no more than one substituent selected from C 3-8 cycloalkyl and C 3-5 heterocyclyl, and wherein each of said C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and C 3-5 heterocyclyl is independently substituted with 0 to 3 substituents independently selected from halo.

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, and C 1-3 alkyl.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

17. The compound according to claim 1, which is selected from the following compounds: 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-dioxido-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-dioxido-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-dioxido-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-dioxido-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-methoxybenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-Chloro-3-fluorophenyl)-3-((2-methoxybenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-Chloro-3-fluorophenyl)-3-((4-methoxybenzyl)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-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 4-Chloro-2-(3-(methylamino)-1,1-dioxido-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-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 2-(3-((Cyclobutylmethyl)amino)-1,1-dioxido-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-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 2-Fluoro-6-(3-((2-methoxypropyl)amino)-1,1-dioxido-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-dioxido-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 the above compounds.

18. A pharmaceutical composition comprising: a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

19. Use of a compound as defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of 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, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

20. Use of a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting MRGX2 in a subject.

21. Use of a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject, 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, mastocytic enterocolitis, mast cell activation syndrome (MCAS), interstitial cystitis, food allergy, pruritus, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

22. A combination comprising a compound as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and at least one additional pharmacologically active agent.

23. The combination according to claim 22, 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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