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3-AMINO-4H-BENZO[E][1,2,4]THIADIAZINE 1,1-DIOXIDE DERIVATIVES AS INHIBITORS OF MRGX2

20220119361 · 2022-04-21

    Inventors

    Cpc classification

    International classification

    Abstract

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

    ##STR00001##

    Claims

    1. A compound of Formula 1, ##STR00217## or a tautomer thereof, or a pharmaceutically acceptable salt of the compound of Formula 1 or tautomer thereof, wherein: L is selected from a bond and C.sub.1-4 alkanediyl; R.sup.1 is selected from (a) C.sub.1-4 alkyl which is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C.sub.1-4 alkoxy, amino and aminocarbonyl, wherein each of the C.sub.1-4 alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with from 0 to 2 substituents independently selected from C.sub.1-4 alkyl; and (b) a cyclic group selected from C.sub.3-8 cycloalkyl, C.sub.2-9 heterocyclyl, C.sub.6-14 aryl and C.sub.1-9 heteroaryl, wherein the cyclic group is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino and aminocarbonyl, wherein each of the C.sub.1-4 alkyl and C.sub.1-4 alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with from 0 to 2 substituents independently selected from C.sub.1-4 alkyl; R.sup.2 is a cyclic group selected from C.sub.3-8 cycloalkyl, C.sub.2-9 heterocyclyl, C.sub.6-14 aryl and C.sub.1-9 heteroaryl, wherein the cyclic group is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, C.sub.3-8 cycloalkyl and C.sub.3-5 heterocyclyl, provided the cyclic group has no more than one optional substituent which is selected from C.sub.3-8 cycloalkyl and C.sub.3-5 heterocyclyl, and wherein each of the C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl and C.sub.3-5 heterocyclyl optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein the amino optional substituent is independently substituted with from 0 to 2 substituents independently selected from C.sub.1-4 alkyl; R.sup.3, R.sup.4, and R.sup.5 are each independently selected from hydrogen, halo, cyano, and C.sub.1-3 alkyl; wherein each of the aforementioned heterocyclyl and heteroaryl moieties independently has 1 to 4 heteroatoms as ring members, each independently selected from N, O, and S.

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

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

    4. The compound, tautomer or pharmaceutically acceptable salt according to claim 2, wherein the R.sup.1 C.sub.1-4 alkyl is substituted with from 0 to 3 optional substituents independently selected from halo, C.sub.1-4 alkoxy and aminocarbonyl, wherein each of the C.sub.1-4 alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein each of the aminocarbonyl optional substituents is independently substituted with from 0 to 2 substituents independently selected from C.sub.1-4 alkyl.

    5. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R.sup.1 is a cyclic group selected from C.sub.3-8 cycloalkyl, C.sub.2-9 heterocyclyl, C.sub.6-14 aryl and C.sub.1-9 heteroaryl, wherein the cyclic group is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino and aminocarbonyl, wherein each of the C.sub.1-4 alkyl and C.sub.1-4 alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo, and wherein each of the amino and aminocarbonyl optional substituents is independently substituted with from 0 to 2 substituents independently selected from C.sub.1-4 alkyl.

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

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

    8. The compound, tautomer or pharmaceutically acceptable salt according to claim 5, wherein the R.sup.1 cyclic group is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy, wherein each of the C.sub.1-4 alkyl and C.sub.1-4 alkoxy optional substituents is independently substituted with from 0 to 3 substituents independently selected from halo.

    9. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein L is selected from a bond, —CH.sub.2—, —CH.sub.2CH.sub.2—, and —CH(CH.sub.3)—.

    10. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein L is —CH.sub.2—.

    11. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein Lisa bond.

    12. (canceled)

    13. (canceled)

    14. (canceled)

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

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

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

    18. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are each independently selected from hydrogen, halo and C.sub.1-3 alkyl.

    19. The compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are each hydrogen.

    20. The compound according to claim 1, which is selected from the following compounds and tautomers thereof: 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-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((4-methoxyphenethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((2-(tetrahydrofuran-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(2-chloro-3-fluorophenyl)-3-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((4-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((2,5-difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-fluorobenzyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((2,6-difluorobenzyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-(((6-methylpyridin-2-yl)methyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-(pyridin-2-yl)ethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-((cyclobutylmethyl)amino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((pyridin-4-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (R)-5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; (S)-5-(3,5-difluorophenyl)-3-((2-methoxypropyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 5-(3,5-difluorophenyl)-3-((2-methoxybutyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 3-(benzylamino)-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; 2-fluoro-6-(3-(methylamino)-1,1-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-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile; 2-(1,1-dioxido-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 a pharmaceutically acceptable salt of any one of the aforementioned compounds and tautomers.

    21. A pharmaceutical composition comprising: a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1; and a pharmaceutically acceptable excipient.

    22. A compound, tautomer or pharmaceutically acceptable salt as defined in claim 1 for use as a medicament.

    23. (canceled)

    24. A method for inhibiting MRGX2 in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1.

    25. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, 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, pruiritis, allergic rhinitis, microbial infection, eosinophilic esophagitis (EOE) and chronic pain.

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

    27. The combination according to claim 26, wherein the additional pharmacologically active agent is selected from anti-inflammatory agents, analgesics, biological response modifiers, disease modifying antirheumatic drugs (DMARDs), antihistamines, mast cell stabilizers, prokinetic agents, antidiarrheals, prosecretory agents, antibiotics, antidepressants, anxiolytics, antipsychotics and anticonvulsants.

    Description

    EXAMPLES

    [0299] The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the present invention.

    [0300] .sup.1H Nuclear magnetic resonance (NMR) spectra were obtained for many of the compounds in the following examples. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl.sub.3 (deuterochloroform), DMSO-d.sub.6 (deuterodimethylsulfoxide), CD.sub.3OD (deuteromethanol), CD.sub.3CN (deuteroacetonitrile), and THF-d.sub.8 (deuterotetrahydrofuran). The mass spectra (m/z for [M+H].sup.+) were recorded using either electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

    [0301] Where indicated, products of certain preparations and examples are purified by mass-triggered HPLC (e.g., Pump: Waters™ 2525; MS: ZQ™; Software: MassLynx™) flash chromatography or preparative thin layer chromatography (TLC). Reverse phase chromatography is typically carried out on a column (e.g., Phenomenex Gemini™ 5μ, C18, 30 mm×150 mm; Axia™, 5μ, 30 mm×75 mm) under acidic conditions (“acid mode”) eluting with CH.sub.3CN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or under basic conditions (“basic mode”) eluting with water and 20/80 (v/v) water/acetonitrile mobile phases, both containing 10 mM NH.sub.4HCO.sub.3. Preparative TLC is typically carried out on silica gel 60 F.sub.254 plates. After isolation by chromatography, the solvent is removed and the product is obtained by drying in a centrifugal evaporator (e.g., GeneVac™), rotary evaporator, evacuated flask, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H2) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

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

    [0302] ##STR00006##

    [0303] 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.sub.3 (20 mL) was added PdCl.sub.2(dppf) (0.641 g, 0.876 mmol). The mixture was heated in a microwave reactor at 75° C. for 30 minutes. The residue was diluted with EtOAc and washed with saturated (aq) NH.sub.4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (Teledyne ISCO CombiFlash™, 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%).

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

    [0304] ##STR00007##

    Step A: 2′-chloro-3′,5-difluoro-[1,1′-biphenyl]-2-amine

    [0305] ##STR00008##

    [0306] To a 300 mL heavy-walled flask were added (2-chloro-3-fluorophenyl)boronic acid (5.51 g, 31.6 mmol), 2-bromo-4-fluoroaniline (5 g, 26.3 mmol) and PdCl.sub.2(dppf) (1.925 g, 2.63 mmol) in dioxane (60 mL) and saturated (aq) NaHCO.sub.3 (60.0 mL) to give an orange solution. The flask was sealed, heated to 100° C. and stirred for 18 hours. The reaction mixture was partially concentrated, then diluted with EtOAc, and washed with saturated (aq) NH.sub.4Cl (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was 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].sup.+ 239.4.

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

    [0307] ##STR00009##

    [0308] To a200 mL round-bottomed flask were added sulfurisocyanatidic 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 trichloride (3.13 g, 23.47 mmol) was added and the reaction mixture was heated to 120° C. for 1.5 hours. Following reaction, the mixture was concentrated and diluted with EtOAc and washed with saturated (aq) NH.sub.4Cl (3×80 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a brown solid. The product was purified by column chromatography (Teledyne ISCO CombiFlash™, 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%). .sup.1H NMR (400 MHz, DMSO-d.sub.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).

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

    [0309] To a 200 mL round-bottomed flask were added 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) in POCl.sub.3 (50 mL, 536 mmol) and N,N-diethylaniline (1.716 mL, 10.73 mmol) to give a black solution. The reaction mixture was heated to 120° C. and stirred for 5 hours, was subsequently cooled to ambient temperature, and left to stir overnight. The reaction mixture was poured into ice water and stirred for 2 hours. The black oil eventually formed a brown precipitate that was collected by vacuum filtration and dried under vacuum to give the title compound as a brown solid (2.55 g, 65%). The product was used without further purification.

    Preparation 3: (3-fluoropyridin-2-yl)methanamine

    [0310] ##STR00010##

    [0311] A stirred solution of 3-fluoropicolinonitrile (500 mg, 4.10 mmol) in EtOH (25 mL) and hydrochloric acid (12 M, 1.02 mL) was reacted with H2 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. Following completion of the reaction, the mixture was filtered to remove the catalyst. The solvents were removed under reduced pressure and the resulting solid was suspended in acetonitrile and filtered to give an HCl salt of the title compound (700 mg), which was used without further purification. .sup.1H NMR (400 MHz, CDCl.sub.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).

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

    [0312] ##STR00011##

    [0313] 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 isopropanol was added Et.sub.3N (1.28 mL, 9.24 mmol) with stirring at 80° C. The reaction mixture was stirred at 80° C. for 30 minutes at which time TLC monitoring (DCM/MeOH=10:1 mobile phase) showed the reaction was complete. The volatiles were removed in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with a gradient of 50-80% EtOAc in petroleum ether, to give the title compound as a light-yellow solid (1.20 g). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 433.0.

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

    [0314] ##STR00012##

    Step A: 2′-chloro-5-fluoro-[1,1′-biphenyl]-2-amine

    [0315] ##STR00013##

    [0316] To a solution of 2-bromo-4-fluoro-aniline (5.00 g, 26.31 mmol) and (2-chlorophenyl)boronic acid (4.53 g, 28.94 mmol) in dioxane (50.00 mL) was added Pd(dppf)Cl.sub.2 (962.56 mg, 1.32 mmol) and NaHCO.sub.3 (4.42 g, 52.62 mmol) in H.sub.2O (10.00 mL). The mixture was purged with N.sub.2 (3×) and heated to 120° C. for 2 hours. The solvent was removed in vacuo and the residue was partitioned between H.sub.2O (80 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were combined, washed with brine (50 mL) and dried over Na.sub.2SO.sub.4. 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%). .sup.1H NMR (400 MHz, CDCl.sub.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).

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

    [0317] ##STR00014##

    [0318] To a solution of sulfurisocyanatidic chloride (4.96 g, 35.06 mmol) in nitromethane (60.00 mL) was added 2′-chloro-5-fluoro-[1,1′-biphenyl]-2-amine (5.18 g, 23.37 mmol) at −5° C. to 0° C. The resulting mixture was stirred at −5° C. to 0° C. for 30 minutes and then AlCl.sub.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. A precipitant was collected by filtration. The collected solid was dissolved in EtOAc (50 mL) and washed with saturated (aq) NaHCO.sub.3 solution (3×50 mL). The aqueous layers were combined, adjusted to pH 1 with concentrated (aq) HCl, and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound as a dark solid (3.80 g, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.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).

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

    [0319] 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.sub.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 hours, then cooled to 25° C., poured into ice water (100 mL), and stirred for 1 hour. The mixture was extracted with EtOAc (3×30 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford the title compound as a dark solid (900 mg, 85%). The product was used without further purification.

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

    [0320] ##STR00015##

    [0321] To a 20 mL microwave vial equipped with a stirring device were added (2,3-difluorophenyl)boronic acid (0.507 g, 3.21 mmol), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.00 g, 2.92 mmol), Cs.sub.2CO.sub.3 (2M, 3.65 mL, 7.30 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (0.238 g, 0.292 mmol) dissolved in dioxane (14.60 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes and then diluted in deionized water (˜100 mL). Next 1 N (aq) HCl was added dropwise until a precipitate formed. The solids were collected by vacuum filtration through a Kiriyama Rohto SB-40 glass filter funnel while washing with copious amounts of deionized water followed by hexanes. The filter cake was dried in a vacuum oven to afford the title compound as a (crude) solid (1.164 g).

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

    [0322] ##STR00016##

    [0323] The title compound was prepared in a manner similar to Preparation 6, using (2-chloro-3,5-difluorophenyl)boronic acid (90 mg, 0.467 mmol), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (80 mg, 0.234 mmol), Cs.sub.2CO.sub.3 (2M, 0.292 mL, 0.584 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (19.07 mg, 0.023 mmol) dissolved in dioxane (1168 μL), and was isolated as a (crude) solid (56.2 mg). ESI-MS m/z [M+H].sup.+ 362.9.

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

    [0324] ##STR00017##

    [0325] 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.sub.2CO.sub.3 (0.807 g, 5.84 mmol) in DMA (11.68 mL) was added 2-methoxyethanamine (0.554 mL, 6.42 mmol). The reaction mixture was heated at 100° C. for 2 hours and then cooled and diluted with water (300 mL). An organic phase (oil) pooled at the bottom of the flask. The aqueous phase was decanted and extracted with DCM (3×50 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%).

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

    [0326] ##STR00018##

    [0327] To a 20 mL microwave vial equipped for stirring and charged with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.000 g, 2.92 mmol), (2-chlorophenyl)boronic acid (0.479 g, 3.07 mmol), Cs.sub.2CO.sub.3 (5.84 mL, 11.68 mmol) and dioxane (14.60 mL), was added Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (0.238 g, 0.292 mmol) under nitrogen. The reaction mixture was heated to 120° C. for 15 minutes in a microwave reactor and then poured into water (200 mL). 1N HCl (aq) was added until a tan solid began to form. The solid was filtered and washed with copious amounts of water followed by hexanes to afford the title compound (0.95 g, 99%). ESI-MS m/z [M+H].sup.+ 326.9.

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

    [0328] ##STR00019##

    [0329] To a 20 mL pressurized microwave vial equipped with a stirring bar were added 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (750 mg, 2.91 mmol), 3-chloro-5-iodo-4H-benzo[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).sub.2.CH.sub.2Cl.sub.2 adduct (216 mg, 0.265 mmol) dissolved in dioxane (8.826 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes. Next 1 N (aq) HCl was added, causing solids to precipitate out of solution. The solids were collected by vacuum filtration through a Kiriyama Rohto SB-21 glass filter funnel while washing with copious amounts of deionized water followed by 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) that was used to prepare Examples 48, 49, 50, and 51.

    [0330] In an effort to lower 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% by weight, 40 mg) was added, and the mixture was heated at 60° C. for 2.5 hours. The mixture was subsequently filtered through a RediSep® pre-packed plug with MeOH rinse and concentrated under vacuum to give the title compound (296.3 mg) which was used to prepare Examples 52, 53, 54, and 55.

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

    [0331] ##STR00020##

    [0332] A 20 mL microwave vial equipped for stirring was charged with 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (421 mg, 1.898 mmol), 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (500 mg, 1.460 mmol), Cs.sub.2CO.sub.3 (2.919 mL, 5.84 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (119 mg, 0.146 mmol) and dioxane (7.298 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes, then diluted in deionized water (75 mL) and extracted with DCM/IPA (4×). Only a nominal amount of product went into the organic phase. The aqueous phase was concentrated with 60-angstrom silica gel and the residue was purified by normal phase column chromatography (RediSep® half-column) eluting with 80/20 DCM/MeOH. The product-containing fractions were collected, concentrated, and dried under vacuum to afford the title compound as the major product (549.8 mg). ESI-MS m/z [M+H].sup.+ 311.0.

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

    [0333] ##STR00021##

    [0334] A 20 mL pressurized microwave vial equipped for stirring was charged with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (700 mg, 2.044 mmol), (3,5-difluorophenyl)boronic acid (355 mg, 2.248 mmol), Cs.sub.2CO.sub.3 (2.55 mL, 5.11 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (167 mg, 0.204 mmol) dissolved in dioxane (10.2 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes and then diluted in about 100 mL of deionized water. To the mixture was added 1N HCl (about 3 mL) dropwise until a precipitate formed. The solid was collected by vacuum filtration through a Kiriyama Rohto SB-40 glass funnel while washing with copious amounts of deionized water followed by hexanes to afford the title compound as a pale pink solid (779.6 mg). The crude product was dried in the vacuum oven prior to use.

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

    [0335] ##STR00022##

    [0336] To a20 mL vial were added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (800 mg, 2.34 mmol), methanamine (2M in MeOH, 1.518 mL, 3.04 mmol) and DIPEA (0.408 mL, 2.335 mmol) in DMA (7 mL) to give a yellow solution. The reaction mixture was heated to 80° C. and stirred overnight. LC/MS indicated the reaction was complete. The reaction mixture was subsequently diluted with EtOAc and washed with saturated (aq) NH.sub.4Cl (3×). The organic layers were combined, dried over MgSO4, 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].sup.+ 338.

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

    [0337] ##STR00023##

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

    [0338] ##STR00024##

    [0339] To a 25 mL round-bottomed flask were added 2-bromo-4-methylaniline (700 mg, 3.76 mmol) in nitromethane (5 mL) and the reaction mixture was cooled to −40° C. Sulfurisocyanatidic chloride (0.425 mL, 4.89 mmol) was added and the reaction mixture was allowed to slowly warm to 25° C. and stirred for another 30 minutes. Next aluminum trichloride (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 afford a tan precipitate. The solids were collected by vacuum filtration and dried under vacuum to give the title compound (685 mg, 63%). .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ ppm 2.4 (s, 3H), 4.4 (s, 1H), 7.6 (s, 1H), 7.8 (s, 1H), 10.3 (s, 1H).

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

    [0340] ##STR00025##

    [0341] To a 50 mL round-bottomed 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 POCl.sub.3 (1.382 mL, 14.82 mmol) alone with N,N-diethylaniline (0.151 mL, 0.941 mmol). The reaction mixture was heated to 100° C. for 16 hours, then cooled to 0° C., quenched with water, and sonicated to give a precipitate. The solids were collected by vacuum filtration to give the title compound as a tan solid (160 mg, 22%). The product was used without purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6), δ ppm 2.4 (s, 3H), 7.5 (s, 1H), 7.7 (s, 1H).

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

    [0342] To a 5 mL microwave vial were added 5-bromo-3-chloro-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (160 mg, 0.517 mmol), Pd.sub.2Cl.sub.2(dppf) (3.78 mg, 5.17 μmol), (2-chloro-3-fluorophenyl)boronic acid (108 mg, 0.620 mmol), and saturated (aq) NaHCO.sub.3 (3.0 mL) in dioxane (3.0 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 75° C., then diluted in EtOAc, and washed with saturated (aq) NH.sub.4Cl (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (ISCO 4 g column) eluting with a gradient of 30-100% EtOAc in hexane to give the title compound as a yellow oil (44 mg, 24%). ESI-MS m/z [M+H].sup.+ 359.0.

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

    [0343] ##STR00026##

    [0344] A 100 mL round-bottomed 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.sub.3N (0.916 ml, 6.57 mmol) and EtOH (20 mL). The resulting brown solution was heated to 65° C. and stirred overnight. LC/MS showed the reaction was not yet complete. The reaction mixture was allowed to stir overnight again, after which LC/MS showed the reaction was mostly complete. The reaction mixture was subsequently concentrated, taken up in EtOAc, and washed with saturated (aq) NH.sub.4Cl (3×). The organic layers were combined, dried over MgSO4, 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 purple solid. ESI-MS m/z [M+H].sup.+ 442.

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

    [0345] ##STR00027##

    [0346] To a solution of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol) in EtOH (mL) was added 3-isopropylaniline (74.0 mg, 0.547 mmol) followed by Et.sub.3N (0.102 mL, 0.730 mmol). The reaction mixture was heated at 80° C. for 2 days and set aside (first reaction mixture). To a 10 mL vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol), 3-isopropylaniline (64.1 mg, 0.474 mmol) and DIPEA (0.127 mL, 0.730 mmol) in DMA (3.5 mL). The second reaction mixture was heated to 100° C. and stirred for 18 hours. The second reaction mixture was combined with the first reaction mixture, diluted with EtOAc and washed with saturated (aq) NH.sub.4Cl (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO) eluting with a gradient of 20-70% EtOAc in hexane to give the title compound (118 mg, 37%). ESI-MS m/z [M+H].sup.+ 442.1.

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

    [0347] ##STR00028##

    [0348] 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.sub.3N (0.102 mL, 0.730 mmol). The reaction mixture was heated at 80° C. for 3 days to give a first batch of product (about 50% conversion of starting material). To a 10 mL vial was added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (125 mg, 0.365 mmol), 6-isopropylpyridin-3-amine (64.6 mg, 0.474 mmol) and DIPEA (0.127 mL, 0.730 mmol) in DMA (3.5 mL). The reaction mixture was heated to 100° C. and stirred for 2 days to give a second batch of product (about 50% conversion). The first and second batches were combined, diluted with EtOAc and washed with saturated (aq) NH.sub.4Cl (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO) eluting with a gradient of 40-95% EtOAc in hexane to give the title compound as a mixture with starting material (87 mg). ESI-MS m/z [M+H].sup.+ 443.0.

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

    [0349] ##STR00029##

    [0350] To a 10 mL vial were added 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (250 mg, 0.730 mmol), (6-methoxypyridin-2-yl)methanamine (131 mg, 0.949 mmol) and DIPEA (0.255 mL, 1.460 mmol) in DMA (3.5 mL). The reaction mixture was heated to 100° C. and stirred for 5 hours. The reaction mixture was subsequently diluted with EtOAc and washed with saturated (aq) NH.sub.4Cl (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO NH column) eluting with a gradient of 0-10% MeOH in DCM. The title compound was isolated as a pale yellow solid (167 mg, 52%). ESI-MS m/z [M+H].sup.+ 445.0.

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

    [0351] ##STR00030##

    [0352] The title compound was prepared in a manner similar to Preparation 18, using 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (175 mg, 0.511 mmol), (3-fluoropyridin-2-yl)methanamine (97 mg, 0.766 mmol) and DIPEA (0.178 mL, 1.022 mmol) in DMA (2 mL), and was isolated as a pale yellow solid (53 mg, 24%). ESI-MS m/z [M+H].sup.+ 433.0.

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

    [0353] ##STR00031##

    [0354] The title compound was prepared in a manner similar to Preparation 18, using 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.200 g, 0.584 mmol) and aniline (0.800 mL, 8.76 mmol), and was isolated as a pale pink solid (35 mg, 15%). ESI-MS m/z [M+H].sup.+ 400.0.

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

    [0355] ##STR00032##

    [0356] To a 2-5 mL microwave vial were 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.sub.2CO.sub.3 (81 mg, 0.584 mmol) in DMA (1.168 mL). The reaction mixture was heated at 100° C. for 2 hours, then poured into water, and extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give the title compound as a light brown oil, which was used without further purification. ESI-MS m/z [M+H].sup.+ 421.2.

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

    [0357] ##STR00033##

    [0358] To a 2-5 mL microwave vial were 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.sub.2CO.sub.3 (81 mg, 0.584 mmol) in DMA (1.168 mL). The reaction mixture was heated at 100° C. for 2 hours, then poured into water, and extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give the title compound as a light brown oil, which was used without further purification. ESI-MS m/z [M+H].sup.+ 396.0.

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

    [0359] ##STR00034##

    [0360] The title compound was prepared in a manner similar 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.sub.2CO.sub.3 (81 mg, 0.584 mmol) in DMA (1.168 mL), and was isolated as an oil. ESI-MS m/z [M+H].sup.+ 391.9.

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

    [0361] ##STR00035##

    [0362] 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 addition of the benzo[e][1,2,4]thiadiazine 1,1-dioxide the mixture was cooled in an ice bath. Following the addition, the reaction mixture was stirred at room temperature overnight. One drop of Et.sub.3N was added and the reaction mixture was stirred at room temperature for 1 hour and then at 65° C. for another hour. Additional pyridin-2-ylmethanamine (0.020 mL, 0.200 mmol) was added and the mixture was stirred at 65° C. for 6 hours. This first reaction mixture was set aside. To a stirred solution of pyridin-2-ylmethanamine (40.9 μL, 0.400 mmol) in 2-propanol (250 μL) was added Et.sub.3N (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 addition of the base and the benzo[e][1,2,4]thiadiazine 1,1-dioxide and was subsequently stirred at room temperature for 96 hours. The first and second reaction mixtures were combined and purified by preparative HPLC, eluting with a gradient of 5-95% ACN in water (formic acid conditions). The title compound was isolated as an off-white solid (42 mg, 51%). ESI-MS m/z [M+H].sup.+ 415.0.

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

    [0363] ##STR00036##

    [0364] To a stirring 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), were added PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (298 mg, 0.365 mmol) and K.sub.2CO.sub.3 (1.110 g, 8.03 mmol). The reaction mixture was heated at 100° C. for 1.5 hours, then cooled to room temperature, and poured into water (50 mL). A tan precipitate formed. A 1N HCl (aq) solution was added to adjust the pH from 8 to 5, precipitating more solids. The mixture was filtered, but only a trace amount of material was recovered. The filtrate was extracted with EtOAc (3×) forming an emulsion, which was separated and extracted with DCM. The product was exclusively in the water layers, which were concentrated. The solids were rinsed with ACN and the salts were filtered off. The filtrate was concentrated and dried in the vacuum oven to give the title compound as a tan solid, which was used without further purification (1.16 g, 95% purity by LC/MS). ESI-MS m/z [M+H].sup.+ 297.0.

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

    [0365] ##STR00037##

    [0366] 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.sub.2(dppf) (50 mg, 0.068 mmol). The mixture was sparged with nitrogen. Saturated (aq) NaHCO.sub.3 (5 mL) was added and the reaction mixture was stirred and heated at 140° C. in a microwave reactor. The solvents were removed under high vacuum. The crude material was suspended in DMA (30 mL) and the residual solids were removed by filtration. The filtrate was used as a stock solution of the title compound (3 mmol/mL). ESI-MS m/z [M+H].sup.+ 329.0.

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

    [0367] ##STR00038##

    [0368] To a mixture of 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.461 g, 1.34 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.28 g, 1.2 mmol), Cs.sub.2CO.sub.3 (2.445 mL, 4.89 mmol) and dioxane (6.11 mL) in a 20 mL microwave vial equipped for stirring, was added Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (0.100 g, 0.122 mmol) under nitrogen. The reaction mixture was heated in a microwave reactor to 120° C. for 20 minutes, then cooled, poured into water (150 mL) and acidified with 1N HCl (aq) until a brown precipitate formed. The solid was filtered and washed with copious amounts of water followed by hexanes to give the (crude) title compound (0.42 g). ESI-MS m/z [M+H].sup.+ 318.0.

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

    [0369] ##STR00039##

    [0370] 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.sub.2CO.sub.3 (3.21 mL, 6.42 mmol) and dioxane (8.03 mL). Next, Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (0.131 g, 0.161 mmol) was added under nitrogen. The reaction mixture was heated in a microwave reactor to 120° C. for 20 minutes, then cooled, poured into water (150 mL) and acidified with 1N HCl (aq) until a brown precipitate formed. The solid was filtered and washed with copious amounts of water followed by hexanes to give the title compound which was used without further purification (0.42 g, 78%).

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

    [0371] ##STR00040##

    [0372] To a 20 mL microwave vial equipped for stirring and charged with 3-chloro-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (0.297 g, 0.867 mmol), 2-(2-cyclopropyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 g, 0.954 mmol), Cs.sub.2CO.sub.3 (1.734 mL, 3.47 mmol) and dioxane (4.34 mL), was added Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (0.071 g, 0.087 mmol) under nitrogen. The reaction mixture was heated to 120° C. for 20 minutes in a microwave reactor and then cooled, poured into water (150 mL) and acidified with 1N HCl (aq) until a brown precipitate formed. The solid was filtered while washing with copious amounts of water followed by hexanes to give the title compound (0.2 g, 66%).

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

    [0373] ##STR00041##

    [0374] 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.sub.3N (0.363 mL, 2.61 mmol) in EtOH (7.00 mL) was added methanamine (2 M MeOH solution, 0.869 mL, 1.74 mmol). The mixture was heated at 65° C. for 12 hours. The solvent was subsequently removed in vacuo, and the residue was suspended in DCM and washed with saturated (aq) NH.sub.4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (Teledyne ISCO CombiFlash™, 24 g column) eluting with a gradient of 40-100% EtOAc in hexanes. The fractions containing the product were combined and the solvent removed to give a white solid, which was dissolved in EtOAc and IPA upon heating and sonication. The solution was cooled in an ice bath and allowed to equilibrate at room temperature over a 12-hour period during which white crystals were formed. The solution was decanted and the crystals were collected by vacuum filtration while washing with IPA. The crystalline solid was dried for several hours at 35° C. under vacuum to give the title compound as a white, crystalline solid (85.0 mg, 29.1%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 340.0.

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

    [0375] ##STR00042##

    [0376] 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 (120 mg, 0.348 mmol), DIPEA (0.121 mL, 0.695 mmol), and methoxyethanamine (31.3 mg, 0.417 mmol) in DMA (0.695 mL), and was isolated as a pale beige solid (76.8 mg, 57.6%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 384.0.

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

    [0377] ##STR00043##

    [0378] To a 20 mL vial were added 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (300 mg, 0.826 mmol) in EtOH (9 mL) along with methanamine (33% in MeOH, 0.134 mL, 1.074 mmol) and Et.sub.3N (0.345 mL, 2.48 mmol). The resulting yellow solution was heated to 65° C. and stirred for 4 hours. The mixture was subsequently concentrated, diluted with EtOAc, and washed with saturated (aq) NH.sub.4Cl (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (Teledyne ISCO CombiFlash™, 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%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 358.0; mp 241-243° C.

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

    [0379] ##STR00044##

    [0380] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol) in EtOH (3 mL), 2-methoxyethanamine (26.9 mg, 0.358 mmol) and Et.sub.3N (0.115 mL, 0.826 mmol), and was isolated as a yellow film (19 mg, 17%); ESI-MS m/z [M+H].sup.+ 402.2.

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

    [0381] ##STR00045##

    [0382] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol) in EtOH (3 mL), thiazol-2-ylmethanamine hydrochloride (53.9 mg, 0.358 mmol) and Et.sub.3N (0.115 mL, 0.826 mmol), and was isolated as a yellow film (15 mg, 12%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 441.2.

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

    [0383] ##STR00046##

    [0384] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol) in EtOH (3 mL), ethanamine (2 M in THF, 0.179 mL, 0.358 mmol) and Et.sub.3N (0.115 mL, 0.826 mmol), and was isolated as a brown oil (10 mg, 10%); ESI-MS m/z [M+H].sup.+ 371.9.

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

    [0385] ##STR00047##

    [0386] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol) in EtOH (3 mL), cyclopropylmethanamine (25.5 mg, 0.358 mmol) and Et.sub.3N (0.115 mL, 0.826 mmol), and was isolated as a yellow oil (25 mg, 23%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 398.1.

    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

    [0387] ##STR00048##

    [0388] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol) in EtOH (3 mL), 1-(thiazol-2-yl)ethanamine hydrochloride (58.9 mg, 0.358 mmol) and Et.sub.3N (0.115 mL, 0.826 mmol), and was isolated as a brown film (8.0 mg, 6%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 455.0.

    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

    [0389] ##STR00049##

    [0390] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.275 mmol) in EtOH (3 mL), 1-(thiazol-4-yl)ethanamine (45.9 mg, 0.358 mmol) and Et.sub.3N (0.115 mL, 0.826 mmol), and was isolated as a brown film (4 mg, 3%); ESI-MS m/z [M+H].sup.+ 454.9.

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

    [0391] ##STR00050##

    [0392] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.138 mmol) in EtOH (0.688 mL), 2,2-difluoroethanamine, HCl (24.27 mg, 0.207 mmol) and Et.sub.3N (57.6 μL, 0.413 mmol), and was isolated as a pale, beige solid (19.1 mg, 34%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 408.0.

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

    [0393] ##STR00051##

    [0394] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chloro-3-fluorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.138 mmol) in EtOH (0.688 mL), 2-fluoroethanamine, HCl (20.56 mg, 0.207 mmol) and Et.sub.3N (57.6 μL, 0.413 mmol), and was isolated as a yellow film (10.8 mg, 20.6%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 390.0.

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

    [0395] ##STR00052##

    [0396] 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.sub.2 (84.9 mg, 116 μmol) and NaHCO.sub.3 (244 mg, 2.90 mmol) under N2 atmosphere. The reaction mixture was stirred at 110° C. for 2 hours, then diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with water (3×20 mL) and then brine (1×15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was purified by preparative HPLC to give the title compound as a light-yellow solid (225 mg, 44.3%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 435.0.

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

    [0397] ##STR00053##

    [0398] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (500 mg, 1.45 mmol) and methanamine (2M in THF, 10.0 mL, 20.0 mmol), except the reaction mixture was heated to 80° C. for 1 hour. The solvent was removed under vacuum and the crude product was purified by preparative HPLC (Phenomenex Gemini® C18, 10 μm, ID 50×250 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%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 340.1

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

    [0399] ##STR00054##

    [0400] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), methoxyethanamine (34.81 mg, 0.463 mmol) and Et.sub.3N (115 μL, 0.826 mmol) in EtOH (3 mL), and was isolated as a white solid (30.14 mg, 34%). .sup.1H NMR (400 MHz, CD3CN) 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].sup.+ 384.0.

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

    [0401] ##STR00055##

    [0402] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), ethanamine (52.24 mg, 1.16 mmol) and Et.sub.3N (151 μL, 0.826 mmol) in EtOH (3 mL), and was isolated as a white solid (17 mg, 20%). .sup.1H NMR (400 MHz, CD3CN) 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].sup.+ 354.0.

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

    [0403] ##STR00056##

    [0404] The title compound was prepared in a manner similar to Example 3, using 3-chloro-5-(2-chlorophenyl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.290 mmol), (3-fluoropyridin-2-yl)methanamine (61.39 mg, 486.70 μmol) and Et.sub.3N (151 μL, 0.826 mmol) in EtOH (3 mL), and was isolated as a white solid (24.87 mg, 14%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 435.0.

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

    [0405] ##STR00057##

    [0406] 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 cyclobutylmethanamine, HCl (16.91 mg, 0.139 mmol) in DMA (0.232 mL), and was isolated as a brown-orange solid (22.8 mg, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 394.0.

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

    [0407] ##STR00058##

    [0408] 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 (6-methoxypyridin-2-yl)methanamine (14.41 mg, 0.104 mmol) in DMA (0.174 mL), and was isolated as a pale, yellow oil (24.5 mg, 63%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 447.0.

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

    [0409] ##STR00059##

    [0410] To a 2 mL conical microwave vial equipped with a stirring device were added 3-chloro-5-(2,3-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.122 mmol), DIPEA (42.5 μL, 0.243 mmol), and (6-methoxypyridin-2-yl)methanamine (20.18 mg, 0.146 mmol) dissolved in DMA (243 μL). The reaction mixture was heated at 90° C. for 4 hours and was subsequently purified by mass-triggered preparative-LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 35-60% ACN in water (acid mode). The product-containing fractions were collected, concentrated, and dried in vacuo to afford the title compound as a pale, yellow solid (27.4 mg, 52%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 431.0.

    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

    [0411] ##STR00060##

    [0412] 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 3-(aminomethyl)-1-methylpyridin-2(1H)-one (20.18 mg, 0.146 mmol) in DMA (243 μL), and was isolated as a pale, yellow solid (1.2 mg, 2%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 431.1.

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

    [0413] ##STR00061##

    [0414] 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 (60 mg, 0.183 mmol), DIPEA (31.9 μL, 0.183 mmol), and 2-fluoroethanamine HCl (23.6 mg, 0.237 mmol) in DMA (365 μL), and was isolated as a tan solid (25 mg, 39%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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).

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

    [0415] ##STR00062##

    [0416] 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 (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 was isolated as a tan solid (14.2 mg, 20.6%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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).

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

    [0417] ##STR00063##

    [0418] 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 (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 was isolated as an orange-brown oil (25.7 mg, 36.9%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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).

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

    [0419] ##STR00064##

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

    [0420] ##STR00065##

    [0421] The racemate prepared in Example 23 was resolved by chiral chromatography using SFC/UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20×150 mm, flow rate at 75 mL/min) eluting with 25% MeOH. The first eluting peak was arbitrarily assigned R-stereochemical configuration (Example 24) and the second eluting peak was assign S-stereochemical configuration (Example 25). Each of the title compounds was isolated as a white solid (7 mg).

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

    [0422] ##STR00066##

    [0423] 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 (60 mg, 0.183 mmol), DIPEA (31.9 μL, 0.183 mmol), and methanamine (2 M MeOH solution, 0.119 mL, 0.237 mmol) in DMA (365 μL), and was isolated as a tan solid (13 mg, 22%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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).

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

    [0424] ##STR00067##

    [0425] 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 was isolated as a colorless oil (5 mg, 10%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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].sup.+ 391.1.

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

    [0426] ##STR00068##

    [0427] 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 was isolated as a pale, beige solid (13.0 mg, 28%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 407.0.

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

    [0428] ##STR00069##

    [0429] 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 cyclopropylmethanamine (9.89 mg, 0.139 mmol) in DMA (0.232 mL), and was isolated as a brown, orange solid (13.6 mg, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 380.0.

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

    [0430] ##STR00070##

    [0431] 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 (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 was isolated as a pale, yellow solid (33.7 mg, 46%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 421.0.

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

    [0432] ##STR00071##

    [0433] 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 pyridin-2-ylmethanamine (15.04 mg, 0.139 mmol) in DMA (232 μL), and was isolated as a pale, green solid (30.4 mg, 63%). .sup.1H NMR (400 MHz, DMSO-d.sub.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 (br s, 1H), 8.60 (d, J=4.55 Hz, 1H), 9.41 (s, 1H); ESI-MS m/z [M+H].sup.+ 417.0.

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

    [0434] ##STR00072##

    [0435] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (56.2 mg, 0.155 mmol), DIPEA (54.1 μL, 0.309 mmol), and 2-methoxyethanamine (13.95 mg, 0.186 mmol) in DMA (500 μL), and was isolated as a clear film (7.1 mg, 11%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 3.35 (s, 3H), 3.49 (br s, 4H), 7.15 (d, J=7.33 Hz, 1H), 7.32-7.48 (m, 3H), 7.89 (dd, J=7.58, 1.77 Hz, 1H); ESI-MS m/z [M+H].sup.+ 402.0.

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

    [0436] ##STR00073##

    [0437] 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-methoxypropan-1-amine, HCl (17.47 mg, 0.139 mmol) in DMA (232 μL), and was isolated as a pale, beige solid (21.6 mg, 47%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 398.0.

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

    [0438] ##STR00074##

    [0439] 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 2,2-difluoroethanamine, HCl (16.34 mg, 0.139 mmol) in DMA (232 μL), and was isolated as a brown, orange solid (13.5 mg, 30%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 390.0.

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

    [0440] ##STR00075##

    [0441] 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.sub.2CO.sub.3 (2M, 0.210 mL, 0.420 mmol) and dioxane (0.525 mL). To the mixture was added Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (4.28 mg, 5.25 μmol) under nitrogen. The reaction mixture was heated to 100° C. in a microwave reactor for 2 hours, then cooled, diluted with MeOH (1 mL) and filtered. The residue was purified by preparative LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 25-90% ACN in water (acid mode). The product-containing fractions were collected, concentrated, and dried in vacuo to give the title compound as a tan solid (2 mg, 5%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 366.0.

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

    [0442] ##STR00076##

    [0443] The title compound was 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), 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).sub.2.CH.sub.2Cl.sub.2 adduct (12.85 mg, 0.016 mmol) in dioxane (525 μL), and was isolated as a white solid (49.7 mg, 82%). 1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 385.0.

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

    [0444] ##STR00077##

    [0445] The title compound was 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 (40 mg, 0.105 mmol), (2,3-difluorophenyl)boronic acid (22 mg, 0.136 mmol), Cs.sub.2CO.sub.3 (2M, 0.210 mL, 0.420 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (8.57 mg, 10.49 μmol) in dioxane (525 μL), and was isolated as a tan solid (19 mg, 49%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 368.0.

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

    [0446] ##STR00078##

    [0447] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (50.6 μL, 0.290 mmol), and (5-methyloxazol-2-yl)methanamine (19.49 mg, 0.174 mmol) in DMA (290 μL), and was isolated as a yellow-orange solid (18.6 mg, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.28 (d, J=1.26 Hz, 3H), 4.53 (dd, J=5.56, 2.27 Hz, 2H), 6.80 (d, J=1.01 Hz, 1H), 7.35 (dd, J=6.44, 1.14 Hz, 1H), 7.41 (d, J=7.58 Hz, 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].sup.+ 421.0.

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

    [0448] ##STR00079##

    [0449] 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 ethanamine, HCl (11.34 mg, 0.139 mmol) in DMA (232 μL), and was isolated as a pale, beige solid (15.6 mg, 38%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.10 (t, J=7.20 Hz, 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, 1.26 Hz, 1H), 8.98 (s, 1H); ESI-MS m/z [M+H].sup.+ 354.1.

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

    [0450] ##STR00080##

    [0451] To a solution of 2-methoxypropan-1-amine, HCl (34.9 mg, 0.278 mmol) and DIPEA (37.4 μL, 0.214 mmol) in DMA (428 μL) was added 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (70 mg, 0.214 mmol). The reaction mixture was heated at 70° C. for 24 hours, then diluted with MeOH (1 mL), and filtered. The residue purified by preparative LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a 25-90% gradient of ACN in water (acid mode). The product-containing fractions were collected, concentrated, and dried in vacuo to afford the title compound as a brown solid (16 mg, 20% yield). ESI-MS m/z [M+H].sup.+ 380.0.

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

    [0452] ##STR00081##

    [0453] The title compound was prepared in a manner similar 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 was isolated as a black oil (34 mg, 56%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 399.8.

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

    [0454] ##STR00082##

    [0455] The title compound was prepared in a manner similar to Example 40, using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), ethanamine, HCl (19.44 mg, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL), and was isolated as a pale, beige solid (14.9 mg, 24%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 336.0.

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

    [0456] ##STR00083##

    [0457] The title compound was prepared in a manner similar to Example 40, using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), methanamine (2M in MeOH) (119 μL, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL), and was isolated as a pale, beige solid (10.6 mg, 18%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 322.0.

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

    [0458] ##STR00084##

    [0459] The title compound was prepared in a manner similar to Example 40, using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), 2,2-difluoroethanamine, HCl (28.0 mg, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL), and was isolated as a pale, beige solid (9.0 mg, 13%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 372.0.

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

    [0460] ##STR00085##

    [0461] The title compound was prepared in a manner similar to Example 40, using 3-chloro-5-(2-chlorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (60 mg, 0.183 mmol), 2-fluoroethanamine, HCl (23.73 mg, 0.238 mmol) and DIPEA (64.1 μL, 0.367 mmol) in DMA (367 μL), and was isolated as a brown, orange solid (26.8 mg, 41%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.48-3.59 (m, 3H), 4.48 (t, J=5.05 Hz, 1H), 4.60 (t, J=4.80 Hz, 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, 1.39 Hz, 2H), 7.79 (dd, J=7.58, 1.77 Hz, 1H), 9.07 (s, 1H); ESI-MS m/z [M+H].sup.+ 354.0.

    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

    [0462] ##STR00086##

    [0463] 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 3-(aminomethyl)-1-methylpyridin-2(1H)-one (16.01 mg, 0.116 mmol) in DMA (232 μL), and was isolated as a pale, beige solid (16.7 mg, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 3.47 (s, 3H), 4.14-4.25 (m, 2H), 6.25 (t, J=6.82 Hz, 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, 1.64 Hz, 1H), 7.73-7.82 (m, 2H), 9.16 (s, 1H); ESI-MS m/z [M+H].sup.+ 447.0.

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

    [0464] ##STR00087##

    [0465] 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 was isolated as a clear film (2.6 mg, 8%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 398.0.

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

    [0466] ##STR00088##

    [0467] To a 2 mL scintillation vial equipped with a stirring device were 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, then filtered through a 12 mL fritted syringe containing a 0.5-inch pad of Celite®. The syringe was rinsed MeOH and the filtrate purified by mass-triggered preparative LC/MS (Waters® XSelect CSH Prep C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 20-50% ACN in water (acid mode). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a brown-orange film (6.5 mg, 14%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 408.0.

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

    [0468] ##STR00089##

    [0469] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), DIPEA (30.3 μL, 0.173 mmol), and thiazol-2-ylmethanamine, HCl (15.66 mg, 0.104 mmol) dissolved in DMA (433 μL), and was isolated as a clear film (1.46 mg, 4%). 1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 424.0.

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

    [0470] ##STR00090##

    [0471] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.4 μL, 0.231 mmol), and cyclopropylmethanamine (9.86 mg, 0.139 mmol) dissolved in DMA (385 μL), and was isolated as a brown-orange solid (6.4 mg, 15%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.22 (d, J=3.79 Hz, 2H), 0.44-0.47 (m, 2H), 1.23 (br s, 3H), 3.03-3.10 (m, 2H), 7.21 (d, J=8.59 Hz, 1H), 7.49-7.52 (m, 1H), 7.57 (s, 1H), 7.79 (br s, 1H), 7.85 (s, 1H), 8.22 (d, J=5.05 Hz, 1H), 8.39 (d, J=5.05 Hz, 1H), 9.15 (s, 1H); ESI-MS m/z [M+H].sup.+ 381.0.

    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

    [0472] ##STR00091##

    [0473] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), DIPEA (40.4 μL, 0.231 mmol), and (3-fluoropyridin-2-yl)methanamine, HCl (22.55 mg, 0.139 mmol) dissolved in DMA (385 μL), and was isolated as a beige solid (3.3 mg, 7%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 1.34 (s, 4H), 4.75 (br s, 2H), 7.36-7.57 (m, 4H), 7.65 (t, J=9.09 Hz, 1H), 7.99 (dd, J=7.58, 1.52 Hz, 1H), 8.28-8.44 (m, 2H); ESI-MS m/z [M+H].sup.+ 436.0.

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

    [0474] ##STR00092##

    [0475] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), Et.sub.3N (24.16 μL, 0.231 mmol), and ethanamine (70% in water, 7.01 μL, 0.087 mmol) dissolved in EtOH (500 μL), and was isolated as a clear film (3.3 mg, 11%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 355.0.

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

    [0476] ##STR00093##

    [0477] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), Et.sub.3N (32.2 μL, 0.231 mmol), and 2,2-difluoroethanamine, HCl (16.30 mg, 0.139 mmol) dissolved in EtOH (500 μL), and was isolated as a clear film (6.9 mg, 15%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 391.1.

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

    [0478] ##STR00094##

    [0479] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), Et.sub.3N (32.2 μL, 0.231 mmol), and (4-fluorophenyl)methanamine (17.35 mg, 0.139 mmol) dissolved in EtOH (500 μL), and was isolated as an orange solid (12.5 mg, 25%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 435.3.

    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

    [0480] ##STR00095##

    [0481] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (40 mg, 0.116 mmol), Et.sub.3N (32.2 μL, 0.231 mmol), and 2-(aminomethyl)thiazole-5-carbonitrile, HCl (24.35 mg, 0.139 mmol) dissolved in EtOH (500 μL), and was isolated as a yellow solid (16.1 mg, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 449.3.

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

    [0482] ##STR00096##

    [0483] The title compound was prepared in a manner similar to Example 48, using 3-chloro-5-(3-chloro-2-fluoropyridin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (19.25 mg, 0.056 mmol), Et.sub.3N (23.25 μL, 0.167 mmol), and methanamine (33% in EtOH) (10.38 μL, 0.083 mmol) dissolved in EtOH (479 μL), and was isolated as a pale, beige film (2.2 mg, 12%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 341.0.

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

    [0484] ##STR00097##

    [0485] 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 was isolated as a pale, beige solid (24.8 mg, 49%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 439.0.

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

    [0486] ##STR00098##

    [0487] 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 was isolated as a pale, yellow film (15.4 mg, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 412.0.

    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

    [0488] ##STR00099##

    [0489] A 5 mL microwave vial equipped for stirring was charged 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), (5-chloropyridin-2-yl)methanamine (35.8 mg, 0.251 mmol), DIPEA (67.4 μL, 0.386 mmol) and DMA (386 μL). The reaction mixture was heated at 70° C. for 21 hours, then diluted in MeOH and filtered through a 12 mL fritted syringe containing a 0.5-inch pad of Celite®. The product was purified by column chromatography and dried on a Biotage TurboVap® II (water bath set at 60° C.) to afford the title compound as a pale, yellow solid (17.9 mg, 22%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 417.0.

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

    [0490] ##STR00100##

    [0491] A 5 mL microwave vial equipped for stirring was charged 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). The reaction mixture was heated at 70° C. for 15 hours, then diluted in MeOH and filtered through a 12 mL fritted syringe containing a 0.5-inch pad of Celite®. The product was purified by mass-triggered preparative LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a 20-45% gradient of ACN in water (acid mode). The product-containing fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow-orange solid (17.9 mg, 26%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 364.0.

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

    [0492] ##STR00101##

    [0493] The title compound was prepared in a manner similar to Example 60, 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), cyclobutylmethanamine, HCl (25.4 mg, 0.209 mmol) and DIPEA (28.1 μL, 0.161 mmol) in DMA (322 μL), and was isolated as colorless oil (34 mg, 56%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 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, 5.43 Hz, 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).

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

    [0494] ##STR00102##

    [0495] 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-amino-N,N-dimethylacetamide (14.20 mg, 0.139 mmol) in DMA (232 μL), and was isolated as a pale, beige solid (12.2 mg, 26%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.88 (s, 3H), 2.97 (s, 3H), 4.11 (d, J=4.29 Hz, 2H), 7.33-7.46 (m, 3H), 7.57-7.66 (m, 2H), 7.76 (t, J=4.29 Hz, 1H), 7.81 (dd, J=7.71, 1.39 Hz, 1H), 9.53 (s, 1H); ESI-MS m/z [M+H].sup.+ 411.0.

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

    [0496] ##STR00103##

    [0497] The title compound was 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.sub.2CO.sub.3 (2M, 197 μL, 0.394 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (12.85 mg, 0.016 mmol) in dioxane (787 μL), and was isolated as a pale, yellow solid (21.2 mg, 36.3%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 372.0.

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

    [0498] ##STR00104##

    [0499] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and isothiazol-3-ylmethanamine (10.75 mg, 0.094 mmol) in EtOH (2 mL), and was isolated as a white solid (2 mg, 7%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 423.0.

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

    [0500] ##STR00105##

    [0501] 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 (75.0 mg, 0.217 mmol), Et.sub.3N (91 μL, 0.652 mmol), and thiazol-2-ylmethanamine hydrochloride (120 mg, 0.796 mmol) in EtOH (3.0 mL), and was isolated as a white solid (115 mg, 46%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 423.0.

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

    [0502] ##STR00106##

    [0503] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and pyrimidine-2-ylmethylamine (15.8 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a yellow oil (12 mg, 40%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 418.0.

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

    [0504] ##STR00107##

    [0505] A TFA salt of the title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), Et.sub.3N (61 μL, 0.435 mmol), and 2-(pyridin-2-yl)ethanamine (26.5 mg, 0.217 mmol) in EtOH (2 mL), and was isolated as an off-white solid (30 mg, 48%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 431.1.

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

    [0506] ##STR00108##

    [0507] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 2-(pyridine-4-yl)ethanamine (13.3 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a white solid (9 mg, 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 431.1.

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

    [0508] ##STR00109##

    [0509] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 2-(pyridine-3-yl)ethanamine (13 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a white solid (10 mg, 32%); ESI-MS m/z [M+H].sup.+ 431.1.

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

    [0510] ##STR00110##

    [0511] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 2-(3-methoxyphenyl)ethanamine (16.4 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a white solid (5 mg, 14%); ESI-MS m/z [M+H].sup.+ 460.1.

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

    [0512] ##STR00111##

    [0513] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 2-(2-methoxyphenyl)ethanamine (16.4 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a white solid (4 mg, 12%); ESI-MS m/z [M+H].sup.+ 460.1.

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

    [0514] ##STR00112##

    [0515] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 2-(4-methoxyphenyl)ethanamine (16.4 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a white solid (3.0 mg, 9%); ESI-MS m/z [M+H].sup.+ 460.1.

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

    [0516] ##STR00113##

    [0517] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 2-(tetrahydrofuran-2-yl)ethanamine (12.5 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a brown film (2.0 mg, 7%); ESI-MS m/z [M+H].sup.+ 424.1.

    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

    [0518] ##STR00114##

    [0519] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.072 mmol), Et.sub.3N (30 μL, 0.217 mmol), and 1-isopropyl-5-methyl-1H-pyrazol-3-amine (15 mg, 0.109 mmol) in EtOH (2 mL), and was isolated as a white solid (1 mg, 3%); ESI-MS m/z [M+H].sup.+ 448.1.

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

    [0520] ##STR00115##

    [0521] 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.sub.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 the reaction was complete. The solvent was removed and the product was taken up in DMF (1 mL), filtered, and purified by supercritical fluid chromatography. The purified fractions were evaporated on a TurboVap® to give the title compound as a white solid (6.7 mg, 21%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 418.1.

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

    [0522] ##STR00116##

    [0523] The title compound was prepared 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.sub.3N (0.032 mL, 0.228 mmol) in EtOH (2 mL), and was isolated as a white solid (2.7 mg, 8%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 436.0.

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

    [0524] ##STR00117##

    [0525] The title compound was prepared 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-fluorophenyl)methanamine (19 mg, 0.152 mmol) and Et.sub.3N (0.032 mL, 0.228 mmol) in EtOH (2 mL), and was isolated as a white solid (3.5 mg, 11%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 418.1.

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

    [0526] ##STR00118##

    [0527] The title compound was prepared 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), (2,6-difluorophenyl)methanamine (22 mg, 0.152 mmol) and Et.sub.3N (0.032 mL, 0.228 mmol) in EtOH (2 mL), and was isolated as a white solid (2 mg, 6%). ESI-MS m/z [M+H].sup.+ 436.0.

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

    [0528] ##STR00119##

    [0529] The title compound was prepared 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), (6-methylpyridin-2yl)methanamine (19 mg, 0.152 mmol) and Et.sub.3N (0.032 mL, 0.228 mmol) in EtOH (2 mL), and was isolated as a white solid (10 mg, 32%). ESI-MS m/z [M+H].sup.+ 415.0.

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

    [0530] ##STR00120##

    [0531] A TFA salt of the title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (75 mg, 0.228 mmol), 2-(pyridine-2-yl)ethanamine (42.0 mg, 0.342 mmol) and Et.sub.3N (0.095 mL, 0.684 mmol) in EtOH (3 mL), and was isolated as an orange oil (21 mg, 23%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 415.5.

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

    [0532] ##STR00121##

    [0533] The title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.152 mmol), cyclobutylmethanamine, HCl (37.0 mg, 0.304 mmol) and Et.sub.3N (0.0636 mL, 0.456 mmol) in EtOH (3.5 mL), and was isolated as a white semi solid (33.0 mg, 58%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 378.1.

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

    [0534] ##STR00122##

    [0535] A formic acid salt of the title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.076 mmol), pyridin-4-ylmethanamine (32.90 mg, 0.304 mmol) and Et.sub.3N (0.032 mL, 0.228 mmol) in EtOH (2.0 mL), and was isolated as a yellow solid (23.92 mg, 35%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 401.1.

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

    [0536] ##STR00123##

    [0537] The title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.152 mmol), pyridin-2-ylmethanamine (21.4 mg, 0.198 mmol) and DIPEA (26.6 μL, 0.152 mmol) in DMA (304 μL), and was isolated as white solid (31 mg, 51%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 401.0.

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

    [0538] ##STR00124##

    [0539] The title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (100 mg, 0.304 mmol), 2-methoxypropan-1-amine, HCl (45.8 mg, 0.365 mmol) and DIPEA (106 μL, 0.608 mmol) in DMA (608 μL), and was isolated as a white solid (56.1 mg, 48%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 382.1.

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

    [0540] ##STR00125##

    [0541] The racemate prepared in Example 84 was resolved by 2D separation using SFC/UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20×150 mm, flow rate at 100 mL/min) eluting with 30% IPA. The title compound, which was the first eluting peak and arbitrarily assigned R-stereochemical configuration, was isolated as a white solid (15.4 mg, 27.5%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 382.1.

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

    [0542] ##STR00126##

    [0543] The racemate prepared in Example 84 was resolved by 2D separation using SFC/UV, PIC system (Chiral Technology AS-H column, 5 μm, ID 20×150 mm, flow rate at 100 mL/min) eluting with 30% IPA. The title compound, which was the second eluting peak and arbitrarily assigned S-stereochemical configuration, was isolated as a white solid (21.2 mg, 37.8%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.10 (d, J=6.32 Hz, 3H), 3.14-3.22 (m, 1H), 3.26 (s, 3H), 3.37-3.51 (m, 2H), 7.29 (d, J=6.06 Hz, 2H), 7.32-7.37 (m, 1H), 7.41-7.50 (m, 2H), 7.59 (t, J=5.18 Hz, 1H), 7.77 (dd, J=7.83, 1.26 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z [M+H].sup.+ 382.1.

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

    [0544] ##STR00127##

    [0545] The title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.152 mmol), 2-methoxybutan-1-amine, HCl (27.6 mg, 0.198 mmol) and DIPEA (26.6 μL, 0.152 mmol) in DMA (304 μL), and was isolated as tan solid (12 mg, 20%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 0.93 (td, J=7.39, 1.64 Hz, 3H), 1.43-1.64 (m, 2H), 3.35 (d, J=2.27 Hz, 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].sup.+ 396.0.

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

    [0546] ##STR00128##

    [0547] The title compound was prepared in a manner similar to Example 75, using 3-chloro-5-(3,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.076 mmol), benzylamine (32.60 mg, 0.304 mmol) and Et.sub.3N (32.0 μL, 0.028 mmol) in EtOH (2.0 mL), and was isolated as a white solid (32.00 mg, 54%). .sup.1H NMR (400 MHz, CDCl.sub.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].sup.+ 400.0.

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

    [0548] ##STR00129##

    [0549] 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.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL). The reaction mixture was heated to 80° C. and stirred overnight. LC/MS indicated the reaction was complete. The solvent was boiled off with mild heating. The crude product was taken up in MeOH, filtered using a 0.45p PTFE syringe filter, and purified by preparative LC/MS (Waters SunFire® C18, 5 μm, ID 4×50 mm column) eluting with a gradient of ACN in water (acid mode). The pure fractions were combined and lyophilized to give a TFA salt of the tile compound as a white solid (1 mg, 5%). ESI-MS m/z [M+H].sup.+ 331.0.

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

    [0550] ##STR00130##

    [0551] A TFA salt of the title compound was prepared in a manner similar to Example 89, using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (5-chloro-2-cyanophenyl)boronic acid (14 mg, 0.077 mmol), saturated (aq) NaHCO.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL), and was isolated as a white solid (1.0 mg, 5%). ESI-MS m/z [M+H].sup.+ 347.0.

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

    [0552] ##STR00131##

    [0553] A TFA salt of the title compound was prepared in a manner similar to Example 89, using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-ethylphenyl)boronic acid (12 mg, 0.077 mmol), saturated (aq) NaHCO.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL), and was isolated as a white solid (1 mg, 5%). ESI-MS m/z [M+H].sup.+ 316.1.

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

    [0554] ##STR00132##

    [0555] A TFA salt of the title compound was prepared in a manner similar to Example 89, using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-chloro-4-methylphenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) NaHCO.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL), and was isolated as a white solid (2 mg, 8%). ESI-MS m/z [M+H].sup.+ 336.0.

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

    [0556] ##STR00133##

    [0557] A TFA salt of the title compound was prepared in a manner similar to Example 89, using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-chloro-5-fluorophenyl boronic acid (13 mg, 0.077 mmol), saturated (aq) NaHCO.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL), and was isolated as a white solid (1 mg, 5%); ESI-MS m/z [M+H].sup.+ 340.0.

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

    [0558] ##STR00134##

    [0559] A TFA salt of the title compound was prepared in a manner similar to Example 89, using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (2-chloro-4-fluorophenyl)boronic acid (13 mg, 0.077 mmol), saturated (aq) NaHCO.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL), and was isolated as a white solid (2 mg, 10%). ESI-MS m/z [M+H].sup.+ 340.0.

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

    [0560] ##STR00135##

    [0561] A TFA salt of the title compound was prepared in a manner similar to Example 89, using 5-iodo-3-(methylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.059 mmol), (3-fluoro-2-methylphenyl)boronic acid (12 mg, 0.077 mmol), saturated (aq) NaHCO.sub.3 aq (2 mL) and PdCl.sub.2(dppf) (4.34 mg, 5.93 μmol) in dioxane (2 mL), and was isolated as a white solid (1 mg, 5%). ESI-MS m/z [M+H].sup.+ 320.1.

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

    [0562] ##STR00136##

    [0563] To a 2-5 mL microwave vial were 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 Cs.sub.2CO.sub.3 (2M, 890 μL, 1.780 mmol) and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (36.3 mg, 0.044 mmol). The mixture was purged with nitrogen and then heated in a microwave reactor for 45 minutes at 120° C. The reaction mixture was then poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting brown oil was dissolved in MeOH (2 mL), filtered, and purified by preparative LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 30-50% ACN in water (acid mode). The title compound was isolated as a white solid (23.6 mg, 16%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 342.0.

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

    [0564] ##STR00137##

    [0565] To a 10 mL vial were added 3-chloro-5-(2-chloro-3-fluorophenyl)-7-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (44 mg, 0.122 mmol) in EtOH (9 mL) along with methanamine (2M in MeOH, 0.122 mL, 0.245 mmol) and Et.sub.3N (0.051 mL, 0.367 mmol). The resulting yellow solution was heated to 65° C. and stirred for 16 hours. The mixture was subsequently concentrated and purified by preparative HPLC (Waters XSelect® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of ACN (0.1% TFA) in water (0.1% TFA). The title compound was isolated as a white solid (26 mg, 60%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 354.5.

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

    [0566] ##STR00138##

    [0567] An 8 mL vial was charged with 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), (5-methyl-1H-pyrazol-3-yl)boronic acid (10.7 mg, 0.085 mmol), saturated (aq) NaHCO.sub.3 (1.5 mL), PdCl.sub.2(dppf) (2.073 mg, 2.83 μmol) and dioxane (1.5 mL). The reaction mixture was heated to 80° C. and stirred overnight. LC/MS indicated the reaction was complete. The reaction mixture was diluted with EtOAc and the organic layer was separated and introduced into a 4 mL vial. The solvent was boiled off. The residue was diluted with MeOH, filtered, and purified to give the title compound as a white solid (1.0 mg, 5%); ESI-MS m/z [M+H].sup.+ 396.5.

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

    [0568] ##STR00139##

    [0569] The title compound was 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.sub.3 (1.5 mL) and PdCl.sub.2(dppf) (2.073 mg, 2.83 μmol) in dioxane (1.5 mL), and was isolated as a white solid (1.0 mg, 5%); ESI-MS m/z [M+H].sup.+ 432.0.

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

    [0570] ##STR00140##

    [0571] An oven-dried 8 mL vial was charged with 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25 mg, 0.057 mmol), 1H-pyrazole (7.71 mg, 0.113 mmol), K.sub.2CO.sub.3 (15.66 mg, 0.113 mmol), copper(I) iodide (1.079 mg, 5.67 μmol) and DMF (2 mL). The reaction mixture was degassed with N2 and then heated to 125° C. and stirred for 18 hours. The reaction mixture was subsequently diluted with DMF (1 mL), filtered through a 0.45 μm PTFE syringe filter, and purified by preparative HPLC (Phenomenex Gemini® C18, 10 μm, ID 50×250 mm column) eluting with a gradient of 40-55% ACN in water (acid mode). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a white solid (6 mg, 28%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 382.1.

    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

    [0572] ##STR00141##

    [0573] To a stirring 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), were added PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (7.40 mg, 9.06 μmol) and K.sub.2CO.sub.3 (27.6 mg, 0.199 mmol). The reaction mixture was heated at 100° C. for 18 hours, then washed with brine (2×) and extracted with EtOAc. The organic layers were combined, dried over MgSO.sub.4, concentrated, filtered, and purified via reverse phase preparative LC/MS (Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 35-60% 10 mM NH.sub.4HCO.sub.3 (aq) in water/ACN (20/80 v/v containing 10 mM NH.sub.4HCO.sub.3) to give the title compound as a white solid (3.2 mg, 8%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 438.3.

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

    [0574] ##STR00142##

    [0575] A TFA salt of the title compound was prepared 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.sub.2CO.sub.3 (27.6 mg, 0.199 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL), and was isolated as a tan solid (14.7 mg, 31%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 410.2.

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

    [0576] ##STR00143##

    [0577] The title compound was prepared 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.sub.2CO.sub.3 (31 mg, 0.224 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (8.33 mg, 10.20 μmol) in water (1 mL) and dioxane (3 mL), and was isolated as an off-white solid (7.0 mg, 17%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 410.2.

    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

    [0578] ##STR00144##

    [0579] A TFA salt of the title compound was prepared in a manner similar to Example 101, using 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.sub.2CO.sub.3 (37.9 mg, 0.274 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (10.18 mg, 0.012 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as an off-white solid (15.9 mg, 22%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 472.2.

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

    [0580] ##STR00145##

    [0581] A TFA salt of the title compound was prepared 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.sub.2CO.sub.3 (27.6 mg, 0.199 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL), and was isolated as a white solid (7.2 mg, 14%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 436.3.

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

    [0582] ##STR00146##

    [0583] 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) were added PdCl.sub.2(dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO.sub.3 (1 mL). The mixture was sparged with nitrogen for 30 seconds. The stirred reaction mixture was heated at 135° C. in a microwave reactor for 60 minutes and then allowed to cool to room temperature. The solution was decanted away from the salts and the product purified by preparative HPLC (Waters XSelect® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of ACN (0.1% formic acid) in water (0.1% formic acid). The product-containing fractions were combined and dried to give the title compound as a white solid (7.2 mg, 32%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 396.2.

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

    [0584] ##STR00147##

    [0585] The title compound was prepared 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.sub.2(dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO.sub.3 (1 mL) in dioxane (3 mL), and was isolated as a white solid (10 mg, 45%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 396.2.

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

    [0586] ##STR00148##

    [0587] The title compound was prepared 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-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.240 mmol), PdCl.sub.2(dppf) (5 mg, 6.83 μmol) and saturated (aq) NaHCO.sub.3 (1 mL) in dioxane (3 mL), and was isolated as a white solid (6.4 mg, 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 396.2.

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

    [0588] ##STR00149##

    [0589] The title compound was prepared in a manner similar to Example 106, using 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (25.0 mg, 0.057 mmol), cyclopropylboronic acid (16.35 mg, 0.190 mmol), PdCl.sub.2(dppf) (10.92 mg, 0.013 μmol) and saturated (aq) NaHCO.sub.3 (1.5 mL mL) in dioxane (1.5 mL), and was isolated as an off-white solid (11.19 mg, 19%). .sup.1H NMR (400 MHz, CDCl.sub.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].sup.+ 356.0.

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

    [0590] ##STR00150##

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

    [0591] ##STR00151##

    [0592] The title compound was prepared 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), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74.25 mg, 441.88 μmol), PdCl.sub.2(dppf) (49.58 mg, 0.059 μmol) and saturated (aq) NaHCO.sub.3 (7.0 mL) in dioxane (7.0 mL), and was isolated as a (crude) brown solid (120 mg); ESI-MS m/z [M+H].sup.+ 356.1.

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

    [0593] To a solution of 5-isopropyl-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120.00 mg, 337.60 μmol) in MeOH (40 mL) was added Pd/C (50 mg, 5%). The reaction mixture was stirred under a hydrogen atmosphere (H2-filled balloon) at 15 psi and 25° C. for 20 hours. Additional Pd/C (100.00 mg, 5%) was added to the reaction mixture which was stirred under H2 at 15 psi and 25° C. for another 20 hours. Following the hydrogenation, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi™ C18, 4 μm, ID 30×150 mm column) eluting with a gradient of 50-80% water (0.225% formic acid) in ACN. The product-containing fractions were combined and dried to give the title compound as a white solid (15.67 mg, 13%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 358.2.

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

    [0594] ##STR00152##

    [0595] To a mixture of 5-iodo-3-((4-isopropylphenyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (160 mg, 0.362 mmol), bromo(cyclobutyl)zinc (0.5 M, 725.14 μL), S-Phos (29.77 mg, 0.073 mmol) in THF (2.00 mL) was added Pd(OAc).sub.2 (16.28 mg, 0.073 mmol). The resulting mixture was heated to 65° C. for 16 hours. The reaction mixture was subsequently poured into saturated (aq) NH.sub.4Cl (40 mL) and extracted with EtOAc (2×30 mL). The organic phase was dried over Na.sub.2SO.sub.4 and then concentrated in vacuo. The crude product was purified by preparative HPLC (Welch Ultimate AQ-C18, 5 μm, ID 30×150 mm column) eluting with a gradient of 50-80% water in ACN (acid mode). The title compound was isolated as a white solid (3.83 mg, 3%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 370.1.

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

    [0596] ##STR00153##

    [0597] The title compound was prepared 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.sub.2CO.sub.3 (34.5 mg, 0.249 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (9.25 mg, 0.011 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as a white solid (28 mg, 59%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 426.1.

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

    [0598] ##STR00154##

    [0599] The title compound was prepared 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.sub.2CO.sub.3 (34.5 mg, 0.249 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (9.25 mg, 0.011 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as a tan solid (10.8 mg, 23%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 407.2.

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

    [0600] ##STR00155##

    [0601] A TFA salt of the title compound was prepared 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), (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (19.03 mg, 0.136 mmol), K.sub.2CO.sub.3 (27.6 mg, 0.199 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (7.40 mg, 9.06 μmol) in water (1 mL) and dioxane (3 mL), and was isolated as a tan solid (4.7 mg, 9%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 410.2.

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

    [0602] ##STR00156##

    [0603] To a stirring 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), were added PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (10.92 mg, 0.013 mmol) and K.sub.2CO.sub.3 (40.7 mg, 0.294 mmol). The reaction mixture was heated at 100° C. for 6 hours. The mixture was neutralized with 1N (aq) HCl and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO.sub.4, and concentrated under vacuum. The product was purified by reverse phase LC/MS (Waters XSelect® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 30-55% (aq) formic acid in ACN (containing 1% formic acid) to give the title compound as an off-white solid (16 mg, 29%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 410.2.

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

    [0604] ##STR00157##

    [0605] The title compound was prepared 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.sub.2CO.sub.3 (40.7 mg, 0.294 mmol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (10.92 mg, 0.013 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as a tan solid (11.3 mg, 24%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 356.2.

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

    [0606] ##STR00158##

    [0607] To a stirring solution of 5-iodo-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (43 mg, 0.097 mmol) and (2-chlorophenyl)boronic acid (18.24 mg, 0.117 mmol) in water (1 mL) and dioxane (3 mL), were added PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (7.94 mg, 9.72 μmol) and K.sub.2CO.sub.3 (29.6 mg, 0.214 mmol). The reaction mixture was heated at 100° C. for 3 hours. The reaction mixture was subsequently neutralized with 1 N HCl (aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO.sub.4, and concentrated under vacuum. The product was purified by reverse phase chromatography (Waters XSelect® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 20-45% water (1% formic acid) in ACN (1% formic acid). The titled compound was isolated as a white solid (8 mg, 19%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 427.1.

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

    [0608] ##STR00159##

    [0609] The title compound was prepared in a manner similar to Example 117, using 5-iodo-3-((6-isopropylpyridin-3-yl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (63 mg, 0.142 mmol), cyclopropylboronic acid (18.35 mg, 0.21 mmol), PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (11.63 mg, 0.014 mmol) and K.sub.2CO.sub.3 (43.3 mg, 0.313 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as a light yellow solid (6.0 mg, 12%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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, 1 H), 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].sup.+ 357.2.

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

    [0610] ##STR00160##

    [0611] To a stirring 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), were added PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (10.01 mg, 0.012 mmol) and K.sub.2CO.sub.3 (37.3 mg, 0.270 mmol). The reaction mixture was heated at 100° C. for 29 hours, then neutralized with 1N HCl (aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous MgSO.sub.4, and concentrated under vacuum. The product was purified by reverse phase column chromatography (Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 25-50% water in ACN (basic mode). The title compound was isolated as a light yellow solid (4.5 mg, 11%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 347.1.

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

    [0612] ##STR00161##

    [0613] The title compound was prepared 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.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (4.60 mg, 5.63 μmol) and K.sub.2CO.sub.3 (17.11 mg, 0.124 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as a tan semi-solid (2.6 mg, 13%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 359.1.

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

    [0614] ##STR00162##

    [0615] The title compound was prepared in a manner similar to Example 119, using 5-iodo-3-(phenylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (35 mg, 0.088 mmol), cyclopropylboronic acid (11.30 mg, 0.132 mmol), PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 adduct (7.16 mg, 8.77 μmol) and K.sub.2CO.sub.3 (26.7 mg, 0.193 mmol) in water (1 mL) and dioxane (3 mL), and was isolated as a light yellow solid (5.7 mg, 21%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 314.1.

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

    [0616] ##STR00163##

    [0617] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50.0 mg, 0.014 mmol), Et.sub.3N (56 μL, 0.760 mmol), and (3-methoxypyridin-2-yl)methanamine hydrochloride (50.60 mg, 0.29 mmol) in EtOH (2.0 mL), and was isolated as an off-white solid (29.8 mg, 46%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 447.1.

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

    [0618] ##STR00164##

    [0619] 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 (16.7 μL, 0.096 mmol), and (tetrahydrofuran-2-yl)methanamine (8.79 mg, 0.087 mmol) in DMA (435 μL), and was isolated as a pale beige solid (8.3 mg, 23%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 410.0.

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

    [0620] ##STR00165##

    [0621] The title compound was 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 (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).sub.2.CH.sub.2Cl.sub.2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL), and was isolated as a light brown solid (34.3 mg, 33%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 400.1.

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

    [0622] ##STR00166##

    [0623] A 20 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 (0.03 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.sub.2CO.sub.3 (0.157 ml, 0.315 mmol) and dioxane (0.394 mL). Next, Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (6.43 mg, 7.87 μmol) was added under nitrogen, and the reaction mixture was heated to 90° C. for 12 hours. The mixture was subsequently cooled, diluted with MeOH (1 mL) and filtered over Celite®. The residue was purified by preparative LC/MS on (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 25-90% ACN in water (acid mode). The fractions were collected, concentrated, and dried in vacuo to give the title compound as a tan solid (5 mg, 17%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 375.0.

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

    [0624] ##STR00167##

    [0625] To a 2-5 mL microwave vial were added 5-iodo-3-((thiazol-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.357 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (211.65 mg, 0.856 mmol), Cs.sub.2CO.sub.3 (0.759 mL, 1.518 mmol), Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (31.0 mg, 0.038 mmol) in dioxane (1.898 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes, then poured into water, and extracted with EtOAc (3×). The organic layers were combined, dried over MgSO.sub.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, after removal of the solvent, a formic acid salt of the title compound as a white solid (10.37 mg, 4%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 414.0.

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

    [0626] ##STR00168##

    [0627] To a 2-5 mL microwave vial were 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.sub.2CO.sub.3 (759 μL, 1.518 mmol) and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (31.0 mg, 0.038 mmol). The mixture was purged with nitrogen and then heated in microwave reactor at 120° C. for 45 minutes. The reaction mixture was poured into water and then extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over MgSO.sub.4, 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, after removal of the solvent, the title compound as a clear oil (8.5 mg, 6%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 400.0.

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

    [0628] ##STR00169##

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

    [0629] ##STR00170##

    [0630] To a 10-20 mL microwave vial were 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.sub.2CO.sub.3 (2.024 mL, 4.05 mmol) and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (83 mg, 0.101 mmol). The mixture was purged with nitrogen and then heated at 120° C. for 80 minutes. The reaction mixture was poured into water and extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over MgSO.sub.4, filtered, and concentrated. The resulting brown oil was filtered oil through a pad of Celite® and purified by supercritical fluid chromatography (SFC) to give, following removal of solvent, the racemate of the title compounds as a clear oil. The racemate was resolved by chiral chromatography using SFC/UV 04 system (Chiral Technology AS-H column, 5 μm, ID 2.1×150 mm, flow rate at 1.25 mL/min) eluting with 30% EtOH.

    [0631] Example 128, which was the first eluting peak and was arbitrarily assigned S-stereochemical configuration, was isolated as a clear oil (15.7 mg, 3.9%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 400.1.

    [0632] Example 129, which was the second eluting peak and was arbitrarily assigned R-stereochemical configuration, was isolated as a clear oil (17.3 mg, 4.3%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 400.1.

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

    [0633] ##STR00171##

    [0634] The title compound was prepared in a manner similar to Example 127, using 3-((cyclobutylmethyl)amino)-5-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (150 mg, 0.383 mmol), (2,3,5-trifluorophenyl)boronic acid (70.8 mg, 0.403 mmol), Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (31.3 mg, 0.038 mmol) and Cs.sub.2CO.sub.3 (767 μL, 1.534 mmol) in dioxane (1.917 mL), and was isolated as a tan solid (5.1 mg, 3%). .sup.1H NMR (400 MHz, DMSO-d.sub.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, 1.52 Hz, 1H), 7.71-7.86 (m, 2H), 9.21 (s, 1H); ESI-MS m/z [M+H].sup.+ 396.1.

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

    [0635] ##STR00172##

    [0636] The title compound was prepared in a manner similar to Example 127, using 5-iodo-3-((pyridin-2-ylmethyl)amino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (120 mg, 0.290 mmol), (2,3,5-trifluorophenyl)boronic acid (53.5 mg, 0.304 mmol), Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (23.66 mg, 0.029 mmol) and Cs.sub.2CO.sub.3 (579 μL, 1.159 mmol) in dioxane (1.449 mL), and was isolated as a white solid (3.4 mg, 3%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 419.0.

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

    [0637] ##STR00173##

    [0638] The title compound was 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 (100 mg, 0.262 mmol), (2-chloro-3-(trifluoromethyl)phenyl)boronic acid (61.8 mg, 0.275 mmol), Cs.sub.2CO.sub.3 (2M, 525 μL, 1.049 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL), and was isolated as a white solid (1.0 mg, 1%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 434.0.

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

    [0639] ##STR00174##

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

    [0640] ##STR00175##

    [0641] To a 2-5 mL microwave vial were 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).sub.2.CH.sub.2Cl.sub.2 adduct (28.6 mg, 0.035 mmol), Cs.sub.2CO.sub.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 TN HCl (aq) (5 mL), forming a precipitate which was difficult to filter. The filtrate was extracted with EtOAc (2×20 mL) and the organic layers were combined, dried over MgSO.sub.4, and filtered. The solvent was removed to give the title compound as reddish-brown oil, which was used without further purification. ESI-MS m/z [M+H].sup.+ 344.9.

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

    [0642] To (crude) 3-chloro-5-(2-chloro-4-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20 mg, 0.058 mmol) were added DMA (290 μL), followed by DIPEA (11.13 μL, 0.064 mmol) and 2-methoxyethanamine (5.49 μL, 0.064 mmol). The reaction mixture was heated at 70° C. overnight, then filtered and purified by preparative LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient 30-50% ACN in water (acid mode). The product-containing fractions were collected and the solvent removed to give the title compound as a white solid (13 mg, 59%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 384.0.

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

    [0643] ##STR00176##

    [0644] The title compound was 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 (100 mg, 0.262 mmol), (2-chloro-5-(trifluoromethyl)phenyl)boronic acid (61.8 mg, 0.275 mmol), Cs.sub.2CO.sub.3 (2M, 525 μL, 1.049 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL), and was isolated as a brown solid (5.5 mg, 5%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 434.0.

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

    [0645] ##STR00177##

    [0646] The title compound was 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 (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.sub.2CO.sub.3 (2M, 328 μL, 0.656 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (21.42 mg, 0.026 mmol) in dioxane (1312 μL), and was isolated as a white film (5.0 mg, 5%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 384.0.

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

    [0647] ##STR00178##

    [0648] To a solution of 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.169 mmol) in DMA (1 mL) was added 4-ethylaniline (0.063 mL, 0.506 mmol). The reaction mixture was heated at 120° C. for 15 hours. The reaction mixture was cooled to room temperature, extracted with EtOAc, and washed with brine (3×). The organic layers were combined, concentrated, filtered, and purified by preparative LC/MS (Waters XSelect® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 20-70% water in ACN (basic mode). The product-containing fractions were collected and concentrated to give the title compound as a brown solid (3.2 mg, 5%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 382.1.

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

    [0649] ##STR00179##

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

    [0650] ##STR00180##

    [0651] 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) were added tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5 μmol) and Na.sub.2CO.sub.3 (0.089 g, 0.837 mmol). The (first) reaction mixture was heated at 100° C. for 1 hour and then cooled to room temperature and set aside. 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) were added tetrakis(triphenylphosphine)palladium(0) (11.56 mg, 10 μmol) and Na.sub.2CO.sub.3 (177 mg, 1.674 mmol). The reaction mixture was heated at 70° C. for 0.5 hours and at 80° C. for 1 hour, then cooled to room temperature, and combined with the first reaction mixture. The combined mixtures were neutralized with a 1 N HCl (aq) and extracted with EtOAc. The organic layers were combined, dried over anhydrous NaSO.sub.4, and concentrated under vacuum. The crude product was purified on a silica gel column, eluting with 50% EtOAc in hexanes. The product-containing fractions were collected and concentrated in vacuo to give the title compound as an off-white solid (49 mg, 53%). ESI-MS m/z [M+H].sup.+ 307.0.

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

    [0652] 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.sub.2CO.sub.3 (100 mg, 0.307 mmol). The reaction mixture stirred at 150° C. for 2 hours in a microwave reactor, then cooled, and purified by preparative LC/MS (Waters XSelect® C18, 5 μm, ID 30×75 mm column). The title compound was isolated as a white solid (50 mg, 44%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 368.1.

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

    [0653] ##STR00181##

    Step A: 2′-chloro-6-fluoro-[1,1′-biphenyl]-2-amine

    [0654] ##STR00182##

    [0655] 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.sub.2CO.sub.3 (1.82 g, 13.15 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 1 hour, then poured into water (20 mL) and extracted with EtOAc (2×2 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The crude material was purified by column chromatography (SiO.sub.2) eluting with petroleum ether/EtOAc (20:1) to afford the title compound as a colorless oil (800.00 mg, 69%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 222.1.

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

    [0656] ##STR00183##

    [0657] To a solution of sulfurisocyanatidic chloride (536.96 mg, 3.79 mmol) in nitromethane (9.00 mL), was added 2′-chloro-6-fluoro-[1,1′-biphenyl]-2-amine (6 mL). The reaction mixture was stirred at a temperature of −20° C. to 0° C. for 30 minutes. AlCl.sub.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 for an additional hour under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then poured into water (30.00 mL), and extracted with EtOAc (2×30 mL). The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated to dryness under vacuum and the remaining residue purified by preparative TLC (DCM/MeOH) to afford the title compound as a white solid (300 mg, 34% yield).

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

    [0658] ##STR00184##

    [0659] 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.sub.3 (5.00 mL) was stirred at 120° C. for 3 hours and then allowed to cool to room temperature. The volatiles were removed under vacuum to give the title (crude) compound as a brown oil which was used without additional purification (300 mg). ESI-MS m/z [M+H].sup.+ 345.1.

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

    [0660] 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 methanamine, HCl (93.89 mg, 1.39 mmol) in IPA (5.00 mL) was added Et.sub.3N (469.04 mg, 4.64 mmol). The resulting mixture was stirred at 70° C. for 2 hours. The solvents were removed and the crude material purified by preparative HPLC (Phenomenex Synergi™ C18, 10 μm, ID 25×150 mm) eluting with a gradient of water (0.225% formic acid) in ACN. The product-containing fractions were combined and dried to give the title compound as a yellow solid (36 mg, 11%). .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 340.0.

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

    [0661] ##STR00185##

    [0662] 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.sub.2CO.sub.3 (100 mg, 0.307 mmol). The reaction mixture was stirred and heated at 150° C. for 2 hours in a microwave reactor. The product was purified by preparative HPLC (Waters XSelect® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of ACN (0.1% formic acid) in water (0.1% formic acid). The title compound was isolated as a white solid (18 mg, 15%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 401.0.

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

    [0663] ##STR00186##

    [0664] The title compound was prepared 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.sub.2CO.sub.3 (100 mg, 0.307 mmol) in DMA (5 mL), and was isolated as a white solid (22 mg, 20%). .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 364.1.

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

    [0665] ##STR00187##

    [0666] The title compound was prepared 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), methoxyethanamine (400 mg, 5.33 mmol) and Cs.sub.2CO.sub.3 (100 mg, 0.307 mmol) in DMA (5 mL), and was isolated as a white solid (65 mg, 58%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 368.1.

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

    [0667] ##STR00188##

    [0668] The title compound was prepared in a manner similar to Example 139, using 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (70 mg, 0.213 mmol), 2-methoxypropan-1-amine, HCl (34.8 mg, 0.277 mmol) and DIPEA (37.2 μL, 0.213 mmol) in DMA (426 μL), and was isolated as a white solid (31 mg, 38%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 1.07 (d, J=6.06 Hz, 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].sup.+ 401.4.

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

    [0669] ##STR00189##

    [0670] The title compound was prepared in a manner similar to Example 139, using 3-chloro-5-(2,5-difluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (70 mg, 0.213 mmol), ethanamine, HCl (22.57 mg, 0.277 mmol) and DIPEA (37.2 μL, 0.213 mmol) in DMA (426 μL), and was isolated as a tan solid (14 mg, 20%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 338.0.

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

    [0671] ##STR00190##

    [0672] The title compound was 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 (100 mg, 0.262 mmol), (2-chloro-5-fluorophenyl)boronic acid (46 mg, 0.262 mmol), Cs.sub.2CO.sub.2 (2M, 525 μL, 1.049 mmol), and Pd(dppf).sub.2.CH.sub.2Cl.sub.2 adduct (32 mg, 0.039 mmol) in dioxane (1312 μL), and was isolated as a pale, yellow oil (5 mg, 5%); ESI-MS m/z [M+H].sup.+ 384.0.

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

    [0673] ##STR00191##

    [0674] 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 hours, then diluted with MeOH (1 mL) and filtered. the residue was purified by preparative LC/MS on (ZQ3) eluting with a gradient of 25-90% ACN in water (acid mode). The product-containing fractions were collected, concentrated, and dried in vacuo to give the title compound as a tan solid (3 mg, 4%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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, 2 H), 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).

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

    [0675] ##STR00192##

    [0676] The title compound was prepared in a manner similar to Example 145, using 2-(3-chloro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)benzonitrile (70 mg, 0.220 mmol), cyclobutylmethanamine, HCl (34.8 mg, 0.286 mmol) and DIPEA (38.5 μL, 0.220 mmol) in DMA (441 μL), and was isolated as a tan solid (32 mg, 40%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 367.1.

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

    [0677] ##STR00193##

    [0678] 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 (20.24 μL, 0.116 mmol), and 2-fluoroethanamine, HCl (15 mg, 0.151 mmol) in DMA (232 μL), and was isolated as a tan solid (11 mg, 26%). .sup.1H NMR (400 MHz, CD.sub.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).

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

    [0679] ##STR00194##

    [0680] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol), and (6-fluoropyridin-2-yl)methanamine (23.8 mg, 0.188 mmol) in DMA (290 μL), and was isolated as a tan solid (1.2 mg, 2%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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).

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

    [0681] ##STR00195##

    [0682] To a solution of 2-fluoroethanamine, 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 hours, then diluted with MeOH (1 mL) and filtered. This residue was purified by preparative LC/MS on (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 25-90% ACN in water (acid mode). The fractions were collected, concentrated, and dried in vacuo to give the title compound as a tan solid (5 mg, 9%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 363.0.

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

    [0683] ##STR00196##

    [0684] The title compound was prepared in a manner similar to Example 149, 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 was isolated as a brown oil (17 mg, 29%); ESI-MS m/z [M+H].sup.+ 389.1.

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

    [0685] ##STR00197##

    [0686] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol), and 3-methoxypropan-1-amine, HCl (24 mg, 0.188 mmol) in DMA (290 μL), and was isolated as a tan solid (20 mg, 35%). .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 398.0.

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

    [0687] ##STR00198##

    [0688] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol), and 3-fluoropropan-1-amine, HCl (18.1 mg, 0.159 mmol) in DMA (290 μL), and was isolated as a tan solid (37 mg, 66%); ESI-MS m/z [M+H].sup.+ 386.0.

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

    [0689] ##STR00199##

    [0690] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (50 mg, 0.145 mmol), DIPEA (25.3 μL, 0.145 mmol), and 3-methoxybutan-1-amine, HCl (26.3 mg, 0.188 mmol) in DMA (290 μL), and was isolated as a colorless oil (19 mg, 32%); ESI-MS m/z [M+H].sup.+ 412.1.

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

    [0691] ##STR00200##

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

    [0692] ##STR00201##

    [0693] The racemate prepared in Example 153 was resolved by chiral chromatography. The first eluting peak was arbitrarily assigned R-stereochemical configuration (Example 154) and the second eluting peak was assign S-stereochemical configuration (Example 155). Each of the title compounds was isolated as a colorless semisolid.

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

    [0694] ##STR00202##

    [0695] 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 hours, then diluted with MeOH (1 mL) and filtered. The product was purified by preparative LC/MS (Waters SunFire® C18, 5 μm, ID 30×75 mm column) eluting with a gradient of 25-90% ACN in water (acid mode). The product-containing fractions were collected, concentrated, and dried in vacuo to give the title compound as a tan glassy solid (14 mg, 25% yield). ESI-MS m/z [M+H].sup.+ 390.1

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

    [0696] ##STR00203##

    [0697] 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), methanamine (93 μL, 0.185 mmol) and DIPEA (24.89 μL, 0.143 mmol) in DMA (285 μL), and was isolated as a tan, glassy solid (10 mg, 20%). ESI-MS m/z [M+H].sup.+ 346.3.

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

    [0698] ##STR00204##

    [0699] 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 was isolated as a yellow film (32 mg, 95%); ESI-MS m/z [M+H].sup.+ 368.8.

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

    [0700] ##STR00205##

    [0701] 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), cyclopropanamine, HCl (10.6 mg, 0.113 mmol) and DIPEA (15.2 μL, 0.087 mmol) in DMA (174 μL), and was isolated as a clear film (32 mg, 95%); ESI-MS m/z [M+H].sup.+ 366.8.

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

    [0702] ##STR00206##

    [0703] The title compound was prepared in a manner similar to Example 1, using 3-chloro-5-(2-chloro-3-fluorophenyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (30 mg, 0.087 mmol), 2-(2,2-difluoroethoxy)ethanamine, HCl (18.3 mg, 0.113 mmol) and DIPEA (15.2 μL, 0.087 mmol) in DMA (174 μL), and was isolated as a yellow film (32 mg, 85%); ESI-MS m/z [M+H].sup.+ 434.8.

    [0704] Each of the compounds shown in Examples 161 to 170, below, are prepared like the compounds above.

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

    [0705] ##STR00207##

    [0706] ESI-MS m/z [M+H].sup.+ 402.1.

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

    [0707] ##STR00208##

    [0708] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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 (br s, 1H), 8.53 (d, J=4.04 Hz, 1H), 9.16 (br s, 1H); ESI-MS m/z [M+H].sup.+ 379.2.

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

    [0709] ##STR00209##

    [0710] .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 360.1.

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

    [0711] ##STR00210##

    [0712] .sup.1H NMR (400 MHz, DMSO-d.sub.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].sup.+ 390.4

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

    [0713] ##STR00211##

    [0714] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.10 (t, J=7.20 Hz, 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, 1.52 Hz, 1H) 7.59-7.69 (m, 1H) 7.76-7.82 (m, 1H) 9.14 (s, 1H); ESI-MS m/z [M+H].sup.+ 338.0.

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

    [0715] ##STR00212##

    [0716] ESI-MS m/z [M+H].sup.+ 382.4

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

    [0717] ##STR00213##

    [0718] ESI-MS m/z [M+].sup.+ 410.6

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

    [0719] ##STR00214##

    [0720] .sup.1H NMR (400 MHz, CD.sub.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].sup.+ 386.4

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

    [0721] ##STR00215##

    [0722] .sup.1H NMR (400 MHz, DMSO-d.sub.6) (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].sup.+ 360.1.

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

    [0723] ##STR00216##

    [0724] .sup.1H NMR (400 MHz, CD.sub.3OD) 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].sup.+ 382.1.

    [0725] Table 1 lists hMRGX2 cellular potency (pEC.sub.50) and binding affinity (pK.sub.d) for the compounds shown in the examples, where larger pEC.sub.50 values represent higher activity or potency, and larger pK.sub.d values represent higher binding affinity. The methods used to measure cellular potency and binding affinity are described in the specification, above, under the heading Biological Activity.

    TABLE-US-00001 TABLE 1 hMRGX2 Cellular Potency (pEC.sub.50) and Binding Affinity (pK.sub.d) Ex. pEC.sub.50 pK.sub.d 1 7.159 6.724 2 7.285 6.984 3 7.939 6.58 4 7.813 6.975 5 7.699 — 6 7.666 6.78 7 7.633 7.27 8 6.960 — 9 6.836 — 10 7.406 — 11 6.895 — 12 7.867 7.45 13 7.450 — 14 7.392 — 15 7.205 — 16 7.986 7.5 17 7.683 — 18 7.671 — 19 7.630 — 20 6.067 — 21 6.132 — 22 7.094 — 23 7.386 — 24 7.193 — 25 5.56 — 26 6.410 — 27 6.464 — 28 7.618 7.03 29 7.572 — 30 7.544 — 31 7.524 — 32 7.447 — 33 7.418 — 34 7.415 7.025 35 7.036 4.7 36 7.298 — 37 6.405 — 38 7.285 — 39 7.284 7.055 40 7.118 — 41 7.579 — 42 7.113 — 43 6.992 6.47 44 6.731 — 45 6.516 — 46 7.056 — 47 7.030 — 48 7.444 — 49 7.617 — 50 7.150 — 51 7.722 — 52 6.882 — 53 6.240 — 54 7.878 — 55 6.865 — 56 6.550 — 57 6.763 — 58 6.747 — 59 6.606 — 60 6.063 — 61 6.367 — 62 6.555 — 63 6.021 — 64 7.807 — 65 7.971 7.055 66 7.531 7.22 67 7.436 — 68 6.516 — 69 6.221 — 70 7.237 — 71 7.082 — 72 7.400 — 73 6.856 — 74 6.127 — 75 7.461 — 76 7.458 — 77 7.457 — 78 6.649 — 79 6.434 — 80 6.047 — 81 6.416 — 82 5.996 — 83 6.374 — 84 — 114 85 6.603 — 86 <4.3 — 87 6.620 — 88 7.124 — 89 7.160 6.35 90 6.012 — 91 7.087 — 92 7.033 — 93 6.742 — 94 6.629 — 95 6.456 — 96 6.223 — 97 6.230 — 98 6.539 — 99 6.119 — 100 6.116 — 101 7.340 — 102 7.068 6.28 103 7.291 6.755 104 7.050 — 105 6.926 6.06 106 7.154 — 107 6.881 6.52 108 6.228 — 109 6.974 6.575 110 7.454 — 111 6.974 — 112 6.782 — 113 6.633 — 114 6.582 6.095 115 7.261 — 116 7.260 6.685 117 6.705 — 118 6.422 — 119 6.315 — 120 6.238 — 121 6.366 — 122 7.518 — 123 7.216 — 124 7.191 — 125 7.107 6.545 126 7.155 — 127 7.060 — 128 7.604 — 129 5.57 — 130 7.056 — 131 7.053 — 132 6.551 — 133 6.529 — 134 6.141 — 135 6.075 — 136 6.924 6.535 137 7.102 6.54 138 6.721 — 139 6.609 — 140 6.160 — 141 6.436 — 142 6.612 — 143 6.354 — 144 6.665 — 145 6.850 — 146 6.790 — 147 7.292 6.67 148 7.770 — 149 6.495 — 150 6.381 — 151 6.250 — 152 6.651 — 153 7.564 — 154 7.492 — 155 7.454 — 156 7.323 — 157 7.250 — 158 6.640 — 159 7.271 — 160 7.030 — 161 7.211 — 162 6.998 6.51 163 6.745 — 164 6.648 — 165 6.540 — 166 6.468 — 167 6.404 — 168 6.328 — 169 6.324 5.95 170 6.195 —

    [0726] As used in this specification and the appended claims, singular articles such as “a,” “an,” and “the,” may refer to a single object or to a plurality of 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. Many embodiments will be apparent to those of skill in the art upon reading the above description. Therefore, the scope of the invention should be determined with reference to the appended claims and includes the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references cited in the disclosure, including patents, patent applications and publications, are herein incorporated by reference in their entirety and for all purposes.