IP Library › Granted Patent US 9,249,160

Granted Patent B2

US 9,249,160 · App. 14/411,269 · Granted Feb 2, 2016

Orexin receptor antagonists

Inventors: Miles Stuart Congreve (Hertfordshire, GB); John Andrew Christopher (Hertfordshire, GB); Benjamin Gerald Tehan (Hertfordshire, GB); Sukhbinder Singh Klair (Hertfordshire, GB); Sarah Joanne Aves (Hertfordshire, GB)

Assignee: Heptares Therapeutics Limited

C07D513/04 C07D285/24 C07D417/04 C07D417/06 C07D417/14

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Patent No.: US 9,249,160
App. No.: 14/411,269
Granted: Feb 2, 2016
Kind: B2

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Abstract

The disclosures herein relate to novel compounds of formula wherein W, X and Y1, Y2, Y3 and Y4 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of neurological or psychiatric disorders associated with orexin receptors.

Claims (168)

1. A compound of formula

Wherein:

(i) Y 1 , Y 2 , Y 3 and Y 4 are independently a carbon or a nitrogen atom,

(ii) W is a methylene group substituted by substituted aryl, or optionally substituted heteroaryl or heterocycloalkyl moiety, wherein the substituents and optional substituents forming part of W are selected from the group consisting of halo, alkyl, hydroxy or alkoxy;

(iii) X comprises an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl moiety, wherein the optional substituents forming part of X are selected from the group consisting of fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyl, C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulphonyl, C 3-6 cycloalkyl, hydroxy, C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, C 2-4 alkenylamino, di-C 1-4 alkylamino, C 1-4 acylamino, phenyl, phenylamino, benzoylamino, benzylamino, phenylamido, carboxy, C 1-4 alkoxycarbonyl, phenyl-C 1-10 alkoxycarbonyl, carbamoyl, mono-C 1-4 carbamoyl, di-C 1-4 carbamoyl and any of the above in which a hydrocarbyl moiety is itself substituted by halo, cyano, hydroxy, C 1-2 , alkoxy, amino, nitro, carbamoyl, carboxy or C 1-2 , alkoxycarbonyl; and

(iv) it is provided that:

either at least one of Y 1 -Y 4 is a nitrogen atom; or X comprises an optionally substituted heteroaryl or optionally substituted heterocycloalkyl moiety; or W is a moiety of formula:

wherein R′ and R″ are independently H or alkyl and R′″ is 2,4,6 tri-substituted aryl or optionally substituted heteroaryl group; wherein the heteroaryl group recited in paragraph (iv) is a 5 or 6-membered ring containing one or more nitrogen atoms; and wherein the substituents and optional substituents recited in paragraph (iv) are selected from the group consisting of halo, alkyl and alkoxy.

2. A method of treating, ameliorating, controlling or reducing the risk of a neurological or psychiatric disorder associated with orexin receptors in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 , wherein the neurological or psychiatric disorder is insomnia, diabetes, obesity, a movement disorder, an anxiety disorder, a panic disorder, a cognitive impairment or Alzheimer's disease.

3. A method of treating insomnia or other sleep disorders in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 .

4. A method of treating migraine, cluster headache or other headache disorders in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 .

5. A method of treating diabetes or obesity in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 .

6. A method of treating movement disorders, anxiety disorders, panic disorders, binge eating disorder, compulsive disorders, impulse control disorders, cognitive impairment or Alzheimer's disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 .

7. The compound of claim 1 , wherein W is a moiety of formula:

wherein R′ and R″ are independently H or alkyl and R′″ is 2,4,6 tri-substituted aryl or R′″ is an optionally substituted heteroaryl group, wherein the heteroaryl group is a 5 or 6 membered ring containing one or more nitrogen atoms, and wherein the substituents and optional substituents forming part of W are selected from the group consisting of halo, alkyl and alkoxy.

8. The compound of claim 7 , wherein W is selected from:

9. The compound of claim 1 , wherein Y 1 is nitrogen.

10. The compound of claim 1 , wherein Y 4 is CH or N.

11. The compound of claim 1 , wherein X is an optionally substituted heteroaryl or heterocycloalkyl moiety, wherein the optional substituents forming part of X are selected from the group consisting of fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyl, C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulphonyl, C 3-6 cycloalkyl, hydroxy, C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, C 2-4 alkenylamino, di-C 1-4 alkylamino, C 1-4 acylamino, phenyl, phenylamino, benzoylamino, benzylamino, phenylamido, carboxy, C 1-4 alkoxycarbonyl, phenyl-C 1-10 alkoxycarbonyl, carbamoyl, mono-C 1-4 carbamoyl, di-C 1-4 carbamoyl and any of the above in which a hydrocarbyl moiety is itself substituted by halo, cyano, hydroxy, C 1-2 , alkoxy, amino, nitro, carbamoyl, carboxy or C 1-2 , alkoxycarbonyl.

12. The compound of claim 10 , wherein X is selected from

13. The compound of claim 1 , wherein the compound is selected from the group consisting of

4-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(3,4-Dimethoxyphenyl)-4-[(2,4-dimethylpyridin-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-[(3,5-Difluoropyridin-4-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-[(3,5-Dimethylpyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-[(3-Methylpyridin-2-yl)methyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(3,4-Dimethoxyphenyl)-4-[(3-fluoropyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-[(5-Bromo-3-fluoropyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-[(3,5-Dichloropyridin-4-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(4-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(3,4-Dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-[(3,5-Difluoropyridin-2-yl)methyl]-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(4-Chloro-2,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(3,4-Dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3 (4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(3,4-dimethylphenyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(3,5-Dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3 (4H)-one 1,1-dioxide,

4-(2,4-Difluoro-6-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(3,4-Dimethoxyphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(3,4-Dimethoxyphenyl)-4-(2,6-difluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-[3-(methylsulfonyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-[3-(Methylsulfonyl)phenyl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(4-Hydroxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(4-methoxy-3,5-dimethylphenyl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-hydroxybenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-[(3-methyloxetan-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-[(3,4-dimethoxypyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-5-fluoro-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(1,3-Benzothiazol-6-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-[(1-methyl-1H-indazol-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-[(2-oxo-1,2-dihydroquinolin-4-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(pyridin-2-ylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(1-methyl-1,2-oxazol-3-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

5-Fluoro-2-(6-methoxypyridin-3-yl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-[(1-methyl-1H-imidazol-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-(1-ethylpiperidin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(4-Chloro-2-fluorobenzyl)-2-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluoro-4-methylbenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(2-methoxypyrimidin-5-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(6-methoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-(6-methoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(6-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(2-methoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(6-Methoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(5,6-Dimethoxypyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-Dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(5,6-Dimethoxypyridin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(2,6-Dimethoxypyridin-4-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(1-ethyl-1H-pyrazol-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-[5-(methylsulfanyl)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-[5-(Methylsulfanyl)pyridin-3-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluoro-4-methoxybenzyl)-2-(6-methoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,4,6-Trifluorobenzyl)-2-[(2-oxo-1,2-dihydroquinolin-4-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-[6-(Dimethylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-[2-(Dimethylamino)pyridin-4-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-[6-(Methylsulfanyl)pyridin-3-yl]-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(2,6-Dimethoxypyridin-4-yl)-4-[(5-fluoro-3-methylpyridin-2-yl)methyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-Difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Chloro-6-fluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2-Difluorobenzyl)-2-(5,6-dimethoxypyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(4,5-dimethoxypyrimidin-2-yl)-4-(2,4,6-trifluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-[6-methoxy-5-(methylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(4,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(6-methoxy-5-methylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

2-(5-methoxy-6-methylpyridin-3-yl)-4-(2,4,6-trifluorobenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methoxy-6-(methylamino)pyridin-2-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2-chloro-4,6-difluorobenzyl)-2-(2,6-dimethoxypyridin-4-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

2-(1,3-benzothiazol-6-yl)-4-(2,6-difluoro-4-methoxybenzyl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-(4,6-dimethoxypyridin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,

4-(2,6-difluoro-4-methoxybenzyl)-2-[5-methyl-6-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide,

4-(2-chloro-4,6-difluorobenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide, and

4-(2,6-difluoro-4-methoxybenzyl)-2-[6-methoxy-5-(methylamino)pyridin-3-yl]-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide.

14. The compound of claim 1 , wherein the compound is selected from the group consisting of: