IP Library › Granted Patent US 9,284,335

Granted Patent B2

US 9,284,335 · App. 14/408,942 · Granted Mar 15, 2016

Substituted pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines, pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidines and/or [1,2,4]triazolo[1,5-c]pteridines for treatment of central nervous system diseases and disorders

Inventors: Amy Allan (Encinitas, CA); Bryan Branstetter (Carlsbad, CA); Brian Dyck (San Diego, CA); Laurent Gomez (San Diego, CA); Tami Jo Marrone (Carlsbad, CA); Marco Peters (San Diego, CA); Michael I. Weinhouse (San Diego, CA)

Assignee: Dart NeuroScience (Cayman) Ltd.

C07D519/00 C07D471/14 C07D487/14 C07D491/107 C07D491/147 C07D491/22 C07D495/14 C07D495/22 C07D498/08

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Quick Facts

Patent No.: US 9,284,335
App. No.: 14/408,942
Granted: Mar 15, 2016
Kind: B2

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Abstract

Described herein are compounds and chemical entities of Formula (I), methods of their synthesis, compositions comprising them, and their use in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.

Claims (385)

1. A chemical entity of Formula

wherein:

Y and Z are each independently —CH— or —N—, with the proviso that at least one Y or Z member is —N—;

M is 0, 1, 2, 3, 4, or 5;

R 1 is each independently selected from H, halo, —CN, —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 haloalkyl, —C 1-6 thioalkyl, —C 1-6 thiohaloalkyl, —C 1-6 alkoxy, —C 1-6 haloalkoxy, —SO 2 C 1-6 alkyl, aryl, pyrazolyl and 2-oxopyrrolidinyl; or

two R 1 members are on adjacent carbons and taken together with the carbons to which they are attached form a 5-6 member saturated or unsaturated monocylic ring system comprising one or more oxygen or nitrogen atoms, wherein the ring system is optionally substituted with one or more groups selected from halo, —C 1-6 alkyl, —C 1-6 alkoxy, and —C 1 -C 6 haloalkoxy;

R 3 and R 4 are each independently selected from the group consisting of H, halo, —CN, —OH, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —CH 2 O-aryl, —C 1-6 alkoxy, —C 1-6 haloalkoxy, —C(O)CH 3 , —CH(OH)(CF 3 ), —(CR 10 R 11 ) 0-3 NR 12 R 13 , aryl, heteroaryl, and heterocycloalkyl, wherein each aryl, heteroaryl and heterocycloalkyl is optionally unsubstituted or substituted with a member each independently selected from the group consisting of —CH 3 and —OCH 3 ;

R 10 and R 11 are each independently selected from the group consisting of: —H, —F, —C 1-6 alkyl, —CF 3 , and —OH;

R 12 and R 13 are each independently selected from the group consisting of —H, —C 1-6 alkyl, —C(O) 2 CH 2 Ph, —C 1-6 alkyl(aryl), C 1-6 alkyl(heterocycloalkyl), aryl, —C 3-6 cycloalkyl, heteroaryl, and heterocycloalkyl, said aryl, —C 3-6 cycloalkyl, heteroaryl, and heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CN, —OH, —NO 2 , —SO 2 NH 2 , —CONH 2 , —CO 2 H, —COH, amino, —(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —N 3 , cyanate, isocyanate, thiocyanate, isothiocyanate, aryloxy, and arylthio;

or R 12 and R 13 are taken together with the nitrogen to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CN, —OH, —NO 2 , —SO 2 NH 2 , —CO 2 H, —COH, amino, —(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —N 3 , cyanate, isocyanate, thiocyanate, isothiocyanate, aryloxy, and arylthio; and

wherein the chemical entity is selected from the group consisting of compounds of Formula (I), and pharmaceutically acceptable salts of compounds of Formula (I).

2. The chemical entity as in claim 1 , wherein Y is —N—.

3. The chemical entity as in claim 2 , wherein R 3 is selected from —H, —CH(OCH 3 ) 2 , —CH 2 O-phenyl, or —(CR 10 R 11 ) 1-3 NR 12 R 13 , where R 10 and R 11 are each independently H, R 12 is H or —C 1-6 alkyl, and R 13 is selected from phenyl, benzyl, (3-methyloxetan-3-yl)methyl, or (tetrahydrofuran-3-yl)methyl.

4. The chemical entity as in claim 1 , wherein Z is —N—.

5. The chemical entity as in claim 1 , wherein Y and Z are each independently —N—.

6. The chemical entity as in claim 1 , wherein M is 1.

7. The chemical entity as in claim 1 , wherein M is 2.

8. The chemical entity as in claim 1 , wherein M is 3.

9. The chemical entity as in claim 1 , wherein M is 4.

10. The chemical entity as in claim 1 , wherein M is 5.

11. The chemical entity as in claim 1 , wherein M is 1, 2, 3, 4, or 5, and R 1 is each independently H, —Br, —Cl, —F, —I, —CN, —C 1-6 alkyl, —C 2-6 alkynyl, —SCH 3 , —OCF 3 , —OCF 2 H, —C 1-6 alkoxy, —SCF 3 , —SO 2 CH 3 , 2-oxopyrrolidine, and pyrazole.

12. The chemical entity as in claim 1 , wherein two R 1 members are on adjacent carbons and taken together with the carbons to which they are attached form a fused 5-membered ring selected from 1-methyl-1H-pyrazolyl or dioxolanyl.

13. The chemical entity as in claim 1 , wherein M is 1, 2, 3 or 4, and R 1 is each independently —Cl, —F or —C 1-6 alkoxy.

14. The chemical entity as in claim 1 , wherein R 4 is H or —CH 3 and R 3 is —(CR 10 R 11 ) 1-3 NR 12 R 13 .

15. The chemical entity as in claim 1 , wherein R 3 is —(CR 10 R 11 )NR 12 R 13 , R 10 and R 11 are each independently selected from H, —OH, and —CH 3 , and R 12 and R 13 are taken together with the nitrogen to which they are attached to form a heterocycloalkyl ring selected from morpholinyl, (2S,6R)-2,6-dimethylmorpholinyl, 4-(methylsulfonyl)piperazin-1-yl and isoindolin-2-yl.

16. The chemical entity as in claim 1 , wherein R 3 is —(CR 10 R 11 ) 1-2 NR 12 R 13 , R 10 and R 11 are each independently selected from H, —OH, or —CH 3 , and R 12 and R 13 are taken together with the nitrogen to which they are attached to form a heterocycloalkyl ring selected from morpholinyl, 2,6-dimethylmorpholinyl, (2S,6R)-2,6-dimethylmorpholinyl, (2R,6S)-2,6-dimethylmorpholinyl and 4-(methylsulfonyl)piperazinyl.

17. The chemical entity as in claim 1 , wherein R 3 is H or —CH 3 and R 4 is —(CR 10 R 11 ) 1-3 NR 12 R 13 .

18. The chemical entity as in claim 1 , wherein R 3 is —H, or —CH 3 , R 4 is H, —Br, —C 1-6 alkyl, —C 2-6 alkenyl, —C(O)CH 3 , —CH(OH)CF 3 , —CH 2 OCH 2 OCH 3 , phenyl, pyridyl, and —(CR 10 R 11 ) 1-3 NR 12 R 13 , said phenyl and pyridyl each optionally substituted with one or more substituents independently selected from the group consisting of —CH 3 and —OCH 3 , R 10 and R 11 are each independently selected from H, —CH 3 , or —OH, and R 12 and R 13 are each independently —H, —C 1-6 alkyl, —C(O) 2 CH 2 Ph, —CH(CH 3 )phenyl, —C 3-6 cycloalkyl, and heterocycloalkyl, said —C 3-6 cycloalkyl and heterocycloalkyl each optionally substituted with one or more substitutents independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CN, —OH, —NO 2 , —SO 2 NH 2 , —CONH 2 , —CO 2 H, —COH, amino, —(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —N 3 , cyanate, isocyanate, thiocyanate, isothiocyanate, aryloxy, and arylthio.

19. The chemical entity as in claim 1 , wherein R 3 is —H, or —CH 3 , R 4 is —(CR 10 R 11 ) 1-3 NR 12 R 13 , R 10 and R 11 are each independently selected from —H, —F, —CH 3 , —CF 3 , and —OH, and R 12 and R 13 are taken together with the nitrogen to which they are attached to form a heterocycloalkyl ring selected from (2R,5R)-2,5-dimethylmorpholinyl, (2R,6S)-2,6-dimethylmorpholinyl, (2S,5S)-2,5-dimethylmorpholinyl, (2S,6R)-2,6-dimethylmorpholinyl, (3S,5R)-(2-methoxyethyl)piperazinyl, (4-((tetrahydrofuran-3-yl)methyl)piperazinyl), 1,4-oxazepanyl, 1-methyl-8-oxa-1,2-diazaspiro[4.5]decanyl, 2,2-dimethylmorpholinyl, 2,5-dimethylmorpholinyl, 2-ethylmorpholinyl, 2-methylmorpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-(dimethylamino)pyrrolidinyl, 3,3-dimethylmorpholinyl, 3,5-dimethylpiperazinyl, 3-hydroxyazetidinyl, 3-methyl-6-oxopyridazin-1(6H)-yl, 3-methylmorpholinyl, 4-(2,2,2-trifluoroacetyl)piperazinyl, 4-(methylsulfonyl)piperazinyl, 4-(propan-2-yl)piperazinyl, 4-(tetrahydrofuran-3-carbonyl)piperazinyl, 4-acetyl-1,4-diazepanyl, 4-cyclopropylpiperazinyl, 4-methoxypiperidinyl, 4-methyl-1,4-diazepanyl, 4-methyl-piperazinyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, isoindolinyl, morpholinyl, N,N-dimethylpiperazinyl-1-sulfonamide, piperazinyl, piperidinyl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-on-7-yl, and thiomorpholinyl.

20. The chemical entity as in claim 1 , wherein R 4 is morpholinomethyl, (3-methylmorpholino)methyl, (2,6-dimethylmorpholino)methyl, ((2S,6R)-2,6-dimethylmorpholino)methyl, ((2R,6S)-2,6-dimethylmorpholin-4-yl)methyl, (4-(methylsulfonyl)piperazin-1-yl)methyl, 1-hydroxy-2-morpholinoethyl or 2-((2S,6R)-2,6-dimethylmorpholino)-1-hydroxyethyl, and R 3 is H or —CH 3 .

21. A pharmaceutical composition comprising an effective amount of at least one chemical entity of claim 1 , and a pharmaceutically acceptable excipient.

22. A compound, or pharmaceutically acceptable salt thereof, of Formula (I):

wherein:

Y and Z are each independently —CH— or —N—, with the proviso that at least one Y or Z member is —N—;

M is 0, 1, 2, 3, 4, or 5;

R 10 and R 11 are each independently selected from the group consisting of: —H, —F, —C 1-6 alkyl, —CF 3 , and —OH;

R 12 and R 13 are each independently selected from the group consisting of —H, —C 1-6 alkyl,

C(O) 2 CH 2 Ph, —C 1-6 alkyl(aryl), —C 1-6 alkyl(heterocyclo alkyl), aryl, —C 3-6 cycloalkyl, heteroaryl, and heterocycloalkyl, said aryl, —C 3-6 cycloalkyl, heteroaryl, and heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CN, —OH, —NO 2 , —SO 2 NH 2 , —CONH 2 , —CO 2 H, —COH, amino, —(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —N 3 , cyanate, isocyanate, thiocyanate, isothiocyanate, aryloxy, and arylthio;

or R 12 and R 13 , taken together with the nitrogen to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CN, —OH, —NO 2 , —SO 2 NH 2 , —CONH 2 , —CO 2 H, —COH, amino, —(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, —N 3 , cyanate, isocyanate, thiocyanate, isothiocyanate, aryloxy, and arylthio.

23. A compound selected from the group consisting of:

9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-Bromo-6-(4-methoxybenzyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-(Dimethoxymethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-Bromo-6-(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

9-(3,4-Dimethoxyphenyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(6-methoxypyridin-3-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(2-methoxypyridin-3-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(3-methyl-6-oxopyridazin-1(6H)-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(4-Cyclopropylpiperazin-1-yl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((1S,2S)-2-Aminocyclohexyl)amino)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(methyl(1-methylpiperidin-4-yl)amino)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

9-((2-(Dimethylamino)ethyl)(methyl)amino)-6-(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(4-(2-methoxyethyl)piperazin-1-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(3-(Dimethylamino)pyrrolidin-1-yl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(4-(Dimethylamino)piperidin-1-yl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((2S,6R)-2,6-Dimethylmorpholino)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((3-(Dimethylamino)propyl)(methyl)amino)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(4-(methylsulfonyl)piperazin-1-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

Benzyl (2-(6-(4-methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yl)ethyl)carbamate;

6-(4-Methoxybenzyl)-8-(morpholinomethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(piperidin-1-ylmethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(thiomorpholinomethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chlorobenzyl)-9-(morpholinomethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chlorobenzyl)-9-(piperidin-1-ylmethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chlorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(2-Aminoethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(2-((tetrahydro-2H-pyran-4-yl)amino)ethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(2((1-phenylethyl)amino)ethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-vinylpyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((methoxymethoxy)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(1-Ethoxyvinyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(Hydroxymethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((Dimethylamino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-methylpiperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(3,3-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((2,2-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((2-Ethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((2,5-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((2,2,6,6-tetrafluoromorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(8-Oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((1-methyl-8-oxa-1,2-diazaspiro[4.5]decan-2-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((2-methylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((3-methylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-methyl-1,4-diazepan-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((1,4-Oxazepan-4-yl)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((4-Acetyl-1,4-diazepan-1-yl)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((Cyclohexyl(methyl)amino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-methoxypiperidin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-((Isopropyl(2-methoxyethyl)amino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-((4-methylpiperazin-1-yl)methyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-(morpholinomethyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-(piperidin-1-ylmethyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-(thiomorpholinomethyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(((2-methoxyethyl)(methyl)amino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

7-((6-(4-Methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yl)methyl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one;

9-(((2S,5S)-2,5-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,5R)-2,5-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(piperazin-1-ylmethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((3S,5R)-3,5-Dimethylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-((tetrahydrofuran-3-yl)methyl)piperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

4-((6-(4-Methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-9-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide;

6-(4-Methoxybenzyl)-9-((4-(2,2,2-trifluoroacetyl)piperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-(tetrahydrofuran-3-carbonyl)piperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(morpholinomethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-((((3-methyloxetan-3-yl)methyl)amino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-((methyl((tetrahydrofuran-3-yl)methyl)amino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-((Cyclopropyl(methyl)amino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-((Benzylamino)methyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-((phenylamino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

8-(Isoindolin-2-ylmethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-Acetyl-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(1-((2S,6R)-2,6-Dimethylmorpholino)ethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(1-Hydroxy-2-morpholinoethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(2-((2S,6R)-2,6-Dimethylmorpholino)-1-hydroxyethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(1-Fluoro-2-morpholinoethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(2-((2S,6R)-2,6-Dimethylmorpholino)-1-fluoroethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(2,2,2-trifluoro-1-hydroxyethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(2,2,2-trifluoro-1-morpholinoethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-(trifluoromethoxy)benzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-fluoro-3-methylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-fluorobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(3-fluoro-4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(2-fluoro-4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3-bromo-4-Fluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

4-((9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-5-oxopyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-6(5H)-yl)methyl)benzonitrile;

6-(4-(tert-Butyl)benzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

3-((9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-5-oxopyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-6(5H)-yl)methyl)benzonitrile;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-(methylsulfonyl)benzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(2-methylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(3-iodobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,5-Difluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2-Bromo-4-methoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,6-Difluoro-4-methoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-((1-methyl-1H-indazol-6-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-(1H-Pyrazol-1-yl)benzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-(Difluoromethoxy)-2-fluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,5-Difluoro-4-methoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-Difluoro-4-methoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(2-((trifluoromethyl)thio)benzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3-Chloro-4-fluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,4-Dichlorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2-Chloro-4-methoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2-(Difluoromethoxy)benzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chloro-3-fluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3-Chloro-5-fluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-(2-oxopyrrolidin-1-yl)benzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-ethoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,4-Difluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-(methylthio)benzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2-Chloro-4-(methylsulfonyl)benzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-8-(phenoxymethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-Difluoro-4-methoxybenzyl)-9-((4-isopropylpiperazin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-Difluoro-4-methoxybenzyl)-9-(piperidin-1-ylmethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(2,4,5-trifluorobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-isopropylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-(Difluoromethoxy)benzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-ethoxy-3,5-difluorobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-ethynylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-iodobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,4-Dimethoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3-Chloro-5-fluoro-4-methoxybenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(4-methoxy-3-methylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(3-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,5-Difluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,4-Difluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(4-(trifluoromethyl)benzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(4-fluoro-3-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(2-fluoro-4-methylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2-Chloro-4,5-difluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3-Chloro-2,4-difluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(3,4,5-trimethoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,4-dichlorobenzyl)-9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,4-Dichloro-5-fluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2-Chloro-4-fluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chloro-2-fluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(2,3,5,6-tetrafluoro-4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chloro-2,6-difluorobenzyl)-9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(4-fluoro-3,5-dimethylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(2,3,4-trifluorobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-dichlorobenzyl)-9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-Difluoro-4-methylbenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Chloro-3-(trifluoromethoxy)benzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,5-Dimethoxybenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3-Chloro-4-ethoxy-5-fluorobenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(4-ethoxy-2,3-difluorobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2R,6S)-2,6-Dimethylmorpholino)methyl)-6-(3,4,5-trifluorobenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-Benzyl-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(3,4-Dimethylbenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,4-Dimethylbenzyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

9-(((2S,6R)-2,6-Dimethylmorpholino)methyl)-6-(2,3,5,6-tetrafluoro-4-methylbenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(Benzo[d][1,3]dioxol-5-ylmethyl)-9-(((2R,6S)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(morpholinomethyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((2-methylmorpholino)methyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

6-(4-Methoxybenzyl)-9-(piperidin-1-ylmethyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

6-(4-Methoxybenzyl)-9-((4-methoxypiperidin-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

9-((4-Acetylpiperazin-1-yl)methyl)-6-(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pteridin-5(6H)-one;

9-((1,4-Oxazepan-4-yl)methyl)-6-(2,3-difluoro-4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-Difluoro-4-methoxybenzyl)-9-((3-methylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

6-(2,3-Difluoro-4-methoxybenzyl)-9-((3-hydroxyazetidin-1-yl)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;

and pharmaceutically acceptable salts thereof.

24. A pharmaceutical composition comprising an effective amount of at least one compound of claim 23 , and a pharmaceutically acceptable excipient.

25. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of: