Triazolone Compounds

Abstract

Described herein are triazalone compounds of formula (I): JPEG2023519362000106.jpg3243 and pharmaceutically acceptable salts thereof. Methods for preparing and using the compounds of formula (I) are also described. The compounds of formula (I) and their pharmaceutically acceptable salts may be useful as adenosine receptor antagonists in the treatment of diseases or conditions mediated by adenosine receptors, such as cancer, movement disorders, or attention disorders.

Description

[Background technology]

[0001] background Adenosine regulates several physiological functions. Intracellularly, adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle; extracellular adenosine is involved in intercellular signaling. For example, extracellular adenosine is a potent immunosuppressant that prevents excessive immune responses during inflammation and infection. Adenosine also acts on other systems, including the cardiovascular and central nervous systems.

[0002] The actions of adenosine are mediated by a family of G protein-coupled receptors. At least four subtypes of adenosine receptors have been identified: A1R, A2aR, A2bR, and A3R. The A1R and A3 subtypes inhibit the activity of the enzyme adenylate cyclase, whereas the A2a and A2b subtypes stimulate the activity of the same enzyme, thereby regulating intracellular cyclic AMP levels.

[0003] In the immune system, engagement of the A2a and A2b adenosine receptors is a key control mechanism that protects tissues against excessive immune responses. In tumors, this pathway is hijacked to thwart antitumor immunity and promote cancer progression. Moreover, the tumor microenvironment often contains high levels of extracellular adenosine. Thus, adenosine receptors, especially A2aR and A2bR, have been identified as targets for cancer therapy.

[0004] A number of adenosine receptor antagonists have been reported. For example, International Application WO2006 / 138734 discloses triazolopyrimidine cannabinoid receptor 1 (CB-1) antagonists. WO2008 / 002596 and WO2009 / 111449 disclose adenosine A2a receptor antagonists containing a triazolone moiety. WO2012 / 038980 discloses fused tricyclic compounds as adenosine receptor antagonists. WO2016 / 161282 discloses heterocyclic compounds as LSD1 inhibitors. WO2018 / 166493 discloses heteroaryl[4,3-c]pyrimidin-5-amine derivatives for use as A2a receptor antagonists. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for highly soluble, highly selective and highly potent adenosine receptor antagonists. [Means for solving the problem]

[0006] overview In one embodiment, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is: [ka] It could be; Each R 1 and each R 2 is independently halo, C 1-3 Alkyl, -OC 1-3 Alkyl, -COR a or -NR 7 R 8 It could be; wherein alkyl is optionally -OR aand substituted with one or more substituents independently selected from halo; R 3 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR a , -NR a R b , -CO2R a , -CONR a R b , -NR a C(O)-R a OR-NHC(O)-OR a It could be; where heterocyclyl and heteroaryl are independently N, O and S(O) k containing 1 to 4 heteroatoms independently selected from: Here, R 3 is optionally halo, cyano, -R a AND -OR a is substituted with 1 to 3 substituents selected from; R 4 Ha-(CHR c ) i -(NR a ) j -R 5 It could be; R 5 are N, O and S(O), respectively. k may be a 5-membered heterocyclyl or a 5-membered heteroaryl containing 1 to 4 heteroatoms independently selected from: Here, R 5 wherein one or two ring atoms are optionally replaced by -C(=O)-; Here, R 5 optionally 1 to 4 groups -XR 6 is replaced by; Each X is independently a bond, -O-, or -NR a -, -S(O) k -, -(CH2) m - or -C(O)-; Each R 6 are independently H, halo, -ORa , C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, heteroaryl, aryl, -COR a , -C(O)NR a R b , -(CH2) n -NR a R b or can be cyano; wherein each of heterocyclyl and heteroaryl is N, O, and S(O) k containing 1 to 4 heteroatoms independently selected from: Here, each C 3-8 one or two ring atoms of the cycloalkyl, heterocyclyl, heteroaryl, or aryl are independently optionally substituted with -C(=O)-; wherein each of alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl is optionally selected from -R a , -OR a , -(CH2) n -NR a R b and substituted with one or more substituents independently selected from halo; Each R 7 and each R 8 is independently R a It could be; or R 7 and R 8 are combined with the atoms to which they are attached, sometimes with -OR a and halo; Each R a and each R b are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 It can be cycloalkylalkyl; Here, each R a and each R b is independently optionally substituted with one or more substituents independently selected from: —OH and halo; Each R c are independently H, halo, and C 1-3 Alkyl or -(CH2) n -NR a R b It could be; wherein alkyl is optionally -OR a and substituted with one or more substituents independently selected from halo; a can be 0 or 1; i can be 0, 1, 2 or 3; j can be 0 or 1; Each k may independently be 0, 1, or 2; each m may independently be 1 or 2; and Each n can independently be 0 or 1.

[0007] The compounds of formula (I) may be selective adenosine receptor antagonists for CB-1. The compounds have a K of 100 nM or less for at least one of the A2aR and the A2bR. i and K of 10,000 nM or more for CB-1. i may have:

[0008] In some embodiments, i can be 1 and R c is H or C 1-3 R can be alkyl. 5 may be selected from imidazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiophenyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R 5 optionally 1 to 4 groups -XR 6 X can be a bond and R 6 is C 1-6 It may be alkyl.

[0009] In one embodiment, R 3R may be phenyl optionally substituted with fluoro or chloro. 1 and R 2 may each independently be selected from halo, -CH3, -CH2OH, or -OCH3.

[0010] In other embodiments, the compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Each R 1 and each R 2 is independently halo, C 1-3 Alkyl or -OC 1-3 It can be alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halo; Ring B can be a 5-membered heterocyclyl or a 5-membered heteroaryl, each containing 1 to 4 heteroatoms independently selected from N and O; Each R 9 are independently halo or C 1-3 It can be alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halo; Each R a and each R b are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 It can be cycloalkylalkyl; Here, each R a and each R b is independently optionally substituted with one or more substituents independently selected from: —OH and halo; R c H, halo, C 1-3 Alkyl or -(CH2) n -NR a R b It could be; wherein alkyl is optionally -OR aand substituted with one or more substituents independently selected from halo; R d can be H or halo; a can be 0 or 1; b may be 0, 1, or 2; and n can be 0 or 1.

[0011] In one embodiment, each ring B is optionally selected from the group consisting of -C 1-3 It may be tetrahydrofuranyl or 1,3-oxazolyl substituted with 1 to 3 substituents selected from alkyl.

[0012] In another embodiment, a compound or a pharma- ceutically acceptable salt thereof is provided, wherein the compound is selected from the group consisting of: 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methylimidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1H-imidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-(1H-tetrazol-5-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-ethylpyrazol-3-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[1-(2-thienyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(isoxazol-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(3-methylimidazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1H-imidazol-5-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1H-imidazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(1H-pyrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,4-triazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1H-triazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyltriazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[1-benzyl-3-(3-methoxyphenyl)pyrazol-4-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-methoxy-6-methyl-4-pyridyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(3,5-dimethylimidazol-4-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylpyrazol-3-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; tert-Butyl 3-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]pyrrolidine-1-carboxylate; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1-methylpyrrolidin-3-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; tert-Butyl 2-[[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyrrolidine-1-carboxylate; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2R)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrrolidin-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-methoxy-6-methyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[[1-(pyridine-3-carbonyl)pyrrolidin-3-yl]amino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-[methyl(1H-pyrazol-4-yl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[1-[[2-(aminomethyl)phenyl]methyl]pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0013] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof may be selected from the group consisting of: 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0014] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent or excipient.

[0015] In another embodiment, there is provided the use of a compound of formula (I) or formula (II), or a pharma- ceutically acceptable salt thereof, for the treatment of a disease or condition mediated by an adenosine receptor.

[0016] In some embodiments, the disease or condition mediated by adenosine receptors is lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma, or other solid tumors.

[0017] Other features, objects, and advantages will become apparent from the description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] explanation The compounds of formula (I) and formula (II) or pharma- ceutically acceptable salts thereof are useful as adenosine receptor antagonists.

[0019] Formula (I): [ka] or a pharma- ceutically acceptable salt thereof is described herein.

[0020] Ring A is: [ka] It is.

[0021] Each R 1 and each R 2 Independently, Halo, C 1-3 Alkyl, -OC 1-3 Alkyl, -COR a or -NR 7 R 8 wherein alkyl is optionally -OR a and substituted with one or more substituents independently selected from halo.

[0022] R 3 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR a , -NR a R b , -CO2R a , -CONR a R b , -NR a C(O)-R a OR-NHC(O)-OR awherein heterocyclyl and heteroaryl are independently N, O and S(O) k wherein R 3 is optionally halo, cyano, -R a AND -OR a It is substituted with 1 to 3 substituents selected from:

[0023] R 4 Ha-(CHR c ) i -(NR a ) j -R 5 It is.

[0024] R 5 are N, O and S(O), respectively. k wherein R is a 5-membered heterocyclyl or a 5-membered heteroaryl containing 1 to 4 heteroatoms independently selected from 5 one or two ring atoms of are optionally replaced by -C(=O)-; 5 optionally 1 to 4 groups -XR 6 has been replaced with.

[0025] Each X is independently a bond, -O-, or -NR a -, -S(O) k -, -(CH2) m - or -C(O)-.

[0026] Each R 6 are independently H, halo, -OR a , C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, heteroaryl, aryl, -COR a , -C(O)NR a R b , -(CH2) n -NR a R b or cyano; where each of heterocyclyl and heteroaryl is selected from N, O and S(O) kwherein each C 3-8 One or two ring atoms of the cycloalkyl, heterocyclyl, heteroaryl, or aryl are independently optionally substituted with -C(=O)-; wherein each of the alkyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with -R a , -OR a , -(CH2) n -NR a R b and substituted with one or more substituents independently selected from halo.

[0027] Each R 7 and each R 8 are independently a or R 7 and R 8 are combined with the atoms to which they are attached, sometimes with -OR a and halo, forming a 3- to 8-membered heterocyclyl substituted with one or more substituents independently selected from.

[0028] Each R a and each R b are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 cycloalkylalkyl; where each R a and each R b is independently optionally substituted with one or more substituents independently selected from -OH and halo.

[0029] Each R c are independently H, halo, and C 1-3 Alkyl or -(CH2) n -NR a R b wherein alkyl is optionally -OR a and substituted with one or more substituents independently selected from halo.

[0030] a is 0 or 1.

[0031] i is 0, 1, 2 or 3.

[0032] j is 0 or 1.

[0033] Each k is independently 0, 1, or 2.

[0034] Each m is independently 1 or 2.

[0035] Each n is independently 0 or 1.

[0036] In some embodiments, i is 1 and R c is H or C 1-3 It is an alkyl.

[0037] In one embodiment, R 5 In another embodiment, R 5 is a 5-membered heteroaryl.

[0038] In one embodiment, R 5 is selected from imidazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiophenyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R 5 optionally 1 to 4 groups -XR 6 has been replaced with.

[0039] In one embodiment, R 5 are each tetrahydrofuranyl or 1,3-oxazolyl optionally substituted with -CH3.

[0040] In some embodiments, i is 1; R c is H; j is 0; and R 5is selected from 1,3-oxazolyl and tetrahydrofuranyl, each optionally substituted with -CH3.

[0041] In one embodiment, R 1 and R 2 are each independently -CH3 or -CH2OH; i is 1; R c is H; j is 0; and R 5 are each tetrahydrofuranyl or 1,3-oxazolyl optionally substituted with -CH3.

[0042] In certain embodiments, X is a bond and R 6 is C 1-6 It is an alkyl.

[0043] In one embodiment, R 3 is phenyl optionally substituted with fluoro or chloro.

[0044] In one embodiment, R 1 and R 2 are each independently selected from halo, -CH3, -CH2OH, or -OCH3.

[0045] In one embodiment, R 1 and R 2 are each independently selected from halo, -CH, -CHOH, or -OCH; and R 3 is phenyl optionally substituted with fluoro or chloro.

[0046] In one embodiment, R 1 and R 2 are each independently selected from halo, -CH, -CHOH, or -OCH; R 3 is phenyl optionally substituted with fluoro or chloro; i is 1; and R c is H.

[0047] In one embodiment, R 1 and R2 are each independently -CH3 or -CH2OH; R 3 is phenyl optionally substituted with fluoro or chloro; i is 1; R c is H; j is 0; and R 5 are each tetrahydrofuranyl or 1,3-oxazolyl optionally substituted with -CH3.

[0048] In one embodiment, R 3 is phenyl optionally substituted with fluoro or chloro; i is 1; R c is H or C 1-3 alkyl; j is 0; and R 5 is selected from imidazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiophenyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R 5 optionally 1 to 4 groups -XR 6 has been replaced with.

[0049] In one embodiment, R 3 is phenyl optionally substituted with fluoro or chloro; i is 1; R c is H or C 1-3 alkyl; j is 0; and R 5 is selected from imidazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiophenyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R 5 optionally 1 to 4 groups -XR 6 where X is a bond and R 6 is C 1-6 It is an alkyl.

[0050] In one embodiment, R 3 is phenyl optionally substituted with fluoro or chloro; i is 1; R c is H or C 1-3 alkyl; j is 0; and R 5 are each tetrahydrofuranyl or 1,3-oxazolyl optionally substituted with -CH3.

[0051] Formula (II): [ka] or a pharma- ceutically acceptable salt thereof. Compounds of formula (II) are included within the broad formula (I).

[0052] Each R 1 and each R 2 Independently, Halo, C 1-3 Alkyl or -OC 1-3 alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from --OH and halo.

[0053] Ring B is a 5-membered heterocyclyl or 5-membered heteroaryl, each containing 1 to 4 heteroatoms independently selected from N and O.

[0054] Each R 9 are independently halo or C 1-3 alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from --OH and halo.

[0055] Each R a and each R b are independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 cycloalkylalkyl; where each R a and each R bis independently optionally substituted with one or more substituents independently selected from -OH and halo.

[0056] R c H, halo, C 1-3 Alkyl or -(CH2) n -NR a R b wherein alkyl is optionally -OR a and substituted with one or more substituents independently selected from halo.

[0057] R d is H or halo.

[0058] a is 0 or 1.

[0059] b is 0, 1 or 2.

[0060] n is 0 or 1.

[0061] In one embodiment, R d is a halo.

[0062] In one embodiment, R 1 and R 2 are each independently selected from halo, -CH3, -CH2OH, or -OCH3.

[0063] In one embodiment, R 1 and R 2 are each independently -CH3 or -CH2OH.

[0064] In certain embodiments, Ring B is imidazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiophenyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R 5 optionally 1 to 4 groups -XR6 has been replaced with.

[0065] In certain embodiments, Ring B is tetrahydrofuranyl or 1,3-oxazolyl, b is 0 or 1, and each R 9 is independently 1-3 It is an alkyl.

[0066] In certain embodiments, Ring B is tetrahydrofuranyl.

[0067] In certain embodiments, Ring B is 1,3-oxazolyl.

[0068] In one embodiment, R 1 and R 2 are each independently -CH or -CHOH; Ring B is tetrahydrofuranyl or 1,3-oxazolyl; b is 0 or 1; and R c is H.

[0069] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0070] The term "alkyl," if specified, refers to a fully saturated straight-chain or branched aliphatic group having the specified number of carbon atoms (e.g., C 1-10 Alkyl refers to an alkyl group having 1 to 10 carbons. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. If no size is specified, "alkyl" refers to a group having 1 to 10 carbon atoms.

[0071] The term "alkenyl" refers to an unsaturated straight or branched aliphatic group containing at least one carbon-carbon double bond and, if specified, having a specific number of carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methylbut-1-enyl, 1-pentenyl, and 4-hexenyl. If no size is specified, "alkenyl" refers to a group having 2 to 10 carbon atoms.

[0072] The term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group containing at least one carbon-carbon triple bond and, if specified, having a specific number of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and but-2-ynyl. If no size is specified, "alkynyl" refers to a group having 2 to 10 carbon atoms.

[0073] Alkenyl and alkynyl groups can contain more than one unsaturated bond or a mixture of double and triple bonds.

[0074] The term "cycloalkyl" refers to a saturated or unsaturated aliphatic ring containing 3 to 10 carbon ring atoms, where one or more carbon ring atoms may be optionally replaced with -C(=O)-. Cycloalkyl groups can include fused and / or bridged rings, where the fused or bridged rings are cycloalkyl. Suitable examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, norbornyl, 4-oxocyclohex-1-yl, and 3-oxocyclohept-5-en-1-yl.

[0075] The term "heterocyclyl" refers to a saturated or unsaturated heterocyclic ring-containing 3 to 10 ring atoms, in which 1 to 4 ring atoms are independently N, O, or S, and in which one or more carbon ring atoms may be optionally replaced by -C(=O)-. The ring nitrogen or sulfur atoms may optionally be oxidized, including, for example, -N(O)-, -S(O)-, or -S(O)2-. The ring nitrogen atoms of a heterocyclyl group may optionally be quaternized, including, for example, -N + (CH3)2-. Heterocyclyl groups can contain fused and / or bridged rings, where the fused or bridged rings are cycloalkyl or heterocyclyl groups. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.

[0076] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group containing 6 to 14 ring atoms. Aryl can contain fused rings, including an aryl ring fused to a cycloalkyl, heterocyclyl, or aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, and dihydro-1H-indenyl.

[0077] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 ring atoms, in which 1 to 4 ring atoms are independently N, O, or S. The ring nitrogen or sulfur atoms may be optionally oxidized, including, for example, -N(O)-, -S(O)-, or -S(O)2-. Heteroaryl groups can contain fused and / or bridged rings, where the fused or bridged rings are cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, pyridyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, 5,6,7,8-tetrahydroquinolinyl, benzofuranyl, pyrrolopyridinyl, pyrrolopyrimidinyl, triazinyl, and tetrazolyl.

[0078] The term "polycyclic ring system" refers to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group that contains two or more fused and / or bridged rings.

[0079] Some compounds described herein can exist in more than one stereoisomeric form. Description of such compounds is intended to include all geometric and optical isomers, including racemates, unless otherwise specified.

[0080] Some compounds described herein may exhibit tautomerism. A structural description herein typically represents only one of the possible tautomeric forms of such a compound. It should be understood that a structural description is intended to include all tautomeric forms of such a compound.

[0081] The term "pharmaceutically acceptable salt" refers to a salt of a compound of formula (I) that retains the biological activity of the free compound and can be administered to humans and / or animals as a pharmaceutical. The desired salt of a basic functional group of a compound can be prepared by treating the compound with an acid. Some examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Some examples of suitable organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid, and salicylic acid. The desired salt of an acidic functional group of a compound can be prepared by treating the compound with a base. Some examples of suitable inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Some examples of suitable organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salts.

[0082] The compounds of formula (I) may contain the specified atoms in any of their isotopic forms. In this regard, particular embodiments of the invention include those in which (a) the compounds of formula (I) are not isotopically enriched or labeled with respect to any atom of the compound; and (b) the compounds of formula (I) are isotopically enriched or labeled with respect to one or more atoms of the compound.

[0083] In this formula, [ka] The use of indicates the point of attachment between the different groups.

[0084] Exemplary compounds of formula (I) or pharma- ceutically acceptable salts thereof include: 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methylimidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1H-imidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-(1H-tetrazol-5-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-ethylpyrazol-3-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[1-(2-thienyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(isoxazol-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(3-methylimidazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1H-imidazol-5-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1H-imidazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(1H-pyrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,4-triazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1H-triazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyltriazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[1-benzyl-3-(3-methoxyphenyl)pyrazol-4-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-methoxy-6-methyl-4-pyridyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(3,5-dimethylimidazol-4-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylpyrazol-3-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; tert-Butyl 3-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]pyrrolidine-1-carboxylate; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1-methylpyrrolidin-3-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; tert-Butyl 2-[[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyrrolidine-1-carboxylate; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2R)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrrolidin-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-methoxy-6-methyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[[1-(pyridine-3-carbonyl)pyrrolidin-3-yl]amino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-[methyl(1H-pyrazol-4-yl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[1-[[2-(aminomethyl)phenyl]methyl]pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0085] The compounds of formula (I) can be adenosine receptor antagonists, i.e., antagonists of one or more of the A1R, A2aR, A2bR and A3R. The term "adenosine receptor antagonist" refers to compounds, such as compounds of formula (I), that bind to and antagonize the activity of adenosine receptors.

[0086] In some cases, the compound of formula (I) is a selective adenosine receptor antagonist. The term "selective" refers to the property of the compound of formula (I) being an adenosine receptor antagonist, but being substantially inactive to other biological targets. As used herein, the term "substantially inactive" refers to a compound that (i) has significantly lower affinity to a certain receptor compared to its affinity to adenosine receptor; (ii) does not show substantial agonist or antagonist activity to a certain receptor; or (i) and (ii) both.

[0087] The term "selective adenosine receptor antagonist" refers to a compound that exhibits a binding affinity for one or more adenosine receptor subtypes that is at least 100-fold greater, at least 1,000-fold greater, or at least 10,000-fold greater than its affinity for a given receptor. i The value ratio (one receptor:adenosine receptor) can be at least 100, at least 1,000 or at least 10,000.

[0088] In particular, selective adenosine receptor antagonists may be substantially inactive at other G protein-coupled receptors, such as the cannabinoid receptors designated CB-1 and CB-2.

[0089] The compounds of formula (I) have a binding affinity K for A2aR of, for example, 100 nM or less, 10 nM or less, or 1 nM or less. imay have:

[0090] The compounds of formula (I) have a binding affinity K for A2bR of, for example, 100 nM or less, 10 nM or less, or 1 nM or less. i may have:

[0091] The compound of formula (I) has a binding affinity K for CB-1 of, for example, 1,000 nM or more, 10,000 nM or more, or 13,000 nM or more. i may have:

[0092] The compounds of formula (I) may be selective adenosine receptor antagonists for CB-1.

[0093] Compounds of formula (I) may be active as adenosine receptor antagonists, but substantially inactive at CB-1.

[0094] The compounds of formula (I) may also be selective between various adenosine receptor subtypes. In certain embodiments, the compounds of formula (I) are A2aR selective; A2bR selective; or dual A2aR / A2bR selective.

[0095] An A2aR selective compound exhibits a binding affinity to A2aR that is at least 100-fold stronger, at least 1,000-fold stronger, or at least 10,000-fold stronger than its binding affinity to each of the A1R, A2bR, and A3R.

[0096] An A2bR selective compound has a binding affinity that is at least 100-fold stronger, at least 1,000-fold stronger, or at least 10,000-fold stronger than its binding affinity to each of the A1R, A2aR, and A3R.

[0097] A dual A2aR / A2bR selective compound exhibits a binding affinity for A2aR that is at least 100 times stronger, at least 1,000 times stronger, or at least 10,000 times stronger than its binding affinity for each of A1R and A3R. A dual A2aR / A2bR selective compound also exhibits a binding affinity for A2bR that is at least 100 times stronger, at least 1,000 times stronger, or at least 10,000 times stronger than its binding affinity for each of A1R and A3R. Furthermore, for a dual A2aR / A2bR selective compound, the ratio of the binding affinity for A2aR to the binding affinity for A2bR is less than 100.

[0098] In certain embodiments, a pharmaceutical composition is provided comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0099] The compositions of the invention may be in a form suitable for oral use (e.g. as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g. as a finely divided powder or liquid aerosol), administration by insufflation (e.g. as a finely divided powder) or parenteral administration (e.g. as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular administration or as a suppository for rectal administration).

[0100] Suitable pharma- ceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to modify disintegration in the gastrointestinal tract and subsequent active ingredient or to improve stability and / or appearance, in either case using conventional coating agents and methods well known in the art.

[0101] Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.

[0102] The compound of formula (I) is useful for treating the disease or condition mediated by adenosine receptor.In some embodiments, the compound of formula (I) or its pharma- ceutically acceptable salt is provided for use in treating the disease or condition mediated by adenosine receptor.In some embodiments, the disease or condition is mediated by A2aR; in other embodiments, A2bR; in still other embodiments, both A2aR and A2bR.

[0103] Some examples of diseases or conditions mediated by adenosine receptors include cancers such as lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, stomach cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma cancer, melanoma or other solid tumors; movement disorders such as Parkinson's disease and Huntington's disease; and attention disorders such as attention deficit disorder and attention deficit hyperactivity disorder. Other diseases and conditions mediated by adenosine receptors are known.

[0104] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by an adenosine receptor.

[0105] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors.

[0106] In certain embodiments, there is provided a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist for CB-1, for use in the treatment of a disease or condition mediated by an adenosine receptor.

[0107] In certain embodiments, there is provided a compound of Formula (I) or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma cancer, melanoma or other solid tumors), wherein the compound is a selective adenosine receptor antagonist for CB-1.

[0108] In certain embodiments, a method is provided for treating a disease or condition mediated by an adenosine receptor, comprising administering to a subject in need of such treatment an effective amount of a disease or condition mediated by an adenosine receptor.

[0109] In certain embodiments, there is provided a method for treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, stomach cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma cancer, melanoma or other solid tumors), comprising administering to a subject in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0110] In certain embodiments, a method of treating a disease or condition mediated by an adenosine receptor is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist for CB-1.

[0111] In certain embodiments, a method of treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma cancer, melanoma or other solid tumors) is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist for CB-1.

[0112] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by an adenosine receptor.

[0113] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, stomach cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors).

[0114] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist for CB-1, for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by an adenosine receptor.

[0115] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutical acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist for CB-1, for use in the manufacture of a medicament for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors).

[0116] Compounds of formula (I) may be prepared according to the following general scheme.

[0117] Schemes 1a and 1b describe the preparation of intermediate 6-substituted-4-hydrazino-2-aminopyrimidine compounds of formula (IV). [ka] [ka]

[0118] Scheme 2 describes the conversion of a compound of formula (IV) to an intermediate 7-substituted-5-amino-8-bromo-[1,2,4]triazolo[4,3-c]pyrimidin-3-one compound of formula (V). Briefly, a compound of formula (IV) is treated with triphosgene to close the triazolone ring, followed by (CH3)3PhN. + Br3 - Brominate with. [ka]

[0119] Scheme 3a describes the conversion of a compound of formula (V) to a compound of formula (I). 4 Alkylation of a compound of formula (V) with may be carried out using a variety of methods, such as the Mitsunobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction. [ka]

[0120] Or, R 4 Compounds of formula (V) may be directly alkylated using compounds such as --Br.

[0121] In some cases, R 4 may be further modified following alkylation of the compound of formula (V).

[0122] Scheme 3b describes an alternative route for the conversion of compounds of formula (V) to compounds of formula (I). In Scheme 3b, [Pg] represents a suitable reagent for the introduction of the protecting group shown as Pg. 4 Alkylation of a compound of formula (Va) with may be carried out using a variety of methods, such as, for example, the Mitsunobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; alcohol chlorination followed by an alkylation reaction. [ka]

[0123] Or, R 4 Compounds of formula (Va) may be directly alkylated using compounds such as --Br.

[0124] In some cases, R 4 may be further modified following alkylation of the compound of formula (V).

[0125] Optionally, the compound of formula (I) may be further modified, for example to form a different compound of formula (I). EXAMPLES

[0126] general technology LCMS method A Instrument: Agilent Technologies 1200 Series, Agilent LC / MSD SL, Column: Waters XBridge C8 3.5 μm, 4.6 × 50 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 5, 8.0 / 100, 8.1 / 100, 8.5 / 5, 10.0 / 5. (Solvent A = 1 mL TFA in 1000 mL Milli-Q water; Solvent B = 1 mL TFA in 1000 mL MeCN); Injection volume 1 μL (variable); UV detection 220-400 nm; Column temperature 25 °C; 2.0 mL / min. For UV-inactive compounds, an ELSD detector (Polymer Laboratories PL-ELS 2100 ICE) is connected to the instrument.

[0127] LCMS method B Instrument: Agilent Technologies 1200 Series, Agilent LC / MSD SL, Column: Atlantis dC18 5 μm, 4.6×xmm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 2.5 / 95, 4.5 / 95, 4.6 / 10, 6.0 / 10. (Solvent A=1 mL TFA in 1000 mL Milli-Q water; Solvent B=1 mL TFA in 1000 mL MeCN); Injection volume 1 μL (variable); UV detection 210-400 nm; Column temperature 25° C.; 1.5 mL / min.

[0128] LCMS method C Instrument: Agilent Technologies 1200 Series, Agilent 6130 quadrupole LC / MS, Column: Zorbax C18 5 μm, 4.6 × 50 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 2.5 / 95, 4.5 / 95, 4.6 / 10, 6.0 / 10. (Solvent A = 1 mL formic acid in 1000 mL Milli-Q water; Solvent B = MeCN); Injection volume 1 μL (variable); UV detection 210-400 nm; Column temperature 25 °C; 1.5 mL / min.

[0129] LCMS method D Instrument: Agilent Technologies 1200 Series, Agilent 6130 quadrupole LC / MS, Column: Zorbax C18 5 μm, 4.6 × 50 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 4.0 / 95, 5.0 / 95, 5.5 / 10, 7.0 / 10. (Solvent A = 770.08 mg ammonium acetate in 1000 mL Milli-Q water; Solvent B = MeCN); Injection volume 1 μL (variable); UV detection 210-400 nm; Column temperature 25 °C; 1.2 mL / min.

[0130] LCMS method E Instrument: Agilent Technologies 1200 Series, Agilent 6130 quadrupole LC / MS, Column: XBridge C8 3.5 μm, 4.6 × 50 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 5, 8.0 / 100, 8.1 / 100, 8.5 / 5, 10.0 / 5. (Solvent A = 790.06 mg ammonium bicarbonate added to 1000 mL Milli-Q water; Solvent B = MeCN); Injection volume 1 μL (variable); UV detection 210-400 nm; Column temperature 25 °C; 1.0 mL / min.

[0131] LCMS method F Instrument: Agilent 1100 Series LC / MSD. Column: Zorbax SB-C18 1.8 μm 4.6×15 mm. Gradient [time (min) / solvent A (%)]: 0.0 / 100; 0.01 / 100; 1.5 / 0; 1.8 / 0; 1.81 / 100. (Solvent A=H2O; Solvent B=MeCN, both modified with 0.1% formic acid). Injection volume 1 μl (variable). UV detection 215 nm. Column temperature 60° C.

[0132] LCMS method G Equipment: Waters Acquity UPLC with Waters ELSD and Waters SQD mass spectrometer; Column: Waters Acquity HSS T3 1.8 μm, 2.1 × 30 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 2, 1.5 / 98, 1.9 / 98, 1.95 / 2, 2.0 / 2. (Solvent A = 1 mL formic acid in 1000 mL HPLC grade water; Solvent B = 1 mL formic acid in 1000 mL MeCN); Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 °C; 1 mL / min.

[0133] Preparative HPLC method A Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvents: A - 0.1% TFA in H2O, B - MeOH. Column: YMC Actus Triart C18 (30 mm x 250 mm) 5 μm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0134] Preparative HPLC method B Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvents: A - 0.1% HCOOH in H2O, B - MeCN. Column: YMC Actus Triart C8 (20 mm x 250 mm) 5 μm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0135] Preparative HPLC method C Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvents: A - 10 mM NH4HCO3 in H2O, B - MeOH or MeCN. Column: XBridge C8 (19 mm x 150 mm), 5 μm or YMC Actus Triart C18 (30 mm x 250 mm) 5 μm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0136] Preparative HPLC method D Instrument: Agilent Technologies 1260 Infinity II Series LC. Mobile phase: Hexane B:IPA (60:40), Column: YMC Silica (19×150) mm, 5 μm, Flow rate: 15 mL / min. Note: The gradient may vary from sample to sample based on sample separation and polarity.

[0137] Preparative HPLC method E Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvents: A - H2O, B - MeOH or MeCN. Column: Waters Sunfire C18 OBD Prep column, 100 Å, 5 μm, 19 mm x 100 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0138] SFC method A Instrument: Thar Multigram III Preparative SFC. Solvents: A-CO2, B-2 mL of NH4OH in 1000 mL of MeOH. Column: Chiralpak IB 5 μm, 21×250 mm. Isocratic 15%; exhaust pressure 100 bar; UV detection 220 nm; column temperature 35° C.; 70.0 mL / min.

[0139] Synthetic route for intermediates Synthetic routes 1-8 used to prepare intermediates used in the synthesis of compounds of formula (I) are set out below. Details of synthetic routes 1-8 are examples of techniques used in the synthesis of other intermediates, as detailed in Table 1 below.

[0140] Synthetic Route 1: Method for Producing Intermediate 1 Intermediate 1: 5-Amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one [ka] Step 1: This reaction was carried out as 2 x 250 g batches. To a degassed suspension of phenylboronic acid (250 g, 2.05 mol), 4,6-dichloro-2-aminopyrimidine (672 g, 4.10 mol) and K2CO3 (848 g, 6.15 mol) in CH3CN (15 L) and H2O (2 L) was added Pd(PPh3)4 (118 g, 0.10 mol) at room temperature and the resulting reaction mixture was heated at 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was stirred vigorously with H2O (4 L) and DCM (10 L) and the insoluble solids were filtered off through a Büchner funnel and rinsed with DCM (3 L). The filtrate was placed in a separatory funnel and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using 230-400 silica mesh, eluting with 0-15% EtOAc in petroleum ether to give 4-chloro-6-phenylpyrimidin-2-amine (350 g, 41%) as an off-white solid. LCMS (Method A): m / z 206 (M+H) + (ES + ), 2.53 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 8.05 - 8.03 (m, 2H), 7.52 - 7.47 (m, 3H), 7.21 (s, 1H). No exchangeable -NH2 protons were observed.

[0141] Step 2: To a stirred suspension of 4-chloro-6-phenylpyrimidin-2-amine (350 g, 1.70 mol) in EtOH (4.0 L) was added hydrazine hydrate (255 g, 5.1 mol) and the mixture was heated at 90° C. for 15 h. The reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (1 L) and 10% sodium bicarbonate solution (1 L). The resulting solid was collected by filtration through a Buchner funnel, rinsed with diethyl ether (200 mL), and dried under reduced pressure to give 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 73%) as an off-white solid. LCMS (Method C): m / z 202 (M+H) + (ES + ), 0.69 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.94 - 7.91 (m, 2H), 7.84 (s, 1H), 7.48 - 7.42 (m, 3H), 6.47 (s, 1H), 6.00 (s, 2H), 4.25 (s, 2H)

[0142] Step 3: To a solution of 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 1.24 mol) in dry THF (3.0 L) cooled to -30°C under N2, triphosgene (735 g, 2.48 mol) was added portionwise and the mixture was stirred at the same temperature for 45 min. The reaction was carefully quenched with ice-cold water (10 L) with vigorous stirring. Once the effervescence had ceased, the reaction was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, rinsed with water (1 L) and dried under reduced pressure to give 5-amino-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 70%) as a yellow solid. LCMS (Method C): m / z 228 (M+H) + (ES + ), 1.64 minutes, UV activity 1H NMR: (400 MHz, DMSO-d6) δ: 12.46 (s, 1H), 8.05 - 7.98 (m, 3H), 7.65 (s, 1H), 7.50 - 7.44 (m, 3H), 6.93 (s, 1H)

[0143] Step 4: To a suspension of 5-amino-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 0.88 mol) in DCM / MeOH 1:1 (2 L) under N2 atmosphere was added CaCO3 (88 g, 0.88 mol) followed by (CH3)3PhN + Br3 - (331 g, 0.88 mol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with a small amount of MeOH / DCM (1:1) and dried under reduced pressure to give intermediate 1, 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (160 g, 59%) as a light brown solid. LCMS (Method C): m / z 306 (M+H) + (ES + ), 1.78 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 12.57 (s, 1H), 7.62 - 7.60 (m, 2H), 7.45 - 7.41 (m, 3H). No exchangeable -NH2 protons were observed.

[0144] Synthetic Route 2: Method for Preparation of Intermediate 6 Intermediate 6: 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one [ka] Step 1: To a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (16.2 g, 53 mmol) in THF (200 mL) was added TEA (19 mL, 136.3 mmol) followed by dropwise addition of (2-(chloromethoxy)ethyl)trimethylsilane (11.3 g, 67.8 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h and then partitioned between EtOAc (250 mL) and water (200 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 100 g silica snap eluting with a gradient of 0-30% EtOAc in hexanes to give intermediate 69, 5-amino-8-bromo-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (12 g, 52%) as an off-white solid. LCMS (Method B): m / z 436 (M+H) + (ES + ), 3.25 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 8.56 (s, 2H), 7.62 (d, J=7.1 Hz, 2H), 7.45 (d, J=6.6 Hz, 3H), 5.18 (s, 2H), 3.66 (t, J=8.2 Hz, 2H), 0.91 (t, J=8.2 Hz, 2H), 0.04 (s, 9H)

[0145] Step 2: To a degassed suspension of 5-amino-8-bromo-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (11 g, 25 mmol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.5 g, 28 mmol) and K2CO3 (8.6 g, 62.5 mmol) in 1,4-dioxane (150 mL) and water (30 mL) was added Pd(PPh3)4 (1.44 g, 1.25 mmol) at room temperature and the reaction mixture was heated at 120° C. for 5 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (200 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 100 g silica snap eluting with a gradient of 0-80% EtOAc in hexanes to give 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (7.5 g, 64%) as a yellow solid. LCMS (Method B): m / z 462 (M+H) + (ES + ), 2.55 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 7.30 - 7.26 (m, 5H), 6.82 (s, 2H), 5.13 (s, 2H), 3.63 (t, J=7.4 Hz, 2H), 2.29 (s, 6H), 0.88 (t, J=7.4 Hz, 2H), 0.06 (s, 9H). No exchangeable -NH2 protons were observed.

[0146] Step 3: 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (7 g, 15 mmol) was dissolved in TFA (40 mL) and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The resulting residue was dissolved in EtOH (30 mL) and aqueous NH4OH (50 mL) was carefully added and the reaction mixture was heated at 60° C. for 2 h. The solid was collected by filtration through a Buchner funnel, washed with water (10 mL) and EtOH (10 mol), and dried under reduced pressure to give intermediate 6, 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (4.5 g, 89%) as a yellow solid. LCMS (Method A): m / z 333 (M+H) + (ES + ), 1.98 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 12.25 (s, 1H), 8.14 (s, 2H), 7.29 - 7.25 (m, 5H), 6.82 (s, 2H), 2.29 (s, 6H)

[0147] Synthetic Route 3: Method for Preparation of Intermediate 26 Intermediate 26: 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one [ka] Step 1: To a stirred suspension of 4,6-dichloropyrimidin-2-amine (400 g, 2.43 mol) in EtOH (5 L) was added hydrazine hydrate (365 g, 7.31 mol) and the mixture was heated at 90° C. for 15 h. The reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (1 L) and 10% sodium bicarbonate solution (1 L). The resulting solid was collected by filtration through a Buchner funnel, rinsed with diethyl ether (200 mL), and dried under reduced pressure to give 4-chloro-6-hydrazinylpyrimidin-2-amine (300 g, 77%) as an off-white solid. LCMS (Method C): m / z 160 (M+H) + (ES + ), 0.37 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 8.10 (s, 1H), 6.36 (s, 2H), 5.97 (s, 1H), 4.26 (s, 2H)

[0148] Step 2: To a degassed suspension of 4-chloro-6-hydrazinylpyrimidin-2-amine (300 g, 1.87 mol), 4-fluorophenylboronic acid (313 g, 2.24 mol) and K2CO3 (774 g, 5.61 mol) in 1,4-dioxane (6 L) and H2O (1 L) was added Pd(PPh3)4 (107 g, 0.093 mol) at room temperature and the resulting reaction mixture was heated at 110 °C for 15 h. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The resulting residue was stirred vigorously with H2O (4 L) to give a solid which was filtered through a Büchner funnel and rinsed with MeOH (1 L). The solid was dried under reduced pressure to give 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 g, 49%) as a green solid. LCMS (Method C): m / z 220 (M+H) + (ES + ), 0.76 minutes, UV activity 1H NMR: (400 MHz, DMSO-d6) δ: 8.00 - 7.96 (m, 2H), 7.854 (s,1H), 7.29 - 7.24 (m, 2H), 6.45 (s, 1H), 6.01 (s, 2H), 4.24 (s, 2H)

[0149] Step 3: A solution of 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 g, 0.91 mol) in dry THF (3.0 L) was cooled to -30°C under N2, triphosgene (538 g, 1.82 mol) was added portionwise and the mixture was stirred at the same temperature for 1 h. The reaction was carefully quenched with ice-cold water (10 L) with vigorous stirring. Once the effervescence had ceased, the reaction was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, rinsed with water (1 L) and dried under reduced pressure to give 5-amino-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 g, 67%) as a yellow solid. LCMS (Method C): m / z 246 (M+H) + (ES + ), 1.77 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 8.19 - 8.01 (m, 2H), 7.95 - 7.52 (m, 2H), 7.50 - 7.27 (m, 2H), 6.92 (s, 1H)

[0150] Step 4: This reaction was carried out in 2 x 75 g batches. A suspension of 5-amino-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 g, 0.66 mol) in 1:1 DCM / MeOH (2 L) was added under N2 atmosphere with CaCO3 (66 g, 0.66 mol) followed by (CH3)3PhN + Br3 -(250 g, 0.66 mol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with a small amount of MeOH / DCM (1:1) and dried under reduced pressure to give intermediate 26, 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (120 g, 60%) as a light brown solid. LCMS (Method C): m / z 323 (M+H) + (ES + ), 1.87 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 12.58 (s, 1H), 8.19 - 8.01 (m, 2H), 7.70 - 7.67 (m, 2H), 7.32 - 7.27 (m, 2H)

[0151] Synthetic Route 4: Representative Preparation of Alkylated Triazolopyrimidinones via Tosylation and Substitution Reactions Intermediate 27: 5-amino-8-bromo-7-(4-fluorophenyl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one [ka] To a solution of tosyl chloride (2.67 g, 14.0 mmol), TEA (5.42 mL, 37.62 mmol) and DMAP (0.197 g, 1.617 mmol) in DCM (15 mL) at 0° C. was added (5-methyloxazol-4-yl)methanol (1.46 g, 12.9 mmol) and the resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated and concentrated under reduced pressure to give the tosylated intermediate. The tosylated intermediate was dissolved in DMSO (30 mL) and 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (3.5 g, 10.82 mmol) and K2CO3 (4.47 g, 32.3 mmol) were added and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 25 g silica snap eluting with a gradient of 0-100% EtOAc in petroleum ether to give intermediate 27, 5-amino-8-bromo-7-(4-fluorophenyl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as an off-white solid. LCMS (Method C): m / z 419 (M+H) + (ES + ), 2.20 minutes, UV activated 1 H NMR: (400 MHz, DMSO-d6) δ: 8.19 (s, 1H), 7.79-7.61 (m, J=7.6, 2H), 7.38-7.28 (m, 2H), 4.91 (s, 2H), 3.77 (s, 3H). No exchangeable -NH2 protons were observed.

[0152] Synthetic Route 5: Representative Preparation of Pyridylboronic Acid Esters Intermediate 32: 2-Methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] To a degassed dry hexane solution of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (108 mg, 0.16 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (54 mg, 0.20 mmol) was added bis-pinacolatodiborane (1.2 g, 4.87 mmol) and heated at 60° C. for 10 min. 2-Methoxy-6-methylpyridine (500 mg, 0.4.05 mmol) was added to the reaction mixture and heated at 60° C. for 14 h. The reaction was concentrated under reduced pressure to give crude intermediate 32, 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (800 mg) as a brown gum, which was used in the next step without further purification.

[0153] Synthetic Route 6: Representative Preparation of Triazolopyrimidine Analogues via Suzuki Coupling Using SEM Protection Intermediate 33: Methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate [ka] Step 1: Prepared analogously to synthetic route a (see below), step 2, using intermediate 34 to give methyl 4-(5-amino-3-oxo-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (6 g, 64%) as a yellow solid. LCMS (Method A): m / z 507 (M+H) + (ES + ), 2.46 minutes, UV activity 1H NMR: (400 MHz, DMSO-d6) δ: 7.67 (s, 1H), 7.32-7.27 (m, 6H), 5.14 (s, 2H), 3.81 (s, 3H), 3.64 (t, J=7.8 Hz, 2H), 2.40 (s, 3H), 0.89 (t, J=7.8 Hz, 2H), 0.01 (s, 9H). No exchangeable -NH2 protons were observed.

[0154] Step 2: A solution of methyl 4-(5-amino-3-oxo-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (1 g, 1.9 mmol) in TFA (15 mL) was stirred at room temperature for 30 min. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (20 mL) and DIPEA (1.7 mL, 9.8 mmol) was added and the resulting reaction mixture was heated at 60° C. for 4 h. The precipitate was collected by filtration, washed with MeOH (2×2 mL) and dried under reduced pressure to give intermediate 33, methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (0.55 g, 67%) as a yellow solid. LCMS (Method A): m / z 377 (M+H) + (ES + ), 1.65 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 12.46 (s, 1H), 8.41 (s, 1H), 7.70 (s, 1H), 7.32-7.25 (m, 6H), 3.85 (s, 3H), 2.47 (s, 3H). One of the exchangeable -NH2 protons was not observed.

[0155] Synthetic Route 7: Representative Method for Alkylation of Amines Intermediate 55: (S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol [ka] To a suspension of (S)-pyrrolidin-2-ylmethanol (400 mg, 3.96 mmol) and K2CO3 (1.09 g, 7.92 mmol) in MeCN (20 mL) at room temperature was added 1-bromo-2-methoxyethane (0.66 g, 4.75 mmol) and the suspension was heated at 80 °C for 15 h. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give intermediate 55, (S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol (400 mg, 63%) as a yellow gum. 1 H NMR: (400 MHz, DMSO-d6) δ: 4.33 (s, 1H), 3.41 - 3.37 (m, 3H), 3.23 (s, 3H), 3.20 - 3.19 (m, 1H), 3.01 - 2.93 (m, 2H), 2.43 - 2.42 (m, 2H), 2.19 - 2.16 (m, 1H), 1.77 - 1.74 (m, 1H), 1.62 - 1.51 (m, 3H)

[0156] Synthetic Route 8: Method for Preparation of Intermediate 71 Intermediate 71, 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)ethyl methanesulfonate [ka] To a suspension of 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(2-hydroxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (4 g, 0.01 mol) and TEA (4 mL, 0.03 mol) in THF (60 mL) was added methanesulfonyl chloride (1 mL, 0.012 mol) dropwise over 10 min at 0° C. After completion of the reaction by TLC, the reaction mixture was partitioned between EtOAc (50 mL) and brine solution (50 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was triturated with n-hexane (2×20 mL), decanted and dried under high vacuum to give intermediate 71, 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)ethyl methanesulfonate (3.4 g, 70%) as a yellow solid. LCMS (Method B): m / z 349 (M+H)+ (ES+), 2.14 min, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.62 - 7.60 (m, 2H), 7.46 - 7.44 (m, 3H), 4.83 (t, J=6.0 Hz, 1H), 3.95-3.81 (m, 5.6 Hz, 2H), 3.72 - 3.68 (m, 2H). No exchangeable -NH2 protons were observed.

[0157] Intermediates used in the preparation of the following examples are listed in Table 1. Compounds were prepared by the methods of the indicated synthetic route ("Rte."). Where no route number or data is given, commercially available materials were used. LCMS and 1 H NMR data is shown for purified products (or as "used crude" when no purification was performed). In some cases, intermediates used in the preparation of other intermediates are indicated in parentheses; for example, intermediate 28 was prepared via synthetic route 4 using intermediates 26 and 29.

[0158] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0159] Synthesis Routes 1-1 to 4-1 of Examples The synthetic routes a-ae used to prepare the compounds of Examples 1-1-4-1 are described below. The methods of synthetic routes a-ae are illustrative of the procedures used to prepare other compounds, detailed in Table 2 below.

[0160] Synthetic route a Example 1-1: 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a suspension of intermediate 1, 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.3 g, 0.98 mmol), 2-(1H-pyrazol-1-yl)ethan-1-ol (0.10 g, 0.89 mmol) and triphenylphosphine (0.38 g, 1.47 mmol) in THF (10 mL) at room temperature, di-tertiary butyl azo-dicarboxylate (0.33 g, 1.47 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 0-50% EtOAc in hexanes to give 2-(2-(1H-pyrazol-1-yl)ethyl)-5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as an off-white solid (200 mg, 51%). LCMS (Method B): m / z 400 (M+H) + (ES + ), 3.52 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.71 - 7.55 (m, 2H), 7.46 - 7.44 (m, 5H), 6.22 (s, 1H), 4.20 (t, J=7.6 Hz, 2H), 3.72 (t, J=7.6 Hz, 2H). No exchangeable -NH2 protons were observed.

[0161] Step 2: A mixture of 2-(2-(1H-pyrazol-1-yl)ethyl)-5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.20 g, 0.49 mmol), intermediate 3, 2,6-dimethylpyridine-4-boronic acid pinacol ester (0.12 g, 0.54 mmol) and K2CO3 (137 mg, 0.99 mmol) in 1,4-dioxane / HO (4 mL / 1 mL) was degassed for a few minutes, Pd(PPh3)4 (29 mg, 0.02 mmol) was added, the vessel was sealed and heated at 120 °C for 5 h. After cooling to rt, the reaction mixture was partitioned between HO (5 mL) and EtOAc (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by Biotage-Isolera using a 10 g silica snap eluting with a gradient of 0-100% EtOAc in hexanes to give Example 1-1, 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (35 mg, 16%) as a yellow solid. LCMS (Method A): m / z 427 (M+H) + (ES+), 2.46 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ 7.68 (d, J=2.0 Hz, 1H), 7.44 (d, J=1.2 Hz, 1H), 7.27 - 7.24 (m, 5H), 6.77 (s, 2H), 6.28-6.01 (m, 1H), 4.42 (t, J=6.0 Hz, 2H), 4.14 (t, J=6.0 Hz, 2H), 2.28 (s, 6H). No exchangeable -NH2 protons were observed.

[0162] Synthetic route b Example 1-4: 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-(1H-tetrazol-5-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.98 mmol) and K2CO3 (406 mg, 2.9 mmol) in MeCN (3 mL) at room temperature was added 3-bromopropanenitrile (196 mg, 0.147 mmol). The reaction mixture was heated at 75° C. for 12 h. The reaction was cooled to room temperature and partitioned between EtOAc (10 mL) and H2O (10 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 50-70% EtOAc in hexanes to give 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanenitrile (90 mg, 25%) as a white solid. LCMS (Method B): m / z 359 (M+H) + (ES + ), 2.44 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 8.60 - 7.90 (s, 2H), 7.64 - 7.61 (m, 2H), 7.47 - 7.44 (m, 3H), 4.13 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H)

[0163] Step 2: Produced according to a method similar to step 2 of route a.

[0164] Step 3: A mixture of 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanenitrile (202 mg, 0.52 mmol), NaN3 (67 mg, 1.03 mmol) and ammonium chloride (69 mg, 1.3 mmol) in N,N-dimethylformamide (5 mL) was stirred at 120° C. for 15 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered through a sintered funnel. The filtrate was concentrated under reduced pressure and the crude compound was purified by preparative HPLC method (Method A). The collected fractions were concentrated under reduced pressure, and the resulting residue was passed through an SCX cartridge and eluted with 2N methanolic ammonia to give Example 1-4, 2-(2-(1H-tetrazol-5-yl)ethyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (110 mg, 49%) as a yellow solid. Data for the title compound are shown in Table 2.

[0165] Synthetic route c Examples 1-5 and 1-6: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one and 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a suspension of 2-(2-(1H-tetrazol-5-yl)ethyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (80 mg, 0.18 mmol) and K2CO3 (74 mg, 0.54 mmol) in MeCN (10 mL) at room temperature was added MeI (30 mg, 0.2 mmol) and the reaction was stirred at room temperature for 1 h. The reaction was filtered and concentrated. The crude product was purified by a preparative HPLC method (Method A). The first eluting peak was concentrated under reduced pressure and partitioned between 15% MeOH (10 mL) and 10% NaHCO3 solution (10 mL) in DCM. The organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure, and dried under high vacuum to give Example 1-5, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (22 mg, 26%) as a yellow solid. The data for the title compound are shown in Table 3. The structure of this compound was confirmed by NOE test. The second eluted peak from HPLC was concentrated under reduced pressure and partitioned between EtOAc (10 mL) and 10% NaHCO3 solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure, and dried under high vacuum to give Example 1-6, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (13 mg, 16%) as a yellow solid. The data for the title compound are shown in Table 2.

[0166] Synthetic route d: Representative preparation of alkylated triazolopyrimidinones via Mitsunobu reaction Example 1-7: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-ethylpyrazol-3-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a mixture of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (75 mg, 0.25 mmol), 2-(1-ethyl-1H-pyrazol-5-yl)ethan-1-ol (38 mg, 0.27 mmol) and triphenylphosphine (77 mg, 0.29 mmol) in THF (3 mL) was added di-tert-butyl-azodicarboxylate (77 mg, 0.27 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Method E) to give Example 1-7, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-ethylpyrazol-3-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (7.7 mg, 7%). Data for the title compound are shown in Table 2.

[0167] Synthetic Route e: Representative Preparation of Alkylated Triazolopyrimidinones via Alcohol Mesylation, Followed by Alkylation Reaction Examples 1-9, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of oxazol-2-ylmethanol (36 mg, 0.36 mmol) and TEA (103 mg, 0.90 mmol) in DCM (10 mL) at 0° C., mesyl chloride (56 mg, 0.45 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the mesylated intermediate. The mesylated intermediate was dissolved in MeCN (20 mL) and 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.30 mmol), K2CO3 (125 mg, 0.90 mmol) was added and heated at 80° C. for 16 h in a sealed vial. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A). The fractions were concentrated, diluted with EtOAc (10 mL), and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness to give Example 1-9, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (21 mg, 0.16%) as a yellow solid. Data for the title compound are shown in Table 2.

[0168] Synthetic route f: Representative preparation of alkylated triazolopyrimidinones via alcohol tosylation followed by alkylation reaction Example 1-12: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of N,N-dimethylpyridin-4-amine (3.6 mg, 0.03 mmol), TEA (45.6 mg, 0.45 mmol) and tosyl chloride (63.1 mg, 0.33 mmol) in DCM (10 mL) was added (1-methyl-1H-pyrazol-5-yl)methanol (40.4 mg, 0.36 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the tosylated intermediate. The tosylated intermediate was dissolved in DMSO (10 mL) and 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.30 mmol) and K2CO3 (125 mg, 0.90 mmol) were added and heated at 80° C. for 16 h in a sealed vial. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A). The fractions were concentrated under reduced pressure and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to obtain Example 1-12, 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (15 mg, 11%) as a yellow solid. The data of the title compound is shown in Table 2.

[0169] Synthetic route g: A representative method for the preparation of alkylated triazolopyrimidinones via chlorination of alcohols followed by alkylation reaction. Example 1-16: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of (1-methyl-1H-pyrazol-3-yl)methanol (41 mg, 0.36 mmol) in THF (10 mL) at 0° C., SOCl2 (1 mL) was added dropwise and stirred at 60° C. for 2 h. (Alternatively, toluene may be used as the solvent and the reaction heated to 110° C.). After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (20 mL) and 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the chloro-intermediate. This chloro-intermediate was dissolved in MeCN / DMSO (20 mL / 1 mL) and 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.30 mmol) and K2CO3 (125 mg, 0.90 mmol) were added and heated at 80° C. for 16 h in a sealed vial. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A). The fractions were concentrated and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to obtain Example 1-16, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (18 mg, 14%) as a yellow solid. The data of the title compound is shown in Table 2.

[0170] Synthetic route h: A representative method for the preparation of alkylated triazolopyrimidinones via alkylation reactions. Example 1-19: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 0.15) and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole (26.6 mg, 0.15 mmol) in DMSO (5 mL) was added K2CO3 (62.3 mg, 0.45 mmol) at room temperature and the resulting reaction mixture was heated at 80° C. for 1 h. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude compound was purified by Biotage-Isolera using a 10 g silica gel snap eluted with a petroleum ether gradient of 0-100% EtOAc to give Example 1-19, 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (22 mg, 34%) as a yellow solid. Data for the title compound are shown in Table 2.

[0171] Synthetic Route I Example 1-20: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of (3-methyl-1,2,4-oxadiazol-5-yl)methanol (90 mg, 0.783 mmol) and TEA (0.4 mL, 3.012 mmol) in DCM (10 mL) at 0° C. was added mesyl chloride (0.07 mL, 0.903 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (20 mL) and water (10 mL). The organic layer was separated and concentrated under reduced pressure to give the mesylated intermediate. The mesylated intermediate was dissolved in DMSO (10 mL), 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.602 mmol) and K2CO3 (249 mg, 1.807 mmol) were added, and the resulting reaction mixture was heated at 80° C. for 2 h in a sealed vial. The reaction mixture was quenched with ice-cold water. The resulting solid was filtered, washed with EtOH, and dried under reduced pressure to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (49 mg, 0.18%) as an off-white solid. Data for the title compound are shown in Table 2.

[0172] Synthetic Route j Example 1-26: 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a solution of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.30 mmol) and KCO (84 mg, 0.60 mmol) in MeCN (8 mL) and DMSO (2 mL) was added 2-bromoacetonitrile (36 mg, 0.30 mmol) dropwise and heated at 80 °C for 16 h in a sealed tube. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)acetonitrile (70 mg, 62%), which was used in the next step without further purification. LCMS (Method A): m / z 372 (M+H) + (ES + ), 2.15 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 7.32 - 7.28 (m, 5H), 6.84 (s, 2H), 5.16 (s, 2H), 2.31 (s, 6H). No exchangeable -NH2 protons were observed.

[0173] Step 2: A solution of 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)acetonitrile (70 mg, 0.18 mmol), NaN3 (37 mg, 0.56 mmol) and NH4Cl (30.2 mg, 0.56 mmol) in DMF (15 mL) was heated at 120° C. for 16 h in a sealed tube. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The crude was purified by preparative HPLC (Method A). The fractions were concentrated and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (30 mg, 38%) as a yellow solid. Data for the title compound are shown in Table 2.

[0174] Synthetic route k Example 1-27: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a solution of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.602 mmol) in DMSO (5 mL), K2CO3 (249 mg, 1.807 mmol) and ethyl bromoacetate (73 mg, 0.662 mmol) were added and the resulting reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was quenched with ice-cold water and stirred. The precipitate was filtered and dried under reduced pressure to give ethyl 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)acetate (150 mg, 59%) as a yellow solid. LCMS (Method A): m / z 419 (M+H) + (ES + ), 2.00 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 8.45 (s, 2H), 7.28 (s, 5H), 6.83 (d, J=9.8 Hz, 2H), 4.73 (s, 2H), 4.19-4.14 (m, 2H), 2.29 (s, 6H), 1.22 (t, J=14.1Hz, 3H)

[0175] Step 2: To a solution of ethyl 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)acetate (150 mg, 0.358 mmol) in EtOH (10 mL) was added hydrazine hydrate (44.8 mg, 0.897 mmol) and the resulting reaction mixture was heated at 90° C. for 16 h. The reaction mixture was evaporated under reduced pressure. The crude product was triturated with EtOAc (2×2 mL), decanted and dried under reduced pressure to give 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)acetohydrazide as a pale green solid (75 mg, 51%) which was used without further purification. LCMS (Method A): m / z 405 (M+H) + (ES + ), 1.67 minutes, UV activity

[0176] Step 3: To a solution of 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)acetohydrazide (75 mg, 0.185 mmol) in xylene (5 mL) was added triethyl orthoformate (55 mg, 0.371 mmol) and catalytic amount of AcOH, and the resulting reaction mixture was heated at 130° C. for 16 h. The reaction mixture was evaporated under reduced pressure to remove volatiles. The crude product was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by preparative TLC (GF254 silica-coated glass plate (20×20 cm); mobile phase: 2% MeOH in DCM) to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (10 mg, 13%) as a yellow solid. Data for the title compound are shown in Table 2.

[0177] Synthetic Route Example 1-29: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1H-triazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a stirring solution of 5-amino-8-(2-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.301 mmol) in DMSO (3 mL) was added K2CO3 (103 mg) followed by 1-bromobut-2-yne (60 mg, 0.45 mmol). The reaction was heated at 50° C. for 1 h, then diluted with ice water and the precipitated compound was filtered and dried to give 5-amino-2-(but-2-yn-1-yl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (70 mg, 63%) as a yellow solid. LCMS (Method C): m / z 385 (M+H) + (ES + ), 1.67 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.27-7.25 (m, 5H), 6.83 (s, 2H), 4.61 (d, J=4.0 Hz, 2H), 2.30 (s, 6H), 1.79-1.78 (m, 3H). No exchangeable -NH2 protons were observed.

[0178] Step 2: A suspension of 5-amino-2-(but-2-yn-1-yl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg), NaN3 (20 mg) and NH4Cl (25 mg) in DMF (75 mL) was heated at 120° C. for 48 h. The reaction mixture was partitioned between ice water (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method-A). The fractions were concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (10 mL) and 10% NaHCO3 solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give (5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((5-methyl-1H-1,2,3-triazol-4-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (14 mg, 25%) as a yellow solid. Data for the title compound are shown in Table 2.

[0179] Synthetic route m Example 1-30: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyltriazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a stirring solution of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (250 mg, 0.75 mmol) and K2CO3 (311 mg, 2.25 mmol) in DMSO (8 mL) at 0 °C was added 3-bromoprop-1-yne (89.5 mg, 0.75 mmol) and the reaction mixture was heated at 50 °C for 1 h. The reaction mixture was diluted with ice-cold water and the precipitated solid was collected by filtration, rinsed with water (10 mL) and dried under reduced pressure to give 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(prop-2-yn-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 74%) as a yellow solid. LCMS (Method C): m / z 371 (M+H) + (ES + ), 1.08 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.28-7.25 (m, 5H), 6.83 (s, 2H), 4.68 (d, J=4.0 Hz, 2H), 3.34 (s, 1H), 2.33 (s, 6H). No exchangeable protons of -NH2 were observed.

[0180] Step 2: A suspension of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(prop-2-yn-1-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.53 mmol), NaN3 (70 mg, 1.09 mmol) and NH4Cl (85.04 mg, 1.59 mmol) in DMF (30 mL) was heated at 120° C. for 48 h. The reaction was diluted with ice-cold water (10 mL) and extracted with EtOAc (15 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 230-400 silica mesh eluting with 0-100% EtOAc in hexanes as a gradient to give (2-((1H-1,2,3-triazol-4-yl)methyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 20%) as a yellow solid. LCMS (Method D): m / z 414 (M+H) + (ES + ), 2.39 minutes, UV activity

[0181] Step 3: To a stirred solution of 2-((1H-1,2,3-triazol-4-yl)methyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 0.121 mmol) and K2CO3 (49 mg, 0.36 mmol) in DMF (5 mL) at 0° C., MeI (0.08 ml, 0.75 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ice-cold water and the precipitated solid was collected by filtration to give the crude product. The crude material was purified by preparative HPLC (Method A). The fractions were concentrated and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyltriazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (10 mg, 19%) as a pale yellow solid. Data for the title compound are shown in Table 2.

[0182] Synthesis Route n: Representative Method for the Preparation of Pyridine-N-Oxide Example 1-34: 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((5-methyloxazol-4-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (95 mg, 0.22 mmol) in DCM at 0° C., m-CPBA (46 mg, 0.26 mmol) was added in portions and the resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A), the fractions were concentrated and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give 4-(5-amino-2-((5-methyloxazol-4-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2,6-dimethylpyridine 1-oxide (7.3 mg, 8%) as a yellow solid. Data for the title compound are shown in Table 2.

[0183] Synthetic Route o: Representative Preparation of Hydroxymethylpyridine Analogues via Alcohol Chlorination and Alkylation Followed by Ester Reduction Example 1-39: 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a solution of 5-methyloxazol-4-yl)methanol (36 mg, 0.32 mmol) in CHCl (5 mL) at 0° C., thionyl chloride (0.05 mL, 0.66 mmol) was added dropwise and the resulting reaction mixture was heated at 50° C. for 60 min. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure to obtain the chlorinated intermediate. The chlorinated intermediate was dissolved in DMSO (2 mL) and methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (100 mg, 0.26 mmol) and KCO (110 mg, 0.79 mmol) were added and the resulting reaction mixture was heated at 80° C. for 2 h in a sealed tube. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 0-100% EtOAc in petroleum ether to give methyl 4-(5-amino-2-((5-methyloxazol-4-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (80 mg, 66%) as a yellow solid. LCMS (Method C): m / z 472 (M+H) + (ES + ), 1.69 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 8.17 (s, 1H), 7.32 (s, 2H), 7.29-7.26 (m, 4H), 7.20 (s, 1H), 4.87 (s, 2H), 3.81 (s, 3H), 2.36 (s, 6H). No exchangeable -NH2 protons were observed.

[0184] Step 2: To a solution of methyl 4-(5-amino-2-((5-methyloxazol-4-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (80 mg, 0.16 mmol) in THF (5 mL) was added dropwise at 0° C. lithium triethylborohydride (1 M in THF, 0.33 mL, 0.33 mmol) and the reaction mixture was stirred at room temperature for 20 min. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A). The fractions were concentrated and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-2-((5-methyloxazol-4-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (18 mg, 24%) as a yellow solid. Data for the title compound are shown in Table 2.

[0185] Synthetic Route P: Representative Preparation of Hydroxymethylpyridine Analogues via Alcohol Tosylation and Alkylation Followed by Ester Reduction Example 1-40: 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a solution of tosyl chloride (55.7 mg, 0.79 mmol), DMAP (3.2 mg, 0.02) and TEA (0.1 mL, 0.07 mmol) in DCM (10 mL) at 0° C., oxazol-2-ylmethanol (32 mg, 0.31 mmol) dissolved in DCM (0.5 mL) was added and the reaction mixture was stirred at room temperature for 30 min. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated and concentrated under reduced pressure to give the tosylated intermediate. The tosylated intermediate was dissolved in DMSO (2 mL) and added to a suspension of methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (100 mg, 0.26 mmol) and K2CO3 (110 mg, 0.29 mmol) in DMSO (2 mL) and the resulting reaction mixture was heated at 50° C. for 6 h in a sealed vial. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 10 g silica gel snap eluting with a petroleum ether gradient of 0-100% EtOAc to give methyl 4-(5-amino-2-(oxazol-2-ylmethyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (70 mg, 57%) as a yellow solid. LCMS (Method C): m / z 458 (M+H) + (ES + ), 1.60 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 8.12 (s, 1H),7.67 (s,1H) 7.27-7.21 (m, 5H), 6.82-6.76 (m, 2H), 3.80 (s, 2H), 2.95 (d, J=5.2 Hz, 3H), 2.51 (s, 3H). No exchangeable -NH2 protons were observed.

[0186] Step 2: Route o, carried out in a manner similar to step 2, gave 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (4.8 mg, 7.3%) as a yellow solid. Data for the title compound are shown in Table 2.

[0187] Synthetic Route Q: Representative Preparation of Hydroxymethylpyridine Analogues via Alcohol Tosylation and Substitution Followed by Suzuki Coupling and Ester Reduction Example 2-29: 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a solution of N,N-dimethylpyridin-4-amine (19.9 mg, 0.16 mmol), TEA (247.5 mg, 2.45 mmol) and tosyl chloride (342.0 mg, 1.79 mmol) in DCM (20 mL) at 0° C., (R)-(tetrahydrofuran-2-yl)methanol (199.9 mg, 1.96 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (20 mL) and H2O (20 mL). The organic layer was separated and concentrated under reduced pressure to give the tosylated intermediate. The tosylated intermediate was dissolved in DMSO (30 mL) and 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (500 mg, 1.63 mmol) and K2CO3 (676 mg, 4.09 mmol) were added, followed by heating at 80° C. for 4 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The organic layer was separated and concentrated under reduced pressure to give (R)-5-amino-8-bromo-7-phenyl-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (400 mg, 62%) as an off-white solid. The crude product was used in the next step without further purification. LCMS (Method A): m / z 390 (M+H) + (ES +), 2.38 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.82 - 7.77 (m, 1H), 7.64 - 7.60 (m, 2H), 7.50 - 7.44 (m, 2H), 4.23 - 4.02 (m, 1H), 4.00 - 3.96 (m, 2H), 3.86 - 3.79 (m, 2H), 3.74 - 3.66 (m, 2H), 1.99 - 1.91 (m, 2H). No exchangeable -NH2 protons were observed.

[0188] Step 2: To a suspension of (R)-5-amino-8-bromo-7-phenyl-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.51 mmol), methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (170 mg, 0.61 mmol) and K2CO3 (212 mg, 1.53 mmol) in 1,4-dioxane (10 mL) and H2O (5 mL) was added Pd(PPh3)4 (59 mg, 0.051 mmol) and heated at 110° C. for 5 h. The reaction mixture was partitioned between H2O (20 mL) and EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 0-100% EtOAc in petroleum ether to give methyl (R)-4-(5-amino-3-oxo-7-phenyl-2-((tetrahydrofuran-2-yl)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (100 mg, 42%). LCMS (Method B): m / z 461 (M+H) + (ES + ), 2.15 minutes, UV active 1H NMR: (400 MHz, DMSO-d6) δ: 7.70 (s, 1H), 7.65 - 7.57 (m, 3H), 7.32 - 7.26 (m, 5H), 4.16 - 4.13 (m, 1H), 3.86 - 3.74 (m, 6H), 3.66 - 3.62 (m, 1H), 2.34 (s, 3H), 2.00 - 1.67 (m, 3H), 1.25 - 1.18 (m, 1H)

[0189] Step 3: To a solution of methyl (R)-4-(5-amino-3-oxo-7-phenyl-2-((tetrahydrofuran-2-yl)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (100 mg, 0.21 mmol) in THF at room temperature was added lithium triethylborohydride (34.5 mg, 0.32 mmol) in portions and stirred for 1 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and H2O (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A), the fractions were concentrated and the residue was diluted with ethyl acetate (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to dryness to give 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (23 mg, 24%) as a yellow solid.

[0190] Example 2-29 was further purified by SFC Method A. During purification, the enantiomer presumably formed during the synthesis of Example 2-29, Example 2-28 (5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one), was isolated from the minor enantiomer of Intermediate 62 that was present in the commercial sample. Using SFC Method A, the first eluting peak was Example 2-28 (9.73 min) and the second eluting peak was Example 2-29 (10.32 min).

[0191] Synthetic Route: Representative Preparation of Hydroxymethylpyridine Analogues via Alkylation Followed by Suzuki and Ester Reduction Example 1-42: 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: Performed in a manner analogous to route h using intermediate 36 to afford 5-amino-8-bromo-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a white solid. LCMS (Method C): m / z 388 (M+H) + (ES + ), 1.82 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 8.37 (s, 1H), 8.14 (s, 1H), 7.60 (d, J=6.4 Hz, 2H), 7.49 - 7.39 (m, 3H), 4.96 (s, 2H). No exchangeable -NH2 protons were observed.

[0192] Step 2: Route a, carried out in a manner similar to step 2 using intermediate 34 to give methyl 4-(5-amino-2-(oxazol-4-ylmethyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate as a yellow solid. LCMS (Method C): m / z 458 (M+H) + (ES + ), 1.58 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 8.36 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 7.31-7.23 (m, 6H), 4.94 (s, 2H), 3.80 (s, 3H), 2.28 (s, 3H). No exchangeable -NH2 protons were observed.

[0193] Step 3: Route o, carried out in a manner similar to step 2, gave 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as an off-white solid. Data for the title compound are shown in Table 2.

[0194] Synthetic Route: Representative preparation of hydroxymethylpyridine analogues via Mitsunobu reaction followed by ester reduction Example 1-43: 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: Prepared in a manner similar to route d using intermediate 14 and DCM as solvent then purified by Biotage-Isolera using a 10 g silica snap eluting with a petroleum ether gradient of 0-100% EtOAc to give methyl 4-(5-amino-2-((5-methylisoxazol-3-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate as a pale yellow solid. LCMS (Method C): m / z 472 (M+H) + (ES + ), 1.82 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.69 (s, 1H), 7.32-7.23 (m, 6H), 6.22 (s, 1H), 5.06 (s, 2H), 3.81 (s, 3H), 2.34 (s, 6H). No exchangeable -NH2 protons were observed.

[0195] Step 2: Route o, carried out in a manner similar to step 2, gave 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-2-((5-methylisoxazol-3-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid. Data for the title compound are shown in Table 2.

[0196] Synthetic Route t: Representative Preparation of Hydroxymethylpyridine Analogues via Alkylation Reaction Followed by Ester Reduction Example 1-46: 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: Prepared analogously to route h to give methyl 4-(5-amino-2-((4-methyl-1,2,5-oxadiazol-3-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate as a yellow solid. LCMS (Method B): m / z 473 (M+H) + (ES + ), 1.91 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.68 (s, 1H), 7.30 - 7.24 (m, 5H), 7.18 (s, 1H), 5.30 (s, 2H), 3.81 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H). No exchangeable -NH2 protons were observed.

[0197] Step 2: Route o, carried out in a manner similar to step 2, gave 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid. Data for the title compound are shown in Table 2.

[0198] Synthetic Route Example 1-53: 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: Prepared analogously to route a, step 2 using intermediate 34 to give methyl 4-(5-amino-2-((2,5-dimethyloxazol-4-yl)methyl)-7-(4-fluorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (1.6 g, 55%) as a yellow solid. LCMS (Method C): m / z 504 (M+H) + (ES + ), 1.76 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.68 (s, 1H), 7.32-7.28 (m, 2H), 7.23 (s, 1H), 7.14-7.09 (m, 2H), 5.76 (s, 2H), 3.82 (s, 3H), 2.40 (s, 9H). No exchangeable -NH2 protons were observed.

[0199] Step 2: Route o, carried out in a manner similar to step 2, gave 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (270 mg, 29%) as a yellow solid. Data for the title compound are shown in Table 2.

[0200] Synthetic Route V: Representative Preparation of Hydroxymethylpyridine Analogues via Alcohol Chlorination and Substitution, Followed by Suzuki Coupling and Ester Reduction Example 1-55: 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a solution of (1-methyl-1H-imidazol-2-yl)methanol (220 mg, 1.960 mmol) in CHCl3, SOCl2 (291 mg, 2.45 mmol) was added at 0°C, and the resulting reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure to obtain the chlorinated intermediate. The chlorinated intermediate was dissolved in DMSO (20 mL), 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (500 mg, 1.633 mmol) and K2CO3 (676 mg, 4.901 mmol) were added, and the reaction mixture was heated at 60°C for 2 hours. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice water to obtain a solid, which was filtered through a Buchner funnel and dried under reduced pressure to obtain 5-amino-8-bromo-2-((1-methyl-1H-imidazol-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (600 mg, 87%) as a yellow solid. LCMS (Method C): m / z 400 (M+H) + (ES + ), 2.27 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ 7.62-7.60 (m, 2H), 7.45 (d, J=6.4 Hz, 3H), 7.15 (s, 1H), 6.82 (s, 1H), 5.12 (s, 2H), 3.72 (s, 3H). No exchangeable -NH2 protons were observed. (Also, for some analogs, the reaction mixture was partitioned between EtOAc (30 mL) and water (3 x 20 mL). The organic layer was separated and concentrated under reduced pressure. The crude material was purified by flash column chromatography using silica mesh (230-400) eluting with a petroleum ether gradient of 0-100% EtOAc to give the desired product.)

[0201] Step 2: Prepared analogously to route a, step 2 using intermediate 44 to give methyl 4-(5-amino-2-((1-methyl-1H-imidazol-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-chloropicolinate (100 mg, 26%) as a yellow solid. LCMS (Method C): m / z 491 (M+H) + (ES + ), 1.29 minutes, UV activity

[0202] Step 3: Route o, carried out in a manner similar to step 2, gave 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (13 mg, 14%) as a yellow solid. Data for the title compound are shown in Table 2.

[0203] Synthetic Route: Representative Method for Boc Deprotection of Amine Analogues Example 2-2: 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a solution of tert-butyl 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)6-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)pyrrolidine-1-carboxylate (120 mg, 0.23 mmol) in DCM was added 20% TFA (5 mL) and the reaction mixture was stirred at room temperature for 15 hours. After completion of the reaction by TLC, the reaction was concentrated under reduced pressure. The crude was dissolved in MeOH (2 mL) and passed through a DSC-SCX column (6 mL) and washed with water (5 mL). The compound was eluted with 2M ammonia in MeOH (10 mL), concentrated and lyophilized to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (26 mg, 27%) as a yellow solid. Data for the title compound are shown in Table 2.

[0204] Synthetic Route x: Representative Method for Reductive Amination of Amines Using Formaldehyde Example 2-6: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] A suspension of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (90 mg, 0.21 mmol) in MeCN (10 mL) was added with 36% formaldehyde solution (0.02 mL, 0.23 mmol) and sodium triacetoxyborohydride (133 mg, 0.63 mmol) and stirred for 1 h at room temperature. The reaction was quenched with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (75 mg, 80%) as a yellow solid. Data for the title compound are shown in Table 2.

[0205] Synthetic Route y: Representative Preparation of Di-Fluorinated Pyrrolidine Analogues Example 2-11: 5-amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a suspension of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2 g, 8.22 mmol) in DCM (30 mL) at 0° C., Dess-Martin periodinane (7 g, 16.44 mmol) was added and stirred at room temperature for 3 h. The reaction was partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Biotage-Isolera using a 25 g silica snap eluted with a gradient of 0-20% EtOAc in hexane to give 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (1.6 g, 74%) as a colorless gum. 1H NMR: (400 MHz, DMSO-d6) δ: 4.67 - 4.62 (m, 1H), 3.88 - 3.80 (m, 1H), 3.72 - 3.66 (m, 4H), 3.15 - 3.07 (m, 1H), 2.63 - 2.55 (m, 1H), 1.40 (d, J=16.0 Hz, 9H)

[0206] Step 2: To a suspension of 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (1.5 g, 6.16 mmol) in DCM at -78 °C was added diethylaminosulfur trifluoride (1.98 g, 12.32 mmol) dropwise and stirred at room temperature for 15 h. The reaction was quenched with saturated NaHCO3 solution (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 25 g silica snap eluted with a gradient of 0-10% EtOAc in hexane to give 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (1.4 g, 94%) as a colorless gum. 1 H NMR: (400 MHz, DMSO-d6) δ: 4.58 - 4.45 (m, 1H), 3.91 - 3.77 (m, 5H), 2.76 - 2.67 (m, 1H), 2.54 - 2.44 (m, 1H), 1.44 (d, J=18.0 Hz, 9H)

[0207] Step 3: To a solution of 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (1.1 g, 4.15 mmol) in THF (20 mL) at 0° C., 2M LiBH4 solution (3.1 mL, 6.22 mmol) was added and stirred at room temperature for 2 h. The reaction was quenched by dropwise addition of saturated NH4Cl solution (25 mL) and extracted with EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give tert-butyl (S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg, 50%) as an off-white gum. 1 H NMR: (400 MHz, DMSO-d6) δ: 4.20 - 4.18 (m, 1H), 3.77 - 3.65 (m, 4H), 2.54 - 2.49 (m, 1H), 2.20 - 2.18 (m, 1H), 1.50 (s, 9H). No exchangeable -OH protons were observed.

[0208] Step 4: Prepared in a manner similar to route e and purified by Biotage-Isolera using a 25 g silica snap eluting with a gradient of 0-100% EtOAc in hexanes to give tert-butyl (S)-2-((5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)methyl)-4,4-difluoropyrrolidine-1-carboxylate (150 mg, 18%) as a yellow solid. LCMS (Method A): m / z 552 (M+H) + (ES + ), 3.68 minutes, UV activity 1H NMR: (400 MHz, DMSO-d6) δ: 8.30 - 7.70 (m, 2H), 7.27 - 7.25 (m, 5H), 6.84 (s, 2H), 4.31 - 4.29 (m, 1H), 4.05 - 4.03 (m, 2H), 3.98 - 3.96 (m, 1H), 3.94 - 3.92 (m, 1H), 2.70 - 2.60 (m, 2H), 2.22 (s, 6H), 1.34 (s, 9H)

[0209] Step 5: To a solution of tert-butyl (S)-2-((5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)methyl)-4,4-difluoropyrrolidine-1-carboxylate (220 mg, 0.39 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (10 mL) and saturated NaHCO3 solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 5-amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (100 mg, 81%) as a yellow solid. Data for the title compound are shown in Table 2.

[0210] Synthetic route z: Representative preparation of alkylated triazolopyrimidinones utilizing a Boc protection strategy Example 2-15: 5-amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] 2-Amino-1-(oxolan-3-yl)ethan-1-ol (131 mg, 1 mmol) was dissolved in MeOH (2 mL), the solution was cooled to 0 °C, and Boc2O (229 mg; 1.05 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2-3 h. The mixture was concentrated under reduced pressure, and the residue was crystallized from an i-Pr / hexane mixture to give the Boc-protected amine. To a solution of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (66 mg; 0.20 mmol), Boc-protected amine (28 mg, 0.22 mmol) and PPh3 (68 mg, 0.26 mmol) in THF (3 mL) was added di-t-butyl-azodicarboxylate (51 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 16-18 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The reaction mixture was sonicated at room temperature for 2 hours, then concentrated under reduced pressure and the crude product was purified by preparative HPLC-MS (C18 column 100×19 mm, H2O / MeOH or MeCN) to give 5-amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (36 mg, 41%). Data for the title compound are shown in Table 2.

[0211] Synthetic Route aa: Representative Preparation of Fluorinated Pyrrolidine Analogues Example 2-18: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a suspension of 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (0.5 g, 2.038 mmol) in DCM at -78 °C was added diethylaminosulfur trifluoride (0.53 mL, 4.076 mmol) dropwise and stirred at room temperature for 15 h. The reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM (20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 0-10% EtOAc in hexane to give 1-(tert-butyl) 2-methyl (2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (0.23 g, 45%) as a colorless gum. 1 H NMR: (400 MHz, CDCl3) δ: 5.30 - 5.17 (m, 1H), 4.51 - 4.40 (m, 1H), 3.98 - 3.82 (m, 1H), 3.78 (s, 3H), 3.71 - 3.51 (m, 1H), 2.67 - 2.56 (m, 1H), 2.21 - 2.04 (m, 1H), 1.44 (s, 9H)

[0212] Step 2: Prepared analogously to route y, step 3, to give tert-butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (180 mg, 88%) as a colorless gum. 1 H NMR: (400 MHz, CDCl3) δ: 5.19 - 5.06 (m, 1H), 4.79 (s, 2H), 4.17 - 3.79 (m, 3H), 3.62 - 3.50 (m, 1H), 3.43 - 3.41 (m, 1H), 2.42 - 2.32 (m, 1H), 1.50 (s, 9H)

[0213] Step 3: Prepared in a manner similar to route d and purified by Biotage-Isolera using a 10 g silica snap eluting with a gradient of 0-50% EtOAc in hexanes to give tert-butyl (2R,4S)-2-((5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)methyl)-4-fluoropyrrolidine-1-carboxylate (60 mg, 14%) as a yellow solid. LCMS (Method A): m / z 533 (M+H) + (ES + ), 3.40 minutes, UV active 1 H NMR: (400 MHz, DMSO-d6) δ: 7.28 - 7.23 (m, 5H), 6.81 (s, 2H), 5.28 - 5.10 (m, 1H), 4.18 - 4.10 (m, 1H), 3.95 - 3.92 (m, 2H), 2.33 - 2.26 (m, 8H), 2.17 - 1.99 (m, 2H), 1.15 (s, 9H). No exchangeable -NH2 protons were observed.

[0214] Step 4: Route y, prepared in a manner similar to step 5, gave 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (20 mg, 36%) as a yellow solid. Data for the title compound are shown in Table 2.

[0215] Synthetic routes ab: Representative preparation of alkylated triazolopyrimidinones using a MOM protection strategy Example 2-22: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: To a suspension of 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (0.5 g, 2.0 mmol) in DMF (50 mL) was added di-isopropylethylamine (1.3 g, 1.0 mmol) at room temperature, cooled to 0° C., and MOM chloride (0.66 g, 8.15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 0-50% EtOAc in hexanes to give 1-(tert-butyl) 2-methyl (2S,4S)-4-(methoxymethoxy)pyrrolidine-1,2-dicarboxylate (0.4 g, 68%) as a yellow liquid. 1 H NMR: (400 MHz, DMSO-d6) δ: 4.56 (m, 2H), 4.29 - 4.24 (m, 2H), 3.58 - 3.58 (m, 4H), 3.23 (s, 4H), 3.23 (s, 1H), 2.01 - 1.99 (m, 1H), 1.20 (s, 9H)

[0216] Step 2: Prepared similarly to route y, step 3 and purified by Biotage-Isolera using a 10 g silica snap eluted with a gradient of 0-50% EtOAc in hexanes to give tert-butyl (2S,4S)-2-(hydroxymethyl)-4-(methoxymethoxy)pyrrolidine-1-carboxylate (0.3 g, 83%) as a colorless liquid. 1 H NMR: (400 MHz, DMSO-d6) δ: 4.68 - 4.62 (m, 1H), 4.60 - 4.56 (m, 2H), 4.15 - 4.05 (m, 1H), 3.69 - 3.57 (m, 4H), 3.21 (s, 4H), 2.00 - 1.99 (m, 2H), 1.40 (s, 9H)

[0217] Step 3: Prepared in a manner similar to route d and purified by Biotage-Isolera using a 10 g silica snap eluting with a gradient of 0-100% EtOAc in hexanes to give tert-butyl (2S,4S)-2-((5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)methyl)-4-(methoxymethoxy)pyrrolidine-1-carboxylate (130 mg, 30%) as a yellow solid. LCMS (Method B): m / z 576 (M+H) + (ES + ), 2.29 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.28 - 7.25 (m, 5H), 6.82 (s, 2H), 4.64 - 4.63 (m, 1H), 4.58 - 4.42 (m, 1H), 4.30 - 4.25 (m, 1H), 4.11 - 4.09 (m, 2H), 4.07 - 4.06 (m, 1H), 3.95 - 3.93 (m, 1H), 3.24 (s, 3H), 2.28 (s, 6H), 2.11 - 2.06 (m, 3H), 1.33 (s, 9H). No exchangeable -NH2 protons were observed.

[0218] Step 4: Prepared in a manner similar to route y, step 5, to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (70 mg, 71%) as a yellow solid. Data for the title compound are shown in Table 2.

[0219] Synthetic route ac Example 2-27: 5-amino-8-(2-methoxy-6-methyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: Prepared in a manner similar to route a, step 2, to give 5-amino-8-(2-fluoro-6-methylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.4 g, 26%) as a yellow solid. LCMS (Method C): m / z 467 (M+H) + (ES + ), 2.60 minutes, UV active

[0220] Step 2: To a solution of 5-amino-8-(2-fluoro-6-methylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.4 g, 2.99 mmol) in MeOH, 25% NaOMe (1.3 mL, 6.0 mmol) was added and the resulting reaction mixture was heated at 90° C. for 16 h in a sealed tube. After completion of the reaction as monitored by TLC, the reaction mixture was partitioned between H2O (25 mL) and EtOAc (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give the crude product. The crude material was purified by Biotage-Isolera using 25 g silica gel snap eluting with a petroleum ether gradient of 0-80% EtOAc to give 5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (600 mg, 43%) as a yellow solid. LCMS (Method C): m / z 479 (M+H) + (ES + ), 2.86 minutes, UV activity 1H NMR: (400 MHz, DMSO-d6) δ: 7.28-7.24 (m, 5H), 6.57 (s, 1H), 6.41 (s, 1H), 5.12 (s, 2H), 3.93 (s, 2H), 3.75 (s, 3H), 3.32 (d, J=8.4 Hz, 2H), 2.24 (s, 3H), 1.07-1.04 (m, 9H). No exchangeable -NH2 protons were observed.

[0221] Step 3: Prepared analogously to Route 6, step 2 to give 5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (250 mg, 57%) as a yellow solid. LCMS (Method C): m / z 349 (M+H) + (ES + ), 1.51 minutes, UV activity 1 H NMR: (400 MHz, DMSO-d6) δ: 7.28 - 7.22 (m, 5H), 6.63 (s, 1H), 6.34 (s, 1H), 3.75 (s, 3H), 2.26 (s, 3H). No exchangeable -NH and -NH2 protons were observed.

[0222] Step 4: Prepared analogously to route f using intermediate 62 to give 5-amino-8-(2-methoxy-6-methyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (7 mg, 5%) as an off-white solid. Data for the title compound are shown in Table 2.

[0223] Synthetic route ad: Representative preparation of alkylated triazolopyrimidinone amine analogues via mesylate substitution Example 3-1: 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] To a suspension of 2-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)ethyl methanesulfonate 1 (73 mg, 0.16 mmol) in MeCN (2 mL) was added K2CO3 (66 mg; 0.48 mmol) and 2-(thiophen-2-yl)pyrrolidine (29 mg, 0.19 mmol). The reaction mixture was heated at 100 °C for 15 h and then partitioned between EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method E) to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (18 mg, 22%). Data for the title compound are shown in Table 2.

[0224] Synthetic Route ae Example 4-1: 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one [ka] Step 1: Prepared similarly to route f using intermediate 77 and purified by Biotage-Isolera using 25 g silica gel snap eluted with a 0-80% EtOAc to petroleum ether gradient to give 5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (560 mg, 40%) as an off-white solid. LCMS (Method C): m / z 386 (M+H) + (ES + ), 0.98 minutes, UV activity 1H NMR: (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 7.09 (s, 2H), 4.80 (s, 2H), 2.43 (s, 6H), 2.30 (s, 3H). No exchangeable -NH2 protons were observed.

[0225] Step 2: A suspension of 5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (560 mg, 1.45 mmol) and piperidine (2 mL) was placed in a sealed tube and heated at 100° C. for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (2×20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (Method A). The fractions were concentrated and the resulting residue was diluted with EtOAc (20 mL) and washed with 10% sodium bicarbonate solution (15 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (70 mg, 11%) as a yellow solid. Data for the title compound are shown in Table 2.

[0226] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

[0227] Example 5: Adenosine receptor binding assay Inhibitory binding assays were performed using BacMam human adenosine A 2A The experiment was carried out using 0.2 μg of membranes prepared from HEK293 cells transfected with the receptor or 1.4 μg of membranes prepared from HEK293 cells transfected with the BacMam human adenosine A1 receptor. The membranes were incubated with various concentrations of compounds and 1 nM [ 3 H]ZM241385(HEK293-hA 2A )or[ 3 H]DPCPX (CHO-hA1) at 25 °C for 1 h in 50 mM Tris-HCl (HEK293-hA 2A Cells were incubated in 50 mM Tris-HCl, 100 mM NaCl, 10 mM MgCl2 (CHO-hA1; pH 7.4) or 50 mM Tris-HCl, 100 mM NaCl, 10 mM MgCl2 (CHO-hA1; pH 7.4). The assay was then terminated by rapid filtration through a GF / B grade Unifilter using a TomTec cell harvester, followed by 5 x 0.5 ml washes with ddH2O. Nonspecific binding was determined using 1 μM CGS15943 (HEK293-hA1; pH 7.4). 2A ) or 1 μM DPCPX (CHO-hA1). Bound radioactivity was determined by liquid scintillation counting and inhibition curves were analyzed using a four-parameter logistic equation. IC 50 value Wochi Using the K values ​​derived from saturation binding studies using the Jan-Prusoff equation, i The results are shown in Table 3.

[0228] [Table 3-1] [Table 3-2] [Table 3-3]

[0229] Example 6: CB-1 Receptor Binding and Antagonism Receptor binding The affinity of compounds for the agonist site of the human CB-1 cannabinoid receptor in transfected CHO cells was determined by a radioligand binding assay: Cell membrane homogenates (20 μg protein) were incubated with 0.5 nM [ 3 3H]CP 55940 for 120 min at 37° C. Nonspecific binding is determined in the presence of 10 μM WIN 55212-2. After incubation, samples are rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked in 0.3% PEI and rinsed several times with ice-cold buffer containing 50 mM Tris-HCl (pH 7.4) and 0.5% BSA using a 96-sample cell harvester (Unifilter, Packard). Filters are dried and radioactivity is then counted in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The standard reference compound was CP 55940, which was tested at several concentrations in each experiment to determine the IC 50 The competitive curve is calculated.

[0230] Receptor antagonism : Evaluation of the antagonist activity of compounds at human CB1 receptors expressed in transfected CHO cells, determined by measuring their effect on agonist-induced cAMP modulation by using the HTRF detection method. The cells were suspended in HBSS buffer (Invitrogen) supplemented with 20 mM HEPES (pH 7.4) and then incubated at 5.10 3Cells are distributed into microplates at a density of cells / well and pre-incubated for 5 min at room temperature in the presence of either: HBSS (stimulation control), 3 μM or various concentrations (IC 50 (determination) the reference antagonist AM 281 (basal control) or the test compound. The reference agonist CP 55940 and the adenylyl cyclase activator NKH 477 are then added to final concentrations of 3 nM and 3 μM, respectively. For basal control measurements, CP 55940 is omitted from wells containing 3 μM AM 281. After 20 min incubation at 37° C., the cells are lysed and a fluorescent acceptor (D2-labeled cAMP) and a fluorescent donor (anti-cAMP antibody labeled with europium cryptate) are added. After 60 min at room temperature, fluorescence transmission was measured using a microplate reader (Rubystar, BMG) at λ ex = 337 nm and λ em = 620 and 665 nm. The cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). Results are expressed as percent inhibition of the control response to 3 nM CP 55940. The standard reference antagonist was AM 281, which was tested in each experiment at several concentrations to determine the IC 50 Concentration-response curves are constructed to calculate values. In Table 4, K i is blank because the observed binding is i indicates that the value was too weak to measure.

[0231] [Table 4]

[0232] Other embodiments are within the scope of the following claims. Furthermore, the present invention includes the following aspects. 1. Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is:

change

change

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: Ring A is: 【Chemistry 2】 and Each R １ and each R ２ are independently halo, C １－３ Alkyl, —O—C １－３ Alkyl, -CO ２ R ａ Or -NR ７ R ８ and wherein alkyl is optionally -OR ａ and substituted with one or more substituents independently selected from halo; R ３ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR ａ , -NR ａ R ｂ , -CO ２ R ａ , -CONR ａ R ｂ , -NR ａ C(O)-R ａ Or -NHC(O)-OR ａ and wherein heterocyclyl and heteroaryl are independently N, O and S(O) ｋ containing 1 to 4 heteroatoms independently selected from: Here, R ３ optionally halo, cyano, -R ａ and -OR ａ Substituted with 1 to 3 substituents selected from: R ４ Ha-(CHR ｃ ) ｉ - (NR ａ ) ｊ -R ５ and R ５ are N, O and S(O), respectively. ｋ a 5-membered heterocyclyl or 5-membered heteroaryl containing 1 to 4 heteroatoms independently selected from: Here, R ５ one or two ring atoms are optionally replaced by -C(=O)-; Here, R ５ optionally 1 to 4 groups -X-R ６ is substituted with; Each X is independently a bond, —O—, or —NR ａ -, -S(O) ｋ -, -(CH ２ ) ｍ - or -C(O)-; Each R ６ are independently H, halo, -OR ａ , C １－６ Alkyl, C ３－８ Cycloalkyl, heterocyclyl, heteroaryl, aryl, -CO ２ R ａ , -C(O)NR ａ R ｂ , -(CH ２ ) ｎ -NR ａ R ｂ or cyano; wherein each of heterocyclyl and heteroaryl is N, O, and S(O) ｋ containing 1 to 4 heteroatoms independently selected from: Here, each C ３－８ one or two ring atoms of the cycloalkyl, heterocyclyl, heteroaryl, or aryl are independently optionally substituted with -C(=O)-; wherein each of alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl is optionally represented by -R ａ , -OR ａ , -(CH ２ ) ｎ -NR ａ R ｂ and substituted with one or more substituents independently selected from halo; Each R ７ and each R ８ are independently R ａ and Or R ７ and R ８ together with the atom to which they are attached, optionally represents -OR ａ and halo; Each R ａ and each R ｂ are independently H, C １－６ Alkyl, C ３－８ Cycloalkyl or C ４－９ cycloalkylalkyl; Here, each R ａ and each R ｂ is independently optionally substituted with one or more substituents independently selected from: —OH and halo; Each R ｃ are independently H, halo, C １－３ Alkyl or -(CH ２ ) ｎ -NR ａ R ｂ and wherein alkyl is optionally -OR ａ and substituted with one or more substituents independently selected from halo; a is 0 or 1; i is 0, 1, 2 or 3; j is 0 or 1; each k is independently 0, 1, or 2; each m is independently 1 or 2; and Each n is independently 0 or 1; A compound or a pharma- ceutically acceptable salt thereof.

2. i is 1, R ｃ is H or C １－３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is 0 or 1;

3. R ５ is selected from imidazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiophenyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R ５ optionally 1 to 4 groups -X-R ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is substituted with R 1 or R 2 .

4. X is a bond and R ６ C １－６ 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein: R is 0 or 1;

5. R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is phenyl optionally substituted with fluoro or chloro.

6. R １ and R ２ each independently represents halo, —CH ３ , -CH ２ OH or -OCH ３ 6. The compound according to claim 1, wherein the compound is selected from the group consisting of:

7. Formula (II): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein: Each R １ and each R ２ became independent, Halo, C １－３ Alkyl or -O-C １－３ is alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from -OH and halo; Ring B is a 5-membered heterocyclyl or 5-membered heteroaryl, each of which contains 1 to 4 heteroatoms independently selected from N and O; Each R ９ are independently halo or C １－３ is alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from -OH and halo; Each R ａ and each R ｂ are independent, H, C １－６ Alkyl, C ３－８ Cycloalkyl or C ４－９ cycloalkylalkyl; Here, each R ａ and each R ｂ is independently optionally substituted with one or more substituents independently selected from: —OH and halo; R ｃ H, halo, C １－３ Alkyl or -(CH ２ ) ｎ -NR ａ R ｂ and wherein alkyl is optionally -OR ａ and substituted with one or more substituents independently selected from halo; R ｄ is H or halo; a is 0 or 1; b is 0, 1 or 2; and n is 0 or 1; A compound or a pharma- ceutically acceptable salt thereof.

8. Ring B is tetrahydrofuranyl or 1,3-oxazolyl, b is 0 or 1, and each R ９ became independent and C １－３ 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof, wherein: R is 0 or 1;

9. A compound or a pharma- ceutically acceptable salt thereof selected from the group consisting of: 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methylimidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1H-imidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-(1H-tetrazol-5-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(2-ethylpyrazol-3-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[1-(2-thienyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(isoxazol-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(3-methylimidazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1H-imidazol-5-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1H-imidazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(1H-pyrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methyl-1,2,4-triazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyl-1H-triazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-methyltriazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[1-benzyl-3-(3-methoxyphenyl)pyrazol-4-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2-methoxy-6-methyl-4-pyridyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(3,5-dimethylimidazol-4-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-(oxazol-4-ylmethyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(1-methylpyrazol-3-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; tert-butyl 3-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]pyrrolidine-1-carboxylate; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(1-methylpyrrolidin-3-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; tert-butyl 2-[[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyrrolidine-1-carboxylate; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[(2R)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2S,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrrolidin-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2-methoxy-6-methyl-4-pyridyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-(4-fluorophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-[[1-(pyridine-3-carbonyl)pyrrolidin-3-yl]amino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-[methyl(1H-pyrazol-4-yl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[[1-[[2-(aminomethyl)phenyl]methyl]pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

10. 10. The compound of claim 9, selected from the group consisting of: 5-amino-8-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent or excipient.

12. 11. A therapeutic agent for a disease or condition mediated by an adenosine receptor, comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

13. The method of claim 12, wherein the disease or condition mediated by adenosine receptors is lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors.

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