5-Amino-8-(4-pyridyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one compounds for anti-cancer

Abstract

This text describes triadimefon compounds of formula (I) and their pharmaceutically acceptable salts. Methods for preparing and using the compounds of formula (I) are also described. The compounds of formula (I) and their pharmaceutically acceptable salts can be used as adenosine receptor antagonists, for example, for treating diseases or disorders mediated by adenosine receptors, such as cancer, movement disorders or attention disorders.

Description

[0001] Background

[0002] Adenosine regulates many physiological functions. Intracellularly, adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle; extracellular adenosine participates 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.

[0003] The actions of adenosine are mediated by the G-protein coupled receptor family. At least four adenosine receptor subtypes have been identified: A1R, A2aR, A2bR, and A3R. The A1R and A3 subtypes inhibit the activity of the enzyme adenylyl cyclase, while the A2a and A2b subtypes stimulate the activity of the same enzyme, thereby regulating the level of cyclic AMP in cells.

[0004] In the immune system, the involvement of A2a and A2b adenosine receptors is a key regulatory mechanism for protecting tissues from excessive immune responses. In tumors, this pathway is hijacked and anti-tumor immunity is hindered, promoting cancer progression. In addition, in many cases, the tumor microenvironment contains high levels of extracellular adenosine. Therefore, adenosine receptors, particularly A2aR and A2bR, have been identified as targets for cancer therapy.

[0005] Many adenosine receptor antagonists have been reported. For example, International Patent Application WO 2006 / 138734 discloses triazolo-pyrimidine cannabinoid receptor 1 (CB-1) antagonists. WO 2008 / 002596 and WO 2009 / 111449 disclose adenosine A2a receptor antagonists comprising a triazolone moiety. WO 2012 / 038980 discloses fused tricyclic compounds as adenosine receptor antagonists. WO 2016 / 161282 discloses heterocyclic compounds as LSD1 inhibitors. WO 2018 / 166493 discloses heteroaryl[4,3-c]pyrimidin-5-amine derivatives as A2a receptor antagonists.

[0006] There remains a need for highly soluble, highly selective, and highly effective adenosine receptor antagonists.

[0007] Brief Description

[0008] In one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein:

[0011] Ring A can be:

[0012]

[0013] Each R 1 and each R 2 independently can be halogen, C 1-3 alkyl, -O-C 1-3 alkyl, -CO 2 R a or -NR 7 R 8 ;

[0014] wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halogen;

[0015] R 3 can be C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heterocyclic group, heteroaryl, halogen, -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 ;

[0016] wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O) k ;

[0017] wherein R 3 is optionally substituted with one to three substituents selected from halogen, cyano, -R a and -OR a ;

[0018] R 4 can be -(CHR c ) i -(NR a ) j -R 5 ;

[0019] R 5 can be a 5-membered heterocyclic group or a 5-membered heteroaryl, each including 1 to 4 heteroatoms independently selected from N, O, and S(O) k ;

[0020] wherein one or two ring atoms of R 5 are optionally replaced by -C(=O)-;

[0021] wherein R5 Optionally substituted with one to four groups -X-R 6 ;

[0022] Each X independently can be a bond, -O-, -NR a -, -S(O) k -, -(CH 2 ) m - or -C(O)-;

[0023] Each R 6 independently can be H, halogen, -OR a , C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclic group, heteroaryl, aryl, -CO 2 R a , -C(O)NR a R b , -(CH 2 ) n -NR a R b or cyano;

[0024] wherein each of the heterocyclic group and the heteroaryl includes 1 to 4 heteroatoms independently selected from N, O, and S(O) k ;

[0025] wherein one or two ring atoms of each C 3-8 cycloalkyl, heterocyclic group, heteroaryl or aryl are independently optionally replaced by -C(=O)-;

[0026] wherein each of the alkyl, cycloalkyl, heterocyclic group, heteroaryl and aryl is optionally substituted with one or more substituents independently selected from -R a , -OR a , -(CH 2 ) n -NR a R b and halogen;

[0027] Each R 7 and each R 8 independently can be R a ;

[0028] or R 7 and R 8 together with the atom to which they are attached can form a 3- to 8-membered heterocyclic group, which is optionally substituted with one or more substituents independently selected from -OR a and halogen;

[0029] Each R a and each Rb Independently can be H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl;

[0030] wherein each R a and each R b is independently optionally substituted with one or more substituents independently selected from -OH and halogen;

[0031] Each R c independently can be H, halogen, C 1-3 alkyl or -(CH 2 ) n -NR a R b ;

[0032] wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halogen;

[0033] a can be 0 or 1;

[0034] i can be 0, 1, 2 or 3;

[0035] j can be 0 or 1;

[0036] Each k independently can be 0, 1 or 2;

[0037] Each m independently can be 1 or 2; and

[0038] Each n independently can be 0 or 1.

[0039] The compound of formula (I) can be a selective adenosine receptor antagonist relative to CB-1. The compound can have a Ki of 100 nM or less for at least one of A2aR and A2bR, and can have a Ki of 10,000 nM or more for CB-1.

[0040] In certain embodiments, i can be 1 and R c can be H or C 1-3 alkyl. R 5 can 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, thienyl, 1,2,3-triazolyl and 1,3,4-triazolyl, wherein R 5 is optionally substituted with one to four groups -X-R 6 Substituent. X can be a bond and R 6 can be C 1-6Alkyl.

[0041] In certain embodiments, R 3 may be phenyl optionally substituted with fluorine or chlorine. R 1 and R 2 may each independently be selected from halogen, -CH 3 , -CH 2 OH or -OCH 3 .

[0042] In another aspect, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0043]

[0044] Wherein:

[0045] Each R 1 and each R 2 independently may be halogen, C 1-3 alkyl or -O-C 1-3 alkyl;

[0046] Wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0047] Ring B may be a 5-membered heterocyclic group or a 5-membered heteroaryl group, each containing 1 to 4 heteroatoms independently selected from N and O;

[0048] Each R 9 independently may be halogen or C 1-3 alkyl;

[0049] Wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0050] Each R a and each R b independently may be H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl;

[0051] Wherein each R a and each R b independently is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0052] R c may be H, halogen, C 1-3 alkyl or -(CH 2 ) n -NR a R b ;

[0053] wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogen;

[0054] R d may be H or halogen;

[0055] a may be 0 or 1;

[0056] b may be 0, 1 or 2; and

[0057] n may be 0 or 1.

[0058] In certain embodiments, ring B may be tetrahydrofuranyl or 1,3-oxazolyl, each of which is optionally substituted with 1 to 3 substituents selected from -C 1-3 alkyl.

[0059] In another aspect, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0060] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0061] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(1-methylimidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0062] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(1H-imidazol-2-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0063] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(1H-tetrazol-5-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0064] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0065] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0066] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(2-ethylpyrazol-3-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0067] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(2-thienyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0068] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0069] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0070] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0071] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0072] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(isoxazol-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0073] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methylisoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0074] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0075] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0076] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0077] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(3-methylimidazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0078] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0079] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0080] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0081] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0082] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1H-imidazol-5-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0083] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1H-imidazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0084] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(1H-pyrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0085] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0086] 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;

[0087] 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;

[0088] 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;

[0089] 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;

[0090] 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;

[0091] 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;

[0092] 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;

[0093] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0094] 5-Amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0095] 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;

[0096] 5-Amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0097] 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;

[0098] 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;

[0099] 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;

[0100] 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;

[0101] 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;

[0102] 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;

[0103] 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;

[0104] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0105] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0106] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0107] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0108] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(1,3-oxazol-4-ylmethyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0109] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0110] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0111] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0112] 5-Amino-2-[(2,5-dimethyl-1,3-oxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0113] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-methyl-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0114] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(1-methyl-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0115] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(1-methyl-imidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0116] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-methyl-oxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0117] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(4-fluorophenyl)-2-[(1-methyl-imidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0118] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(4-fluorophenyl)-2-[(5-methyl-oxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0119] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0120] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(1-methyl-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0121] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(1-methyl-imidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0122] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0123] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl][1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0124] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl][1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0125] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0126] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0127] tert-Butyl 3-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]pyrrolidine-1-carboxylate;

[0128] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-pyrrolidin-3-yl[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0129] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1-methylpyrrolidin-3-yl)-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0130] tert-Butyl 2-[[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyrrolidine-1-carboxylate;

[0131] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0132] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0133] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0134] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0135] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0136] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0137] 5-Amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0138] 5-Amino-2-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0139] 5-Amino-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0140] 5-Amino-2-[[(2R)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0141] 5-Amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0142] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0143] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0144] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0145] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0146] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0147] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0148] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0149] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0150] 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;

[0151] 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;

[0152] 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;

[0153] 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;

[0154] 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;

[0155] 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;

[0156] 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;

[0157] 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;

[0158] 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;

[0159] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0160] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(4-fluorophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0161] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0162] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0163] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0164] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0165] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0166] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[[1-(pyridine-3-carbonyl)pyrrolidin-3-yl]amino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0167] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[methyl(1H-pyrazol-4-yl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0168] 5-Amino-2-[[1-[[2-(aminomethyl)phenyl]methyl]pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0169] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0170] In certain embodiments, the compound or its pharmaceutically acceptable salt may be selected from:

[0171] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0172] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0173] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0174] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0175] In another aspect, there is provided the use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder mediated by an adenosine receptor.

[0176] In certain embodiments, the disease or disorder mediated by an adenosine receptor 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.

[0177] Other features, objects and advantages will be apparent from the description and from the claims.

[0178] Description

[0179] The compounds of formula (I) and formula (II) or their pharmaceutically acceptable salts can be used as adenosine receptor antagonists.

[0180] The compounds of formula (I) or their pharmaceutically acceptable salts are described herein:

[0181] 。

[0182] Ring A is:

[0183] 。

[0184] Each R 1 and each R 2 is independently halogen, C 1-3 alkyl, -O-C 1-3 alkyl, -CO 2 R a or -NR 7 R 8 ; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halogen.

[0185] R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heterocyclic group, heteroaryl, halogen, -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 ; wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; wherein R 3 is optionally substituted with one to three substituents selected from halogen, cyano, -R a , and -OR a 。

[0186] R 4 is -(CHR c ) i -(NR a ) j -R 5 。

[0187] R 5is a 5-membered heterocyclic group or 5-membered heteroaryl group, each comprising 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; wherein one or two ring atoms of R 5 are optionally replaced by -C(=O)-; wherein R 5 is optionally substituted by one to four groups -X-R 6 .

[0188] Each X is independently a bond, -O-, -NR a -, -S(O) k -, -(CH 2 ) m - or -C(O)-.

[0189] Each R 6 is independently H, halogen, -OR a , C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclic group, heteroaryl, aryl, -CO 2 R a , -C(O)NR a R b , -(CH 2 ) n -NR a R b or cyano; wherein each of the heterocyclic group and heteroaryl group comprises 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; wherein one or two ring atoms of each C 3-8 cycloalkyl, heterocyclic group, heteroaryl or aryl are independently optionally replaced by -C(=O)-; wherein each of the alkyl, cycloalkyl, heterocyclic group, heteroaryl and aryl is optionally substituted by one or more substituents independently selected from -R a , -OR a , -(CH 2 ) n -NR a R b and halogen.

[0190] Each R 7 and each R 8 are independently R a ; or R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocyclic group, which heterocyclic group is optionally substituted by one or more substituents independently selected from -OR a and halogen.

[0191] Each R a and each R bindependently is H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl; wherein each R a and each R b is independently optionally substituted with one or more substituents independently selected from -OH and halogen.

[0192] Each R c is independently H, halogen, C 1-3 alkyl or -(CH 2 ) n -NR a R b ; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halogen.

[0193] a is 0 or 1.

[0194] i is 0, 1, 2 or 3.

[0195] j is 0 or 1.

[0196] Each k is independently 0, 1 or 2.

[0197] Each m is independently 1 or 2.

[0198] Each n is independently 0 or 1.

[0199] In certain embodiments, i is 1 and R c is H or C 1-3 alkyl.

[0200] In certain embodiments, R 5 is a 5 - membered heterocyclic group. In other embodiments, R 5 is a 5 - membered heteroaryl.

[0201] In certain embodiments, 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, thienyl, 1,2,3 - triazolyl and 1,3,4 - triazolyl, wherein R 5 is optionally substituted with one to four groups -X - R 6 .

[0202] In certain embodiments, R 5 is tetrahydrofuranyl or 1,3 - oxazolyl, each of which is optionally substituted with -CH 3 .

[0203] In certain embodiments, i is 1; R c is H; j is 0; and R 5 is selected from 1,3-oxazolyl and tetrahydrofuranyl, each of which is optionally substituted with -CH 3 .

[0204] In certain embodiments, R 1 and R 2 are each independently -CH 3 or -CH 2 OH; i is 1; R c is H; j is 0; and R 5 is tetrahydrofuranyl or 1,3-oxazolyl, each of which is optionally substituted with -CH 3 .

[0205] In certain embodiments, X is a bond and R 6 is C 1-6 alkyl.

[0206] In certain embodiments, R 3 is phenyl optionally substituted with fluorine or chlorine.

[0207] In certain embodiments, R 1 and R 2 are each independently selected from halogen, -CH 3 , -CH 2 OH or -OCH 3 .

[0208] In certain embodiments, R 1 and R 2 are each independently selected from halogen, -CH 3 , ‌-CH 2 OH or -OCH 3 ; and R 3 is phenyl optionally substituted with fluorine or chlorine.

[0209] In certain embodiments, R 1 and R 2 are each independently selected from halogen, -CH 3 , ‌-CH 2 OH or -OCH 3 ; R 3 is phenyl optionally substituted with fluorine or chlorine; i is 1; and R c is H.

[0210] In certain embodiments, R 1 and R 2 are each independently -CH 3 or -CH 2 OH; R3 is a phenyl group optionally substituted with fluorine or chlorine; i is 1; R c is H; j is 0; and R 5 is tetrahydrofuranyl or 1,3-oxazolyl, each of which is optionally substituted with -CH 3 .

[0211] In certain embodiments, R 3 is a phenyl group optionally substituted with fluorine or chlorine; 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, thienyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, wherein R 5 is optionally substituted with one to four groups -X-R 6 .

[0212] In certain embodiments, R 3 is a phenyl group optionally substituted with fluorine or chlorine; 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, thienyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, wherein R 5 is optionally substituted with one to four groups -X-R 6 , wherein X is a bond and R 6 is C 1-6 alkyl.

[0213] In certain embodiments, R 3 is a phenyl group optionally substituted with fluorine or chlorine; i is 1; R c is H or C 1-3 alkyl; j is 0; and R 5 is tetrahydrofuranyl or 1,3-oxazolyl, each of which is optionally substituted with -CH 3 .

[0214] There is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0215] .

[0216] The compound of formula (II) is encompassed by the broader formula (I).

[0217] Each R 1 and each R 2 is independently halogen, C 1-3 alkyl or -O-C 1-3 alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0218] Ring B is a 5-membered heterocyclic group or a 5-membered heteroaryl group, each comprising 1 to 4 heteroatoms independently selected from N and O.

[0219] Each R 9 is independently halogen or C 1-3 alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0220] Each R a and each R b is independently H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl; wherein each R a and each R b is independently optionally substituted with one or more substituents independently selected from -OH and halogen.

[0221] R c is H, halogen, C 1-3 alkyl or -(CH 2 ) n -NR a R b ; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halogen.

[0222] R d is H or halogen.

[0223] a is 0 or 1.

[0224] b is 0, 1 or 2.

[0225] n is 0 or 1.

[0226] In certain embodiments, R d is halogen.

[0227] In certain embodiments, R 1 and R 2 are each independently selected from halogen, -CH 3 , -CH 2 OH or -OCH 3 .

[0228] In certain embodiments, R 1 and R 2 are each independently -CH 3 or -CH 2 OH.

[0229] 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, thienyl, 1,2,3-triazolyl, and 1,3,4-triazolyl, where R 5 is optionally substituted with one to four groups -X-R 6 substituted.

[0230] In certain embodiments, ring B is tetrahydrofuranyl or 1,3-oxazolyl, b is 0 or 1, and each R 9 is independently C 1-3 alkyl.

[0231] In certain embodiments, ring B is tetrahydrofuranyl.

[0232] In certain embodiments, ring B is 1,3-oxazolyl.

[0233] In certain embodiments, R 1 and R 2 are each independently -CH 3 or -CH 2 OH; ring B is tetrahydrofuranyl or 1,3-oxazolyl; b is 0 or 1; and R c is H.

[0234] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0235] The term "alkyl" refers to a fully saturated straight-chain or branched-chain aliphatic group that, if specified, has the specified number of carbon atoms (e.g., C 1-10 alkyl refers to an alkyl group having one to ten carbons). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. If the size is not specified, "alkyl" refers to a group having 1 to 10 carbon atoms.

[0236] The term "alkenyl" refers to an unsaturated straight-chain or branched aliphatic group that contains at least one carbon-carbon double bond and, if specified, has a specified 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 the size is not specified, "alkenyl" refers to a group having 2 to 10 carbon atoms.

[0237] The term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group that contains at least one carbon-carbon triple bond and, if specified, has a specified number of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and but-2-ynyl. If the size is not specified, "alkynyl" refers to a group having 2 to 10 carbon atoms.

[0238] Alkenyl and alkynyl groups can contain more than one unsaturated bond, or a mixture of double and triple bonds.

[0239] The term "cycloalkyl" refers to a saturated or unsaturated aliphatic ring containing 3 to 10 carbon ring atoms, where one or more of the carbon ring atoms can optionally be replaced by -C(=O)-. Cycloalkyl groups can contain fused rings and / or bridged rings, including cases where the fused or bridged ring is 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.

[0240] The term "heterocyclyl" refers to a saturated or unsaturated heterocycle containing 3 to 10 ring atoms, where 1 to 4 of the ring atoms are independently N, O, or S; and one or more of the carbon ring atoms can optionally be replaced by -C(=O)-. Ring nitrogen or ring sulfur atoms can independently optionally be oxidized, including, for example, -N(O)-, -S(O)-, or -S(O) 2 -. The ring nitrogen atoms in heterocyclyl groups can optionally be quaternized, for example, -N + (CH 3 ) 2 -. Heterocyclyl groups can contain fused rings and / or bridged rings, including cases where the fused or bridged ring is cycloalkyl or heterocyclyl. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, morpholinyl, thiomorpholinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.

[0241] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 ring atoms. The aryl may contain fused rings, including aryl rings fused to cycloalkyl rings, heterocyclic rings, or aryl rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, and dihydro-1H-indenyl.

[0242] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group having 6 to 14 ring atoms, wherein 1 to 4 ring atoms are independently N, O, or S. The ring nitrogen or ring sulfur atoms may independently be optionally oxidized, including, for example, -N(O)-, -S(O)-, or -S(O) 2 -. The heteroaryl group may contain fused rings and / or bridged rings, including cases where the fused ring or bridged ring is a cycloalkyl, heterocyclic, aryl, or heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, pyridyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, 5,6,7,8-tetrahydroquinolinyl, benzofuryl, pyrrolopyridyl, pyrrolopyrimidinyl, triazinyl, and tetrazolyl.

[0243] The term "polycyclic ring system" refers to a cycloalkyl, heterocyclic, aryl, or heteroaryl group including two or more fused rings and / or bridged rings.

[0244] Some of the compounds described herein may exist in more than one stereoisomeric form. Unless otherwise indicated, the description of such compounds is intended to include all geometric and optical isomers, including racemates.

[0245] Some of the compounds described herein may exhibit tautomerism. The structural diagrams herein generally represent only one of the possible tautomeric forms of such compounds. It should be understood that the structural diagrams are intended to include all tautomeric forms of such compounds.

[0246] The term "pharmaceutically acceptable salt" refers to those salts of the compounds of formula (I) which retain the biological activity of the free compound and which can be administered as a medicine to humans and / or animals. Desired salts of the basic functional groups of the compounds can be prepared by treating the compounds 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. Desired salts of the acidic functional groups of the compounds can be prepared by treating the compounds with a base. Some examples of suitable inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Some examples of suitable organic salts of acidic compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, Ν,Ν'-dibenzylethylenediamine, and triethylamine salts.

[0247] The compounds of formula (I) can contain said atoms in any isotopic form thereof. In this regard, embodiments of the invention that may be mentioned 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.

[0248] The application in the formula herein refers to the point of attachment between different groups.

[0249] Exemplary compounds of formula (I) or pharmaceutically acceptable salts thereof include:

[0250] 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;

[0251] 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;

[0252] 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;

[0253] 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;

[0254] 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;

[0255] 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;

[0256] 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;

[0257] 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;

[0258] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0259] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0260] 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;

[0261] 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;

[0262] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(isoxazol-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0263] 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;

[0264] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-methyl-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0265] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methyl-pyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0266] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0267] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(3-methyl-imidazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0268] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0269] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0270] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0271] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyl-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0272] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1H-imidazol-5-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0273] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1H-imidazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0274] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(1H-pyrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0275] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0276] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0277] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(4-methyl-1,2,4-triazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0278] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(5-methyl-1H-triazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0279] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(2-methyltriazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0280] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0281] 5-Amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0282] 5-Amino-2-[[1-benzyl-3-(3-methoxyphenyl)pyrazol-4-yl]methyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0283] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0284] 5-Amino-2-[(2,5-dimethyl-oxazol-4-yl)methyl]-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0285] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(1-methyl-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0286] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-[(5-methyl-oxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0287] 5-Amino-8-(2-methoxy-6-methyl-pyridin-4-yl)-2-[(1-methyl-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0288] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-pyridin-4-yl]-2-[(5-methyl-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0289] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-pyridin-4-yl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0290] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-pyridin-4-yl]-2-[(1-methyl-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0291] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-pyridin-4-yl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0292] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-pyridin-4-yl]-2-[(5-methyl-isoxazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0293] 5-Amino-2-[(3,5-dimethyl-1H-imidazol-4-yl)methyl]-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0294] 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0295] 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0296] 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0297] 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0298] 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-(oxazol-4-ylmethyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0299] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0300] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0301] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0302] 5-Amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0303] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0304] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0305] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(1-methylimidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0306] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0307] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(4-fluorophenyl)-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0308] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0309] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0310] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(1-methylimidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0311] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0312] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0313] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0314] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0315] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0316] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0317] tert-Butyl 3-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]pyrrolidine-1-carboxylate;

[0318] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0319] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1-methylpyrrolidin-3-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0320] tert-Butyl 2-[[5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyrrolidine-1-carboxylate;

[0321] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0322] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0323] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0324] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0325] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0326] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2R)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0327] 5-Amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0328] 5-Amino-2-[[(2R)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0329] 5-Amino-2-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-pyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0330] 5-Amino-2-[[(2R)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-pyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0331] 5-Amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethyl-pyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0332] 5-Amino-8-(2,6-dimethyl-pyridin-4-yl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0333] 5-Amino-8-(2,6-dimethyl-pyridin-4-yl)-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0334] 5-Amino-8-(2,6-dimethyl-pyridin-4-yl)-2-[[(2R,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0335] 5-Amino-8-(2,6-dimethyl-pyridin-4-yl)-2-[[(2R,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0336] 5-Amino-8-(2,6-dimethyl-pyridin-4-yl)-2-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0337] 5-Amino-8-(2,6-dimethyl-pyridin-4-yl)-2-[[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0338] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0339] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0340] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0341] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0342] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2-pyrrolidin-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0343] 5-Amino-8-(2-methoxy-6-methyl-4-pyridinyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0344] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0345] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0346] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0347] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0348] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0349] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0350] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-(4-fluorophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0351] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0352] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0353] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0354] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0355] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0356] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[[1-(pyridine-3-carbonyl)pyrrolidin-3-yl]amino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0357] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[methyl(1H-pyrazol-4-yl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0358] 5-amino-2-[[1-[[2-(aminomethyl)phenyl]methyl]pyrrolidin-2-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0359] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0360] The compound of formula (I) can be an adenosine receptor antagonist, i.e., an antagonist of one or more of A1R, A2aR, A2bR, and A3R. The term "adenosine receptor antagonist" refers to a compound that binds to an adenosine receptor and antagonizes its activity, e.g., the compound of formula (I).

[0361] In certain 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) that it is an adenosine receptor antagonist but is substantially inactive against other biological targets. The term "substantially inactive" as used herein describes a compound that (i) has a significantly weaker affinity for a given receptor compared to its affinity for the adenosine receptor; (ii) does not exhibit substantial agonist or antagonist activity against the given receptor; or both (i) and (ii).

[0362] The term "selective adenosine receptor antagonist" refers to a compound that shows a binding affinity for one or more adenosine receptor subtypes that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold greater than its affinity for a given receptor. In other words, the ratio of the binding Ki values (given receptor:adenosine receptor) can be at least 100, at least 1,000, or at least 10,000.

[0363] Specifically, the selective adenosine receptor antagonist can be substantially inactive against other G-protein coupled receptors such as cannabinoid receptors, referred to as CB-1 and CB-2.

[0364] The compound of formula (I) may have a binding affinity Ki for A2aR of, for example, 100 nM or less, 10 nM or less, or 1 nM or less.

[0365] The compound of formula (I) may have a binding affinity Ki for A2bR of, for example, 100 nM or less, 10 nM or less, or 1 nM or less.

[0366] The compound of formula (I) may have a binding affinity Ki for CB-1 of, for example, 1,000 nM or greater, 10,000 nM or greater, 13,000 nM or greater.

[0367] The compound of formula (I) may be a selective adenosine receptor antagonist relative to CB-1.

[0368] The compound of formula (I) may be active as an adenosine receptor antagonist but substantially inactive against CB-1.

[0369] The compound of formula (I) may also be selective between different subtypes of adenosine receptors. In certain embodiments, the compound of formula (I) is A2aR-selective; A2bR-selective; or dual A2aR / A2bR-selective.

[0370] An A2aR-selective compound shows a binding affinity for A2aR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than its binding affinity for each of A1R, A2bR, and A3R.

[0371] An A2bR-selective compound shows a binding affinity for A2bR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than its binding affinity for each of A1R, A2aR, and A3R.

[0372] A dual A2aR / A2bR-selective compound shows a binding affinity for A2aR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than its binding affinity for each of A1R and A3R. The dual A2aR / A2bR-selective compound also shows a binding affinity for A2bR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than its binding affinity for each of A1R and A3R. Additionally, 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.

[0373] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient.

[0374] The compositions of the present invention may be in a form suitable for the following uses: oral use (e.g., as tablets, lozenges, hard or soft gelatin 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 a 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 depot administration, or as a suppository for rectal depot administration).

[0375] Suitable pharmaceutically 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 p-hydroxybenzoate or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulations may be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case using conventional coating agents and procedures well known in the art.

[0376] 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 (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0377] The compounds of formula (I) can be used for the treatment of diseases or disorders mediated by adenosine receptors. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by adenosine receptors. In certain embodiments, the disease or disorder is mediated by A2aR; in other embodiments, by A2bR; in still other embodiments, by both A2aR and A2bR.

[0378] Some examples of diseases or disorders mediated by adenosine receptors include cancer, such as 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; 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 disorders mediated by adenosine receptors are known.

[0379] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or disorder mediated by an adenosine receptor.

[0380] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for 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, melanoma or other solid tumors).

[0381] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or disorder mediated by an adenosine receptor, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0382] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for 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, melanoma or other solid tumors), wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0383] In one embodiment, there is provided a method of treating a disease or disorder mediated by an adenosine receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0384] In one embodiment, there is provided 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, melanoma or other solid tumors), the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0385] In one embodiment, there is provided a method of treating a disease or disorder mediated by an adenosine receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0386] In one embodiment, 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, melanoma or other solid tumors) is provided, the method 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 relative to CB-1.

[0387] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating a disease or disorder mediated by an adenosine receptor is provided.

[0388] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for 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, melanoma or other solid tumors) is provided.

[0389] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating a disease or disorder mediated by an adenosine receptor is provided, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0390] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for 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, melanoma or other solid tumors) is provided, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0391] The compounds of formula (I) can be prepared according to the following general scheme.

[0392] Schemes 1a and 1b illustrate the preparation of the intermediate 6-substituted-4-hydrazino-2-aminopyrimidine compounds of formula (IV).

[0393] Scheme 1a

[0394]

[0395] Scheme 1b

[0396]

[0397] Scheme 2 explains the conversion of the compound of formula (IV) to the intermediate 7-substituted-5-amino-8-bromo-[1,2,4]triazolo[4,3-c]pyrimidin-3-one compound of formula (V). Briefly, the compound of formula (IV) is treated with triphosgene to effect the closure of the triazolone ring, followed by bromination with (CH 3 ) 3 PhN + Br 3 - Bromination.

[0398] Scheme 2

[0399]

[0400] Scheme 3a explains the conversion of the compound of formula (V) to the compound of formula (I). Alkylation of the compound of formula (V) with R 4 can be achieved using a variety of methods, for example, the Mitsonobu reaction; alcohol mesylation followed by alkylation; alcohol tosylation followed by alkylation; or alcohol chlorination followed by alkylation.

[0401] Scheme 3a

[0402]

[0403] Alternatively, compounds such as R 4 -Br can be used for the direct alkylation of the compound of formula (V).

[0404] Optionally, R 4 can be further modified after alkylation of the compound of formula (V).

[0405] Scheme 3b explains an alternative route for the conversion of the compound of formula (V) to the compound of formula (I). In Scheme 3b, [Pg] represents a suitable reagent for installing the protecting group represented by Pg. Alkylation of the compound of formula (Va) with R 4 can be achieved using a variety of methods, for example, the Mitsonobu reaction; alcohol mesylation followed by alkylation; alcohol tosylation followed by alkylation; or alcohol chlorination followed by alkylation.

[0406] Scheme 3b

[0407]

[0408] Alternatively, compounds such as R 4 -Br can be used for the direct alkylation of the compound of formula (Va).

[0409] Optionally, R 4。

[0410] Optionally, the compound of formula (I) can be further modified, for example, to form different compounds of formula (I). Examples

[0411] General techniques

[0412] LCMS method A

[0413] Instrument: Agilent Technologies 1200 Series, Agilent LC / MSD SL, column: Waters XBridge C8 3.5 µm, 4.6 x 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 of TFA in 1000 mL of Milli-Q water; solvent B = 1 mL of TFA in 1000 mL of MeCN); injection volume 1 µL (can vary); UV detection 220 - 400 nm; column temperature 25 °C; 2.0 mL / min.

[0414] For UV-inactive compounds, connect an ELSD detector (Polymer Laboratories PL-ELS 2100ICE) to the above instrument.

[0415] LCMS method B

[0416] Instrument: Agilent Technologies 1200 Series, Agilent LC / MSD SL, column: Atlantis dC18 5 µm, 4.6 x 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 of TFA in 1000 mL of Milli-Q water; solvent B = 1 mL of TFA in 1000 mL of MeCN); injection volume 1 µL (can vary); UV detection 210 to 400 nm; column temperature 25 °C; 1.5 mL / min.

[0417] LCMS method C

[0418] Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Zorbax C18 5µm, 4.6 x 50mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 2.5 / 95, 4.5 / 95, 4.6 / 10, 6.0 / 10. (Solvent A = 1 mL of formic acid in 1000 mL of Milli-Q water; Solvent B = MeCN); Injection volume 1 µL (variable); UV detection 210 to 400 nm; Column temperature 25 °C; 1.5 mL / min.

[0419] LCMS Method D

[0420] Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Zorbax C18 5µm, 4.6 x 50mm. 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 of ammonium acetate in 1000 mL of Milli-Q water; Solvent B = MeCN); Injection volume 1 µL (variable); UV detection 210 to 400 nm; Column temperature 25 °C; 1.2 mL / min.

[0421] LCMS Method E

[0422] Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Xbridge C8 3.5µm, 4.6 x 50mm. 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 of ammonium bicarbonate added to 1000 mL of Milli-Q water; Solvent B = MeCN); Injection volume 1 µL (variable); UV detection 210 to 400 nm; Column temperature 25 °C; 1.0 mL / min.

[0423] LCMS Method F

[0424] 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 = H 2 O; solvent B = MeCN, both adjusted with 0.1% formic acid). Injection volume 1 µL (can vary). UV detection at 215 nm. Column temperature 60 °C.

[0425] LCMS method G

[0426] Instrument: Waters Acquity UPLC with Waters ELSD and Waters SQD mass spectrometers. Column: Waters Acquity HSS T3 1.8 µm, 2.1 x 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 of formic acid in 1000 mL of HPLC-grade water; solvent B = 1 mL of formic acid in 1000 mL of MeCN); injection volume 1 µL; UV detection from 210 to 400 nm; column temperature 25 °C; 1 mL / min.

[0427] Preparative HPLC method A

[0428] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - 0.1% TFA in H 2 O, 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.

[0429] Preparative HPLC method B

[0430] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - 0.1% in H 2HCOOH in O, B - MeCN, column: YMC Actus Triart C8 (20 mm x 250 mm) 5µm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0431] Preparative HPLC method C

[0432] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - 10 mM in H 2 O of NH 4 HCO 3 , B - MeOH or MeCN, column: Xbridge C8 (19 mm X 150mm), 5µm or YMC Actus Triart C18 (30 mm x 250 mm) 5µm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0433] Preparative HPLC method D

[0434] Instrument: Agilent Technologies 1260 Infinity II Series LC. Mobile phase: hexane B: IPA (60:40), column: YMC Silica (19x150) mm, 5 μm, flow rate: 15 mL / min. Note: Based on sample separation and polarity, the gradient can vary between samples.

[0435] Preparative HPLC method E

[0436] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - H 2 O, B - MeOH or MeCN. Column: Waters Sunfire C18 OBD preparative column, 100Å, 5µm, 19 mm×100 mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0437] SFC method A

[0438] Instrument: Thar Multigram III preparative SFC. Solvent: A - CO 2, B-2 mL of NH 4 OH in 1000 mL of MeOH, column: CHIRALPAK IB 5 µm, 21 x 250 mm. Isocratic 15%; outlet pressure 100 bar; UV detection at 220 nm; column temperature 35 °C; 70.0 mL / min.

[0439] Synthetic routes of intermediates

[0440] The synthetic routes 1 - 8 are described below, which are used for preparing the intermediates used in the synthesis of the compounds of formula (I). The details of synthetic routes 1 - 8 are examples of the techniques used in the preparation of other intermediates detailed in Table 1 below.

[0441] Synthetic Route 1: Procedure for Preparing Intermediate 1

[0442] Intermediate 1: 5-Amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0443]

[0444] Step 1: The reaction was carried out as a 2 x 250 g batch. At room temperature, phenylboronic acid (250 g, 2.05 mol), 4,6-dichloro-2-aminopyrimidine (672 g, 4.10 mol) and K 2 CO 3 (848 g, 6.15 mol) in a degassed suspension of CH 3 CN (15 L) and H 2 O (2 L) was added Pd(PPh 3 ) 4 (118 g, 0.10 mol), and the resulting reaction mixture was heated to 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was vigorously stirred with H 2 O (4 L) and DCM (10 L), and the undissolved solid was filtered off through a Buchner funnel and washed with DCM (3 L). The filtrate was placed in a separatory funnel, the organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using 230 - 400 silica gel mesh and eluted with 0 - 15% EtOAc in petroleum ether to afford 4-chloro-6-phenylpyrimidin-2-amine (350 g, 41%) as an off-white solid.

[0445] LCMS (Method A): m / z 206 (M+H) + (ES +), at 2.53 min, UV-active.

[0446] 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 -NH 2 Proton.

[0447] 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 to 90 °C for 15 h. The reaction was concentrated under reduced pressure. The resulting residue was triturated with ether (1 L) and 10% sodium bicarbonate solution (1 L). The resulting solid was collected by filtration on a Buchner funnel, rinsed with ether (200 mL) and dried under vacuum to provide 4-hydrazine-6-phenylpyrimidin-2-amine (250 g, 73%) as an off-white solid.

[0448] LCMS (Method C): m / z 202 (M+H) + (ES + ), at 0.69 min, UV-active.

[0449] 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).

[0450] Step 3: In N 2 Triphosgene (735 g, 2.48 mol) was added portionwise to a solution of 4-hydrazino-6-phenylpyrimidin-2-amine (250 g, 1.24 mol) in dry THF (3.0 L) cooled to -30°C, and the mixture was stirred at the same temperature for 45 min. The reaction was carefully quenched into ice-cold water (10 L) under vigorous stirring. After effervescence ceased, the reaction mass was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, rinsed with water (1 L) and dried under vacuum to provide 5-amino-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 70%) as a yellow solid.

[0451] LCMS (Method C): m / z 228 (M+H) + (ES + ), UV active at 1.64 min.

[0452] 1 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).

[0453] Step 4: Under N 2 atmosphere, CaCO 3 (88 g, 0.88 mol) was added 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), followed by the addition of (CH 3 ) 3 PhN + Br 3 - (331 g, 0.88 mol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with small portions of MeOH / DCM (1:1), and dried under vacuum to afford 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.

[0454] LCMS (Method C): m / z 306 (M+H) + (ES + ), UV active at 1.78 min.

[0455] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 12.57 (s, 1H), 7.62 - 7.60 (m, 2H), 7.45 - 7.41 (m, 3H). No exchangeable -NH 2 protons were observed.

[0456] Synthetic Route 2: Procedure for Preparing Intermediate 6

[0457] Intermediate 6: 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0458]

[0459] Step 1: At 0 °C, TEA (19 mL, 136.3 mmol) was added 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), and then (2-(chloromethoxy)ethyl)trimethylsilane (11.3 g, 67.8 mmol) was added dropwise. The reaction mixture 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 Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 100 g of silica snap and eluted with a gradient of 0 - 30% EtOAc in hexane to afford 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.

[0460] LCMS (Method B): m / z 436 (M+H) + (ES + ), at 3.25 min, UV active.

[0461] 1 1H 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).

[0462] Step 2: At room temperature, add Pd(PPh 2 CO 3 ) (1.44 g, 1.25 mmol) 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 K 3 ) 4 (8.6 g, 62.5 mmol) in 1,4-dioxane (150 mL) and water (30 mL), and heat the reaction mixture at 120 °C for 5 h. Partition the reaction mixture between EtOAc (300 mL) and water (200 mL). Separate the organic layer, dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure. Purify the crude product using 100 g of silica snap by Biotage-Isolera and elute with a gradient of 0 - 80% EtOAc in hexane to afford 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.

[0463] LCMS (Method B): m / z 462 (M+H) + (ES + ) at 2.55 min, UV active.

[0464] 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 -NH 2 protons were observed.

[0465] Step 3: Dissolve 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) in TFA (40 mL) and stir at room temperature for 30 min. Concentrate the reaction mixture under reduced pressure and dry under high vacuum. Place the resulting residue in EtOH (30 mL) and carefully add aqueous NH 4 OH (50 mL), and heat the reaction mixture at 60 °C for 2 h. Collect the solid by filtration through a Buchner funnel, wash with water (10 mL) and EtOH (10 mol), and dry under vacuum to afford 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.

[0466] LCMS (Method A): m / z 333 (M+H) + (ES + ), at 1.98 min, UV active.

[0467] 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).

[0468] Synthetic Route 3: Procedure for Preparing Intermediate 26

[0469] Intermediate 26: 5-Amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0470]

[0471] Step 1: Hydrazine hydrate (365 g, 7.31 mol) was added to a stirred suspension of 4,6-dichloropyrimidin-2-amine (400 g, 2.43 mol) in EtOH (5 L), and the mixture was heated to 90 °C for 15 h. The reaction mass was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (1 L) and 10% sodium bicarbonate solution (1 L). The solid obtained was collected by filtration through a Buchner funnel, rinsed with diethyl ether (200 mL) and dried under vacuum to afford 4-chloro-6-hydrazinylpyrimidin-2-amine (300 g, 77%) as an off-white solid.

[0472] LCMS (Method C): m / z 160 (M+H) + (ES + ), at 0.37 min, UV active.

[0473] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 8.10 (s, 1H), 6.36 (s, 2H), 5.97 (s,1H), 4.26 (s, 2H).

[0474] Step 2: Pd(PPh 2 CO 3 (107 g, 0.093 mol) was added 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 K 2 O (774 g, 5.61 mol) in 1,4-dioxane (6 L) and H 3 ) 4 in 1,4-dioxane (6 L) and H 2 O (1 L), and the resulting reaction mixture was heated to 110 °C for 15 h. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The resulting residue was vigorously stirred with H

[0475] LCMS (Method C): m / z 220 (M+H) + (ES + ), at 0.76 min, UV active.

[0476] 11H 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).

[0477] Step 3: Under N 2 , phosgene (538 g, 1.82 mol) was added portionwise to a solution of 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 g, 0.91 mol) in dry THF (3.0 L) cooled to -30 °C, and the mixture was stirred at the same temperature for 1 h. The reaction mixture was carefully quenched into ice-cold water (10 L) with vigorous stirring. After the effervescence ceased, the reaction mixture was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, washed with water (1 L), and dried under vacuum to afford 5-amino-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 g, 67%) as a yellow solid.

[0478] LCMS (Method C): m / z 246 (M+H) + (ES + ), at 1.77 min, UV active.

[0479] 1 1H 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).

[0480] Step 4: The reaction was carried out in 2 x 75 g batches. Under N 2 atmosphere, CaCO 3 (66 g, 0.66 mol) was added to 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 DCM / MeOH 1:1 (2 L), followed by the addition of (CH 3 ) 3 PhN + Br 3 -(250 g, 0.66 mol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with small portions of MeOH / DCM (1:1), and dried under vacuum to afford the 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.

[0481] LCMS (Method C): m / z 323 (M+H) + (ES + ), at 1.87 min, UV active.

[0482] 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).

[0483] Synthetic Route 4: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Tosylation and Substitution Reaction

[0484] 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

[0485]

[0486] 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 afford the tosylated intermediate. The tosylated intermediate was placed 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 K 2 CO 3(4.47 g, 32.3 mmol), and the reaction mixture was heated to 80 °C and maintained 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 25 g of silica snap and eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford 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.

[0487] LCMS (Method C): m / z 419 (M+H) + (ES + ), at 2.20 min, UV active.

[0488] 1 1H 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 -NH 2 protons were observed.

[0489] Synthetic Route 5: Typical Procedure for Preparing Pyridyl Borate

[0490] Intermediate 32: 2-Methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine

[0491]

[0492] To a degassed solution of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (108 mg, 0.16 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridine (54 mg, 0.20 mmol) in dry hexane was added bis(pinacolato)diboron (1.2 g, 4.87 mmol) and the mixture was heated at 60 °C for 10 min. 2-Methoxy-6-methylpyridine (500 mg, 0.405 mmol) was added to the reaction mixture and the mixture was heated at 60 °C for 14 h. The reaction mixture was concentrated under reduced pressure to afford the 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.

[0493] Synthetic Route 6: Typical Procedure for Preparing Triazolopyrimidine Analogs via Suzuki Coupling Using SEM-Protection

[0494] Intermediate 33: Methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate

[0495]

[0496] Step 1: Prepared in a similar manner to Synthesis Route a (see below), Step 2, using Intermediate 34, to afford 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-methylpyridinecarboxylate (6 g, 64%) as a yellow solid.

[0497] LCMS (Method A): m / z 507 (M+H) + (ES + ) at 2.46 min, UV active.

[0498] 1 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 -NH 2 protons were observed.

[0499] 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-methylpyridinecarboxylate (1 g, 1.9 mmol) in TFA (15 mL) was stirred at room temperature for 30 minutes. After monitoring the depletion of the starting material by TLC, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (20 mL), DIPEA (1.7 mL, 9.8 mmol) was added, and the resulting reaction mixture was heated to 60 °C for 4 h. The precipitate was collected by filtration, washed with MeOH (2 x 2 mL) and dried under vacuum to afford intermediate 33, methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (0.55 g, 67%) as a yellow solid.

[0500] LCMS (Method A): m / z 377 (M+H) + (ES + ), at 1.65 min, UV active.

[0501] 1 1H 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). No exchangeable -NH 2 proton was observed.

[0502] Synthetic Route 7: Typical Procedure for Alkylation of Amine

[0503] Intermediate 55: (S)-(1-(2-Methoxyethyl)pyrrolidin-2-yl)methanol

[0504]

[0505] At room temperature to (S)- pyrrolidin-2-ylmethanol (400 mg, 3.96 mmol) and K 2 CO 3A suspension of [[ID=]] (1.09 g, 7.92 mmol) in MeCN (20 mL) was added to 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 H 2 O (50 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated to afford the intermediate 55, (S) -(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol (400 mg, 63%) as a yellow gum.

[0506] 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).

[0507] Synthetic Route 8: Procedure for Preparing Intermediate 71

[0508] 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

[0509]

[0510] 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) at 0 °C was added methanesulfonyl chloride (1 mL, 0.012 mol) dropwise over 10 min. After depletion of the starting material was determined by TLC, the reaction mixture was partitioned between EtOAc (50 mL) and brine solution (50 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. The crude product was triturated with n-hexane (2 x 20 mL), decanted and dried under high vacuum to afford the intermediate 71, 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)methanesulfonate (3.4 g, 70%) as a yellow solid.

[0511] LCMS (Method B): m / z 349 (M+H)+ (ES+), retention time 2.14 min, UV active.

[0512] 1 1H 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 -NH 2 protons were observed.

[0513] The intermediates used in the following examples are listed in Table 1. Compounds were prepared according to the methods of the indicated synthetic pathways (“Routes”). Where no route number or data is shown, commercially available materials were used. LCMS and 1 1H NMR data are shown for purified products (if not purified, shown as “used crude”). In some cases, the intermediate used to prepare another intermediate is shown in parentheses; for example, Intermediate 28 was prepared from Intermediate 26 and Intermediate 29 via Route 4.

[0514] Table 1: Intermediates

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521] Synthetic Routes for Examples 1-1 to 4-1

[0522] Synthetic routes a to ae are described below for preparing the compounds of Examples 1-1 to 4-1. The methods of synthetic routes a to ae are examples of techniques for preparing other compounds, as detailed in Table 2 below.

[0523] Synthetic Route a

[0524] 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

[0525]

[0526] Step 1: At room temperature, di-tert-butyl azodicarboxylate (0.33 g, 1.47 mmol) was added 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), and the reaction mixture was stirred at room temperature for 10 min. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by Biotage-Isolera using 10 g of silica snap and eluted with a 0-50% gradient of EtOAc in hexane to afford 2-(2-(1H-pyrazol-1-yl)ethyl)-5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 51%) as an off-white solid.

[0527] LCMS (Method B): m / z 400 (M+H) + (ES + )), at 3.52 min, UV-active.

[0528] 1 1H 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 -NH 2 protons were observed.

[0529] 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 K 2 CO 3 (137 mg, 0.99 mmol) in 1,4-dioxane / H 2 O (4 mL / 1mL) was degassed for a few minutes, Pd(PPh 3 ) 4 (29 mg, 0.02 mmol) was added, the vessel was sealed and heated to 120 °C for 5 h. After cooling to room temperature, the reaction mixture was partitioned between H 2 O (5 mL) and EtOAc (10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with a gradient of 0 - 100% EtOAc in hexane to afford Example 1-1, 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(2-pyrazol-1-yl-ethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (35 mg, 16%) as a yellow solid.

[0530] LCMS (Method A): m / z 427 (M+H) + (ES+), at 2.46 min, UV active

[0531] 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 -NH 2 proton

[0532] Synthetic Route b

[0533] Examples 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

[0534]

[0535] Step 1: At room temperature, 3-bromopropionitrile (196 mg, 0.147 mmol) was added 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 K 2 CO 3 (406 mg, 2.9 mmol) in MeCN (3 mL). The reaction mixture was heated at 75 °C for 12 h. The reaction mass was cooled to room temperature and partitioned between EtOAc (10 mL) and H 2 O (10 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure and purified by Biotage-Isolera using 10 g silica snap, eluting with a gradient of 50 - 70% EtOAc in hexane to afford 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propionitrile (90 mg, 25%) as a white solid.

[0536] LCMS (Method B): m / z 359 (M+H) + (ES + ), at 2.44 min, UV active.

[0537] 1 1H 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)

[0538] Step 2: Prepared in a similar manner to Step 2 of Route a.

[0539] 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), NaN 3 (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 fractions collected were concentrated under reduced pressure and the resulting residue was passed through an SCX cartridge and eluted with 2N methanolic ammonia to afford 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.

[0540] Synthetic Route c

[0541] Examples 1-5 and 1-6: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-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-pyridinyl)-2-[2-(2-methyltetrazol-5-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0542]

[0543] 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 K 2 CO 3 (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 preparative HPLC method (Method A). The first eluted peak was concentrated under reduced pressure and in 15% MeOH in DCM (10 mL) and 10% NaHCO3 Partitioned between the solution (10 mL). The organic layer was separated, passed through anhydrous Na 2 SO 4 dried, concentrated under reduced pressure and dried under high vacuum to afford 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 of the title compound are shown in Table 3. The structure of the compound was confirmed by NOE studies. The peak eluted second from the HPLC was concentrated under reduced pressure and partitioned between EtOAc (10 mL) and 10% NaHCO 3 solution (10 mL). The organic layer was separated, passed through anhydrous Na 2 SO 4 dried, concentrated under reduced pressure and dried under high vacuum to afford 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 of the title compound are shown in Table 2.

[0544] Synthetic Route d: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Mitsunobu Reaction

[0545] 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

[0546]

[0547] 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 mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Method E) to afford 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.

[0548] Synthetic Route e: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Methanesulfonylation of Alcohol Followed by Alkylation Reaction Procedure

[0549] 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

[0550]

[0551] 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 was added methanesulfonyl chloride (56 mg, 0.45 mmol), 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 Na 2 SO 4 and concentrated under reduced pressure to give the mesylated intermediate. The mesylated intermediate was taken up 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), K 2 CO 3 (125 mg, 0.90 mmol) were added, and the mixture was heated to 80 °C in a sealed bottle for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. Purify the crude product by preparative HPLC (Method A). Concentrate the fractions and dilute with EtOAc (10 mL), wash with 10% sodium bicarbonate solution (10 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4 Dry and concentrate to dryness to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (21 mg, 0.16%). Data for the title compound are shown in Table 2.

[0552] Synthetic Route f: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Tosylation of Alcohol Followed by Alkylation Reaction Procedure

[0553] Examples 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(2H)-one

[0554]

[0555] 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) at 0 °C was added (1-methyl-1H-pyrazol-5-yl)methanol (40.4 mg, 0.36 mmol), and the reaction mixture was stirred at room temperature for 1 h. After monitoring the depletion of the starting materials by TLC, the reaction mixture was partitioned between DCM (20 mL) and water (20 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain the tosylated intermediate. Place the tosylated intermediate in DMSO (10 mL), add 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 K 2 CO 3 (125 mg, 0.90 mmol) and heat to 80 °C in a sealed tube for 16 h. After monitoring the depletion of the starting materials by TLC, the reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. Purify the crude product by preparative HPLC (Method A). Concentrate the fractions under reduced pressure and dilute the resulting residue with EtOAc (10 mL), wash with 10% sodium bicarbonate solution (10 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4 Dry and concentrate to afford 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 as a yellow solid (15 mg, 11%). Data for the title compound are shown in Table 2.

[0556] Synthetic Route g: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Chlorination of Alcohol Followed by Alkylation Reaction

[0557] Examples 1 - 16: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methylpyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0558]

[0559] To a solution of (1-methyl-1H-pyrazol-3-yl)methanol (41 mg, 0.36 mmol) in THF (10 mL) at 0 °C, add SOCl 2 (1 mL) dropwise and stir at 60 °C for 2 h. (Alternatively, toluene can be used as the solvent and the reaction mixture heated to 110 °C). After monitoring the depletion of the starting material by TLC, partition the reaction mixture between EtOAc (20 mL) and 10% sodium bicarbonate solution (10 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain the chloro-intermediate. Place the chloro-intermediate in MeCN / DMSO (20 mL / 1 mL), add 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 K 2 CO 3 (125 mg, 0.90 mmol) and heat in a sealed vial at 80 °C for 16 h. After monitoring the depletion of the starting material by TLC, partition the reaction mixture between EtOAc (20 mL) and water (20 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. Purify the crude product by preparative HPLC (Method A). Concentrate the fractions and dilute the resulting residue with EtOAc (10 mL), then wash with 10% sodium bicarbonate solution (10 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4 Dry and concentrate to afford 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. Data for the title compound are shown in Table 2.

[0560] Synthetic Route h: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Alkylation Reaction

[0561] Examples 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

[0562]

[0563] 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) at room temperature was added K 2 CO 3 (62.3 mg, 0.45 mmol), and the resulting reaction mixture was heated to 80 °C for 1 h. After monitoring the depletion of the starting material by TLC, the reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). Separate the organic layer and dry over anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain the crude product. Purify the crude compound by Biotage-Isolera using 10 g silica gel snap and elute with a gradient of 0-100% EtOAc in petroleum ether to afford Examples 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.

[0564] Synthetic Route i

[0565] Examples 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

[0566]

[0567] At 0 °C, methanesulfonyl chloride (0.07 mL, 0.903 mmol) was added 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), 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 placed 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 (200 mg, 0.602 mmol), K 2 CO 3 (249 mg, 1.807 mmol) were added, and the resulting reaction mixture was heated at 80 °C for 2 h in a sealed bottle. The reaction mixture was quenched with ice - cold water. The resulting solid was filtered, washed with EtOH and dried under vacuum to afford 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.

[0568] Synthetic Route j

[0569] Examples 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

[0570]

[0571] Step 1: To 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 K2 CO 3 A solution of CO (84 mg, 0.60 mmol) in MeCN (8 mL) and DMSO (2 mL) was added dropwise to 2-bromoacetonitrile (36 mg, 0.30 mmol) and heated in a sealed tube at 80 °C for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 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.

[0572] LCMS (Method A): m / z 372 (M+H) + (ES + ), UV active at 2.15 min.

[0573] 1 1H 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 -NH 2 protons were observed.

[0574] Step 2: 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), NaN 3 (37 mg, 0.56 mmol) and NH 4 Cl (30.2 mg, 0.56 mmol) in DMF (15 mL) were heated in a sealed tube at 120 °C for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated. 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 Na 2 SO 4Dry and concentrate to dryness to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-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.

[0575] Synthetic Route k

[0576] Examples 1-27: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1,3,4-oxadiazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0577]

[0578] 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) was added K 2 CO 3 (249 mg, 1.807 mmol) and ethyl bromoacetate (73 mg, 0.662 mmol), 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 afford 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.

[0579] LCMS (Method A): m / z 419 (M+H) + (ES + ) at 2.00 min, UV active.

[0580] 1 1H 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 = 14.1 Hz, 3H).

[0581] 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 x 2 mL), decanted and dried in vacuo to afford 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, 51%) as a pale green solid, which was used without further purification.

[0582] LCMS (Method A): m / z 405 (M+H) + (ES + ), at 1.67 min, UV active.

[0583] 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 a catalytic amount of AcOH, and the resulting reaction mixture was heated to 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 Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by preparative TLC (GF254 silica gel-coated glass plate (20x20 cm); mobile phase: 2% MeOH in DCM) to afford 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.

[0584] Synthetic Route l

[0585] 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

[0586]

[0587] Step 1: To a stirred 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 K 2 CO 3 (103 mg), followed by the addition of 1 - bromobut - 2 - yne (60 mg, 0.45 mmol). The reaction mixture was heated to 50 °C for 1 h, then diluted with ice - water, and the precipitated compound was filtered and dried to afford 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.

[0588] LCMS (Method C): m / z 385 (M + H) + (ES + ), at 1.67 min, UV - active.

[0589] 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 - NH 2 protons were observed.

[0590] 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), NaN 3 (20 mg) and NH 4 Cl (25 mg) in DMF (75 mL) was heated to 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 Na 2 SO4 Dry and concentrate under vacuum. Purify the crude product by preparative HPLC (Method - A). Concentrate the fractions under reduced pressure and partition the resulting residue between EtOAc (10 mL) and 10% NaHCO 3 solution (10 mL). Separate the organic layer, dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure to afford (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) as a yellow solid (14 mg, 25%). Data for the title compound are shown in Table 2.

[0591] Synthetic Route m

[0592] Examples 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

[0593]

[0594] Step 1: To a stirred 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 K 2 CO 3 (311 mg, 2.25 mmol) in DMSO (8 mL) at 0 °C, add 3 - bromoprop - 1 - yne (89.5 mg, 0.75 mmol) and heat the reaction mixture to 50 °C for 1 h. Dilute the reaction mixture with ice - cold water and collect the precipitated solid by filtration, wash with water (10 mL) and dry under vacuum to afford 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 as a yellow solid (200 mg, 74%).

[0595] LCMS (Method C): m / z 371 (M + H) + (ES + )), at 1.08 min, UV - active.

[0596] 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 -NH 2 proton was observed.

[0597] 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), NaN 3 (70 mg, 1.09 mmol) and NH 4 Cl (85.04 mg, 1.59 mmol) in DMF (30 mL) was heated to 120 °C and maintained for 48 h. The reaction mixture was diluted with ice - cold water (10 mL) and extracted with EtOAc (15 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under vacuum. The crude product was purified using 230 - 400 silica gel mesh by Biotage - Isolera and eluted with a gradient of 0 - 100% EtOAc in hexane to afford (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.

[0598] LCMS (Method D): m / z 414 (M + H) + (ES + ), at 2.39 min, UV - active.

[0599] Step 3: At 0 °C, to 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 K 2 CO 3A stirred solution of 2 SO 4 (49 mg, 0.36 mmol) in DMF (5 mL) was treated with MeI (0.08 mL, 0.75 mmol) 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 filtered to afford 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% aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na

[0600] Synthetic Route n: Typical Procedure for Preparing Pyridine-N-Oxide

[0601] Examples 1 - 34: 5 - Amino - 8 - (2,6 - dimethyl - 1 - oxidopyridin - 1 - ium - 4 - yl) - 2 - [(5 - methyloxazol - 4 - yl)methyl] - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0602]

[0603] 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 was added portionwise m -CPBA (46 mg, 0.26 mmol) 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 Na 2 SO 4 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% aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4Dried and concentrated to afford 4-(5-amino-2-((5-methyl-oxazol-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 as a yellow solid (7.3 mg, 8%). Data for the title compound are shown in Table 2.

[0604] Synthetic Route o: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Chlorination and Alkylation of Alcohol Followed by Ester Reduction

[0605] Examples 1 - 39: 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0606]

[0607] Step 1: Thionyl chloride (0.05 mL, 0.66 mmol) was added dropwise to a solution of (5-methyl-oxazol-4-yl)methanol (36 mg, 0.32 mmol) in CH 3 Cl (5 mL) at 0 °C, and the resulting reaction mixture was heated to 50 °C for 60 min. After monitoring the depletion of the starting material by TLC, the reaction mixture was concentrated under reduced pressure to afford the chlorinated intermediate. The chlorinated intermediate was taken up in DMSO (2 mL) and 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylic acid methyl ester (100 mg, 0.26 mmol) and K 2 CO 3 (110 mg, 0.79 mmol) were added, and the resulting reaction mixture was heated to 80 °C in a sealed tube for 2 h. After monitoring the depletion of the starting material 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 10 g silica snap and eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford 4-(5-amino-2-((5-methyl-oxazol-4-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylic acid methyl ester as a yellow solid (80 mg, 66%).

[0608] LCMS (Method C): m / z 472 (M+H) + (ES +), at 1.69 min, ultraviolet active.

[0609] 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 -NH 2 protons were observed.

[0610] Step 2: At 0 °C, lithium triethylborohydride (1 M in THF, 0.33 mL, 0.33 mmol) was added dropwise to a solution of methyl 4-(5-amino-2-((5-methyl-oxazol-4-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (80 mg, 0.16 mmol) in THF (5 mL), and the reaction mixture was stirred at room temperature for 20 min. After monitoring the depletion of the starting material by TLC, the reaction mixture was partitioned between EtOAc (5 mL) and H 2 O (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 Na 2 SO 4 dried and concentrated to afford 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-2-((5-methyl-oxazol-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.

[0611] Synthetic Route p: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Tosylation and Alkylation of Alcohol Followed by Ester Reduction Procedure

[0612] Examples 1 - 40: 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0613]

[0614] Step 1: At 0 °C, oxazol-2-ylmethanol (32 mg, 0.31 mmol) dissolved in DCM (0.5 mL) was added 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), and the reaction mixture was stirred at room temperature for 30 min. After monitoring the depletion of the starting materials 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 afford the tosylated intermediate. The tosylated intermediate was placed 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-methylpyridinecarboxylate (100 mg, 0.26 mmol) and K 2 CO 3 (110 mg, 0.29 mmol) in DMSO (2 mL), and the resulting reaction mixture was heated in a sealed bottle to 50 °C for 6 h. After monitoring the depletion of the starting materials 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 using 10 g of silica gel snap via Biotage-Isolera and eluted with a 0 - 100% gradient of EtOAc in petroleum ether to afford 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-methylpyridinecarboxylate (70 mg, 57%) as a yellow solid.

[0615] LCMS (Method C): m / z 458 (M+H) + (ES + ), at 1.60 min, UV active.

[0616] 1 1H 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 -NH 2 protons were observed.

[0617] Step 2: Conducted in a similar manner to Route o, Step 2, to afford 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-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.

[0618] Synthetic Route q: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Tosylation and Substitution of Alcohol Followed by Suzuki Coupling and Ester Reduction Procedure

[0619] Example 2-29: 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0620]

[0621] 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 was added R )-(tetrahydrofuran-2-yl)methanol (199.9 mg, 1.96 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (20 mL) and H 2 O (20 mL). The organic layer was separated and concentrated under reduced pressure to afford the tosylated intermediate. The tosylated intermediate was placed 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 K 2 CO 3 (676 mg, 4.09 mmol) were added, and then the mixture was heated to 80 °C for 4 h. The reaction mixture was partitioned between EtOAc (20 mL) and H 2 O (20 mL). The organic layer was separated and concentrated under reduced pressure to afford ([[]] R 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.

[0622] LCMS (Method A): m / z 390 (M+H) + (ES + ), UV active at 2.38 min.

[0623] 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 -NH 2 protons were observed.

[0624] 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 K 2 CO 3 (212 mg, 1.53 mmol) in 1,4-dioxane (10 mL) and H 2 O (5 mL) was added Pd(PPh 3 ) 4 (59 mg, 0.051 mmol), and the mixture was heated to 110 °C for 5 h. The reaction mixture was partitioned between H 2 O (20 mL) and EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford 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%).

[0625] LCMS (Method B): m / z 461 (M+H) + (ES + ), UV active at 2.15 min.

[0626] 1 H 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).

[0627] Step 3; Lithium triethylborohydride (34.5 mg, 0.32 mmol) was added portionwise 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 and stirred for 1 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and H 2 O (10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 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 Na 2 SO 4 and concentrated to dryness to afford 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.

[0628] Example 2-29 was further purified by SFC method A. During the purification, the enantiomers were separated. 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 speculated to be formed from the enantiomers of a small amount of intermediate 62 present in the commercial sample during the synthesis of Example 2-29. Using SFC method A, the first eluted peak was Example 2-28, (9.73 min), and the second eluted peak was Example 2-29 (10.32 min).

[0629] Synthetic Route r: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Alkylation Followed by Suzuki and Ester Reduction

[0630] 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

[0631]

[0632] Step 1: Using intermediate 36, proceed in a similar manner to route h to provide 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.

[0633] LCMS (method C): m / z 388 (M+H) + (ES + ), at 1.82 min, UV active.

[0634] 1 1H 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 -NH 2 protons were observed.

[0635] Step 2: Using intermediate 34, proceed in a similar manner to step 2 of route a to provide 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-methylpyridinecarboxylate as a yellow solid.

[0636] LCMS (Method C): m / z 458 (M+H) + (ES + ), at 1.58 min, UV active.

[0637] 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 -NH 2 protons were observed.

[0638] Step 3: Conducted in a similar manner to that of Route o, Step 2, to afford 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.

[0639] Synthetic Route s: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Mitsunobu Reaction Followed by Ester Reduction

[0640] Examples 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

[0641]

[0642] Step 1: Prepared in a similar manner to that of Route d, using Intermediate 14 and DCM as the solvent, then purified by Biotage - Isolera using 10 g silica snap and eluted with a 0 - 100% gradient of EtOAc in petroleum ether to afford 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.

[0643] LCMS (Method C): m / z 472 (M+H) + (ES + ), at 1.82 min, UV active.

[0644] 11H 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 -NH 2 proton was observed.

[0645] Step 2: Conducted in a similar manner to Route o, Step 2 to afford 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.

[0646] Synthetic Route t: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Alkylation Reaction Followed by Ester Reduction

[0647] Examples 1 - 46: 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0648]

[0649] Step 1: Prepared in a similar manner to Route h to afford 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.

[0650] LCMS (Method B): m / z 473 (M+H) + (ES + ) at 1.91 min, UV active.

[0651] 1 1H 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 -NH 2 proton was observed.

[0652] Step 2: Carry out in a similar manner to that of Route o, Step 2 to afford 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.

[0653] Synthetic Route u

[0654] Examples 1 - 53: 5-Amino-2-[(2,5-dimethyl-oxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0655]

[0656] Step 1: Using Intermediate 34, prepare in a similar manner to that of Route a, Step 2 to afford methyl 4-(5-amino-2-((2,5-dimethyl-oxazol-4-yl)methyl)-7-(4-fluorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (1.6 g, 55%) as a yellow solid.

[0657] LCMS (Method C): m / z 504 (M+H) + (ES + )), at 1.76 min, UV active.

[0658] 1 1H 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 -NH 2 protons were observed.

[0659] Step 2: Carry out in a similar manner to that of Route o, Step 2 to afford 5-amino-2-[(2,5-dimethyl-oxazol-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.

[0660] Synthetic Route v: Typical Procedure for Preparing Hydroxymethyl Pyridine Analogs via Chlorination and Substitution of Alcohol Followed by Suzuki Coupling and Ester Reduction Procedure

[0661] Examples 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

[0662]

[0663] Step 1: To a solution of (1 - methyl - 1H - imidazol - 2 - yl)methanol (220 mg, 1.960 mmol) in CHCl 3 was added SOCl 2 (291 mg, 2.45 mmol) at 0 °C, and the resulting reaction mixture was stirred at 50 °C for 2 h. After monitoring the depletion of the starting material by TLC, the reaction mixture was concentrated under reduced pressure to afford the chlorinated intermediate. The chlorinated intermediate was taken up 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 K 2 CO 3 (676 mg, 4.901 mmol) were added, and the reaction mixture was heated to 60 °C for 2 h. After monitoring the depletion of the starting material by TLC, the reaction mixture was poured into ice water to obtain a solid, and the resulting solid was filtered through a Buchner funnel and dried in vacuo to afford 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 as a yellow solid (600 mg, 87%).

[0664] LCMS (Method C): m / z 400 (M + H) + (ES + ), at 2.27 min, UV - active.

[0665] 1 1H 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 - NH 2 protons were observed.

[0666] (Alternatively, 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 product was purified by flash column chromatography using silica gel mesh (230 - 400) and eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford the desired product)

[0667] Step 2: Prepared in a similar manner to that of Step 2 of Route a using Intermediate 44 to afford 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.

[0668] LCMS (Method C): m / z 491 (M+H) + (ES + ), at 1.29 min, UV active.

[0669] Step 3: Conducted in a similar manner to that of Step 2 of Route o to afford 5-amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-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.

[0670] Synthetic Route w: Typical Procedure for Boc-Deprotection of Amine Analogs

[0671] Example 2 - 2: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0672]

[0673] 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 20% TFA / DCM (5 mL) was stirred at room temperature for 15 h. After confirmation of the exhaustion of the starting material by TLC, the reaction mass was concentrated under reduced pressure. The crude material was dissolved in MeOH (2 mL) and passed through a DSC-SCX column (6 mL), washed with water (5 mL). The compound was eluted with 2M ammonia in MeOH (10 mL), concentrated and lyophilized to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-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.

[0674] Synthetic Route x: Typical Procedure for Reductive Amination of Amine Using Formaldehyde

[0675] Example 2-6: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0676]

[0677] To 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 36% formaldehyde solution (0.02 mL, 0.23 mmol) and sodium triacetoxyborohydride (133 mg, 0.63 mmol) and stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-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.

[0678] Synthetic Route y: Typical Procedure for Preparing Difluoropyrrolidine Analogs

[0679] Example 2-11: 5-Amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0680]

[0681] Step 1: At 0 °C, Dess-Martin periodinane (7 g, 16.44 mmol) was added to a suspension of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (2 g, 8.22 mmol) in DCM (30 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc (100 mL) and saturated NaHCO 3 solution (10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by Biotage-Isolera using 25 g of silica snap, and eluted with a gradient of 0 - 20% EtOAc in hexane to afford (S)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.6 g, 74%) as a colorless gum.

[0682] 1 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).

[0683] Step 2: At -78 °C, diethylaminosulfur trifluoride (1.98 g, 12.32 mmol) was added dropwise to a suspension of (S)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.5 g,6.16 mmol) in DCM, and the mixture was stirred at room temperature for 15 h. The reaction mixture was quenched with saturated NaHCO 3 solution (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. The crude product was purified by Biotage-Isolera using 25 g of silica snap and eluted with a 0 - 10% EtOAc in hexane gradient to afford (S)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester as a colorless gum (1.4 g, 94%).

[0684] 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).

[0685] Step 3: To a solution of (S)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.1 g,4.15 mmol) in THF (20 mL) at 0 °C was added 2M LiBH 4 solution (3.1 mL, 6.22 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched by dropwise addition of saturated NH 4 Cl solution (25 mL) and extracted with EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford (S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester as an off-white gum (500 mg, 50%).

[0686] 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 proton was observed.

[0687] Step 4: Prepared in a similar manner to route e, using 25 g of silica snap, purified by Biotage-Isolera, and eluted with a 0 - 100% EtOAc in hexane gradient to afford (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-carboxylic acid tert-butyl ester (150 mg, 18%) as a yellow solid.

[0688] LCMS (Method A): m / z 552 (M+H) + (ES + ), at 3.68 min, UV active.

[0689] 1 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).

[0690] Step 5: To a solution of (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-carboxylic acid tert-butyl ester (220 mg, 0.39 mmol) in 1,4-dioxane (3 mL) at room temperature was added 4N HCl in 1,4-dioxane (3 mL), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (10 mL) and saturated NaHCO 3 solution (10 mL). The organic layer was separated and dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure to afford 5-amino-2-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (100 mg, 81%). Data for the title compound are shown in Table 2.

[0691] Synthetic Route z: Typical Procedure for Preparing Alkylated Triazolopyrimidinone Using Boc-Protection Strategy

[0692] Example 2-15: 5-Amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0693]

[0694] Dissolve 2-amino-1-(oxolan-3-yl)ethan-1-ol (131 mg, 1 mmol) in MeOH (2 mL), cool the solution to 0 °C and add Boc 2 O (229 mg; 1.05 mmol) in one portion. Stir the reaction mixture at room temperature for 2 - 3 h. Concentrate the mixture under reduced pressure and crystallize the residue from a mixture of i-Pr / hexanes to afford 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), the Boc-protected amine (28 mg, 0.22 mmol) and PPh3 (68 mg, 0.26 mmol) in THF (3 mL) add di-tert-butyl azodicarboxylate (51 mg, 0.22 mmol). Stir the reaction mixture at room temperature for 16 - 18 h. Concentrate the mixture under reduced pressure, dissolve the residue in DCM (3 mL) and add TFA (0.5 mL). Sonicate the reaction mixture at room temperature for 2 h, then concentrate under reduced pressure and purify the crude product by preparative HPLC-MS (C18 column 100x19mm, H 2 O / MeOH or MeCN) to afford 5-amino-2-(2-amino-1-tetrahydrofuran-3-yl-ethyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (36 mg, 41%). Data for the title compound are shown in Table 2.

[0695] Synthetic Route aa: Typical Procedure for Preparing Fluoropyrrolidine Analogs

[0696] 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

[0697]

[0698] Step 1: Diethylaminosulfur trifluoride (0.53 mL, 4.076 mmol) was added dropwise to a suspension of (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (0.5 g, 2.038 mmol) in DCM at -78 °C and stirred at room temperature for 15 h. The reaction mixture was quenched with saturated NaHCO 3 solution (10 mL) and extracted with DCM (20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with a gradient of 0 - 10% EtOAc in hexane to afford (2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester as a colorless gum (0.23 g, 45%).

[0699] 1 1H NMR: (400 MHz, C D Cl 3 ) 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).

[0700] Step 2: Prepared in a similar manner to step -3 of route y to afford (2R, 4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless gum (180 mg, 88%).

[0701] 1 1H NMR: (400 MHz, C D Cl 3) 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).

[0702] Step 3: Prepared in a similar manner to route d, purified by Biotage-Isolera using 10 g of silica snap, and eluted with a 0 - 50% EtOAc in hexane gradient to afford 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.

[0703] LCMS (Method A): m / z 533 (M+H) + (ES + ), at 3.40 min, UV active.

[0704] 1 1H 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 -NH 2 protons were observed.

[0705] Step 4: Prepared in a similar manner to step 5 of route y to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-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.

[0706] Synthetic Route ab: Typical Procedure for Preparing Alkylated Triazolopyrimidinone Using MOM-Protection Strategy

[0707] 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

[0708]

[0709] Step 1: At room temperature, diisopropylethylamine (1.3 g, 1.0 mmol) was added to a suspension of (2S,4S) - 4 - hydroxypyrrolidine - 1,2 - dicarboxylic acid 1 - (tert - butyl) 2 - methyl ester (0.5 g, 2.0 mmol) in DMF (50 mL), and the mixture was cooled to 0 °C. MOM chloride (0.66 g, 8.15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched by adding water (20 mL), and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using 10 g of silica snap on a Biotage - Isolera with a gradient elution of 0 - 50% EtOAc in hexane to afford (2S,4S) - 4 - (methoxymethoxy)pyrrolidine - 1,2 - dicarboxylic acid 1 - (tert - butyl) 2 - methyl ester as a yellow liquid (0.4 g, 68%).

[0710] 1 1H 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).

[0711] Step 2: Prepared in a similar manner to Step - 3 of Route y, purified using 10 g of silica snap on a Biotage - Isolera with a gradient elution of 0 - 50% EtOAc in hexane to afford (2S,4S) - 2 - (hydroxymethyl) - 4 - (methoxymethoxy)pyrrolidine - 1 - carboxylic acid tert - butyl ester as a colorless liquid (0.3 g, 83%).

[0712] 1 1H 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).

[0713] Step 3: Prepared in a similar manner to route d, purified by Biotage - Isolera using 10 g silica snap, and eluted with a 0 - 100% EtOAc in hexane gradient to afford 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.

[0714] LCMS (Method B): m / z 576 (M + H) + (ES + ), at 2.29 min, UV - active.

[0715] 1 1H 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 - NH 2 protons were observed.

[0716] Step 4: Prepared in a similar manner to route y, step - 5 to afford 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.

[0717] Synthetic Route ac

[0718] 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

[0719]

[0720] Step 1: Prepared in a similar manner to that of Route a, Step 2 to afford 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.

[0721] LCMS (Method C): m / z 467 (M + H) + (ES + ), at 2.60 min, UV - active.

[0722] 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 in a sealed tube was added NaOMe (1.3 mL, 6.0 mmol) in 25% MeOH, and the resulting reaction mixture was heated to 90 °C for 16 h. After monitoring the depletion of the starting material by TLC, the reaction mixture was partitioned between H 2 O (25 mL) and EtOAc (50 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated to give the crude material. The crude was purified by Biotage - Isolera using 25 g of silica gel snap and eluted with a gradient of 0 - 80% EtOAc in petroleum ether to afford 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.

[0723] LCMS (Method C): m / z 479 (M + H) + (ES + ), at 2.86 min, UV - active.

[0724] 1 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 -NH 2 protons were observed.

[0725] Step 3: Prepared in a similar manner to Step 2 of Route 6 to afford 5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (250 mg, 57%).

[0726] LCMS (Method C): m / z 349 (M+H) + (ES + ), at 1.51 min, UV active.

[0727] 1 1H 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 -NH 2 protons were observed.

[0728] Step 4: Prepared using Intermediate 62 in a similar manner to Route f to afford 5-amino-8-(2-methoxy-6-methyl-4-pyridinyl)-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as an off-white solid (7 mg, 5%). Data for the title compound are shown in Table 2.

[0729] Synthetic Route ad: Typical Procedure for Preparing Alkylated Triazolopyrimidinone Amine Analogs via Mesylate Substitution

[0730] Example 3-1: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0731]

[0732] To a suspension 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)ethanesulfonate 1 (73 mg, 0.16 mmol) in MeCN (2 mL) was added K 2 CO 3 (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 H 2 O (5 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (method E) to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-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.

[0733] Synthetic Route ae

[0734] Example 4-1: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0735]

[0736] Step 1: Using Intermediate 77, prepared in a similar manner to Route f, purified by Biotage-Isolera using 25 g silica snap, and eluted with a 0-80% gradient of EtOAc in petroleum ether to afford 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.

[0737] LCMS (method C): m / z 386 (M+H) + (ES + ), at 0.98 min, UV active.

[0738] 1 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 -NH 2 protons were observed.

[0739] 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 to 100 °C for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and H 2 2O (2 x 20 mL). The organic layer was separated, dried over anhydrous Na 2 2SO 4 4 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 Na 2 2SO 4 4 and concentrated to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidinyl)-[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.

[0740] Table 2: Examples 1-1 to 4-1

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782] Example 5: Adenosine Receptor Binding Assay

[0783] Inhibition binding assays were performed using 0.2 μg of membranes prepared from HEK293 cells infected with BacMam human adenosine A 2A receptor, or 1.4 μg of membranes prepared from HEK293 cells infected with BacMam human adenosine A1 receptor. The membranes were incubated at 25 °C for 1 h in different concentrations of the test compound and 1 nM 3 [H]ZM241385 (HEK293-hA 2A ) or 3 [H]DPCPX (CHO-hA 1 ) in the presence of 50 mM Tris-HCl (HEK293-hA 2A ; pH 7.4) or 50 mM Tris-HCl, 100 mM NaCl, 10 mM MgCl2 (CHO-hA 1 ; pH 7.4). The assays were then terminated as follows: rapid filtration onto a GF / B Unifilter plate using a TomTec cell harvester, followed by 5 x 0.5 ml washes with ddH2O. Nonspecific binding was defined in the presence of 1 μM CGS15943 (HEK293-hA 2A ) or 1 μM DPCPX (CHO-hA 1 ). Bound radioactivity was determined by liquid scintillation counting, and inhibition curves were analyzed using a four-parameter logistic equation. Using the KD value derived from saturation binding studies, the IC 50 values were converted to Ki values using the Cheng-Prusoff equation. The results are summarized in Table 3.

[0784] Table 3: Adenosine Receptor Binding

[0785]

[0786]

[0787]

[0788] Example 6: CB-1 Receptor Binding and Antagonism

[0789] Receptor Binding : Evaluation of the Affinity of Compounds for the Agonist Site of the Human CB-1 Cannabinoid Receptor in Transfected CHO Cells Determined in a Radioligand Binding Assay: Membrane homogenates (20 µg protein) were incubated with 0.5 nM 3 [3H]CP 55940 in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2.5 mM EDTA, and 0.3% BSA for 120 min at 37 °C in the absence or presence of the test compound. Nonspecific binding was determined in the presence of 10 µM WIN 55212-2.

[0790] After incubation, the samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) pre-soaked with 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). The filters were dried and then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).

[0791] The standard reference compound was CP 55940, which was tested at multiple concentrations in each experiment to obtain a competition curve from which its IC 50 .

[0792] Receptor Antagonism : Evaluation of the Antagonist Activity of Compounds for the Human CB1 Receptor Expressed in Transfected CHO Cells, Determined by Measuring Their Effect on Agonist-Induced cAMP Modulation Using the HTRF Assay Method.

[0793] Cells were suspended in HBSS buffer (Invitrogen) supplemented with 20 mM HEPES (pH 7.4), and then at 5.10 3The density distribution of cells per well was plated in a microtiter plate and pre-incubated at room temperature for 5 min in the presence of any of the following: HBSS (stimulated control), at 3 µM (basal control) or various concentrations (IC 50 determined) of the reference antagonist AM281, or the test compound.

[0794] Thereafter, the reference agonist CP 55940 and the adenylate cyclase activator NKH 477 were added at final concentrations of 3 nM and 3 µM, respectively.

[0795] For basal control measurements, CP 55940 was omitted from the wells containing 3 µM AM 281.

[0796] After incubation at 37 °C for 20 min, the cells were lysed and a fluorescent acceptor (D2-labeled cAMP) and a fluorescent donor (anti-cAMP antibody labeled with an europium cryptate) were added.

[0797] After 60 min at room temperature, fluorescence transfer was measured using a microplate reader (Rubystar, BMG) at λ ex = 337 nm and λ em = 620 and 665 nm. The cAMP concentration was determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio).

[0798] The results were expressed as the percentage of inhibition of the control response to 3 nM CP 55940.

[0799] The standard reference antagonist was AM 281, which was tested at multiple concentrations in each experiment to generate a concentration-response curve from which its IC 50 value was calculated.

[0800] In Table 4, the blank entries for K i indicate that the binding observed was too weak to measure the K i value.

[0801] Table 4: CB1 Receptor Binding and Functional Assays

[0802]

[0803] Other embodiments are within the scope of the following claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, selected from: 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2-pyrazol-1-ylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-7-phenyl-2-[1-(2-thienyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-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-pyridinyl)-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-pyridinyl)-2-(isoxazol-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-2-(1H-imidazol-5-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1H-imidazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(1H-pyrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2H-tetrazol-5-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-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-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-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-methylpyridin-4-yl)-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 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-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-(oxazol-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-(oxazol-4-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 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-one; 5-Amino-2-[(3,5-dimethyl-1H-imidazol-4-yl)methyl]-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-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-methylpyridin-4-yl]-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-pyridinyl]-2-[(1-methyl-1H-imidazol-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-pyridinyl]-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-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(2,5-dimethyl-1,3-oxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-methyl-1,3-oxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(1-methyl-1H-imidazol-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-pyridinyl]-2-[(5-methyl-1,3-oxazol-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-pyridinyl]-7-(4-fluorophenyl)-2-[(1-methyl-1H-imidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-2-[(1-methylimidazol-2-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-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-pyridinyl]-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-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]pyrrolidine-1-carboxylate; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-pyrrolidin-3-yl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-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-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyrrolidine-1-carboxylate; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(pyrrolidin-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(1-methylpyrrolidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-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-dimethylpyridin-4-yl)-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-dimethylpyridin-4-yl)-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-dimethylpyridin-4-yl)-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-dimethylpyridin-4-yl)-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-dimethylpyridin-4-yl)-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-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-methyloxazol-4-yl)methyl]-7-(1-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from: 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-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-pyridinyl]-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-pyridinyl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

4. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by an adenosine receptor.

5. The use according to claim 4, wherein the disease or disorder mediated by an adenosine receptor 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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