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 system and the central nervous system.

[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 adenylate 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, especially 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. Summary of the Invention

[0007] In one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Wherein:

[0010] Ring A can be:

[0011]

[0012] 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 ;

[0013] wherein the alkyl is optionally substituted by one or more substituents independently selected from -OR a and halogen;

[0014] 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 ;

[0015] wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; and

[0016] wherein R 3 is optionally substituted by one to three substituents selected from halogen, cyano, -R a and -OR a ;

[0017] R 4 may be absent or be -(CHR c ) i -(NR a ) j -R 5 ;

[0018] R 5 can be:

[0019] (1) C 3-8 cycloalkyl, aryl, 3-, 4-, 6-, or 7-membered heterocyclic group, or 3-, 4-, 6-, or 7-membered heteroaryl;

[0020] wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O)k ; and

[0021] wherein one or two ring atoms of R 5 are optionally replaced by -C(=O)-;

[0022] (2) a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic or heteroaryl ring system;

[0023] wherein the heterocyclic and heteroaryl independently include 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O and S(O) k ; and

[0024] wherein one or two ring atoms of R 5 are optionally replaced by -C(=O)-; or

[0025] (3) C 1-6 alkyl, -OR a , -NR a R b , cyano, -OS(O) 2 -C 1-3 alkyl, -CO 2 R a , -C(O)NR a R b , -NR a -C(O)-OR a or -O-C(O)-NR a R b ; and

[0026] wherein R 5 may optionally be substituted by one to four groups -X-R 6 ;

[0027] each X independently may be a bond, -O-, -NR a -, -S(O) k -, -(CH 2 ) m - or -C(O)-;

[0028] each R 6 independently may be H, halogen, -OR a , C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclic, heteroaryl, aryl, -CO 2 R a , -C(O)NR a R b , -(CH 2 ) n -NR a Rb or cyano;

[0029] wherein the heterocyclic group and heteroaryl group independently include 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O, and S(O) k ;

[0030] wherein one or two ring atoms of each C 3-8 cycloalkyl group, heterocyclic group, heteroaryl group, or aryl group are independently optionally replaced by -C(=O)-;

[0031] wherein each of the alkyl group, cycloalkyl group, heterocyclic group, heteroaryl group, and aryl group is optionally substituted by one or more substituents, and the substituents are independently selected from -R a , -OR a , -(CH 2 ) n -NR a R b and halogen;

[0032] Each R 7 and each R 8 independently may be R a ;

[0033] or R 7 and R 8 together with the atom to which they are attached may form a 3- to 8-membered heterocyclic group, and the heterocyclic group is optionally substituted by one or more substituents, and the substituents are independently selected from -OR a and halogen;

[0034] Each R a and each R b independently may be H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-9 cycloalkylalkyl;

[0035] wherein each R a and each R b are independently optionally substituted by one or more substituents, and the substituents are independently selected from -OH and halogen;

[0036] Each R c independently may be H, halogen, C 1-3 alkyl, or -(CH 2 ) n -NR a R b ;

[0037] wherein the alkyl group is optionally substituted by one or more substituents, and the substituents are independently selected from -OR a and halogen;

[0038] a can be 0 or 1;

[0039] i can be 0, 1, 2, or 3;

[0040] j can be 0 or 1;

[0041] Each k can independently be 0, 1, or 2;

[0042] Each m can independently be 1 or 2; and

[0043] Each n can independently be 0 or 1.

[0044] 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 a Ki of 10,000 nM or greater for CB-1.

[0045] In certain embodiments, R 5 can be C 1-6 alkyl, -OR a , -NR a R b , cyano, -OS(O) 2 , -C 1-3 alkyl, -CO 2 R a , -C(O)NR a R b , -NR a , -C(O)-OR a or -O-C(O)-NR a R b .

[0046] In certain embodiments, R 5 can be aryl, 6-membered heterocyclic group, or 6-membered heteroaryl.

[0047] In certain embodiments, R 5 can be polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic group, or heteroaryl ring system.

[0048] In certain embodiments, R 3 can be C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclic group, heteroaryl, halogen, -OR a , -NR a R b , -CO 2 R a , -CONR a Rb 、 -NR a C(O)-R a or -NHC(O)-OR a 。

[0049] In certain embodiments, i can be 1 and R c can be H or C 1-3 alkyl; or i can be 2 and each R c can be H.

[0050] In another aspect, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0051]

[0052] Wherein:

[0053] Each R 1 and each R 2 independently can be halogen, C 1-3 alkyl or -O-C 1-3 alkyl;

[0054] wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0055] Ring B can be C 3-8 cycloalkyl, aryl, 6- or 7-membered heterocyclic group or 6- or 7-membered heteroaryl;

[0056] wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms independently selected from N and O;

[0057] Each R 9 independently can be halogen, -R a or -OR a ;

[0058] Each R a and each R b independently can be H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl;

[0059] wherein each R a and each R b is independently optionally substituted with one or more substituents independently selected from -OH and halogen;

[0060] L can be -(CHR c ) e -;

[0061] Each Rc Independently can be H, halogen, C 1-3 alkyl or -(CH 2 ) n -NR a R b ;

[0062] wherein the alkyl is optionally substituted by one or more substituents independently selected from -OR a and halogen;

[0063] R d can be H or halogen;

[0064] a can be 0 or 1;

[0065] b can be 0, 1 or 2;

[0066] d can be 0, 1, 2, 3 or 4;

[0067] e can be 1 or 2; and

[0068] n can be 0 or 1.

[0069] In another aspect, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0070]

[0071] wherein:

[0072] 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 ;

[0073] wherein the alkyl is optionally substituted by one or more substituents independently selected from -OR a and halogen;

[0074] R 4 can be -(CHR c ) 2 -R 5 ;

[0075] R 5 can be H, halogen, C 1-3 alkyl, -OR e , -COR e , -COOR e , -OS(O) 2 Re 、 -OCO-NR e R f or -CO-NR e R f ;

[0076] Wherein the alkyl group is optionally substituted by one or more substituents independently selected from -OH and halogen;

[0077] Each R a and each R b independently can be H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl;

[0078] Wherein each R a and each R b are independently optionally substituted by one or more substituents independently selected from -OH and halogen;

[0079] Each R c independently can be H, halogen, C 1-3 alkyl or -(CH 2 ) n -NR a R b ;

[0080] Wherein the alkyl group is optionally substituted by one or more substituents independently selected from -OR a and halogen;

[0081] R d can be H or halogen;

[0082] Each R e and each R f independently can be H or C 1-6 alkyl;

[0083] Wherein the alkyl group is optionally substituted by one or more substituents independently selected from -OH and halogen;

[0084] a can be 0 or 1; and

[0085] each n independently can be 0 or 1.

[0086] In certain embodiments, R 5 can be H, -CH 3 , -CH 2 F, -CHF 2 or -CF 3 .

[0087] In another aspect, there is provided a compound selected from the following or a pharmaceutically acceptable salt thereof:

[0088] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-fluorophenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0089] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0090] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0091] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-hydroxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0092] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

[0094] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-methoxy-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0095] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0096] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0097] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-1-methyl-6-oxo-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0098] 5-Amino-2-[1-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0099] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(4-pyridinylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0100] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isothiochroman-4-yl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0101] (R)-5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(7-fluorotetralin-1-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0102] 5-Amino-2-[1-(2,5-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0103] 5-Amino-2-[[2-(difluoromethylthio)phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0104] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(o-tolylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

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

[0107] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0108] 5-Amino-2-[(2-chloro-3-fluorophenyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0109] 5-Amino-2-[[2-(cyclopropylmethoxy)phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0110] 5-Amino-2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0111] 5-Amino-2-[[2-[(dimethylamino)methyl]phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

[0113] (R)-5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0114] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0115] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0116] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methoxy-6-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0117] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[2-(4-piperidinyl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0118] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-phenyl-2-(2,2,2-trifluoroethylamino)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

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

[0121] 5-Amino-2-(2-amino-1-(2,6-difluorophenyl)ethyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0122] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoropyrimidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0123] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0124] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-hydroxypyridazin-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0125] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0126] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0127] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

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

[0130] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0131] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0132] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

[0134] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0135] 5-Amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0136] 5-Amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0137] 5-Amino-2-[(3-fluoro-5-methoxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0138] 5-Amino-2-[(5-fluoro-6-hydroxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0139] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0140] 5-Amino-2-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0141] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

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

[0144] 6-[[5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyridine-3-carbonitrile;

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

[0146] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0147] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0148] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0149] 5-Amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0150] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0151] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0152] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0153] 6-[[5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-3-oxo-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyridine-3-carbonitrile;

[0154] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0155] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0156] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0157] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0158] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

[0160] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0161] 5-Amino-8-[2-(dimethylamino)-6-methyl-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0162] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-methyl-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

[0164] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(2-hydroxy-6-methyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0165] 5-Amino-8-[2-(azetidin-1-yl)-6-methyl-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0166] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0167] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-2-[(5-methoxy-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0168] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(2-methoxy-6-methyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0169] 5-Amino-8-[2-chloro-6-(trifluoromethyl)-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0170] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0171] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1-methyl-2-phenyl-ethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0172] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(4-hydroxyphenyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0173] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(4-fluorophenyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0174] Methyl 4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoate;

[0175] 4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoic acid;

[0176] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0177] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0178] 5-Amino-8-[2-methyl-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0179] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0180] 5-Amino-8-[2-(azetidin-1-yl)-6-methyl-4-pyridinyl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0181] 5-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-2-chloro-N-methyl-benzamide;

[0182] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[1-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)ethylamino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0183] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[methyl-(1-phenyl-4-piperidinyl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0184] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[(1S)-1-(6-methyl-2-pyridinyl)ethyl]amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0185] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[1-(3-methyl-1H-pyrazol-5-yl)-4-piperidinyl]amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0186] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[2-(1-methylpyrrol-2-yl)azepan-1-yl]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0187] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[4-[(5-methyl-2-pyridinyl)amino]-1-piperidinyl]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0188] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[3-(3-methyl-5-oxo-4H-pyrazol-1-yl)anilino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0189] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[2-(hydroxymethyl)tetralin-2-yl]-methyl-amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0190] 5-Amino-2-[1-(aminomethyl)-2-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0191] 5-Amino-2-[[(3R)-4-benzylmorpholin-3-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0192] 5-Amino-2-[(4-benzyl-4-piperidinyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0193] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(2-morpholin-3-yl-1-phenyl-ethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0194] 5-Amino-2-(5-aminoindan-2-yl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0195] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2H-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0196] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-methyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0197] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-ethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0198] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-isopropyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0199] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-isopentyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0200] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0201] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(2-hydroxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0202] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0203] 2-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl methanesulfonate;

[0204] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(2-methoxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0205] 3-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propionitrile;

[0206] Ethyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate;

[0207] Ethyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-N-methylcarbamate;

[0208] tert-Butyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate;

[0209] Methyl 3-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propionate;

[0210] Ethyl N-ethylcarbamate 2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl;

[0211] 5-Amino-2-(3,3-difluoropropyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0212] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-[ethyl(methyl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0213] 5-Amino-2-[2-[cyclopropyl(methyl)amino]ethyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0214] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0215] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isobutyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0216] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]acetamide;

[0217] 3-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-propionamide;

[0218] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[3-hydroxy-2-(hydroxymethyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0219] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-acetamide;

[0220] 5-Amino-2-[(3,3-difluorocyclopentyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0221] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-ethyl-2-methyl-cyclopropyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0222] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N-cyclopropyl-N-methyl-acetamide;

[0223] Methyl 1-[[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]cyclopentanecarboxylate;

[0224] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[2-(trifluoromethoxy)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0225] 3-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propanamide;

[0226] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0227] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0228] 5-Amino-7-(2,4-difluorophenyl)-8-(2,6-dimethyl-4-pyridyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0229] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-methoxyphenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0230] 4-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl]benzonitrile;

[0231] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(2-pyridyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0232] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-pyridyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0233] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(3-pyridyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0234] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(5-fluoro-2-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0235] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methylpyrazol-1-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0236] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2-furyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0237] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(5-methyl-2-furyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0238] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methylthiazol-2-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0239] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0240] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0241] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0242] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0243] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0244] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0245] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0246] Methyl 4-[5-amino-3-oxo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl]-6-methyl-pyridine-2-carboxylate;

[0247] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0248] 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]piperidine-1-carboxylate;

[0249] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(3-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0250] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0251] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-isobutyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0252] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0253] 5-Amino-2-[(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0254] 5-Amino-2-[(4-fluorocubane-1-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0255] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0256] 5-Amino-2-(cubane-1-ylmethyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0257] 5-Amino-2-(3-bicyclo[1.1.1]pentylmethyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0258] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0259] (R)-tert-Butyl 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)morpholine-4-carboxylate;

[0260] (R)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0261] tert-Butyl 4-[[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]piperidine-1-carboxylate;

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

[0263] (2S)-2-[[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]morpholine-4-carboxylic acid tert-butyl ester;

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

[0265] (S)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

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

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

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

[0269] (3S)-3-[[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]morpholine-4-carboxylic acid tert-butyl ester;

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

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

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

[0273] (R)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0274] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3R)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0275] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0276] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0277] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0278] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0279] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0280] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0281] (S)-tert-Butyl 3-((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-methylpiperazine-1-carboxylate;

[0282] (R)-tert-Butyl 3-((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-methylpiperazine-1-carboxylate;

[0283] (R)-5-Amino-2-((1,4-dimethylpiperazin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0284] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0285] (S)-5-Amino-2-((1,4-dimethylpiperazin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0286] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

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

[0289] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1,1-dioxothietan-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

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

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

[0293] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0294] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(3,4,5,6-tetrahydropyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0295] 5-Amino-2-[2-(azetidin-1-yl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0296] 2-(2-(2-Azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0297] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0298] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(1-methyl-4-piperidinyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0299] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(3-methyl-1-piperidinyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0300] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(2-morpholinoethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0301] 5-Amino-2-[2-((cis)-2,6-dimethylmorpholin-4-yl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0302] 5-Amino-2-[2-(4,4-difluoro-1-piperidinyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0303] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(4-methylpiperazin-1-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0304] 5-Amino-2-[2-(8-azabicyclo[3.2.1]octan-8-yl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0305] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0306] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-(4-fluorophenyl)-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0307] Methyl 3-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]piperidine-1-carboxylate;

[0308] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[2-(4-hydroxy-1-piperidinyl)-2-oxo-ethyl]-methyl-amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0309] 3-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-N-cyclopropyl-cyclohexanecarboxamide;

[0310] Methyl 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propionate;

[0311] 3-[4-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propanoic acid;

[0312] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[3-(1-piperidinyl)propyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0313] 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(3-(2-oxopyridin-1(2H)-yl)propyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0314] 3-(5-Amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)-N-methylpropanamide;

[0315] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-morpholino-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0316] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(1-piperidinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0317] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-ethoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0318] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-[ethyl(methyl)amino]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

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

[0320] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-7-carboxylic acid methyl ester;

[0321] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-prop-1-ynyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0322] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-methoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0323] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-[(Z)-1-methylprop-1-enyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0324] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-[(E)-1-methylprop-1-enyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0325] In another aspect, 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.

[0326] In another aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder mediated by an adenosine receptor.

[0327] 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.

[0328] Other features, objects, and advantages will be apparent from the description and from the claims.

[0329] Description

[0330] The compounds of formula (I), formula (II) and formula (III) can be used as adenosine receptor antagonists.

[0331] There is described herein a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0332] .

[0333] Ring A is:

[0334] .

[0335] Each R1 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 ; provided that the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halogen.

[0336] R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heterocycloalkyl, 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 ; provided that the heterocycloalkyl and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; and provided that R 3 is optionally substituted with one to three substituents selected from halogen, cyano, -R a and -OR a .

[0337] R 4 is absent or is -(CHR c ) i -(NR a ) j -R 5 .

[0338] R 5 is: (1) C 3-8 cycloalkyl, aryl, 3-, 4-, 6-, or 7-membered heterocycloalkyl, or 3-, 4-, 6-, or 7-membered heteroaryl; provided that the heterocycloalkyl and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; provided that one or two ring atoms of R 5 are optionally replaced by -C(=O)-; (2) a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring system; provided that the heterocycloalkyl and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O, and S(O) k ; provided that R5 One or two ring atoms are optionally replaced by -C(=O)-; or (3) C 1-6 alkyl, -OR a , -NR a R b , cyano, -OS(O) 2 -C 1-3 alkyl, -CO 2 R a , -C(O)NR a R b , -NR a -C(O)-OR a or -O-C(O)-NR a R b .

[0339] R 5 is optionally substituted by one to four groups -X-R 6 .

[0340] Each X is independently a bond, -O-, -NR a -, -S(O) k -, -(CH 2 ) m - or -C(O)-.

[0341] 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 the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms, and the heteroatoms are 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)-; and wherein each of 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.

[0342] Each R 7 and each R 8 is independently R a .

[0343] 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 with one or more substituents independently selected from -OR a and halogen.

[0344] 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.

[0345] 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.

[0346] a is 0 or 1.

[0347] i is 0, 1, 2 or 3.

[0348] j is 0 or 1.

[0349] Each k is independently 0, 1 or 2.

[0350] Each m is independently 1 or 2.

[0351] Each n is independently 0 or 1.

[0352] In certain embodiments, R 5 is C 1-6 alkyl, -OR a , -NR a R b , cyano, -OS(O) 2 -C 1-3 alkyl, -CO 2 R a , -C(O)NR a R b, -NR a -C(O)-OR a or -O-C(O)-NR a R b 。

[0353] In certain embodiments, R 5 is aryl, 6 - membered heterocyclic, or 6 - membered heteroaryl.

[0354] In certain embodiments, R 5 is a polycyclic, 6 - to 11 - membered, cycloalkyl, aryl, heterocyclic, or heteroaryl ring system.

[0355] In certain embodiments, R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclic, 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 。

[0356] In certain embodiments, i is 1 and R c is H or C 1-3 alkyl; or i is 2 and each R c is H.

[0357] In certain embodiments, R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclic, 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 ; i is 1 or 2; and each R c is independently H or C 1-3 alkyl.

[0358] In certain embodiments, R 3 is C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 ; i is 1 or 2; each R c is independently H or C 1-3 alkyl; and R 5 is C 3-8 cycloalkyl, aryl, 3-, 4-, 6- or 7-membered heterocyclic group, or 3-, 4-, 6- or 7-membered heteroaryl; wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms, the heteroatoms being independently selected from N, O, and S(O) k ; and wherein one or two ring atoms of R 5 are optionally replaced by -C(=O)-.

[0359] In certain embodiments, R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 ; i is 1 or 2; each R c is independently H or C 1-3 alkyl; and R 5 is a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic group or heteroaryl ring system; wherein the heterocyclic group and heteroaryl independently include 1 to 4 heteroatoms, the heteroatoms being independently selected from N, O, and S(O) k ; and wherein one or two ring atoms of R 5 are optionally replaced by -C(=O)-.

[0360] In certain embodiments, R 5is a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic or heteroaryl ring system; wherein the heterocyclic and heteroaryl groups independently include 1 to 4 heteroatoms, said heteroatoms independently selected from N, O and S(O) k ; and wherein R 5 one or two ring atoms of are optionally replaced by -C(=O)-.

[0361] In certain embodiments, R 5 is a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic or heteroaryl ring system; wherein the heterocyclic and heteroaryl groups independently include 1 to 4 heteroatoms, said heteroatoms independently selected from N, O and S(O) k ; and wherein R 5 one or two ring atoms of are optionally replaced by -C(=O)-; i is 0; and j is 0.

[0362] In certain embodiments, R 5 is a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic or heteroaryl ring system; wherein the heterocyclic and heteroaryl groups independently include 1 to 4 heteroatoms, said heteroatoms independently selected from N, O and S(O) k ; and wherein R 5 1 or 2 ring atoms of are optionally replaced by -C(=O)-; i is 1 or 2; and j is 0.

[0363] In certain embodiments, j is 1.

[0364] In certain embodiments, j is 1; and i is 1 or 2.

[0365] In certain embodiments, j is 1; i is 1 or 2; and R 5 is C 3-8 cycloalkyl, aryl, 3-, 4-, 6- or 7-membered heterocyclic, or 3-, 4-, 6- or 7-membered heteroaryl; wherein the heterocyclic and heteroaryl groups independently include 1 to 4 heteroatoms, said heteroatoms independently selected from N, O and S(O) k ; and wherein R 5 one or two ring atoms of are optionally replaced by -C(=O)-.

[0366] In certain embodiments, j is 1; i is 1 or 2; and R 5 is a polycyclic, 6- to 11-membered, cycloalkyl, aryl, heterocyclic or heteroaryl ring system; wherein the heterocyclic and heteroaryl groups independently include 1 to 4 heteroatoms, said heteroatoms independently selected from N, O and S(O) k ; and wherein R 5 one or two ring atoms of are optionally replaced by -C(=O)-.

[0367] In certain embodiments, R 5 is C 1-6 alkyl, -OR a -, -NR a R b -, cyano, -OS(O) 2 -C 1-3 alkyl, -CO 2 R a -, -C(O)NR a R b -, -NR a -C(O)-OR a or -O-C(O)-NR a R b .

[0368] In certain embodiments, R 5 is C 1-6 alkyl, -OR a -, -NR a R b -, cyano, -OS(O) 2 -C 1-3 alkyl, -CO 2 R a -, -C(O)NR a R b -, -NR a -C(O)-OR a or -O-C(O)-NR a R b ; and j is 0.

[0369] Compounds of formula (II) or pharmaceutically acceptable salts thereof are described herein:

[0370] .

[0371] 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;

[0372] Ring B is C 3-8 cycloalkyl, aryl, 6- or 7-membered heterocyclic or 6- or 7-membered heteroaryl; wherein the heterocyclic and heteroaryl independently include 1 to 4 heteroatoms independently selected from N and O.

[0373] Each R 9 is independently halogen, -R a or -OR a。

[0374] 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.

[0375] L is -(CHR c ) e -.

[0376] 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.

[0377] R d is H or halogen.

[0378] a is 0 or 1.

[0379] b is 0, 1 or 2.

[0380] d is 0, 1, 2, 3 or 4.

[0381] e is 1 or 2.

[0382] n is 0 or 1.

[0383] The compound of formula (II) is included by the broader formula (I).

[0384] In certain embodiments, ring B is phenyl, pyridyl, 2-oxo-pyridyl, pyrimidinyl or pyridazinyl.

[0385] In certain embodiments, ring B is phenyl.

[0386] In certain embodiments, e is 1; and ring B is phenyl.

[0387] In certain embodiments, e is 2; and ring B is phenyl.

[0388] In certain embodiments, ring B is phenyl, pyridyl, 2-oxo-pyridyl, pyrimidinyl or pyridazinyl; and each R 9 is independently C 1-3An alkyl group, wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0389] In certain embodiments, e is 2; and ring B is phenyl, pyridyl, 2-oxo-pyridyl, pyrimidinyl or pyridazinyl.

[0390] Compounds of formula (III) or pharmaceutically acceptable salts thereof are described herein:

[0391] 。

[0392] 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 group is optionally substituted with one or more substituents independently selected from -OR a and halogen.

[0393] R 4 is -(CHR c ) 2 -R 5 。

[0394] R 5 is H, halogen, C 1-3 alkyl, -OR e 、-COR e 、-COOR e 、-OS(O) 2 R e 、-OCO-NR e R f or -CO-NR e R f ; wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0395] 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.

[0396] Each R c is independently H, halogen, C1-3 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.

[0397] R d is H or halogen.

[0398] Each R e and each R f is independently H or C 1-6 alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0399] a is 0 or 1.

[0400] Each n is independently 0 or 1.

[0401] The compound of formula (III) is included by the broader formula (I).

[0402] In certain embodiments, R 5 is H, -CH 3 , -CH 2 F, -CHF 2 or -CF 3 .

[0403] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0404] The term "alkyl" refers to a fully saturated straight-chain or branched-chain aliphatic group, having the specified number of carbon atoms if specified (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.

[0405] The term "alkenyl" refers to an unsaturated straight-chain or branched-chain aliphatic group containing at least one carbon-carbon double bond, and having the specified number of carbon atoms if specified. 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.

[0406] 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.

[0407] Alkenyl and alkynyl groups may contain more than one unsaturated bond, or a mixture of double and triple bonds.

[0408] 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 may optionally be replaced by -C(=O)-. Cycloalkyl groups may 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.

[0409] 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 may optionally be replaced by -C(=O)-. Ring nitrogen or ring sulfur atoms may independently optionally be oxidized, including, for example, -N(O)-, -S(O)-, or -S(O) 2 -. The ring nitrogen atoms in heterocyclyl groups may optionally be quaternized, for example, -N + (CH 3 ) 2 -. Heterocyclyl groups may contain fused rings and / or bridged rings, including cases where the fused or bridged ring is a cycloalkyl or heterocyclyl group. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.

[0410] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group containing 6 to 14 ring atoms. Aryl may contain fused rings, including aryl rings fused to cycloalkyl rings, heterocyclyl rings, or aryl rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, and dihydro-1H-indenyl.

[0411] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 ring atoms, where 1 to 4 of the ring atoms are independently N, O, or S. Ring nitrogen or ring sulfur atoms may independently optionally be oxidized, including, for example, -N(O)-, -S(O)-, or -S(O) 2- A heteroaryl group may contain fused and / or bridged rings, including the case where the fused 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.

[0412] The term "polycyclic ring system" refers to a cycloalkyl, heterocyclic, aryl or heteroaryl group comprising two or more fused and / or bridged rings.

[0413] 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.

[0414] 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.

[0415] 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 drug 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.

[0416] The compounds of formula (I) may contain the 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.

[0417] The application in the formula herein refers to the point of connection between different groups.

[0418] Exemplary compounds of formula (I) or pharmaceutically acceptable salts thereof include:

[0419] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-fluorophenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0420] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0421] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0422] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-hydroxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0423] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0424] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-methoxy-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0425] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-methoxy-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0426] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0427] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0428] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-1-methyl-6-oxo-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0429] 5-Amino-2-[1-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0430] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(4-pyridinylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0431] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isothiochroman-4-yl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0432] (R)-5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(7-fluorotetralin-1-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0433] 5-Amino-2-[1-(2,5-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0434] 5-Amino-2-[[2-(difluoromethylthio)phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0435] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(o-tolylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0436] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-fluoro-2-methyl-phenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0437] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[(2-pyrazol-1-yl-3-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0438] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0439] 5-Amino-2-[(2-chloro-3-fluorophenyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0440] 5-Amino-2-[[2-(cyclopropylmethoxy)phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0441] 5-Amino-2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0442] 5-Amino-2-[[2-[(dimethylamino)methyl]phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0443] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-ethoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0444] (R)-5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0445] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0446] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0447] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methoxy-6-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0448] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[2-(4-piperidinyl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0449] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-phenyl-2-(2,2,2-trifluoroethylamino)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0450] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[2-(4-piperidinylmethyl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0451] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-methoxypyridazin-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0452] 5-Amino-2-(2-amino-1-(2,6-difluorophenyl)ethyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0453] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoropyrimidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0454] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0455] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-hydroxypyridazin-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0456] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0457] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0458] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0459] 5-Amino-2-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0460] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0461] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0462] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0463] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0464] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0465] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0466] 5-Amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0467] 5-Amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0468] 5-Amino-2-[(3-fluoro-5-methoxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0469] 5-Amino-2-[(5-fluoro-6-hydroxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0470] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0471] 5-Amino-2-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0472] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0473] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0474] 5-Amino-2-[(5-bromo-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0475] 6-[[5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyridine-3-carbonitrile;

[0476] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0477] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0478] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0479] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0480] 5-Amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0481] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0482] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0483] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0484] 6-[[5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-3-oxo-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyridine-3-carbonitrile;

[0485] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0486] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0487] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0488] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0489] 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0490] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0491] 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0492] 5-Amino-8-[2-(dimethylamino)-6-methyl-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0493] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-methyl-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0494] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0495] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(2-hydroxy-6-methyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0496] 5-Amino-8-[2-(azetidin-1-yl)-6-methyl-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0497] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0498] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-2-[(5-methoxy-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0499] 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(2-methoxy-6-methyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0500] 5-Amino-8-[2-chloro-6-(trifluoromethyl)-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0501] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0502] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1-methyl-2-phenylethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0503] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(4-hydroxyphenyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0504] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(4-fluorophenyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0505] Methyl 4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoate;

[0506] 4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoic acid;

[0507] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0508] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0509] 5-Amino-8-[2-methyl-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0510] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0511] 5-Amino-8-[2-(azetidin-1-yl)-6-methyl-4-pyridinyl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0512] 5-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-2-chloro-N-methyl-benzamide;

[0513] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[1-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)ethylamino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0514] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[methyl-(1-phenyl-4-piperidinyl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0515] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[(1S)-1-(6-methyl-2-pyridinyl)ethyl]amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0516] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[1-(3-methyl-1H-pyrazol-5-yl)-4-piperidinyl]amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0517] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[2-(1-methylpyrrol-2-yl)azepan-1-yl]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0518] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[4-[(5-methyl-2-pyridinyl)amino]-1-piperidinyl]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0519] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[3-(3-methyl-5-oxo-4H-pyrazol-1-yl)phenylamino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0520] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[2-(hydroxymethyl)tetralin-2-yl]methyl-amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0521] 5-Amino-2-[1-(aminomethyl)-2-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0522] 5-Amino-2-[[(3R)-4-benzylmorpholin-3-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0523] 5-Amino-2-[(4-benzyl-4-piperidinyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0524] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(2-morpholin-3-yl-1-phenyl-ethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0525] 5-Amino-2-(5-aminoindan-2-yl)-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0526] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2H-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0527] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-methyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0528] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-ethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0529] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isopropyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0530] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isopentyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0531] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0532] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(2-hydroxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0533] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0534] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl methanesulfonate;

[0535] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(2-methoxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0536] 3-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propionitrile;

[0537] Ethyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate;

[0538] Ethyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-N-methylcarbamate;

[0539] tert-Butyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate;

[0540] Methyl 3-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propionate;

[0541] Ethyl N-ethylcarbamate 2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl;

[0542] 5-Amino-2-(3,3-difluoropropyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0543] 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-[ethyl(methyl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0544] 5-Amino-2-[2-[cyclopropyl(methyl)amino]ethyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0545] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0546] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isobutyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0547] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]acetamide;

[0548] 3-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-propionamide;

[0549] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[3-hydroxy-2-(hydroxymethyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0550] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-acetamide;

[0551] 5-Amino-2-[(3,3-difluorocyclopentyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0552] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-ethyl-2-methyl-cyclopropyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0553] 2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N-cyclopropyl-N-methyl-acetamide;

[0554] Methyl 1-[[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]cyclopentanecarboxylate;

[0555] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(trifluoromethoxy)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0556] 3-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propanamide;

[0557] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0558] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0559] 5-Amino-7-(2,4-difluorophenyl)-8-(2,6-dimethyl-4-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0560] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methoxyphenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0561] 4-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl]benzonitrile;

[0562] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0563] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0564] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(3-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0565] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(5-fluoro-2-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0566] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methylpyrazol-1-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0567] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2-furyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0568] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(5-methyl-2-furyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0569] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methylthiazol-2-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0570] 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0571] 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0572] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0573] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0574] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0575] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0576] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0577] Methyl 4-[5-amino-3-oxo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl]-6-methyl-pyridine-2-carboxylate;

[0578] 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0579] 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]piperidine-1-carboxylate;

[0580] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(3-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0581] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0582] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-isobutyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0583] 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0584] 5-Amino-2-[(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0585] 5-Amino-2-[(4-fluorocubane-1-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0586] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0587] 5-Amino-2-(cubane-1-ylmethyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0588] 5-Amino-2-(3-bicyclo[1.1.1]pentylmethyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0589] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0590] (R)-tert-Butyl 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)morpholine-4-carboxylate;

[0591] (R)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0592] tert-Butyl 4-[[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]piperidine-1-carboxylate;

[0593] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(4-piperidinylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0594] (2S)-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]morpholine-4-carboxylate;

[0595] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1-methyl-3-piperidinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0596] (S)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0597] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-4-methylmorpholin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0598] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-4-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0599] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-4-methylmorpholin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0600] (3S)-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]methyl]morpholine-4-carboxylate;

[0601] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3S)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0602] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3S)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0603] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methyl-4-piperidinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0604] (R)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0605] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3R)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0606] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0607] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0608] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0609] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0610] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0611] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0612] (S)-3-((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-methylpiperazine-1-carboxylic acid tert-butyl ester;

[0613] (R)-3-((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-methylpiperazine-1-carboxylic acid tert-butyl ester;

[0614] (R)-5-Amino-2-((1,4-dimethylpiperazin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0615] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0616] (S)-5-Amino-2-((1,4-dimethylpiperazin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0617] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0618] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1,1-dioxothiacyclohexan-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0619] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1,1-dioxothiacyclohexan-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0620] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1,1-dioxothietan-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0621] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0622] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0623] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0624] 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0625] 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(3,4,5,6-tetrahydropyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0626] 5-Amino-2-[2-(azetidin-1-yl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0627] 2-(2-(2-Azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0628] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0629] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(1-methyl-4-piperidinyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0630] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(3-methyl-1-piperidinyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0631] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(2-morpholinoethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0632] 5-Amino-2-[2-((cis)-2,6-dimethylmorpholin-4-yl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0633] 5-Amino-2-[2-(4,4-difluoro-1-piperidinyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0634] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(4-methylpiperazin-1-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0635] 5-Amino-2-[2-(8-azabicyclo[3.2.1]octan-8-yl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0636] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0637] 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-(4-fluorophenyl)-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0638] Methyl 3-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]piperidine-1-carboxylate;

[0639] 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[2-(4-hydroxy-1-piperidinyl)-2-oxo-ethyl]-methyl-amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0640] 3-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-N-cyclopropyl-cyclohexanecarboxamide;

[0641] Methyl 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propionate;

[0642] 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propanoic acid;

[0643] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[3-(1-piperidinyl)propyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0644] 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(3-(2-oxopyridin-1(2H)-yl)propyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one;

[0645] 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)-N-methylpropanamide;

[0646] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-morpholino-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0647] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-(1-piperidinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0648] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-ethoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0649] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-[ethyl(methyl)amino]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0650] 5-amino-7-chloro-8-(2,6-dimethyl-4-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0651] 5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-7-carboxylic acid methyl ester;

[0652] 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-prop-1-ynyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0653] 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-methoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0654] 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-[(Z)-1-methylprop-1-enyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0655] 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-[(E)-1-methylprop-1-enyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0656] 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., a compound of formula (I).

[0657] In some cases, the compound of formula (I) is a selective adenosine receptor antagonist. The term "selective" refers to the property of the compound of formula (I) that 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 an adenosine receptor; (ii) does not exhibit substantial agonist or antagonist activity against a given receptor; or both (i) and (ii).

[0658] The term "selective adenosine receptor antagonist" refers to a compound that exhibits a binding affinity for one or more adenosine receptor subtypes that is at least 100-fold, 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.

[0659] Specifically, the selective adenosine receptor antagonist can be substantially inactive against other G-protein coupled receptors (such as cannabinoid receptors, designated CB-1 and CB-2).

[0660] 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.

[0661] 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.

[0662] 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.

[0663] The compound of formula (I) may be a selective adenosine receptor antagonist relative to CB-1.

[0664] The compound of formula (I) may be active as an adenosine receptor antagonist but substantially inactive against CB-1.

[0665] 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.

[0666] 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.

[0667] 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.

[0668] 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.

[0669] 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.

[0670] 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).

[0671] 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.

[0672] 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).

[0673] 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; and in still other embodiments, by both A2aR and A2bR.

[0674] Some examples of diseases or disorders mediated by adenosine receptors include 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; movement disorders, including Parkinson's disease and Huntington's disease; and attention disorders, including attention deficit disorder and attention deficit - hyperactivity disorder. Other diseases and disorders mediated by adenosine receptors are known.

[0675] 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.

[0676] 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).

[0677] 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.

[0678] 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.

[0679] In one embodiment, there is provided a method for treating a disease or disorder mediated by an adenosine receptor, 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.

[0680] In one embodiment, there is provided a method for treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, 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 of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0681] In one embodiment, there is provided a method for treating a disease or disorder mediated by an adenosine receptor, 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.

[0682] 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.

[0683] 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.

[0684] 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.

[0685] 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.

[0686] 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.

[0687] The compounds of formula (I) can be prepared according to the following general scheme.

[0688] Schemes 1a and 1b illustrate the preparation of the intermediate 6-substituted-4-hydrazino-2-aminopyrimidine compounds of formula (IV).

[0689] Scheme 1a

[0690]

[0691] Scheme 1b

[0692]

[0693] 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.

[0694] Scheme 2

[0695]

[0696] 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 an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction.

[0697] Scheme 3a

[0698]

[0699] Alternatively, compounds such as R 4 -Br can be used for the direct alkylation of the compound of formula (V).

[0700] Optionally, R 4 can be further modified after the alkylation of the compound of formula (V).

[0701] 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 an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction.

[0702] Scheme 3b

[0703]

[0704] Alternatively, compounds such as R 4 -Br can be used for the direct alkylation of the compound of formula (Va).

[0705] Optionally, R 4。

[0706] Optionally, the compound of formula (I) can be further modified, for example, to form different compounds of formula (I). Examples

[0707] General Techniques

[0708] LCMS Method A

[0709] 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.

[0710] For UV-inactive compounds, connect an ELSD detector (Polymer Laboratories PL-ELS 2100 ICE) to the above instrument.

[0711] LCMS Method B

[0712] 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.

[0713] LCMS Method C

[0714] 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 1µL (variable); UV detection 210 to 400 nm; Column temperature 25°C; 1.5 mL / min.

[0715] LCMS Method D

[0716] 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 1µL (variable); UV detection 210 to 400 nm; Column temperature 25°C; 1.2 mL / min.

[0717] LCMS Method E

[0718] 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 1µL (variable); UV detection 210 to 400 nm; Column temperature 25°C; 1.0 mL / min.

[0719] LCMS Method F

[0720] 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.

[0721] LCMS method G

[0722] 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.

[0723] Preparative HPLC method A

[0724] 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.

[0725] Preparative HPLC method B

[0726] 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.

[0727] Preparative HPLC method C

[0728] 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.

[0729] Preparative HPLC method D

[0730] 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.

[0731] Preparative HPLC method E

[0732] 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.

[0733] MD automatic preparation method A

[0734] Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD. Solvent: A - 0.1% TFA in H 2 2

[0735] Chiral SFC Method A

[0736] Instrument: SFC Investigator - Waters. Solvent: A - CO 2 , B - 20 mM ammonia in MeOH. Column: LUX C2 (cellulose) (250X4.6) mm, 5 μm. Isocratic 40%. Outlet pressure; 100 bar. Column temperature 25°C; 1.6 mL / min.

[0737] Chiral SFC Method B

[0738] Instrument: SFC Investigator - Waters. Solvent: A - CO 2 , B - 0.1% DEA in n - hexane:EtOH: 70:30. Column: CHIRALCEL C4 (Cellulose) (250X4.6) mm, 5 μm. Outlet pressure; 100 bar. Column temperature 25°C; 1.0 mL / min.

[0739] Chiral SFC Method C

[0740] Instrument: SFC Investigator - Waters. Solvent: A - CO 2 , B - 20 mM ammonia in MeOH. Column: Lux A1 (Amylose); (250X4.6) mm, 5 μm. Isocratic 30%. Outlet pressure; 100 bar. Column temperature 35°C; 3.0 mL / min.

[0741] Chiral SFC Method D

[0742] Instrument: SFC Investigator - Waters. Solvent: A - CO 2, B - 20 mM ammonia in MeOH. Column: Chiralcel ODH (Cellulose); (250X4.6) mm, 5 μm. Isocratic 40%. Outlet pressure; 100 bar. Column temperature 35 °C; 4.0 mL / min.

[0743] Chiral SFC Method E

[0744] Instrument: SFC Investigator - Waters. Solvent: A - CO 2 , B - 20 mM ammonia in MeOH. Column: Lux A1 (Amylose); (250X4.6) mm, 5 μm. Isocratic 30%. Outlet pressure; 100 bar. Column temperature 35 °C; 3.0 mL / min.

[0745] Synthetic Route of Intermediate

[0746] Synthetic routes 1 to 10 are described below, which are used to prepare the intermediates used in the synthesis of the compounds of formula (I). The details of synthetic routes 1 to 10 are examples of the techniques used in the preparation of other intermediates detailed in Table 2 below.

[0747] Synthetic Route 1: Procedure for Preparing Intermediate 1

[0748] Intermediate 1, 5 - Amino - 8 - bromo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one

[0749]

[0750] Step 1: The reaction was carried out as 2 x 250 g batches. 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) were added to a degassed suspension in CH 3 CN (15 L) and H 2 O (2 L), and Pd(PPh 3 ) 4 (118 g, 0.10 mol) was added, 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), the undissolved solid was filtered off through a Buchner funnel and rinsed with DCM (3 L). The filtrate was placed in a separating funnel, the organic layer was separated, and passed through anhydrous Na 2 SO4 Dry and concentrate under reduced pressure. Purify the crude product by flash chromatography using 230 - 400 silica gel mesh and elute with 0 - 15% EtOAc in petroleum ether to afford 4-chloro-6-phenylpyrimidin-2-amine (350 g, 41%) as an off-white solid.

[0751] LCMS (Method A): m / z 206 (M+H) + (ES + ), retention time 2.53 min, UV active.

[0752] 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 protons were observed.

[0753] 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. Concentrate the reaction mixture under reduced pressure. Grind the resulting residue with diethyl ether (1 L) and 10% sodium bicarbonate solution (1 L). Collect the resulting solid by filtration through a Buchner funnel, wash with diethyl ether (200 mL) and dry in vacuo to afford 4-hydrazino-6-phenylpyrimidin-2-amine (250 g, 73%) as an off-white solid.

[0754] LCMS (Method C): m / z 202 (M+H) + (ES + ), retention time 0.69 min, UV active.

[0755] 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).

[0756] Step 3: In N 2A solution of 4-hydrazino-6-phenylpyrimidin-2-amine (250 g, 1.24 mol) cooled to -30 °C was added portionwise with triphosgene (735 g, 2.48 mol) in dry THF (3.0 L), and the mixture was stirred at the same temperature for 45 min. The reactant was carefully quenched into ice-cold water (10 L) with vigorous stirring. After the effervescence ceased, the reaction mass 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-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 70%) as a yellow solid.

[0757] LCMS (Method C): m / z 228 (M+H) + (ES + ), at 1.64 min, UV active.

[0758] 1 H 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).

[0759] Step 4: Under a 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, washed 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. The data for the title compound are in Table 2.

[0760] Synthetic Route 2: Procedure for Preparing Intermediate 7

[0761] Intermediate 7: 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0762]

[0763] 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 H 2 O (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 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. The data for the title compound are in Table 2.

[0764] Step 2; At room temperature, Pd(PPh 3 ) 4 (1.44 g, 1.25 mmol) was added 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 2 CO 3 (8.6 g, 62.5 mmol) in 1,4-dioxane (150 mL) and H 2 O (30 mL), and the reaction mixture was heated at 120 °C for 5 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (200 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. The crude product was purified by Biotage-Isolera using 100 g of silica snap and eluted with a gradient of 0 - 80% EtOAc in hexanes 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 as a yellow solid (7.5 g, 64%).

[0765] LCMS (Method B): m / z 462 (M+H) + (ES + ), at 2.55 min, UV active.

[0766] 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.

[0767] 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 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (4.5 g, 89%). Data for the title compound are in Table 2.

[0768] Synthetic Route 3: Procedure for Preparing Intermediate 11

[0769] Intermediate 11: 6-(Bromomethyl)-3-fluoro-2-methoxypyridine

[0770]

[0771] At 0 °C, N-bromosuccinimide (700 mg, 3.89 mmol) and AIBN (57 mg, 0.35 mmol) were added to a stirred solution of 3-fluoro-2-methoxy-6-methylpyridine (500 mg, 3.54 mmol) in CCl 4 (10 mL). The reaction mixture was heated to 80 °C and maintained for 16 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. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with petroleum ether to afford 6-(bromomethyl)-3-fluoro-2-methoxypyridine as a pale yellow gum (720 mg, 89%). Data for the title compound are in Table 2.

[0772] Synthetic Route 4: Procedure for Preparing Intermediate 38

[0773] Intermediate 38: N,N-Di-tert-butoxycarbonyl(6-(bromomethyl)-3-fluoropyridin-2-yl)-amine

[0774]

[0775] Step 1; TEA (240 mg, 2.37 mmol), DMAP (9 mg, 0.08 mmol) and Boc-anhydride (432 mg, 1.98 mmol) were added to a stirred solution of 3-fluoro-6-methylpyridin-2-amine (100 mg, 0.79 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), the organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with a 0-10% gradient of EtOAc in petroleum ether to afford N,N-di-tert-butoxycarbonyl(3-fluoro-6-methylpyridin-2-yl)amine as a white liquid.

[0776] LCMS (Method B): m / z 327 (M+H) + (ES + ), at 2.82 min, UV active.

[0777] 11H NMR: (400 MHz, DMSO- d6 ) δ: 7.79 - 7.73 (m, 1H), 7.38 - 7.34 (m, 1H), 2.44 (s, 3H), 1.38 (s, 18H).

[0778] Step 2; To a stirred solution of N,N - di - tert - butoxycarbonyl(3 - fluoro - 6 - methylpyridin - 2 - yl)amine (160 mg, 0.49 mmol) in CCl 4 (10 mL) was added N - bromosuccinimide (174 mg, 0.98 mmol) and AIBN (16 mg, 0.10 mmol). The reaction mixture was heated to 80 °C for 16 h. 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 N,N - di - tert - butoxycarbonyl(6 - (bromomethyl)-3 - fluoropyridin - 2 - yl)amine as a brown gum (crude), which was used without purification in the next step. The data for the title compound are in Table 2.

[0779] Synthetic Route 5: Procedure for Preparing Intermediate 41

[0780] Intermediate 41: 5 - Amino - 8 - bromo - 7 - (4 - fluorophenyl)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H)-one

[0781]

[0782] Step 1; To a stirred suspension of 4,6 - dichloropyrimidin - 2 - amine (400 g, 2.43 mol) in EtOH (5 L) was added hydrazine hydrate (365 g, 7.31 mol), and the mixture was heated 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 in vacuo to afford 4 - chloro - 6 - hydrazinylpyrimidin - 2 - amine as an off - white solid (300 g, 77%).

[0783] LCMS (Method C): m / z 160 (M + H) + (ES + ) at 0.37 min, UV - active.

[0784] 1 1H NMR: (400 MHz, DMSO - d6) δ: 8.10 (s, 1H), 6.36 (s, 2H), 5.97 (s, 1H), 4.26 (s, 2H).

[0785] Step 2: at room temperature to 4-chloro-6-hydrazinopyrimidine-2-amine (300 g, 1.87 mol), 4-fluorophenylboronic acid (313 g, 2.24 mol) and K 2 CO 3 (774 g, 5.61 mol) in 1,4-dioxane (6 L) and H 2 Pd(PPh 3 ) 4 (107 g, 0.093 mol), 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 mixed with H 2 O (4 L) was stirred vigorously to give a solid, which was filtered through a Buchner funnel and rinsed with MeOH (1 L). The solid was dried under vacuum to provide 4-(4-fluorophenyl)-6-hydrazinopyrimidin-2-amine (200 g, 49%) as a green solid.

[0786] LCMS (Method C): m / z 220 (M+H) + (ES + ), at 0.76 min, UV-active.

[0787] 1 H 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).

[0788] Step 3: In N 2A solution of 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 g, 0.91 mol) cooled to -30 °C was added portionwise with triphosgene (538 g, 1.82 mol) in dry THF (3.0 L), 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 mass 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 as a yellow solid (150 g, 67%).

[0789] LCMS (Method C): m / z 246 (M+H) + (ES + ), at 1.77 min, UV active.

[0790] 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).

[0791] Step 4; The reaction was carried out in 2 x 75 g batches. Under a 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, washed with small portions of MeOH / DCM (1:1), and dried under vacuum to afford 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a light brown solid (120 g, 60%). Data for the title compound are in Table 2.

[0792] Synthetic Route 6: Procedure for Preparing Intermediate 42

[0793] Intermediate 42: Methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate

[0794]

[0795] A degassed solution of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (51 mg, 0.33 mmol), 4,4'-di-tert-butyl-2,2'-dipyridine (41 mg, 0.155 mmol), and bis(pinacolato)diboron (600 mg, 2.48 mmol) in hexane was heated at 55 °C for 10 min. Methyl 6-methylpicolinate (500 mg, 3.1 mmol) was added to the mixture via syringe and heated at 60 °C for 14 h. The reaction mixture was concentrated under reduced pressure to afford methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate as a brown gum, which was used as a crude product without purification. The data for the title compound are in Table 2.

[0796] Synthetic Route 7: Typical Procedure for Preparing Triazolopyrimidine Analogs via Suzuki Coupling with SEM-Protection

[0797] Intermediate 45: Methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate

[0798]

[0799] 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), followed by dropwise addition of (2-(chloromethoxy)ethyl)trimethylsilane (11.3 g, 67.8 mmol). 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 and dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. The crude product was purified by Biotage-Isolera using 100 g silica snap and eluted with a gradient of 0 - 30% EtOAc in hexanes to afford 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.

[0800] LCMS (Method B): m / z 436 (M+H)+ (ES+), retention time 3.25 min, UV active.

[0801] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.56 (s, 2H), 7.62 (d, J = 7.1 Hz, 2H), 7.45 (d, J = 6.6 Hz, 3H), 5.18 (s, 2H), 3.66 (t, J = 8.2 Hz, 2H), 0.91 (t, J = 8.2 Hz, 2H), 0.04 (s, 9H).

[0802] Step 2; Prepared in a manner similar to Step 2 of Route a 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-methylpyridine-2-carboxylate (6 g, 64%) as a yellow solid. Data for the title compound are in Table 2.

[0803] Step 3; A solution of methyl 4-(5-amino-3-oxo-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (1 g, 1.9 mmol) in TFA (15 mL) was stirred at room temperature for 30 min. After 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 methyl 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (0.55 g, 67%) as a yellow solid. Data for the title compound are in Table 2.

[0804] Synthetic Route 8: Typical Procedure for Preparing Triazolopyrimidine Analogs Using SEM-Protection Strategy

[0805] Intermediate 53: 5-Amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0806]

[0807] Step 1; Lithium triethylborohydride (1 M in THF, 13.8 mL, 13.81 mmol) was added dropwise to a solution of methyl 4-(5-amino-3-oxo-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (3.5 g, 6.90 mmol) in THF (30 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc (50 mL) and H 2 O (50 mL). The organic layer was separated, washed with brine solution (20 mL), and dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. Purify the crude product by flash column chromatography using silica gel (230 - 400) mesh and elute with a gradient of 0 - 3% MeOH in DCM to afford 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2.2 g, 66%) as a yellow solid.

[0808] LCMS (Method C): m / z 479 (M+H) + (ES + ), at 1.82 min, UV active.

[0809] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.42 - 8.26 (m, 2H), 7.29 - 7.25 (m,5H), 7.09 (s, 1H), 6.88 (s, 1H), 5.25 (t, J = 5.7 Hz, 1H), 5.12 (s, 2H), 4.42(d, J = 5.7 Hz, 2H), 3.65 - 3.61 (m, 2H), 2.31 (s, 3H), 0.88 (t, J = 8.0 Hz,2H), 0.01 (s, 9H).

[0810] Step 2; Heat a suspension of 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.1 g, 2.29 mmol) in TFA (10 mL) to 60 °C for 1 h. Concentrate the reaction mixture under reduced pressure. Dilute the crude product with EtOH and cool to 0 °C. Add ammonium hydroxide solution (50 mL) dropwise and heat to 60 °C for 1 h. Concentrate the reaction mixture under reduced pressure and reduce the volume to approximately half. Filter the precipitate, wash with EtOH and dry to afford 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (450 mg, 56%) as a yellow solid. Data for the title compound are in Table 2.

[0811] Synthetic Route 9: Procedure for Preparing Intermediate 83

[0812] Intermediate 83: 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

[0813]

[0814] 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. 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 4 and concentrated under reduced pressure. The crude product was triturated with n-hexane (2 x 20 mL), decanted and dried 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)ethyl methanesulfonate as a yellow solid (3.4 g, 70%). Data for the title compound are in Table 2.

[0815] Synthetic Route 10: Procedure for Preparing Intermediate 138

[0816] Intermediate 138: 4-Methyl-2-(trimethylstannyl)thiazole

[0817]

[0818] To a solution of 4-methylthiazole (150 mg, 1.51 mmol) in diethyl ether (20 mL) at -78 °C was added methyllithium (470 mg, 2.25 mmol) dropwise, and the reaction was stirred at the same temperature for 1 h. At -78 °C, tributyltin chloride (180 mg, 1.65 mmol) was added, and the reaction was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and H 2 O(10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 4-methyl-2-(trimethylstannyl)thiazole, which was used in the next step without further purification.

[0819] Synthetic Route of the Examples

[0820] Route a: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Alkylation Reaction Followed by Suzuki Coupling

[0821] Example 1-1, 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-fluorophenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0822]

[0823] Step 1; At room temperature, 1-(Bromomethyl)-4-fluorobenzene (0.18 g, 1.18 mol) was added to a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.3 g, 0.98 mmol) and K 2 CO 3 (0.4 g, 2.94 mmol) in MeCN, and the reaction mixture was heated at 50 °C for 5 h. (In some analogs, a mixture of MeCN / DMSO was used as the solvent.) The reaction mixture was partitioned between EtOAc (15 mL) and H 2 O (15 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 a gradient of 0-20% EtOAc in hexane to afford 5-amino-8-bromo-2-(4-fluorobenzyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 24%) as a white solid.

[0824] LCMS (Method C): m / z 413 (M+H) + (ES + ) at 2.85 min, UV active.

[0825] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.61 (d, J = 6.0 Hz, 2H), 7.46 - 7.38 (m, 5H), 7.23 - 7.18 (m, 2H), 5.05 (s, 2H). No exchangeable -NH 2 proton

[0826] Step 2; 5-Amino-8-bromo-2-(4-fluorobenzyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.38 mmol), 2,6-dimethylpyridin-4-ylboronic acid pinacol ester (108 mg, 0.46 mmol) and K 2 CO 3 (104 mg, 0.76 mmol) in a mixture of 1,4-dioxane (4 mL) and H 2 O (1 mL) was degassed for a few minutes, Pd(PPh 3 ) 4 (22 mg, 0.02 mmol) was added, the vessel was sealed and heated to 120 °C for 6 h. After cooling to room temperature, 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 under reduced pressure and purified by Biotage-Isolera using 10 g of silica snap, eluting with hexane / EtOAc (50:50) to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-fluorophenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (46 mg, 43%) as a yellow solid. Data for the title compound are shown in Table 3.

[0827] Route b: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Methanesulfonylation and Displacement of Alcohol Followed by Suzuki Coupling

[0828] Examples 1-2, 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0829]

[0830] Step 1; Methanesulfonyl chloride (135 mg, 1.18 mmol) was added to a solution of (5-fluoropyridin-2-yl)methanol (150 mg, 1.18 mmol) and TEA (395 mg, 3.92 mmol) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was in DCM (20 mL) and H 2Partitioned between O (20 mL), the organic layer was separated and concentrated under reduced pressure to give the mesylated intermediate. The intermediate was placed in MeCN (20 mL) and 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 (405 mg, 2.94 mmol) were added, and the mixture was heated to 70 °C in a sealed tube for 16 h. (For other analogues, DMSO or a MeCN / DMSO mixture was used as the solvent.) 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. 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 5-amino-8-bromo-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as an off-white solid. Data for the title compound are in Table 2.

[0831] Step 2; A mixture of 5-amino-8-bromo-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.17 g, 0.41 mmol), 2,6-dimethylpyridin-4-ylboronic acid pinacol ester (113 mg, 0.49 mmol) and K 2 CO 3 (169 mg, 1.22 mmol) in 1,4-dioxane (15 mL) and H 2 O (5 mL) was degassed for a few minutes, Pd(PPh 3 ) 4 (46 mg, 0.04 mmol) was added, the vessel was sealed and heated to 120 °C for 5 h. The reaction mixture was partitioned between H 2 O (25 mL) and EtOAc (50 mL). The organic layer was separated, passed through anhydrous Na 2 SO 4Dry and concentrate. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with a 0 - 100% EtOAc in petroleum ether gradient to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid (82 mg, 44%). Data for the title compound are in Table 3.

[0832] Route c

[0833] Examples 1 - 3, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0834]

[0835] Step 1; To a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.98 mmol), (4-methoxyphenyl)methanol (162 mg, 1.1 mmol) and triphenylphosphine (385 mg, 1.4 mmol) in THF (10 mL) at room temperature was added di-tert-butyl azodicarboxylate (332 mg, 1.4 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by Biotage-Isolera using 10 g of silica snap and eluted with a 30 - 100% EtOAc in petroleum ether gradient to afford 5-amino-8-bromo-2-(4-methoxybenzyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as an off-white solid (180 mg, 44%).

[0836] LCMS (Method B): m / z 426 (M+H) + (ES + )), at 2.93 min, UV active.

[0837] 1 H NMR: (400 MHz, DMSO- d6) δ: 7.60 - 7.44 (m, 5H), 7.29 (d, J = 10.8 Hz, 2H), 6.93 (d, J = 10.8 Hz, 2H), 4.98 (s, 2H), 3.75 (s, 3H). No exchangeable -NH was observed. 2 proton

[0838] Step 2; Prepared in a similar manner to that of Route a, Step 2 to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (70 mg, 37%) as a yellow solid. Data for the title compound are in Table 3.

[0839] Route d: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Methanesulfonylation and Displacement of Alcohol

[0840] Examples 1-5, 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0841]

[0842] To a solution of pyridazin-3-ylmethanol (40 mg, 0.36 mmol) and TEA (90 mg, 0.90 mmol) in DCM (10 mL) at 0 °C was added methanesulfonyl chloride (45 mg, 0.39 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 give the mesylated intermediate. This intermediate was placed 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) and K 2 CO 3 (124 mg, 0.90 mmol) were added, and the mixture was heated in a sealed tube at 80 °C for 6 h. (In other examples, the reaction can be carried out in a mixture of MeCN / DMSO or in DMSO only). The reaction mixture was in EtOAc (20 mL) and H 2Partition between O (20 mL), separate the organic layer and concentrate it under reduced pressure. Purify the crude product using 10 g of silica snap by Biotage-Isolera, and elute with a gradient of 0 - 100% EtOAc in petroleum ether to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid (33 mg, 26%). Data for the title compound are in Table 3.

[0843] Route e: Typical Procedure for Preparing Triazolopyrimidinone via Demethylation Reaction

[0844] Examples 1 - 8, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0845]

[0846] Cool a mixture of 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((5-fluoro-6-methoxypyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.42 mmol) in MeCN (10 mL) to 0 °C, add trimethylsilyl iodide (212 mg, 1.06 mmol) and stir at room temperature for 2 h. Partition the reaction mixture between EtOAc (20 mL) and saturated NaHCO 3 (20 mL), separate the organic layer, wash it with saturated sodium bisulfate solution (20 mL), dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure. Triturate the crude product with MeOH to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid (130 mg, 67%). Data for the title compound are in Table 3.

[0847] Route f

[0848] Examples 1 - 10, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-1-methyl-6-oxo-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0849]

[0850] To a solution of 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (40 mg, 0.08 mmol) in MeCN (5 mL) was added K 2 CO 3 (33.1 mg, 0.24 mmol) and iodomethane (14.8 mg, 0.10 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and H 2 O (10 mL), the organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage isolera using 10 g of silica snap, eluting with 0-100% EtOAc in petroleum ether to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-1-methyl-6-oxo-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (9 mg, 25%) as a yellow solid. Data for the title compound are in Table 3.

[0851] Route g: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Mitsunobu Reaction

[0852] Examples 1-11, 5-amino-2-[1-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0853]

[0854] To 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (56 mg, 0.19 mmol), 1-(2,4-difluorophenyl)ethan-1-ol (38 mg, 0.24 mmol) and PPh 3A mixture of (62 mg, 0.24 mmol) in THF (3 mL) was added with di-tert-butyl azodicarboxylate (55 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 16 - 18 h. The mixture was concentrated and the product was purified by preparative HPLC (Method E) to afford 5-amino-2-[1-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (16 mg, 20%). Data for the title compound are in Table 3.

[0855] Route h: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Mitsunobu Reaction and Using Boc-Protection Strategy

[0856] Examples 1 - 30, 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[2-(piperidin-4-yl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0857]

[0858] At 0 °C, Boc 2 O (229 mg, 1.05 mmol) was added to a solution of [2-(piperidin-4-yl)phenyl]methanol (191 mg, 1 mmol) in MeOH (2 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was crystallized from a mixture of isopropanol / hexane to give the Boc-protected amine.

[0859] Di-tert-butyl azodicarboxylate (51 mg, 0.22 mmol) was added to a mixture of 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (66 mg, 0.20 mmol), Boc-protected amine (42 mg, 0.22 mol) and PPh 3 (68 mg, 0.26 mmol) in THF (3 mL). The reactants were stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure, the residue was dissolved in DCM (3 mL) and TFA (0.5 mL) was added, and the reactants were sonicated at room temperature for 2 h. The mixture was concentrated in vacuo and the product was purified by preparative HPLC (Method E) to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-[[2-(4-piperidinyl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (51 mg, 50%). Data for the title compound are in Table 3.

[0860] Route i

[0861] Examples 1 - 36, 5 - amino - 2 - [(6 - amino - 5 - fluoro - 2 - pyridinyl)methyl] - 8 - (2,6 - dimethyl - 4 - pyridinyl) - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0862]

[0863] Step 1: Conducted in a manner similar to Step - 1 of Route a, the reactants were heated to 80 °C and maintained for 16 h to provide N,N - di - tert - butoxycarbonyl(6 - ((5 - amino - 8 - (2,6 - dimethylpyridin - 4 - yl) - 3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2(3H) - yl)methyl) - 3 - fluoropyridin - 2 - yl)amine (30 mg, 15%) as a pale yellow solid.

[0864] LCMS (Method B): m / z 657 (M + H) + (ES + ), at 2.57 min, UV - active.

[0865] 1 1H NMR: (400 MHz, DMSO - d6 ) δ: 7.92 - 7.86 (m, 1H), 7.52 - 7.49 (m,1H), 7.26 - 7.25 (m, 5H), 6.76 (s, 2H), 5.11 (s, 2H), 2.25 (s, 6H), 1.29 (s,18H). No exchangeable - NH 2 protons were observed.

[0866] Step 2; To a stirred solution of N,N - di - tert - butoxycarbonyl(6 - ((5 - amino - 8 - (2,6 - dimethylpyridin - 4 - yl)-3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2(3H)-yl)methyl)-3 - fluoropyridin - 2 - yl)amine (30 mg, 0.04 mmol) in diethyl ether (3 mL) was added 2 M HCl in diethyl ether (2 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was loaded onto an SCX column and eluted with 20% ammonia in MeOH to afford 5 - amino - 2 - ((6 - amino - 5 - fluoropyridin - 2 - yl)methyl)-8 - (2,6 - dimethylpyridin - 4 - yl)-7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H)-one (5 mg, 27%) as a pale yellow solid. Data for the title compound are in Table 3.

[0867] Route j

[0868] Examples 1 - 38, 5 - amino - 8 - (2,6 - dimethyl - 4 - pyridyl)-2 - [1 - (5 - fluoro - 2 - pyridyl)propyl]-7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one and chiral resolution into enantiomers 1 - 38 iso - 1 and 1 - 38 iso - 2

[0869]

[0870] Step 1; To a suspension of 2 - bromo - 5 - fluoropyridine (5 g, 28.4 mmol) in THF (100 mL) at - 78 °C was added n - butyllithium (2 M in THF, 17 mL, 34.09 mmol) and the reaction mixture was stirred at - 78 °C for 1 h. At the same temperature, propionaldehyde (2.5 mL, 34.09 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by dropwise addition of NH 4 Cl solution (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by Biotage - Isolera using 50 g silica snap and eluted with a (0 - 100%) EtOAc in petroleum ether gradient to afford 1 - (5 - fluoropyridin - 2 - yl)propan - 1 - ol (1.5 g, 39%) as a brown liquid.

[0871] LCMS (method A): m / z 156 (M + H) + (ES+ ), at 0.86 min, ultraviolet active.

[0872] Step 2; At 0 °C, NaH (dispersion in mineral oil, 60%, 280 mg, 11.68 mmol) was added portionwise to a suspension of tosyl chloride (2.78 g, 14.61 mmol) and a catalytic amount of DMAP in THF (30 mL), followed by the addition of 1-(5-fluoropyridin-2-yl)propan-1-ol (1.5 g, 9.67 mmol) in THF (10 mL) at 0 °C, and then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with NH 4 Cl solution (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na 2 SO 4 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 1-(5-fluoropyridin-2-yl)propyl 4-methylbenzenesulfonate (1.5 g, 34%) as an off-white solid. The data are in Table 2.

[0873] Step 3; To a suspension 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) in MeCN (10 mL) and DMSO (2 mL) was added 1-(5-fluoropyridin-2-yl)propyl 4-methylbenzenesulfonate (232 mg, 0.75 mmol) and K 2 CO 3 (311 mg, 0.22 mmol). The reaction mixture was heated to 80 °C for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and H 2 O (10 mL). The organic layer was separated, dried over 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 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[1-(5-fluoro-2-pyridyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (110 mg, 29%) as a yellow solid. The data for the title compound are in Table 3.

[0874] The racemic compound was purified by chiral SFC (Method A) to provide 1-38 iso-1 as the first elution peak and 1-38 iso-2 as the second elution peak. The data for the title compound are in Table 3.

[0875] Route k: Typical Procedure for Preparing Pyridine N-Oxide via Oxidation Using mCPBA

[0876] Example 1-42, 5-Amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0877]

[0878] To a solution of 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (100 mg, 0.22 mmol) in DCM (10 mL) was added 3-chloroperoxybenzoic acid (50 mg, 0.18 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 10% sodium bicarbonate solution (10 mL) and extracted with EtOAc (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 Biotage-Isolera using 10 g of silica snap and eluted with a gradient of 0-100% EtOAc in hexane to afford 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid (28 mg, 27%). The data for the title compound are in Table 3.

[0879] Route l

[0880] Example 1-44, 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0881]

[0882] Step 1; Conducted in a manner similar to step - 2 of route a to afford methyl 4-(5-amino-2-((5-fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (70 mg, 19%) as a yellow solid.

[0883] LCMS (Method B): m / z 485 (M+H) + (ES + ), at 2.38 min, UV active.

[0884] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 8.54 - 8.52 (m, 1H), 7.77 - 7.75 (m,1H), 7.73 - 7.71 (m, 1H), 7.47 - 7.42 (m, 1H), 7.31 - 7.21 (m, 6H), 5.16 -5.13 (m, 2H), 3.81 (s, 3H), 2.01 (s, 3H). No exchangeable - NH 2 protons were observed.

[0885] Step 2; To a degassed solution of methyl 4-(5-amino-2-((5-fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (70 mg, 0.14 mmol) in MeOH at room temperature was added portionwise NaBH 4 (24 mg, 0.9 mmol) and the mixture was stirred for 15 h. The reaction mixture was partitioned between DCM (20 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 product was purified by Biotage-Isolera using 230 - 400 silica snap and eluted with a gradient of 0 - 100% EtOAc in hexane to afford 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (10 mg, 15%) as a yellow solid. Data for the title compound are in Table 3.

[0886] Route m

[0887] Examples 1 - 45, 5 - amino - 2 - [(6 - amino - 5 - fluoro - 2 - pyridinyl)methyl] - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridinyl] - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0888] Examples 1 - 48, 5 - amino - 2 - [(5 - fluoro - 6 - hydroxy - 2 - pyridinyl)methyl] - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridinyl] - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0889]

[0890] Step 1; To a solution of 5 - amino - 8 - bromo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one (350 mg, 1.143 mmol) and N,N - di - tert - butoxycarbonyl(6 - (bromomethyl) - 3 - fluoropyridin - 2 - yl) - amine (507 mg, 1.258 mmol) in DMSO (10 mL) was added K 2 CO 3 (473 mg, 3.430 mmol), and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was quenched with ice - cold water. The precipitate was filtered and dried under vacuum to afford 5 - amino - 2 - ((6 - di - Boc - protected amino - 5 - fluoropyridin - 2 - yl)methyl) - 8 - bromo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one (600 mg, 83%) as a yellow solid.

[0891] LCMS (Method A): m / z 431 (M + H - 2xBoc) + (ES + ), at 3.02 min, UV - active.

[0892] 1 H NMR: (400 MHz, DMSO - d6 ) δ: 7.92 (s, 2H), 7.61 - 7.56 (m, 3H), 7.46 - 7.45 (m, 4H), 5.15 (s, 2H), 1.37 (s, 18H).

[0893] Step 2; Prepared in a manner similar to Step - 2 of Route a to afford methyl 4-(5-amino-2-((6-di-Boc-protected amino-5-fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (250 mg, 37%) as a yellow solid.

[0894] LCMS (Method A): m / z 701 (M+H) + (ES + ), at 2.76 min, UV active.

[0895] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.91 - 7.87 (m, 2H), 7.65 - 7.56 (m, 3H), 7.32 - 7.20 (m, 5H), 5.12 (s, 2H), 3.78 (s, 3H), 2.36 (s, 3H), 1.29 (s, 18H). No exchangeable -NH 2 protons were observed.

[0896] Step 3; To a solution of methyl 4-(5-amino-2-((6-di-Boc-protected amino-5-fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (250 mg, 0.357 mmol) in THF (10 mL) at 0 °C was added dropwise lithium triethylborohydride (1 M solution in THF, 75.7 mg, 0.714 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and H 2 O (10 mL). The organic layer was separated, washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to afford 5-amino-2-((6-di-Boc-protected amino-5-fluoropyridin-2-yl)methyl)-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 41%) as a yellow solid. The crude product was used without purification in the next step.

[0897] LCMS (Method A): m / z 673 (M+H) + (ES +), at 4.09 min, UV-active.

[0898] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.91 - 7.87 (m, 2H), 7.66 - 7.50 (m, 3H), 7.25 - 7.13 (m, 5H), 5.15 (s, 2H), 4.85 (s, 2H), 2.19 (s, 3H), 1.24 (s, 18H). No exchangeable -NH 2 protons were observed.

[0899] Step 4; At room temperature, 4.0 M HCl (3 mL) in dioxane at 0 °C was added to a solution of 5-amino-2-((6-di-Boc-protected amino-5-fluoropyridin-2-yl)methyl)-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.14 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A), and 2 peaks were observed. The collected fractions were concentrated, and the residue was partitioned between EtOAc (10 mL) and 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-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (30 mg, 45%) as an off-white solid and 5-amino-2-[(5-fluoro-6-hydroxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (1.5 mg, 2%) as an off-white solid. Data for the title compound are in Table 3.

[0900] Route n

[0901] Examples 1 - 46 Isomers 1 and 2, 5-amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0902]

[0903] Step 1; To a stirred solution of 1-(6-fluoropyridin-2-yl)propyl 4-methylbenzenesulfonate (506 mg, 1.63 mmol) in DMSO (5 mL) was added 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 (674 mg, 4.89 mmol), and the resulting reaction mixture was heated to 80 °C for 2 h. The reaction mixture was poured into ice, and the precipitate was filtered and dried to afford 5-amino-8-bromo-2-(1-(6-fluoropyridin-3-yl)propyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a brown solid.

[0904] LCMS (Method A): m / z 442 (M+H) + (ES + ), at 2.69 min, UV active.

[0905] Step 2; Prepared in a similar manner to Step -2 of Route a to afford methyl 4-(5-amino-2-(1-(6-fluoropyridin-3-yl)propyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (300 mg, 41%) as a yellow solid.

[0906] LCMS (Method A): m / z 514 (M+H) + (ES + ), at 3.32 min, UV active.

[0907] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 8.47 (d, J = 6.4 Hz, 2H), 7.61 - 7.60 (m, 3H), 7.58 - 7.45 (m, 3H), 7.32 (d, J = 2.4 Hz, 2H), 5.50 (s, 1H), 4.04 - 4.03 (m, 2H), 3.93 (s, 3H), 2.38 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). No exchangeable -NH 2 protons were observed.

[0908] Step 3; At 0 °C, lithium triethylborohydride (1 M in THF, 1.16 mL, 1.16 mmol) was added to a solution of methyl 4-(5-amino-2-(1-(6-fluoropyridin-3-yl)propyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (300 mg, 0.58 mmol) in THF (20 mL), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by dropwise addition of water (20 mL) and extracted with EtOAc (10 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 25 g silica snap and eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford 5-amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid. The racemic compound was purified by chiral SFC (Method B) to afford 1-46 iso-1 as the first elution peak and 1-46 iso-2 as the second elution peak. The data for the title compound are in Table 3.

[0909] Route o: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Toluenesulfonylation and Displacement of Alcohol Followed by Ester Reduction Procedure

[0910] Example 1-47, 5-Amino-2-[(3-fluoro-5-methoxypyridin-2-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0911]

[0912] Step 1; At 0 °C, (3-fluoro-5-methoxypyridin-2-yl)methanol (90 mg, 0.57 mmol) was added to tosyl chloride (120 mg, 0.63 mmol), TEA (0.2 mL, 1.7 mmol) and a catalytic amount of DMAP in DCM (5 mL), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was in DCM (10 mL) and H 2Partitioned between O (10 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 4-(5-amino-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinic acid methyl ester (192 mg, 0.51 mmol), K 2 CO 3 (235 mg, 1.71 mmol) were added, and the resulting reaction mixture was heated in a sealed tube at 80 °C for 2 h. The reaction mixture was partitioned between EtOAc (10 mL) and H 2 O (10 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified using 10 g silica snap by Biotage-Isolera and eluted with a 0 - 100% EtOAc in petroleum ether gradient to afford methyl 4-(5-amino-2-((3-fluoro-5-methoxypyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (60 mg, 23%) as a yellow solid.

[0913] LCMS (Method A): m / z 516 (M+H) + (ES + ), at 2.56 min, UV active.

[0914] Step 2; Conducted in a manner similar to Step - 3 of Route m and 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 and concentrated to afford 5-amino-2-[(3-fluoro-5-methoxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (10 mg, 18%) as a yellow solid. Data for the title compound are in Table 3.

[0915] Route p: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Methanesulfonylation and Displacement of Alcohol Followed by Suzuki Coupling and Ester Reduction

[0916] Examples 1 - 49, 5 - Amino - 2 - [(5 - fluoro - 2 - pyridyl)methyl] - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridyl] - 7 - (2,3,4,5,6 - pentadeuterophenyl) - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0917]

[0918] Step 1; Using intermediates 47 and 4, carried out in a similar manner to step - 1 of route b to afford 5 - amino - 8 - bromo - 2 - ((5 - fluoropyridin - 2 - yl)methyl) - 7 - (phenyl - d5) - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one (450 mg, 83%) as a brown solid.

[0919] LCMS (Method C): m / z 421 (M + H) + (ES + ), at 2.06 min, UV - active.

[0920] 1 1H NMR: (400 MHz, DMSO - d6 ) δ: 8.55 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 4.4 Hz, 1H), 5.17 (s, 2H). No exchangeable - NH 2 protons were observed.

[0921] Step 2; Carried out in a similar manner to step - 2 of route a to afford methyl 4 - (5 - amino - 2 - ((5 - fluoropyridin - 2 - yl)methyl) - 3 - oxo - 7 - (phenyl - d5) - 2,3 - dihydro - [1,2,4]triazolo[4,3 - c]pyrimidin - 8 - yl) - 6 - methylpyridinecarboxylate (160 mg, 30%) as a yellow solid.

[0922] LCMS (Method C): m / z 491 (M + H) + (ES + ), at 2.06 min, UV - active.

[0923] Step 3; Carried out in a similar manner to step - 3 of route m and 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 and passed through anhydrous Na 2 SO 4Dried and concentrated to afford 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuterophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (40 mg, 26%) as a yellow solid. Data for the title compound are in Table 3.

[0924] Route q: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Mitsunobu Reaction Followed by Ester Reduction

[0925] Examples 1 - 50, 5-amino-2-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0926]

[0927] Step 1; Using intermediates 45 and 39, carried out in a manner similar to Step - 1 of Route c to afford methyl 4-(5-amino-2-((3-chloro-5-fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpyridinecarboxylate (25 mg, 14%) as a yellow solid.

[0928] LCMS (Method C): m / z 520 (M + H) + (ES + ) at 2.01 min, UV active.

[0929] 1 1H NMR: (400 MHz, DMSO - d6 ) δ: 8.56 (d, J = 2.8 Hz, 1H), 8.19 - 8.16 (m, 1H), 7.64 (s, 1H), 7.32 - 7.20 (m, 5H), 7.20 (s, 1H), 5.25 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H). No exchangeable - NH 2 protons were observed.

[0930] Step 2; Carried out in a manner similar to Step - 3 of Route m and 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 and passed through anhydrous Na 2 SO 4Dried and concentrated to afford 5-amino-2-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid (4 mg, 17%). Data for the title compound are in Table 3.

[0931] Route r: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Alkylation Reaction Followed by Ester Reduction and Boc-Deprotection

[0932] Examples 1 - 51, 5-amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0933]

[0934] Step 1; Using intermediates 49 and 38, carried out in a similar manner to step -1 of Route m to afford methyl 4-(5-amino-2-((6-di-boc-amino-5-fluoropyridin-2-yl)methyl)-3-oxo-7-(phenyl-d5)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate as a yellow solid (80 mg, 57%).

[0935] LCMS (Method C): m / z 706 (M+H) + (ES + )), at 2.44 min, UV active.

[0936] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.90 - 7.85 (m, 1H), 7.60 (s, 1H), 7.51(s, 1H), 7.18 (s, 1H), 5.10 (s, 2H), 3.77 (s, 3H), 2.34 (s, 3H), 1.27 (s,18H). No exchangeable -NH 2 protons were observed.

[0937] Step 2; Conducted in a similar manner to Step - 3 of Route m, and purified by flash column chromatography using a silica gel (230 - 400) mesh, and eluted with a gradient of 0 - 40% EtOAc in petroleum ether to afford 5 - amino - 2 - ((6 - diboc - amino - 5 - fluoropyridin - 2 - yl)methyl)-8-(2-(hydroxymethyl)-6 - methylpyridin - 4 - yl)-7-(phenyl - d5)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H)-one as a yellow solid (70 mg, 92%).

[0938] LCMS (Method C): m / z 578 (M + H - Boc) + (ES + ), at 1.43 min, UV - active.

[0939] Step 3; Conducted in a similar manner to Step - 4 of Route m to afford 5 - amino - 2 - [(6 - amino - 5 - fluoropyridin - 2 - yl)methyl]-8-[2-(hydroxymethyl)-6 - methylpyridin - 4 - yl]-7-(2,3,4,5,6 - pentadeuterophenyl)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one as a yellow solid (10 g, 20%). Data for the title compound are in Table 3.

[0940] Route s: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Methanesulfonylation and Displacement of Alcohol Followed by Ester Reduction

[0941] Examples 1 - 53, 5 - amino - 2 - [(5 - bromopyridin - 2 - yl)methyl]-8-[2-(hydroxymethyl)-6 - methylpyridin - 4 - yl]-7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0942]

[0943] Step 1; Conducted in a similar manner to Step - 1 of Route b to afford methyl 4-(5 - amino - 2 - ((5 - bromopyridin - 2 - yl)methyl)-3 - oxo - 7 - phenyl - 2,3 - dihydro - [1,2,4]triazolo[4,3 - c]pyrimidin - 8 - yl)-6 - methylpyridinecarboxylate as a pale yellow solid (120 mg, 36%).

[0944] LCMS (Method C): m / z 547 (M + H) + (ES + ), at 2.16 min, UV - active.

[0945] 1 1H NMR: (400 MHz, DMSO - d6) δ: 8.64 (s, 1H), 7.99 (s, 1H), 7.49 (s, 1H), 7.32 - 7.26 (m, 7H), 5.18 - 5.14 (m, 2H), 3.86 (s, 3H), 2.42 (s, 3H). No exchangeable -NH 2 protons.

[0946] Step 2; carried out in a manner similar to that of Route o Step -2 to afford 5 - amino - 2 - [(5 - bromo - 2 - pyridyl)methyl] - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridyl] - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one (12 mg, 10%) as a yellow solid. Data for the title compound are in Table 3.

[0947] Route t: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Alkylation Reaction

[0948] Examples 1 - 54, 6 - [[5 - amino - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridyl] - 3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2 - yl]methyl]pyridine - 3 - carbonitrile

[0949]

[0950] To a stirred solution of 5 - amino - 8 - (2 - (hydroxymethyl) - 6 - methylpyridin - 4 - yl) - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one (450 mg, 1.29 mmol) in DMSO (10 mL) was added 6 - (bromomethyl)nicotinonitrile (254 mg, 1.29 mmol) and K 2 CO 3 (535 mg, 3.87 mmol), and the reaction mixture was heated to 70 °C for 1 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. The crude product was purified by flash column chromatography using silica gel (230 - 400) mesh and eluted with a gradient of 0 - 3% MeOH in DCM to afford 6 - [[5 - amino - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridyl] - 3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2 - yl]methyl]pyridine - 3 - carbonitrile (290 mg, 48%) as a yellow solid. Data for the title compound are in Table 3.

[0951] Route u: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Ester Reduction Followed by Alkylation Reaction

[0952] Examples 1 - 63, 6 - [[5 - amino - 7 - (4 - fluorophenyl) - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridinyl] - 3 - oxo - [1,2,4]triazolo[4,3 - c]pyrimidin - 2 - yl]methyl]pyridine - 3 - carbonitrile

[0953]

[0954] Step 1; Conducted in a manner similar to that of Route o Step - 2 to afford 5 - amino - 7 - (4 - fluorophenyl) - 8 - (2 - (hydroxymethyl) - 6 - methylpyridin - 4 - yl) - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one (460 mg, 48%) as a yellow solid.

[0955] LCMS (Method C): m / z 367 (M + H) + (ES + ), UV - active at 2.16 min.

[0956] 1 1H NMR: (400 MHz, DMSO - d6 ) δ: 12.42 (s, 1H), 7.33 - 7.29 (m, 2H), 7.12 - 7.08 (m, 3H), 6.87 (s, 1H), 5.26 (t, J = 5.8 Hz, 1H), 4.43 (d, J = 5.8 Hz, 2H), 2.32 (s, 3H). No exchangeable - NH 2 protons were observed.

[0957] Step 2; Conducted in a manner similar to that of Route t to afford 6 - [[5 - amino - 7 - (4 - fluorophenyl) - 8 - [2 - (hydroxymethyl) - 6 - methyl - 4 - pyridinyl] - 3 - oxo - [1,2,4]triazolo[4,3 - c]pyrimidin - 2 - yl]methyl]pyridine - 3 - carbonitrile (250 g, 41%). Data for the title compound are in Table 3.

[0958] Route v: Typical procedure for preparing alkylated triazolopyrimidinones via Suzuki coupling and Ar substitution N Ar substitution

[0959] Examples 1 - 71, 5 - amino - 8 - [2 - (dimethylamino) - 6 - methyl - 4 - pyridinyl] - 2 - [(5 - fluoropyridin - 2 - yl)methyl] - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[0960]

[0961] Step 1; Conducted in a manner similar to Step - 2 of Route a to afford 5 - amino - 8-(2 - fluoro - 6 - methylpyridin - 4 - yl)-2-((5 - fluoropyridin - 2 - yl)methyl)-7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H)-one as a yellow solid (700 mg, 33%).

[0962] LCMS (Method C): m / z 446 (M + H) + (ES + ), at 1.93 min, UV - active.

[0963] 1 1H NMR: (400 MHz, DMSO - d6 ) δ: 8.55 - 8.02 (m, 1H), 8.00 (s, 1H), 7.77 - 7.72 (m, 2H), 7.29 - 6.93 (m, 5H), 6.68 (s, 1H), 5.15 - 5.11 (m, 2H), 2.26 (s,3H). No exchangeable - NH 2 protons were observed.

[0964] Step 2; To a solution of 5 - amino - 8-(2 - fluoro - 6 - methylpyridin - 4 - yl)-2-((5 - fluoropyridin - 2 - yl)methyl)-7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H)-one (350 mg, 0.78 mmol) in NMP (5 mL) was added TEA (0.3 mL, 2.34 mmol) and N,N - dimethylamine hydrochloride (130 mg, 0.56 mmol), and the resulting reaction mixture was heated to 120 °C for 16 h. (In other analogs, TEA can be omitted and an excess of amine (free base) can be used.) The reaction mixture was partitioned between H 2 2O (20 mL) and EtOAc (40 mL). The organic layer was separated, dried over anhydrous Na 2 2SO 4 4 and concentrated. The crude product was purified by preparative HPLC (Method A). The collected fractions were concentrated under reduced pressure, and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na 2 2SO 4Dried and concentrated to afford 5-amino-8-(2-(dimethylamino)-6-methylpyridin-4-yl)-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (45 mg, 12%) as a yellow solid. Data for the title compound are in Table 3.

[0965] Route w

[0966] Example 1-77, 5-amino-8-(2-chloro-6-methyl-4-pyridinyl)-2-[(5-methoxy-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0967]

[0968] To a stirred solution of 5-amino-8-(2-chloro-6-methylpyridin-4-yl)-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.2 mmol) in DMSO (1 mL) was added NaOMe (35 mg, 0.6 mmol), and the reaction mixture was heated to 120 °C for 5 h. The reaction mixture was partitioned between H 2 O (10 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 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 and concentrated to afford 5-amino-8-(2-chloro-6-methylpyridin-4-yl)-2-((5-methoxypyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (12 mg, 12%) as an off-white solid. Data for the title compound are in Table 3.

[0969] Route x: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Aldol Condensation Reaction

[0970] Example 1-80, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0971]

[0972] Step 1; At room temperature, add phenylacetaldehyde (0.357 g, 2.98 mmol) to a solution of 4-hydrazino-6-phenylpyrimidin-2-amine (0.6 g, 2.98 mmol) in MeOH (5 mL), and stir the resulting reactant for 3 h. Concentrate the mixture under reduced pressure and dry it under vacuum. Grind the resulting residue with petroleum ether (3 x 3 mL), decant, and dry under high vacuum to afford (E)-4-phenyl-6-(2-(2-phenylethylidene)hydrazino)pyrimidin-2-amine (0.62 g, 68%) as an off-white solid.

[0973] LCMS (Method D): m / z 304 (M+H) + (ES + ), at 3.86 min, UV active.

[0974] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 10.55 (br s, 1H), 7.98 - 7.96 (m, 2H), 7.49 - 7.46 (m, 4H), 7.37 - 7.32 (m, 2H), 7.30 - 7.23 (m, 3H), 6.76 (s, 1H), 6.20 (br s, 2H), 3.61 (d, J = 5.8 Hz, 2H)

[0975] Step 2; At -30 °C, add lithium aluminum hydride (1 M in THF, 9.9 mL, 9.9 mmol) dropwise over 2 min to a solution of 4-phenyl-6-(2-(2-phenylethylidene)hydrazino)pyrimidin-2-amine (0.6 g, 1.98 mmol) in THF (20 mL). Stir the reaction mixture at room temperature for 2 h. Quench the reactant with saturated Na 2 SO 4 solution (20 mL), and extract with EtOAc (2 x 15 mL). Dry and concentrate the combined organic layers over anhydrous Na 2 SO 4 to afford 4-(2-phenethylhydrazino)-6-phenylpyrimidin-2-amine as a brown gum, which is used in the next step without purification.

[0976] Step 3; In N 2A solution of 4-(2-phenethylhydrazino)-6-phenylpyrimidin-2-amine (600 mg, 1.96 mmol) cooled to -20 °C in dry THF (10 mL) was treated with triphosgene (1152 mg, 3.92 mmol), and the mixture was stirred for 45 min. The reaction mixture was concentrated and purified by flash chromatography using gradient elution with CH 2 Cl 2 / MeOH 95:5 to afford 5-amino-2-phenethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (350 mg, 53%) as a pale yellow solid.

[0977] LCMS (Method D): m / z 332 (M+H) + (ES + ), retention time 3.86 min, UV active.

[0978] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.91 (d, J = 9.6 Hz, 2H), 7.49 - 7.46 (m, 3H), 7.35 - 7.31 (m, 2H), 7.27 - 7.24 (m, 3H), 6.70 (s, 1H), 4.17 - 4.13 (m, 2H), 3.18 - 3.15 (m, 2H). No exchangeable -NH 2 protons were observed.

[0979] Step 4; To a suspension of 5-amino-2-phenethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (350 mg, 1.05) in CH 2 Cl 2 / MeOH 1:1 (10 mL) was added CaCO 2 (105 mg, 1.05 mmol) and (CH 3 ) 3 3 PhN + Br 3 - (392 mg, 1.05 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with H 2 O and extracted with CH 2 Cl 2 . The organic layer was dried over Na 2 SO 4 ​Dry and concentrate. The crude product was purified by flash column chromatography using a gradient of CH 2 Cl 2 / MeOH 95:5 to afford 5-amino-8-bromo-2-phenethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (140 mg, 30%) as a yellow solid.

[0980] LCMS (Method D): m / z 409 (M+H) + (ES + ), retention time 4.19 min, UV active.

[0981] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.64 - 7.61 (m, 2H), 7.49 - 7.44 (m,3H), 7.33 - 7.21 (m, 5H), 4.06 (t, J = 14.4 Hz, 2H), 3.06 (t, J = 14.4 Hz,2H). No exchangeable -NH 2 protons were observed.

[0982] Step 5; was carried out in a similar manner to Step - 2 of Route a to afford 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-phenethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (68 mg, 45%) as a pale yellow solid. Data for the title compound are in Table 3.

[0983] Route y

[0984] Example 1 - 85, 4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoic acid

[0985]

[0986] To a solution of methyl 4-(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)benzoate (50 mg, 0.1 mmol) in THF (2 mL) and H 2 O (1 mL) was added LiOH.H 2O (9 mg, 0.20 mmol), and the reactants were stirred at room temperature for 6 h. The reaction mixture was acidified to pH~6 and concentrated. The crude product was purified by passing through an SCX cartridge (SolEx SCX, 6 mL, 500 mg), eluted with methanolic ammonia and dried to afford 4-(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)benzoic acid (12 mg, 25%) as a yellow solid. Data for the title compound are in Table 3.

[0987] Route z

[0988] Examples 1 - 90, 5-amino-8-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0989]

[0990] A solution of 5-amino-8-(2-chloro-6-methylpyridin-4-yl)-2-phenylethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg, 0.13 mmol) and azetidine (12 mg, 0.19 mmol) in NMP (2 mL) was heated at 150 °C for 16 h. The reaction mixture was partitioned between EtOAc (10 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 compound was purified using 10 g of silica snap by Biotage-Isolera and gradient of EtOAc in hexane to afford 5-amino-8-(2-(azetidin-1-yl)-6-methylpyridin-4-yl)-2-phenylethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (7 mg, 10%) as a pale yellow solid. Data for the title compound are in Table 3.

[0991] Route aa: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Displacement Reaction

[0992] Examples 1 - 91, 5-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-2-chloro-N-methyl-benzamide

[0993]

[0994] 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 5-amino-2-chloro-N-methylbenzamide hydrochloride (42 mg, 0.19 mmol). The reaction mixture was heated at 100 °C for 15 h. The mixture was 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-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-2-chloro-N-methyl-benzamide (7 mg, 8%). Data for the title compound are in Table 3.

[0995] Route ab

[0996] Example 2 - 16, Ethyl N-ethylcarbamate 2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl ester

[0997]

[0998] Step 1; 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 (50 mg, 0.13 mmol), di-tert-butyl dicarbonate (31 mg, 0.14 mmol), TEA (0.69 ml, 0.52 mmol) in THF (5 mL) at room temperature was added DMAP (8 mg, 0.006 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was partitioned between EtOAc (20 mL) and sodium bicarbonate (10 mL). The organic layer was dried over anhydrous Na 2 SO 4Dry, concentrate under reduced pressure to afford tert-butyl (2-(2-((tert-butoxycarbonyl)oxy)ethyl)-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate (80 mg, crude), which was used without purification.

[0999] LCMS (Method B): m / z 677 (M+H) + (ES + ), retention time 2.89 min, UV active.

[1000] Step 2; To a suspension of tert-butyl (2-(2-((tert-butoxycarbonyl)oxy)ethyl)-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate (80 mg, 0.118 mmol) in 1,4-dioxane (2 mL) was added 2 N aqueous NaOH solution (3 mL). The reaction mixture was stirred at room temperature for 48 h and then partitioned between EtOAc (10 mL) and water (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 10% MeOH in DCM to afford tert-butyl (8-(2,6-dimethylpyridin-4-yl)-2-(2-hydroxyethyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate (40 mg, 21%) as a yellow solid.

[1001] LCMS (Method B): m / z 477 (M+H) + (ES + ), retention time 2.32 min, UV active.

[1002] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 10.24 (s, 1H), 7.38 - 7.27 (m, 5H), 6.91 (s, 2H), 4.89 (s, 1H), 3.87 (t, J = 7.6 Hz, 2H), 3.63 (t, J = 7.6 Hz, 2H), 2.35 (s, 6H), 1.51 - 1.49 (m, 9H).

[1003] Step 3; At room temperature, ethyl isocyanate (5 mg, 0.066 mmol) was added to a suspension of tert-butyl (8-(2,6-dimethylpyridin-4-yl)-2-(2-hydroxyethyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate (35 mg, 0.073 mmol) and TEA (0.02 ml, 0.014 mmol) in THF (5 mL). The reaction mixture was heated to 60 °C and maintained for 12 h. The reaction mixture 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 , concentrated under reduced pressure and purified by Biotage-Isolera using 10 g of silica snap, eluting with a gradient of 10% MeOH in DCM to afford tert-butyl (tert-butoxycarbonyl)(8-(2,6-dimethylpyridin-4-yl)-2-(2-((ethylcarbamoyl)oxy)ethyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate (30 mg, 74%) as a yellow solid.

[1004] LCMS (Method B): m / z 547 (M+H) + (ES + ), UV active at 2.50 min.

[1005] Step 4; 5 mL of 20% TFA / DCM was added to a suspension of tert-butyl (tert-butoxycarbonyl)(8-(2,6-dimethylpyridin-4-yl)-2-(2-((ethylcarbamoyl)oxy)ethyl)-3-oxo-7-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)carbamate (30 mg, 0.054 mmol) in DCM. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, loaded onto an SCX cartridge and eluted with 2 M ammonia in methanol 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)ethylcarbamate (4 mg, 7%) as a yellow solid. Data for the title compound are in Table 3.

[1006] Route ac

[1007] Example 2-17, 5-Amino-2-(3,3-difluoropropyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1008]

[1009] Step 1; Prepared in a manner similar to Step 1 of Route a and purified by trituration with diethyl ether to afford 5-amino-8-bromo-2-(3,3-dimethoxypropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.2 g, 45%) as an off-white solid.

[1010] LCMS (Method B): m / z 408 (M+H) + (ES + ), at 2.68 min, UV active.

[1011] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.62 - 7.61 (m, 2H), 7.48 - 7.43 (m,3H), 4.47 (t, J = 5.6 Hz, 1H), 3.85 (t, J = 7.2 Hz, 2H), 3.26 (s, 6H), 1.99 -1.94 (m, 2H). No exchangeable -NH 2 protons were observed.

[1012] Step 2; To a solution of 5-amino-8-bromo-2-(3,3-dimethoxypropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.2 g, 2.94 mmol) in 1,4-dioxane (10 mL) at room temperature was added 2 N HCl (30 mL) and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc (30 mL) and saturated NaHCO 3 solution (20 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanal (0.6 g) as a brown gum, which was used immediately in the next step.

[1013] LCMS (Method B): m / z 362 (M+H) +(ES + ) is UV-active at 2.32 min.

[1014] Step 3; At -78 °C, DAST (0.58 g, 3.63 mmol) was added to a solution of 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanal (0.6 g, 1.65 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for 15 h. The reaction mixture was carefully quenched by dropwise addition of saturated sodium bicarbonate solution (40 mL) and extracted with DCM (2 x 30 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 25 g of silica snap and eluted with a gradient of 0 - 40% EtOAc in hexane to afford 5-amino-8-bromo-2-(3,3-difluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.2 g, 31%) as an off-white solid.

[1015] LCMS (Method B): m / z 384 (M+H) + (ES + ) is UV-active at 2.80 min.

[1016] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.63 - 7.61 (m, 2H), 7.48 - 7.45 (m, 3H), 6.35 - 6.05 (m, 1H), 3.99 (t, J = 6.8 Hz, 2H), 2.39 - 2.22 (m, 2H). No exchangeable -NH 2 protons

[1017] Step 4; Was carried out in a manner similar to Step 2 of Route a to afford 5-amino-2-(3,3-difluoropropyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (100 mg, 47%) as a yellow solid. Data for the title compound are in Table 3.

[1018] Route ad: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Alkylation Reaction

[1019] Example 2-20, 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1020]

[1021] Carried out in a manner analogous to Step 1 of Route a to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (45 mg, 40%) as a yellow solid. Data for the title compound are in Table 3.

[1022] Route ae: Typical Procedure for Preparing Amide

[1023] Example 2-23, 3-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-propionamide

[1024]

[1025] Step 1; Using ethyl 3-bromopropionate and Intermediate 7, carried out in a manner analogous to Step 1 of Route a to afford ethyl 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propionate (180 mg, 69%) as a yellow solid. Data for this compound are in Table 2.

[1026] Step 2; To a suspension of ethyl 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propionate (90 mg, 0.20 mmol) in THF (5 mL), H 2 O (5 mL) and MeOH (1 mL) was added lithium hydroxide monohydrate (43 mg, 1.04 mmol), and the reaction mixture was stirred at room temperature for 45 min. The reaction was partitioned between EtOAc (5 mL) and H 2 O (5 mL). The aqueous layer was separated and acidified with 6 N HCl (2 mL) and extracted with EtOAc (10 mL). The organic layer was dried over anhydrous Na 2 SO 4Dry and concentrate under reduced pressure to afford 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanoic acid (80 mg, 84%) as a yellow solid.

[1027] LCMS (Method A): m / z 405 (M+H) + (ES + ), retention time 2.11 min, UV active.

[1028] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.26 - 7.23 (m, 5H), 6.82 (s, 2H), 3.98 (t, J = 8.0 Hz, 2H), 2.74 (t, J = 8.0 Hz, 2H), 2.30 (s, 6H). No exchangeable protons were observed.

[1029] Step 3; To a suspension 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)propanoic acid (80 mg, 0.19 mmol) in THF (10 mL) was added DIPEA (196 mg, 1.5 mmol), dimethylamine hydrochloride (100 mg, 1.14 mmol) and HATU (108 mg, 0.28 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc (10 mL) and H 2 2O (5 mL). The organic layer was separated, dried over anhydrous Na 2 2SO 4 4 and concentrated under reduced pressure. The crude product was dissolved in MeOH (5 mL), passed through an SCX column and eluted with 2 N ammonia in methanol (10 mL) and concentrated to afford 3-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-propanamide (29 mg, 33%) as a yellow solid. Data for the title compound are in Table 3.

[1030] Route af

[1031] Example 2-24, 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[3-hydroxy-2-(hydroxymethyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1032]

[1033] Step 1; Using (2,2-dimethyl-1,3-dioxan-5-yl)methanol and Intermediate 7, proceed in a similar manner as in Step 1 of Route b to afford 5-amino-2-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a white solid (55 mg, 20%).

[1034] LCMS (Method B): m / z 461 (M+H) + (ES + ), at 2.08 min, UV active.

[1035] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.26 - 7.24 (m, 5H), 6.82 (s, 2H), 3.90 - 3.85 (m, 4H), 3.65 - 3.63 (m, 2H), 2.30 (s, 6H), 2.00 - 1.88 (m, 1H), 1.33 (s, 6H). No exchangeable -NH 2 protons were observed.

[1036] Step 2; To a solution of 5-amino-2-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (50 mg, 0.1 mmol) in 1,4-dioxane (5 mL) was added 6 N HCl (2 mL), and the reaction mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and partitioned between 10% sodium bicarbonate (15 mL) and EtOAc (15 mL). The organic layer was separated and dried over anhydrous Na 2 SO 4Dry and concentrate. Recrystallize the crude product from diethyl ether to afford 5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(3-hydroxy-2-(hydroxymethyl)propyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (40 mg, 88%). Data for the title compound are in Table 3.

[1037] Route ag

[1038] Example 2-31, 3-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propanamide

[1039]

[1040] 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)acetate (90 mg, 0.28 mmol) in a 2 N ammonia in methanol solution was heated at 100 °C for 16 h. The reaction mixture was concentrated, dissolved in MeOH (5 mL), passed through an SCX column and eluted with 2 N ammonia in methanol solution (10 mL) and concentrated to afford 3-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propanamide as a yellow solid (35 mg, 35%). Data for the title compound are in Table 3.

[1041] Route ah: Typical Procedure for Preparing Alkylated Triazolopyrimidinone via Alkylation Reaction

[1042] Example 2-37, 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1043]

[1044] Step 1; To a suspension of 5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.25 mmol) in THF (10 mL) was added TEA (0.07 mL, 0.77 mmol), Boc anhydride (218 mg, 0.77 mmol) and a catalytic amount of DMAP. The reaction mixture was heated to 50 °C for 5 h. The reaction mixture was partitioned between EtOAc (10 mL) and H 2 O (10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford di-boc protected-5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 14%), which was used in the next step without purification.

[1045] LCMS (Method A): m / z 587 (M+H) + (ES + ), retention time 2.66 min, UV active.

[1046] Step 2; To a solution of di-boc protected-5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.17 mmol) in 1,4-dioxane (20 mL) was added 2-(tributylstannyl)pyridine (75.3 mg, 0.20 mmol) and Pd(PPh 3 ) 4 (19.6 mg, 0.01 mmol). The reaction mixture was heated to 120 °C in a sealed tube for 4 h, then partitioned between EtOAc (20 mL) and H 2 O (15 mL). The organic layer was separated, dried over Na 2 SO 4Dry and concentrate under reduced pressure. Purify the crude product by Biotage-Isolera using 10 g of silica snap, eluting with a gradient of 0 - 100% EtOAc in hexane to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (20 mg, 27%). Data for the title compound are in Table 3.

[1047] Route ai

[1048] Example 2 - 41, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methylpyrazol-1-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[1049]

[1050] A suspension of 5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.25 mmol), 4-methyl-1H-pyrazole (0.5 mL), and DIPEA (0.5 mL) was placed in a sealed vial and heated to 120 °C for 16 h. The reaction mixture was partitioned between EtOAc (10 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 recrystallized from hexane to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methylpyrazol-1-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (11 mg, 11%). Data for the title compound are in Table 3.

[1051] Route aj

[1052] Example 2 - 51, 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[1053]

[1054] Step 1; At 0 °C, TEA (1.3 mL, 9.6 mmol) was added to a solution of 3,3,3-trifluoropropan-1-ol (400 mg, 3.6 mmol) in DCM (10 mL), and then methanesulfonyl chloride (0.4 mL, 4.8 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h and then partitioned between DCM (20 mL) and brine solution (20 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 3,3,3-trifluoropropyl methanesulfonate. This intermediate was added to a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1 g, 3.2 mmol) and K 2 CO 3 (1.3 g, 9.6 mmol) in MeCN (20 mL), and the reaction mixture was stirred at 80 °C for 15 h. The reaction 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 under reduced pressure. The crude product was triturated with MeOH (5 mL), filtered through a Buchner funnel and dried in vacuo to afford 5-amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (700 mg, 53%) as an off-white solid.

[1055] LCMS (Method B): m / z 402 (M+H) + (ES + ), at 2.69 min, UV active.

[1056] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 8.26 (s, 2H), 7.64 - 7.61 (m, 2H), 7.47 - 7.44 (m, 3H), 4.10 (t, J = 8.8 Hz, 2H), 2.84 - 2.76 (m, 2H).

[1057] Step 2; 5-Amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.6 g, 1.49 mmol), methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (1 g, 3.6 mmol) and K 2 CO 3 (0.61 g, 4.47 mmol) in a mixture of 1,4-dioxane (20 mL) and H 2 O (2 mL) were degassed for a few minutes, Pd(PPh 3 ) 4 (17 mg, 0.015 mmol) was added, the vessel was sealed and heated to 120 °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. The crude product was purified by Biotage-Isolera using 10 g of silica snap and eluted with a gradient of 0 - 80% EtOAc in hexane to afford methyl 4-(5-amino-3-oxo-7-phenyl-2-(3,3,3-trifluoropropyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (150 mg, 22%) as a yellow solid.

[1058] LCMS (Method A): m / z 472 (M+H) + (ES + ), at 3.52 min, UV active.

[1059] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.67 (s, 1H), 7.30 - 7.26 (m, 6H), 4.06 (t, J = 6.5 Hz, 2H), 3.81 (s, 3H), 2.76 - 2.73 (m, 2H), 2.41 (s, 3H). No exchangeable -NH 2 protons were observed.

[1060] Step 3; At room temperature, NaBH 4 (48 mg, 1.27 mmol) was added portionwise to a solution of methyl 4-(5-amino-3-oxo-7-phenyl-2-(3,3,3-trifluoropropyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylpicolinate (120 mg, 0.25 mmol) in MeOH and the reactants were stirred for 15 h. The reaction mixture was partitioned between DCM (20 mL) and saturated NaHCO 3 solution (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 230-400 silica snap and eluted with a gradient of 0-100% EtOAc in hexanes to afford 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (63 mg, 55%) as a yellow solid. Data for the title compound are in Table 3.

[1061] Route ak: Typical Procedure for Boc-Deprotection Using TFA

[1062] Example 2-55, 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(3-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1063]

[1064] A solution of tert-butyl 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)piperidine-1-carboxylate (70 mg, 0.13 mmol) in 20% TFA / DCM (5 mL) was stirred at room temperature for 15 h and then concentrated. The crude material was dissolved in MeOH (2 mL) and passed through a DSC-SCX column (6 mL), washed with water (5 mL) and finally the compound was eluted with a 2M solution of ammonia in MeOH (10 mL), concentrated and lyophilized to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(3-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (34 mg, 60%) as a yellow solid. Data for the title compound are in Table 3.

[1065] Route al: Typical Procedure for Preparing Pyridine N-Oxide

[1066] Example 2-56, 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1067]

[1068] To a stirred solution of 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (60 mg, 0.14 mmol) in DCM at 0 °C was added portionwise m -CPBA (30 mg, 0.16 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and H 2 O (10 mL). The organic layer was separated and 2 SO 4 The crude product was purified by preparative HPLC (method A). The collected fractions were concentrated under reduced pressure, and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated and purified by anhydrous Na 2 SO 4 Drying and concentration gave 5-amino-8-(2,6-dimethyl-1-oxido-pyridin-1-ium-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (30 mg, 48%) as a yellow solid. The data for the title compound are in Table 3.

[1069] Route am: Typical Procedure for Alkylation of Amine via Reductive Amination

[1070] Example 2-72, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-4-methylmorpholin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1071]

[1072] To a suspension of (S)-5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (80 mg, 0.185 mmol) in MeCN was added aqueous 35% formaldehyde (16 mg, 0.185 mmol) and the mixture was stirred for 10 min. Sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added to the reaction mixture and stirred at room temperature for 15 min. The reaction mixture was partitioned between H 2 O (10 mL) and EtOAc (10 mL), the organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified using 10 g silica snap by Biotage-Isolera and eluted with a gradient of 0 - 20% EtOAc in MeOH to afford (S)-5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((4-methylmorpholin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (30 mg, 38%) as a yellow solid. Data for the title compound are in Table 3.

[1073] Route an

[1074] Example 2 - 79, (R)-5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[1075]

[1076] Step 1; was carried out in a similar manner to Step 1 of Route b and purified by preparative HPLC (Method - C) to afford (R)-5-amino-2-((4-benzylmorpholin-3-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (320 mg, 40%) as a yellow solid.

[1077] LCMS (Method A): m / z 522 (M + H) + (ES + ) at 2.37 min, UV active.

[1078] Step 2; To a mixture of (R)-5-amino-2-((4-benzylmorpholin-3-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.57 mmol) in MeOH (10 mL) was added Pd(OH) 2 , and the reaction mixture was stirred under H 2 atmosphere (balloon pressure) for 15 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product was purified using 25 g of silicasnap by Biotage isolera, eluting with a gradient of 0 - 10% MeOH in EtOAc to afford (R)-5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (120 mg, 48%) as a yellow solid. Data for the title compound are in Table 3.

[1079] Route ao: Typical procedure for preparing alkylated triazolopyrimidinones via tosylation of alcohol and substitution reaction

[1080] Example 2 - 81, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (subsequently chiral resolved into its enantiomers, 2 - 81 iso - 1 and 2 - 81 iso - 2)

[1081]

[1082] To a solution of tosyl chloride (189.4 mg, 0.99 mmol), DMAP (11 mg, 0.09) and TEA (0.4 mL, 2.71 mmol) in DCM (10 mL) at 0 °C was added dropwise (tetrahydro-2H-pyran-3-yl)methanol (126 mg, 1.08 mmol) in DCM (1 mL), and the resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (20 mL) and H 2 O (20 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the tosylated intermediate. The tosylated intermediate was placed into a vessel containing 5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.90 mmol) and K2 CO 3 (374 mg, 2.71 mmol) in MeCN (20 mL), and the resulting reaction mixture was heated to 50 °C in a sealed bottle for 6 h. The reaction mixture was partitioned between EtOAc (20 mL) and H 2 O (20 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified using 10 g of silica gel snap via Biotage-Isolera and eluted with a gradient of 0 - 100% EtOAc in petroleum ether to afford 5-amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid.

[1083] The racemic compound was purified by chiral SFC (Method C) to afford 2-81 iso-1 as the first eluted peak and 2-81 iso-2 as the second eluted peak. The data for the title compound are in Table 3.

[1084] Route ap: Typical procedure for Boc deprotection using HCl

[1085] Example 2-86, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1086]

[1087] To a solution of (R)-tert-butyl 3-((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-methylpiperazine-1-carboxylate (250 mg, 0.45 mmol) in 1,4-dioxane (10 mL) at 0 °C was added HCl in 1,4-dioxane (4 N solution, 5 mL) and the mixture was stirred at room temperature for 6 h. The mixture was concentrated and the residue was washed and decanted with diethyl ether (10 mL). The crude product was purified by preparative HPLC (Method A), the pure fractions were concentrated and the residue was diluted with 10% MeOH in DCM (10 mL) and loaded onto an SCX cartridge. The cartridge was eluted with H 2Washed with O and MeOH, and the product was eluted with 20% ammonia in MeOH (10 mL) and concentrated under reduced pressure to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[[(2R)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (175 mg, 87%) as a yellow solid. Data for the title compound are in Table 3.

[1088] Route aq: Typical procedure for preparing alkylated triazolopyrimidinones via tosylation of alcohol and substitution reaction, followed by Suzuki coupling and ester reduction Route ar: Typical procedure for preparing amine analogs via tosylation of alcohol and substitution reaction, followed by Suzuki coupling

[1089] Example 2 - 91 ios-1 and 2 - 91 iso-2, 5-amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridyl]-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1090]

[1091] Step 1; To a solution of (tetrahydro-2H-pyran-2-yl)methanol (500 mg, 4.30 mmol) in pyridine (5 mL) at 0 °C was added 4-toluenesulfonyl chloride (984 mg, 5.16 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and diluted with H 2 O (10 mL). The reaction mixture was extracted with EtOAc (2 x 10 mL), and the combined organic layers were washed with brine solution (20 mL), dried over Na 2 SO 4 and concentrated to afford the tosylated intermediate. The resulting tosylated intermediate was placed in DMSO containing 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (770 mg, 2.52 mmol) and K 2 CO 3 (1.04 g, 7.57 mmol), and the resulting reaction mixture was heated to 70 °C for 7 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. The crude product was purified by Biotage Isolera column chromatography using silica gel (230 - 400) mesh, eluting with a 0 - 100% gradient of EtOAc in petroleum ether to afford 5-amino-8-bromo-7-phenyl-2-((tetrahydro-2H-pyran-2-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (420 mg, 41%) as a white solid.

[1092] LCMS (Method A): m / z 404 (M+H) + (ES + ), UV active at 2.26 min.

[1093] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.63 - 7.61 (m, 2H), 7.48 - 7.44 (m, 3H), 3.92 - 3.83 (m, 2H), 3.76 - 3.69 (m, 2H), 3.34 (m, 1H), 1.79 (s, 1H), 1.67 (d, J = 12.40 Hz, 1H), 1.47 (s, 3H), 1.27 - 1.18 (m, 1H). No exchangeable -NH 2 protons were observed.

[1094] Step 2; carried out in a manner similar to Step 2 of Route a to afford methyl 4-(5-amino-3-oxo-7-phenyl-2-((tetrahydro-2H-pyran-2-yl)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)picolinate (350 mg, 70%) as a yellow solid.

[1095] LCMS (Method A): m / z 473 (M-H) - (ES - ), UV active at 2.26 min.

[1096] Step 3; carried out in a manner similar to Step 2 of Route o to afford 5-amino-8-(2-(hydroxymethyl)-6-methylpyridin-4-yl)-7-phenyl-2-((tetrahydro-2H-pyran-2-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid.

[1097] The racemic compound was purified by chiral SFC (Method D) to afford 2-91 iso-1 as the first elution peak and 2-91 iso-2 as the second elution peak. The data for the title compound are in Table 3.

[1098] Route as

[1099] Example 2-98, 5-amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-(3-methyl-1-piperidinyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1100]

[1101] Step 1; At room temperature, 2-bromoethan-1-ol (0.98 g, 7.87 mmol) was added to a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2 g, 6.56 mmol) and K 2 CO 3 (1.81 g, 13.12 mmol) in MeCN (40 mL), and the reaction mixture was heated at 80 °C for 15 h. The reaction mixture was partitioned between EtOAc (50 mL) and H 2 O (30 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 5-amino-8-bromo-2-(2-hydroxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1 g, 44%) as an off-white solid.

[1102] LCMS (Method B): m / z 350 (M+H) + (ES + ), at 2.26 min, UV active.

[1103] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.62 - 7.60 (m, 2H), 7.46 - 7.44 (m, 3H), 4.83 (t, J = 6.0 Hz, 1H), 3.86 (t, J = 5.6 Hz, 2H), 3.72 - 3.68 (m, 2H). No exchangeable -NH 2 proton was observed.

[1104] Step 2; At 0 °C, methanesulfonyl chloride (0.14 g, 1.03 mmol) was slowly added to a suspension of 5-amino-8-bromo-2-(2-hydroxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.3 g, 0.86 mmol) and TEA (0.17 g, 1.72 mmol) in THF (5 mL), and the reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in MeCN (5 mL) and K 2 CO 3(0.36 g, 2.58 mmol) and 3-methylpiperidine (0.11 g, 1.29 mmol). The reaction mixture was heated at 100 °C for 15 h. The reaction mixture was partitioned between EtOAc (15 mL) and H 2 O (15 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated, then purified by Biotage-Isolera using 10 g of silica snap and eluted with a gradient of 1 - 100% EtOAc in hexane to afford 5-amino-8-bromo-2-(2-(3-methylpiperidin-1-yl)ethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as an off-white solid (120 mg, 32%).

[1105] LCMS (Method B): m / z 431 (M+H) + (ES + ), UV active at 2.26 min.

[1106] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.62 - 7.60 (m, 2H), 7.45 - 7.44 (m, 3H), 3.92 (t, J = 5.2 Hz, 2H), 2.78 (t, J = 5.2 Hz, 2H), 2.66 - 2.60 (m, 4H), 1.62 - 1.52 (m, 4H), 1.41 - 1.38 (m, 1H), 0.81 (d, J = 6.4 Hz, 3H). No exchangeable -NH 2 protons were observed.

[1107] Step 3; Prepared in a manner similar to Step 2 of Route a to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-(3-methyl-1-piperidinyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one as a yellow solid. Data for the title compound are in Table 3.

[1108] Route au

[1109] Example 2 - 109, Methyl 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propionate

[1110] Example 2 - 110,3 - [4 - [2 - [5 - amino - 8 - (2,6 - dimethyl - 4 - pyridyl) - 3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2 - yl]ethyl] - 1 - piperidinyl]propanoic acid

[1111]

[1112] Step 1; Conducted in a similar manner to Step 1 of Route b to provide tert - butyl 4 - (2 - (5 - amino - 8 - bromo - 3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2(3H) - yl)ethyl)piperidine - 1 - carboxylate (400 mg, 57%) as a yellow solid.

[1113] LCMS (Method A): m / z 417 (M + H - Boc) + (ES + ), at 3.23 min, UV - active.

[1114] 1 1H NMR: (400 MHz, DMSO - d6 ) δ: 7.62 - 7.61 (m, 2H), 7.46 - 7.44 (m,3H), 3.88 - 3.86 (m, 4H), 2.51 (t, J = 2.0 Hz, 2H), 1.72 - 1.68 (m, 4H), 1.66(t, J = 1.6 Hz, 1H), 1.65 (s, 9H), 1.39 - 1.38 (m, 2H). No exchangeable - NH 2 protons were observed.

[1115] Step 2; To a solution of tert - butyl 4 - (2 - (5 - amino - 8 - bromo - 3 - oxo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 2(3H) - yl)ethyl)piperidine - 1 - carboxylate (400 mg, 0.77 mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (10 mL) and 1.5 N sodium bicarbonate solution (5 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated to provide 5 - amino - 8 - bromo - 7 - phenyl - 2 - (2 - (piperidin - 4 - yl)ethyl) - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one (300 mg, 90%) as a yellow solid.

[1116] LCMS (Method A): m / z 417 (M+H) + (ES + ), UV active at 3.23 min.

[1117] 1 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.62 - 7.61 (m, 2H), 7.46 - 7.44 (m, 3H), 3.88 - 3.86 (m, 4H), 2.51 (t, J = 2.0 Hz, 2H), 1.72 - 1.68 (m, 4H), 1.66 (t, J = 1.6 Hz, 2H), 1.39 - 1.38 (m, 2H). No exchangeable -NH 2 protons were observed.

[1118] Step 3; carried out in a manner similar to Step 1 of Route a to afford methyl 3-(4-(2-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)ethyl)piperidin-1-yl)propionate (200 mg, 45%) as a yellow solid.

[1119] LCMS (Method A): m / z 503 (M+H) + (ES + ), UV active at 2.28 min.

[1120] Step 4; carried out in a manner similar to Step 2 of Route a and purified by preparative HPLC (Method -A). The fractions were concentrated under reduced pressure and the resulting residue was partitioned between 10% MeOH in DCM (15 mL) and 10% NaHCO 3 solution (10 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford methyl 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propionate (22 mg, 21%) as a yellow solid. Methyl 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propionate (20 mg, 20%) was also isolated as a yellow solid during the purification process. The data for the title compound are in Table 3.

[1121] Route at: via S N Typical procedure for preparing analogues by Ar reaction

[1122] Example 3-1, 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-morpholino-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1123]

[1124] 5-Amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.25 mmol) in morpholine (2 mL) was placed in a sealed tube and heated with stirring at 120 °C in a pre-heated oil bath for 15 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. The crude compound was purified by Biotage-Isolera using 10 g of silica snap, eluting with a gradient of 0 - 100% EtOAc in hexane to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-morpholino-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (55 mg, 45%) as a yellow solid. Data for the title compound are in Table 3.

[1125] Route av

[1126] Example 3-6, 5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-7-carboxylic acid methyl ester

[1127]

[1128] To a suspension of 5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.25 mmol) in MeOH (10 mL) was added TEA (0.3 mL, 0.35 mmol) and PdCl 2(dppf).DCM (50 mg, 1.09 mmol). The reaction materials were stirred in an autoclave at 100 °C under a carbon monoxide pressure of 5 kg / cm 2 for 16 h. The reaction mixture was partitioned between EtOAc (10 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 using 10 g of silica snap by Biotage-Isolera and eluted with a gradient of 0 - 100% EtOAc in hexane to afford methyl 5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-7-carboxylate (14 mg, 14%) as a yellow solid. The data for the title compound are in Table 3.

[1129] Route aw

[1130] Example 3 - 8, 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-methoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[1131]

[1132] A suspension of di-Boc protected 5-amino-7-chloro-8-(2,6-dimethylpyridin-4-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.25 mmol) in MeOH (10 mL) was cooled to -20 °C and purged with ammonia gas in an autoclave vessel for 5 min. The vessel was sealed and heated to 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A). The collected 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 and concentrated to afford 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-methoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (16 mg, 24%) as a yellow solid. The data for the title compound are in Table 3.

[1133] Receptor binding

[1134] Examples 3 - 9, 5 - Amino - 8 - (2,6 - dimethyl - 4 - pyridyl)-7 - [(Z)-1 - methylprop - 1 - enyl]-2 - (3,3,3 - trifluoropropyl)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[1135] Examples 3 - 10, 5 - Amino - 8 - (2,6 - dimethyl - 4 - pyridyl)-7 - [(E)-1 - methylprop - 1 - enyl]-2 - (3,3,3 - trifluoropropyl)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one

[1136]

[1137] Step 1; At - 78 °C, t - BuLi (1.7 M in pentane, 0.43 mL, 1.629 mmol) was added dropwise to a solution of 2 - bromo - 2 - butene (100 mg, 0.740 mmol) in THF (5 mL). The solution was stirred at - 78 °C for 1 h, then triisopropyl borate (0.26 mL, 1.111 mmol) was added. The reaction mixture was stirred at - 78 °C for 4 h. The reaction mixture was quenched with saturated NH 4 Cl (5 mL) and extracted with ether (10 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated to afford but - 2 - en - 2 - ylboronic acid as a white solid. The crude product was used in the next step without purification or analysis.

[1138] Step 2; It was carried out in a similar manner to Step 2 of Route a to produce a mixture of olefin positional isomers. These were separated by MD automated preparation (Method A) to afford 5 - amino - 8 - (2,6 - dimethyl - 4 - pyridyl)-7 - [(Z)-1 - methylprop - 1 - enyl]-2 - (3,3,3 - trifluoropropyl)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one (50 mg, 13%) and 5 - amino - 8 - (2,6 - dimethyl - 4 - pyridyl)-7 - [(E)-1 - methylprop - 1 - enyl]-2 - (3,3,3 - trifluoropropyl)-[1,2,4]triazolo[4,3 - c]pyrimidin - 3 - one (16 mg, 4%). Data for the title compounds are in Table 3. The olefin geometry was assigned by NOE.

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155] Intermediates used for preparing the examples are listed in Table 2. Compounds are prepared by the method according to the indicated synthetic route (“Route”). In cases where no route number or data is shown, commercially available materials are used. LCMS and 1 H NMR data are shown for the purified product (or “used crude” if purification was not performed). In some cases, the intermediate used to prepare another intermediate is shown in parentheses; for example, Intermediate 56 is prepared using Intermediates 41 and 42.

[1156] Table 2: Intermediates

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166] 。

[1167] Table 3: Data of Examples 1-1 to 3-10

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219] 。

[1220] Example 4: Adenosine Receptor Assay

[1221] 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 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: rapidly filtered 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 ). The bound radioactivity was determined by liquid scintillation counting, and the 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 4.

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228] Example 5: CB1 Receptor Binding and Antagonism

[1229] Receptor antagonism : 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 [[H]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.

[1230] 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).

[1231] 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 .

[1232] ​ : Evaluation of the antagonist activity of compounds on the human CB1 receptor expressed in transfected CHO cells, determined by measuring their effect on agonist-induced cAMP modulation using the HTRF assay.

[1233] The 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 / well was plated in a microtiter plate and pre-incubated for 5 min at room temperature in the presence of any of the following: HBSS (stimulated control), 3 µM (basal control) or various concentrations (IC 50 determined) of the reference antagonist AM281, or the test compound.

[1234] 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.

[1235] For basal control measurements, CP 55940 was omitted from the wells containing 3 µM AM 281.

[1236] 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.

[1237] After 60 min at room temperature, fluorescence resonance energy 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).

[1238] The results were expressed as the percentage of inhibition of the control response to 3 nM CP 55940.

[1239] 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.

[1240] In Table 5, blank entries for K i indicate that the binding observed was too weak to measure the K i value.

[1241]

[1242] 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-pyridyl)-2-[(4-fluorophenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-methoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(4-hydroxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(6-methoxy-2-pyridyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-fluoro-6-methoxy-2-pyridyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-fluoro-6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(6-oxo-1H-pyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(5-fluoro-1-methyl-6-oxo-2-pyridyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[1-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(4-pyridinylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isothiochroman-4-yl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (R)-5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(7-fluorotetralin-1-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[1-(2,5-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[[2-(difluoromethylthio)phenyl]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-4-pyridinyl)-2-(o-tolylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-fluoro-2-methyl-phenyl)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-pyrazol-1-yl-3-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(2-chloro-3-fluorophenyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[[2-(cyclopropylmethoxy)phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[[2-[(dimethylamino)methyl]phenyl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-ethoxyphenyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; (R)-5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(4-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-(3-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(4-methoxy-6-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[2-(4-piperidinyl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[1-phenyl-2-(2,2,2-trifluoroethylamino)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[[2-(4-piperidinylmethyl)phenyl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(6-methoxypyridazin-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-2-(2-amino-1-(2,6-difluorophenyl)ethyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(5-fluoropyrimidin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)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-4-pyridinyl)-2-[(6-hydroxypyridazin-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[1-(5-fluoro-2-pyridinyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(3-chloro-5-fluoro-2-pyridinyl)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-4-pyridinyl)-2-[(5-fluoro-2-methoxy-3-pyridinyl)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-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-[(5-fluoro-2-pyridinyl)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-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[1-(5-fluoro-2-pyridinyl)propyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(3-fluoro-5-methoxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoro-6-hydroxy-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-(2,3,4,5,6-pentadeuteriophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-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-[(5-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-bromo-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 6-[[5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyridine-3-carbonitrile; 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[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-2-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 6-[[5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-3-oxo-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]pyridine-3-carbonitrile; 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-2-[(5-methyl-2-pyridinyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(6-amino-5-fluoro-2-pyridinyl)methyl]-8-[2-chloro-6-(hydroxymethyl)-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(dimethylamino)-6-methyl-4-pyridinyl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-methyl-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-[2-(hydroxymethyl)-6-methoxy-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(2-hydroxy-6-methyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-2-[(5-fluoropyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methylpyridin-4-yl)-2-[(5-fluoropyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methylpyridin-4-yl)-2-[(5-methoxypyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(5-fluoropyridin-2-yl)methyl]-8-(2-methoxy-6-methylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-2-[(5-fluoropyridin-2-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(1-methyl-2-phenylethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[2-(4-hydroxyphenyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[2-(4-fluorophenyl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; Methyl 4-[2-[5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoate; 4-[2-[5-Amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]benzoic acid; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(2-pyridinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-methyl-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methyl-4-pyridinyl)-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(azetidin-1-yl)-6-methyl-4-pyridinyl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-2-chloro-N-methyl-benzamide; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-[1-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)ethylamino]ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[methyl-(1-phenyl-4-piperidinyl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[(1S)-1-(6-methyl-2-pyridinyl)ethyl]amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[1-(3-methyl-1H-pyrazol-5-yl)-4-piperidinyl]amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[2-(1-methylpyrrol-2-yl)azepan-1-yl]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[4-[(5-methyl-2-pyridinyl)amino]-1-piperidinyl]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[3-(3-methyl-5-oxo-4H-pyrazol-1-yl)phenylamino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[2-[[2-(hydroxymethyl)tetrahydronaphthalen-2-yl]methylamino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[1-(aminomethyl)-2-(2,4-difluorophenyl)ethyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[[(3R)-4-benzylmorpholin-3-yl]methyl]-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(4-benzyl-4-piperidinyl)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-4-pyridinyl)-2-(2-morpholin-3-yl-1-phenyl-ethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-(5-aminoindan-2-yl)-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2H-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-methyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-ethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-isopropyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-isopentyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(2-hydroxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 2-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl methanesulfonate; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-(2-methoxyethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 3-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propionitrile; Ethyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate; Ethyl N-methyl-N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate; tert-Butyl N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate; Methyl 3-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propionate; Ethyl N-ethyl-N-[2-[5-amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]carbamate; 5-Amino-2-(3,3-difluoropropyl)-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[2-[ethyl(methyl)amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[2-[cyclopropyl(methyl)amino]ethyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-isobutyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 2-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]acetamide; 3-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-propionamide; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[3-hydroxy-2-(hydroxymethyl)propyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 2-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N,N-dimethyl-acetamide; 5-Amino-2-[(3,3-difluorocyclopentyl)methyl]-8-(2,6-dimethyl-4-pyridyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-2-[(2-ethyl-2-methyl-cyclopropyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 2-[5-Amino-8-(2,6-dimethyl-4-pyridyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]-N-cyclopropyl-N-methyl-acetamide; Methyl [[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]cyclopentanecarboxylate; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[2-(trifluoromethoxy)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 3-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]propanamide; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2,3,4,5,6-pentadeuteriophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(2,4-difluorophenyl)-8-(2,6-dimethyl-4-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-methoxyphenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 4-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl]benzonitrile; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(2-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(4-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(3-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(5-fluoro-2-pyridyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-methylpyrazol-1-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(2-furyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(5-methyl-2-furyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-(4-methylthiazol-2-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-chloro-6-(hydroxymethyl)-4-pyridyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methoxy-4-pyridyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methyl-4-pyridyl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methyl-4-pyridyl)-7-(4-fluorophenyl)-2-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methyl-4-pyridyl)-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; Methyl 4-[5-amino-3-oxo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl]-6-methyl-pyridine-2-carboxylate; 5-Amino-8-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridinyl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[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]piperidine-1-carboxylate; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(3-piperidinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)-2-isobutyl-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-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[(4-fluorocubane-1-yl)methyl]-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[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-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-(cubane-1-ylmethyl)-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-(3-bicyclo 1.1.1] (Pentylmethyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (R)-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)morpholine-4-carboxylic acid tert-butyl ester; (R)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 4-[[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(4-piperidinylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (2S)-2-[[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]morpholine-4-carboxylic acid tert-butyl ester; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-(1-methyl-3-piperidinyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (S)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-2-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2S)-4-methylmorpholin-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-(tetrahydropyran-4-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(2R)-4-methylmorpholin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (3S)-3-[[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]methyl]morpholine-4-carboxylic acid tert-butyl ester; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3S)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3S)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[(1-methylpiperidin-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (R)-5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(morpholin-3-ylmethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-2-[[(3R)-4-methylmorpholin-3-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-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (S)-3-((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-methylpiperazine-1-carboxylic acid tert-butyl ester; (R)-3-((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-methylpiperazine-1-carboxylic acid tert-butyl ester; (R)-5-Amino-2-((1,4-dimethylpiperazin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2R)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; (S)-5-Amino-2-((1,4-dimethylpiperazin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[[(2S)-1-methylpiperazin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(1,1-dioxothian-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(1,1-dioxothian-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[(1,1-dioxothietan-3-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-2-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-7-phenyl-2-(tetrahydropyran-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-(4-fluorophenyl)-8-[2-(hydroxymethyl)-6-methylpyridin-4-yl]-2-(3,4,5,6-tetrahydropyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[2-(azetidin-1-yl)ethyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 2-(2-(2-Azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-2-[2-(piperidin-1-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[2-(1-methylpiperidin-4-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[2-(3-methylpiperidin-1-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(2-morpholinoethyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[2-((cis)-2,6-dimethylmorpholin-4-yl)ethyl]-8-(2,6-dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[2-(4,4-difluoropiperidin-1-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-dimethylpyridin-4-yl)-2-[2-(4-methylpiperazin-1-yl)ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-2-[2-(8-azabicyclo[3.2.1]octan-8-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-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-2-[2-(piperidin-1-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2-chloro-6-methylpyridin-4-yl)-7-(4-fluorophenyl)-2-[2-(piperidin-1-yl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; Methyl 3-[2-[5-amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]piperidine-1-carboxylate; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-[2-[[2-(4-hydroxypiperidin-1-yl)-2-oxo-ethyl]-methyl-amino]ethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 3-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethylamino]-N-cyclopropyl-cyclohexanecarboxamide; Methyl 3-[4-[2-[5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propionate; 3-[4-[2-[5-Amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl]ethyl]-1-piperidinyl]propanoic acid; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-phenyl-2-[3-(1-piperidinyl)propyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethylpyridin-4-yl)-2-(3-(2-oxopyridin-1(2H)-yl)propyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one; 3-(5-Amino-8-(2,6-dimethylpyridin-4-yl)-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)-N-methylpropanamide; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-morpholino-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-(1-piperidinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-ethoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-[ethyl(methyl)amino]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-7-chloro-8-(2,6-dimethyl-4-pyridinyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; Methyl 5-amino-8-(2,6-dimethyl-4-pyridinyl)-3-oxo-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-7-carboxylate; 5-Amino-8-(2,6-dimethyl-4-pyridinyl)-7-prop-1-ynyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-methoxy-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(2,6-dimethyl-4-pyridyl)-7-[(Z)-1-methylprop-1-enyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-Amino-8-(2,6-dimethyl-4-pyridyl)-7-[(E)-1-methylprop-1-enyl]-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

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

3. Use of the compound according to claim 1 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.

4. Use according to claim 3, 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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