TRIAZOLONE COMPOUNDS

CLAIM OF PRIORITY

This application claims priority to US Application No. 62/994,902, filed 26 March 2020, the contents of which are hereby incorporated by reference.

BACKGROUND

Adenosine modulates of a number of physiological functions. Intracellularly, adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle; extracellular adenosine engages in intercellular signaling. For example, extracellular adenosine is a potent immunosuppressor, preventing an overzealous immune response during inflammation and infection. Adenosine also acts on other systems, including the cardiovascular system, and the central nervous system.

The action of adenosine is mediated by a family of G-protein coupled receptors. At least four subtypes of adenosine receptors have been identified: AIR, A2aR, A2bR, and A3R. The AIR and A3 subtypes inhibit the activity of the enzyme adenylate cyclase, whereas the A2a and A2b subtypes stimulate the activity of the same enzyme, thereby modulating the level of cyclic AMP in cells.

In the immune system, engagement of A2a and A2b adenosine receptors is a critical regulatory mechanism that protects tissues against excessive immune reactions. In tumors, this pathway is hijacked and hinders antitumor immunity, promoting cancer progression.

Furthermore, in many cases, the tumor microenvironment contains high levels of extracellular adenosine. Thus, the adenosine receptor, notably A2aR and A2bR, have been identified as targets for cancer therapies.

Numerous adenosine receptor antagonists have been reported. For example, international patent application WO 2006/138734 discloses triazolopyrimidine cannabinoid receptor 1 (CB-1) antagonists. WO 2008/002596 and WO 2009/111449 disclose adenosine A2a receptor antagonists which include 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]pyrimidine-5-amine derivatives for use as A2a receptor antagonists.

There remains a need for adenosine receptor antagonists that are highly soluble, highly selective, and highly potent.

SUMMARY

In one aspect, a compound of Formula (I): or a pharmaceutically acceptable salt thereof, is provided, wherein: ring A is:

R ¹ is H, Ci-6alkyl, or C3-6cyclolkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR ^a , halo and cyano; each R ² , independently, is halo, cyano, Ci-3alkyl, -0-Ci-3alkyl, -CCkR ³ , or -NR ⁷ R ⁸ ; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR ^a , halo, and cyano;

R ³ is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R ^a , and -OR ^a ;

R ⁴ is -CH2-R ⁵ ;

R ⁵ is Ci-3alkyl wherein alkyl is optionally substituted with one or more substituents independently selected from -OR ^a , halo, and cyano; wherein R ⁵ is optionally substituted with from one to four groups R ⁶ ; or R ⁵ is a 3 to 7-membered heterocyclyl or 5 to 7-membered heteroaryl, each including from 1 to 4 heteroatoms independently selected from N, O, and S(0)k; wherein one or two ring atoms of R ⁵ is optionally replaced by -C(=0)-; wherein R ⁵ is optionally substituted with from one to four groups R ⁶ ; each R ⁶ , independently, is H, halo, cyano, Ci- ₆ alkyl, C3- ₆ cycloalkyl, -0-Ci- ₆ alkyl, -0C(0)-Ci- ₆ alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo, cyano, -R ^a , and -OR ^a ; each R ⁷ and each R ⁸ , independently, is R ^a ; each R ^a , independently, is H, Ci- ₆ alkyl, C3-8cycloalkyl, or C4-9cycloalkylalkyl; wherein each R ^a , independently, is optionally substituted with one or more substituents independently selected from -OH and halo; and each k, independently, is 0, 1, or 2.

In another aspect, a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, is provided.

In another aspect, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition mediated by the adenosine receptor, such as cancer, is provided.

In some embodiments, the disease or condition mediated by the adenosine receptor is lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor.

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

DESCRIPTION

Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful as adenosine receptor antagonists.

A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: ring A is:

R ¹ is H, Ci-6alkyl, or C3-6cyclolkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR ^a , halo and cyano; each R ² , independently, is halo, cyano, Ci-3alkyl, -0-Ci-3alkyl, -CCkR ³ , or -NR ⁷ R ⁸ ; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR ^a , halo, and cyano;

R ³ is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R ^a , and -OR ^a ;

R ⁴ is -CH2-R ⁵ ;

R ⁵ is Ci-3alkyl wherein alkyl is optionally substituted with one or more substituents independently selected from -OR ^a , halo, and cyano; wherein R ⁵ is optionally substituted with from one to four groups R ⁶ ; or R ⁵ is a 3 to 7-membered heterocyclyl or 5 to 7-membered heteroaryl, each including from 1 to 4 heteroatoms independently selected from N, O, and S(0)k; wherein one or two ring atoms of R ⁵ is optionally replaced by -C(=0)-; wherein R ⁵ is optionally substituted with from one to four groups R ⁶ ; each R ⁶ , independently, is H, halo, cyano, Ci-6alkyl, C3-6cycloalkyl, -0-Ci-6alkyl, -0C(0)-Ci- 6alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo, cyano, -R ^a , and -OR ^a ; each R ⁷ and each R ⁸ , independently, is R ^a ; each R ^a , independently, is H, Ci-6alkyl, C3-8cycloalkyl, or C4-9cycloalkylalkyl; wherein each R ^a , independently, is optionally substituted with one or more substituents independently selected from -OH and halo; and each k, independently, is 0, 1, or 2.

In some embodiments, R ¹ can be H, -CH3, or -CH2CN. Each R ² , independently, can be H or -CH3.

In some embodiments, R ³ can be phenyl or phenyl substituted by halo.

In some embodiments, R ⁵ can be Ci-3alkyl.

In some embodiments, R ⁵ can be heterocyclyl. R ⁵ can be tetrahydrofuranyl.

In some embodiments, R ⁵ can be heteroaryl. R ⁵ can be pyridyl or oxazolyl.

In some embodiments, R ⁵ can be substituted by one or to four groups R ⁶ , wherein each R ⁶ , independently, can be halo, -OR ^a , or Ci- ₆ alkyl; wherein alkyl can be optionally substituted with one or more substituents independently selected from halo. Each R ⁶ , independently, can be halo, methyl, difluoromethyl, trifluoromethyl, or methoxy.

A pharmaceutical composition can include the compound of Formula (I), and a pharmaceutically acceptable carrier, diluent, or excipient.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be for use of the compound of any one of claims 1 to 12 in the treatment of a disease or condition mediated by the adenosine receptor, for example, cancer. The disease or condition mediated by the adenosine receptor can be lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor.

The term “halo” refers to fluoro, chloro, bromo and iodo.

The term “alkyl” refers to a fully saturated straight-chain or branched aliphatic group, having the number of carbon atoms specified, if designated (e.g., Ci-ioalkyl refers to an alkyl group having one to ten carbons). Examples include as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. If no size is designated, “alkyl” refers to a group having from 1 to 10 carbon atoms.

The term “alkenyl” refers to an unsaturated straight-chain or branched aliphatic group, which contain at least one carbon-carbon double bond, and having the number of carbon atoms specified, if designated. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methylbut-l-enyl, 1-pentenyl and 4-hexenyl. If no size is designated, “alkenyl” refers to a group having from 2 to 10 carbon atoms.

The term “alkynyl” refers to an unsaturated straight-chain or branched aliphatic group, which contain at least one carbon-carbon triple bond, and having the number of carbon atoms specified, if designated. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and but-2-ynyl. If no size is designated, “alkynyl” refers to a group having from 2 to 10 carbon atoms.

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

The term “cycloalkyl” refers to a saturated or unsaturated aliphatic ring containing from 3 to 10 carbon ring atoms, where one or more carbon ring atoms can optionally be replaced by -C(=0)-. A cycloalkyl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl. Suitable examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, norbornyl, 4-oxocyclohex-l-yl and 3-oxocyclohept-5-en-l-yl.

The term “heterocyclyl” refers to a saturated or unsaturated heterocyclic ring containing from 3 to 10 ring atoms, where from 1 to 4 ring atoms are independently N, O, or S; and one or more carbon ring atoms can optionally be replaced by -C(=0)-. A ring nitrogen or a ring sulfur atom, independently, can optionally be oxidized, including for example -N(O)-, -S(O)-, or - S(0) ₂ -. A ring nitrogen atom in a heterocyclyl group can optionally be quaternized, for example, -N ⁺ (CH3)2-. A heterocyclyl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl or heterocyclyl groups. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorphonlinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.

The term “aryl” refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group containing from 6 to 14 ring atoms. Aryl may contain fused rings, including aryl rings fused to cycloalkyl, heterocyclyl, or aryl rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, and dihydro- lH-indenyl. The term “heteroaryl” refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 ring atoms, where from 1 to 4 ring atoms are independently N, O, or S.

A ring nitrogen or a ring sulfur atom, independently, can optionally be oxidized, including for example -N(O)-, -S(O)-, or -S(0)2-. A heteroaryl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, pyridyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, 5,6,7,8-tetrahydroquinolinyl, benzofuranyl, pyrrolopyridinyl, pyrrolopyrimidinyl, triazinyl, and tetrazolyl.

The term “multicyclic ring system” refers to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group which includes two or more fused and/or bridged rings.

Some compounds described herein can exist in more than one stereoisomeric form. Descriptions of such compounds, unless otherwise specified, are intended to encompass all geometric and optical isomers, including racemates.

Some compounds described herein can exhibit tautomerism. The structural drawings herein typically represent only one of the possible tautomeric forms of such compounds. It will be understood that the structural drawings are intended to encompass all tautomeric forms of such compounds.

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

Compounds of Formula (I) may contain the stated atoms in any of their isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which: (a) the compound of Formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of Formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound.

The use of “«A/W” i _n formulas herein denotes the point of attachment between different groups.

Illustrative compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include:

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[5-(trif luoromethyl)oxazol-4- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[5-(trif luoromethyl)thiazol-4- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[3-(difluoromethyl)-2-pyridyl]methyl]-8-(l-met hyl-6-oxo-3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(3-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridaz in-4-yl-[l,2,4]triazolo[4,3- c]pyrimidin-3-one;

5-amino-2-[(5-methyloxazol-4-yl)methyl]-8-(l-methyl-6-oxo -3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[5-(difluoromethyl)oxazol-4-yl]methyl]-8-(l-me thyl-6-oxo-3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(3-fluoro-2-pyridyl)methyl]-8-(l-methyl-6-oxo- 3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[4-(trif luoromethyl)oxazol-5- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridaz in-4-yl-[l,2,4]triazolo[4,3- c]pyrimidin-3-one;

5-amino-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-8-pyrida zin-4-yl-[l,2,4]triazolo[4,3- c]pyrimidin-3-one; 5-amino-2-[(5-methyloxazol-4-yl)methyl]-8-(6-oxo-lH-pyridin- 3-yl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(l-methyl-6-oxo- 3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-ethyl-6-oxo-3-pyridyl)-2-[(5-methyloxazol-4- yl)methyl]-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5 -amino-8-( 1 , 5 -dimethyl-6-oxo-3 -pyridyl)-7-phenyl-2-(3 , 3,3-trifluoropropyl)-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-phenyl-8-pyridazin-4-yl-2-[[5-(trifluoromethyl) oxazol-4-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-cyclopropyloxazol-4-yl)methyl]-8-(l-methyl- 6-oxo-3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-(3,3,3-tr ifluoropropyl)-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-methylisoxazol-3-yl)methyl]-8-(l-methyl-6-o xo-3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[(2R)-te trahydrofuran-2-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[5-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl -8-pyridazin-4-yl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-cyclopropyl-6-oxo-3-pyridyl)-2-[(5-methyloxa zol-4-yl)methyl]-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(6-oxo-lH-pyridin-3-yl)-7-phenyl-2-[[5-(trifluo romethyl)oxazol-4-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-[l-(difluoromethyl)-6-oxo-3-pyridyl]-2-[(5-meth yloxazol-4-yl)methyl]-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[4-(difluoromethyl)oxazol-5-yl]methyl]-8-(l-me thyl-6-oxo-3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-phenyl-8-pyridazin-4-yl-2-[[(2R)-tetrahydrofura n-2-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(6-methylpyridazin- 4-yl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-ethyl-6-oxo-3-pyridyl)-7-phenyl-2-[[5-(trifl uoromethyl)oxazol-4- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(4-methyloxazol-5-yl)methyl]-8-(l-methyl-6-oxo -3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(6-oxo-lH-pyridi n-3-yl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(5-fluoro-l-methyl-6-oxo-3-pyridyl)-2-[(5-methy loxazol-4-yl)methyl]-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

2-[5-[5-amino-2-[(5-methyloxazol-4-yl)methyl]-3-oxo-7-phe nyl-[l,2,4]triazolo[4,3- c] py rimi din- 8 -y 1 ] -2-oxo- 1 -py ri dy 1 ] acetonitril e;

5-amino-8-(6-oxo-lH-pyridin-3-yl)-7-phenyl-2-[[(2R)-tetra hydrofuran-2-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-2-(l-oxazol-4-ylethy l)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-(2-oxabicyclo[2.1 l]hexan-4-ylmethyl)-7-phenyl-8-pyridazin-4-yl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-2-(2-oxabicyclo[2.1. l]hexan-4-ylmethyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(6-methoxypyridazin-4-yl)-2-[(5-methyloxazol-4- yl)methyl]-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[5-(difluoromethyl)-2-pyridyl]methyl]-8-(l-met hyl-6-oxo-3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[6-(l-hydroxy-l-methyl-ethyl)-2-pyridyl]methyl ]-8-(l-methyl-6-oxo-3- pyridyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l,5-dimethyl-6-oxo-3-pyridyl)-2-[(5-methyloxaz ol-4-yl)methyl]-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l,5-dimethyl-6-oxo-3-pyridyl)-7-phenyl-2-[[(2R )-tetrahydrofuran-2- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one; 2-[5-[5-amino-3-oxo-7-phenyl-2-[[5-(trifluoromethyl)oxazol-4 -yl]methyl]- [ 1 ,2,4]triazolo[4,3 -c]pyrimidin-8-yl]-2-oxo- 1 -pyridyljacetonitrile;

5-amino-8-(l-isopropyl-6-oxo-3-pyridyl)-2-[(5-methyloxazo l-4-yl)methyl]-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-methyloxazol-4-yl)methyl]-8-[6-oxo-l-(2,2,2 -trifluoroethyl)-3-pyridyl]-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-2-[[l-methyl-5-(trif luoromethyl)imidazol-4- yl]methyl]-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-[6-oxo-l-(2,2,2-trifluoroethyl)-3-pyridyl]-7-ph enyl-2-[[5-

(trifluoromethyl)oxazol-4-yl]methyl]-[l,2,4]triazolo[4,3- c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl ]-8-(6-oxo-lH-pyridin-3-yl)-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5 -amino-7-(4-fluorophenyl)-2- [(5 -fluoro-2-pyridyl)methyl] -8-(6-oxo- 1 H-pyri din-3 -yl)-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl ]-8-(l-methyl-6-oxo-3- pyridyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-8-(6-oxo-lH-pyridin-3-yl)-2-[[ (2R)-tetrahydrofuran-2- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)methyl] -8-pyridazin-4-yl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-3-pyridyl)-2 -[[5-(trifluoromethyl)oxazol-

4-yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(5-methylisoxazol-3-yl)meth yl]-8-(6-oxo-lH-pyri din-3- yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-3-pyridyl)-2 -[[(2R)-tetrahydrofuran-2- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5 -amino-7-(4-fluorophenyl)-2- [(5 -fluoro-2-pyridyl)methyl] -8-( 1 -methyl-6-oxo-3 - pyridyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-8-(5-methyl-6-oxo-lH-pyridin-3 -yl)-2-(3,3,3- trifluoropropyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-pyridazin-4-yl-2-[[5-(trifluoro methyl)oxazol-4-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(5-methylisoxazol-3-yl)meth yl]-8-(l-methyl-6-oxo-3- pyridyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(5-methyloxazol-4-yl)methyl ]-8-(5-methyl-6-oxo-lH- pyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-8-pyridazin-4-yl-2-[[(2R)-tetr ahydrofuran-2-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l,5-dimethyl-6-oxo-3-pyridyl)-7-(4-fluoropheny l)-2-[(5-methyloxazol-4- yl)methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl] -8-(l-methyl-6-oxo-3- pyridyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(3,5-difluoro-2-pyridyl)methyl]-8-(l-methyl-6- oxo-3-pyridyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-phenyl-8-pyridazin-4-yl-2-[[(2R)-tetrahydrofura n-2-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[(2R)-te trahydrofuran-2-yl]methyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[rel-(lR) -l-oxazol-4-ylethyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[rel-(lS) -l-oxazol-4-ylethyl]-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S ,3S)-3- methyltetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyr imidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R ,3R)-3- methyltetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyr imidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R ,3R)-3-

(trifluoromethyl)tetrahydrofuran-2-yl]methyl]-[l,2,4]tria zolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S ,3S)-3-

(trifluoromethyl)tetrahydrofuran-2-yl]methyl]-[l,2,4]tria zolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(4,4-difluorotetrahydrofuran-2-yl)methyl]-8-(l-me thyl-6-oxo-3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R )-4,4- difluorotetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]p yrimidin-3-one;

5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S )-4,4- difluorotetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]p yrimidin-3-one;

5-amino-7-phenyl-8-pyridazin-4-yl-2-[[rel-(2R)-3,3-difluo rotetrahydrofuran-2- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-7-phenyl-8-pyridazin-4-yl-2-[[rel-(2S)-3,3-difluo rotetrahydrofuran-2- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(5-methylisoxazol-3-yl)methyl]-8-(6-oxo-lH-pyr idin-3-yl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-[5-(difluoromethyl)-6-oxo-lH-pyridin-3-yl]-2-(3 -fluoropropyl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[[5-(difluoromethyl)-2-pyridyl]methyl]-8-(6-oxo -lH-pyridin-3-yl)-7-phenyl-

[1.2.4]triazolo[4,3-c]pyrimidin-3-one; tert-butyl (2S)-2-[[5-amino-8-(l-methyl-6-oxo-3-pyridyl)-3-oxo-7-phenyl -

[1.2.4]triazolo[4,3-c]pyrimidin-2-yl]methyl]morpholine-4- carboxylate;

5-amino-8-[6-(hydroxymethyl)pyridazin-4-yl]-2-[(5-methylo xazol-4-yl)methyl]-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-[6-(hydroxymethyl)pyridazin-4-yl]-7-phenyl-2-[[ 5-(trifluoromethyl)oxazol-4- yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-8-[6-(difluoromethyl)pyridazin-4-yl]-2-[(5-fluoro -2-pyridyl)methyl]-7-phenyl-

[1.2.4]triazolo[4,3-c]pyrimidin-3-one;

5-amino-2-[(3-fluoro-2-pyridyl)methyl]-8-(l-methyl-6-oxo- pyridazin-3-yl)-7-phenyl-

[l,2,4]triazolo[4,3-c]pyrimidin-3-one; and

5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl] -8-(l-methyl-6-oxo-pyridazin-

3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one.

Compounds of Formula (I) can be adenosine receptor antagonists, i.e. antagonists of one or more of AIR, A2aR, A2bR, and A3R. The term “adenosine receptor antagonist” refers to a compound, e.g., a compound of Formula (I) that binds to the adenosine receptor and antagonizes its activity.

In some cases, the compound of Formula (I) is a selective adenosine receptor antagonist. The term “selective” refers the property of a compound of Formula (I) that is an adenosine receptor antagonist but is substantially inactive at other biological targets. The term “substantially inactive” as used herein describes a compound that (i) has significantly weaker affinity for a given receptor as compared to its affinity for the adenosine receptor; (ii) does not show substantial agonist or antagonist activity at a given receptor; or both (i) and (ii).

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

In particular, a selective adenosine receptor antagonist can be substantially inactive toward other G-protein coupled receptors, such as the cannabinoid receptors, referred to as CB-1 and CB-2.

A compound of Formula (I) can have a binding affinity Ki for A2aR of, e.g., 100 nM or less, 10 nM or less, or 1 nM or less.

A compound of Formula (I) can have a binding affinity Ki for A2bR of, e.g., 100 nM or less, 10 nM or less, or 1 nM or less.

A compound of Formula (I) can have a binding affinity Ki for CB-1 of, e.g., 1,000 nM or greater, 10,000 nM or greater, 13,000 nM or greater.

A compound of Formula (I) can be a selective adenosine receptor antagonist with respect to CB-1.

A compound of Formula (I) can be active as an adenosine receptor antagonist but substantially inactive at CB-1.

The compounds of Formula (I) can also be selective between the different subtypes of adenosine receptor. In some embodiments, the compounds of Formula (I) are A2aR-selective; A2bR-selective; or dual A2aR/A2bR-selective.

In some embodiments, the selectivity is determined in a binding affinity assay. In other embodiments, the selectivity is determined as an ICso value in a cell-based assay, e.g., a cell- based cAMP accumulation assay. One illustrative cell based assay is described in detail in the Examples below. In some embodiments, the cell based assay is carried out with concentrations of adenosine of 1 micromolar and above, 2 micromolar and above, 5 micromolar and above, 10 micromolar and above, or 100 micromolar and above.

A dual A2aR/A2bR antagonist shows an ICso in a cell based assay for A2aR that is less than 20 nM and an ICso in a cell based assay for A2bR that is less than 20 nM. In addition, for a dual A2aR/A2bR antagonist, the ratio of an ICso in a cell based assay for A2aR to ICso for A2bR is less than 100, or less than 25.

In one embodiment, there is provided a pharmaceutical composition which includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

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

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl / hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within 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.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or 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.

Compounds of Formula (I) are useful in the treatment of diseases or conditions mediated by the adenosine receptor. In one embodiment, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions mediated by the adenosine receptor. In some embodiments the disease or condition is mediated by A2aR; in other embodiments, by A2bR; in still other embodiments, by both A2aR and A2bR.

Some examples of disease or conditions mediated by the adenosine receptor include cancer, including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor; 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 conditions mediated by the adenosine receptor are known.

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by the adenosine receptor.

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor).

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by the adenosine receptor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.

In one embodiment, there is provided a method of treating a disease or condition mediated by the adenosine receptor, which includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

In one embodiment, there is provided a method of treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor) which includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

In one embodiment, there is provided a method of treating a disease or condition mediated by the adenosine receptor, which includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.

In one embodiment, there is provided a method of treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor), which includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by the adenosine receptor.

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor).

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by the adenosine receptor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.

In one embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.

Compounds of Formula (I) can be prepared according to the following general schemes.

Schemes la and lb illustrate the preparation of intermediate 6-substituted-4-hydrazino-2- aminopyrimidine compounds of Formula (IV).

Scheme la

Scheme 2 illustrates the conversion of compounds of Formula (IV) into the intermediate 7-substituted-5-amino-8-bromo-[l,2,4]triazolo[4,3-c]pyrimidi n-3-one compounds of Formula (V). Briefly, the compound of Formula (IV) is treated with triphosgene to effect closure of the triazolone ring, followed by bromination with (CFb^PhlSCBn . Scheme 2

Scheme 3 a illustrates the conversion of compounds of Formula (V) into compound of Formula (I). The alkylation of the compound of Formula (V) with R ⁴ can be carried out using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction.

Scheme 3a

Alternatively, a compound such as R ⁴ -Br may be used in a direct alkylation of the compound of Formula (V).

Optionally, R ⁴ can be further modified after alkylation of the compound of Formula (V).

Scheme 3b illustrates an alternate route for the conversion of compounds of Formula (V) into compounds of Formula (I). In Scheme 3b, [Pg] represents a suitable reagent for installing the protecting group denoted Pg. The alkylation of the compound of Formula (Va) with R ⁴ can be carried out using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; alcohol chlorination followed by an alkylation reaction. Scheme 3b

Alternatively, a compound such as R ⁴ -Br may be used in a direct alkylation of the compound of Formula (Va).

Optionally, R ⁴ can be further modified after alkylation of the compound of Formula (V). Optionally, a compound of Formula (I) can be further modified, for example, to form a different compound of Formula (I).

EXAMPLES

General techniques

'H NMR spectra were obtained using a Bruker 300 MHz, 400 MHz or 500 MHz spectrometer at 27 °C unless otherwise noted; chemical shifts are expressed in parts per million (ppm, d units) and are referenced to the residual mono- ¹ H isotopologue of the solvent (CHCb: 7.24 ppm; CHDCh: 5.32 ppm; CD3S(=0)CD2H: 2.49 ppm). Coupling constants are given in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br s (broad singlet). LC-MS was carried out using a Waters UPLC fitted with a Waters SQD mass spectrometer or Shimadzu LC- 20AD LC-20XR LC-30AD with a Shimadzu 2020 mass spectrometer. Reported molecular ions correspond to [M+H]+ unless otherwise noted; for molecules with multiple isotopic patterns (Br, Cl, etc.) the reported value is the one obtained for the lowest isotope mass unless otherwise specified. Flash chromatography was performed using straight phase flash chromatography on a SPl™ Purification system from Biotage™, CombiFlash ^® Rf from ISCO or on Gilson system from Thermo Fisher using normal phase silica FLASH+™ (40M, 25M or 12 M) or SNAP™ KP- Sil Cartridges (340, 100, 50 or 10), Flash Column silica-CS columns from Agela, with C18-flash columns or standard flash chromatography. In general, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for reactions. Phase Separators used in the examples are ISOLUTE® Phase Separator columns. The intermediates and examples named below were named using ACD/Name 12.01 from Advanced Chemistry Development, Inc. (ACD/Labs). The starting materials were obtained from commercial sources or made via literature routes.

General procedures

LCMS:

Method A

Instrument: Agilent Technologies 1200 Series, Agilent LC/MSD SL, Column: Waters XBridge C8 3.5 m, 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=lmL of TFA in 1000 mL ofMilli-Q Water; Solvent B=lmL of TFA in 1000 mL of MeCN); Injection volume 1 pL (may vary); UV detection 220 to 400 nm; Column temperature 25 ^° C; 2.0 mL/min.

Note: For UV inactive compounds an ELSD detector (Polymer Laboratories PL-ELS 2100 ICE) is connected with the above instrument.

Method B

Instrument: Agilent Technologies 1200 Series, Agilent LC/MSD SL, Column: Atlantis dC18 5m, 4.6x50mm. Gradient [time (min)/ solvent B (%)] :0.0/l 0, 2.5/95, 4.5/95, 4.6/10, 6.0/10. (Solvent A=lmL of TFA in 1000 mL of Milli-Q Water; Solvent B=lmL of TFA in 1000 mL of MeCN); Injection volume lpL (may vary); UV detection 210 to 400 nm; Column temperature 25 ^° C; 1.5 mL/min.

Method C

Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC/MS, Column: Zorbax C18 5m, 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=lmL of Formic Acid in 1000 mL of Milli-Q Water; Solvent B= MeCN); Injection volume lpL (may vary); UV detection 210 to 400 nm; column temperature 25 ^° C; 1.5 mL/min.

Method D Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC/MS,

Column: Zorbax C18 5m, 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 lpL (may vary); UV detection 210 to 400 nm; column temperature 25 ^° C; 1.2 mL/min.

Method E

Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC/MS,

Column: XBridge C8 3.55m, 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 is added to 1000 mL of Milli-Q Water; Solvent B= MeCN); Injection volume lpL (may vary); UV detection 210 to 400 nm; column temperature 25 ^° C; 1.0 mL/min.

Method F

Instrument: Agilent 1100 Series LC/MSD. Column: Zorbax SB-C18 1.8 pm 4.6x15 mm. Gradient [time (min)/solvent B(%)]:0.0/100; 0.01/100; 1.5/0; 1.8/0; 1.81/100. (Solvent A = MeCN; Solvent B = LbO, both modified with 0.1% formic acid). Injection volume 1 pL (may vary). UV detection 215 nm. Column temperature 60 °C.

Prep-HPLC Conditions:

Method A

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

Method B

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

Method C

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

Instrument: Agilent Technologies 1260 Infinity II Series LC. Mobile Phase: HEXANE B: IPA (60:40), Column: YMC Silica (19x150) mm, 5 pm, Flow: 15 mL/min. Note: Gradient may vary from sample to sample based on sample separation and Polarity.

Method E

Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - H2O, B-MeOH or MeCN. Column: Waters Sunfire C18 OBD Prep Column, IOOA, 5 pm, 19 mmx lOO mm. Gradient [time (min)/solvent B (%)] :0.0/l 0, 20/95, 23/95, 24/10, 26/10.

Synthesis Routes

Route A: Preparation of 5-amino-8-bromo-7-phenyl-ri.2.41triazolor4.3-c1pyrimidin-

3(2HVone

Step 1: This reaction was performed as 2x 250 g batches. To a degassed suspension of phenyl boronic acid (250 g, 2.05 mol), 4,6-dichloro-2-aminopyrimidine (672 g, 4.10 mol) and K2CO3 (848 g, 6.15 mol) in CTbCN (15 L) and H2O (2 L) at room temperature was added Pd(PPh3)4 (118 g, 0.10 mol) and the resultant reaction mixture was heated to 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was vigorously stirred with H2O (4 L) and DCM (10 L), undissolved solids were filtered-off through a Buchner funnel and rinsed with DCM (3 L). The filtrate was taken in a separating funnel, the organic layer was separated, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using 230-400 silica mesh and was eluted with 0-15% EtOAc in Pet-Ether to afford 4-chloro-6-phenylpyrimidin-2-amine (350 g, 41%) as an off-white solid. ¾NMR (DMSO-de, 400 MHz) d: 8.05 - 8.03 (m, 2H), 7.52 - 7.47 (m, 3H), 7.21 (s, 1H).

Step 2: To a stirred suspension of 4-chloro-6-phenylpyrimidin-2-amine (350 g, 1.70 mol) in EtOH (4.0 L), hydrazine hydrate (255 g, 5.1 mol) was added and the mixture was heated to 90 °C for 15 h. The reaction was concentrated under reduced pressure. The residue obtained was triturated with diethyl ether (1 L) and 10 % sodium bicarbonate solution (1 L). The solid obtained was collected by filtration through a Buchner funnel, rinsed with Diethyl ether (200 mL) and dried under vacuum to afford 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 73%) as an off-white solid. ¾NMR (DMSO-de, 400 MHz) d: 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).

Step 3: To a solution of 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 1.24 mol) in dry THF (3.0 L) under N2, cooled to -30 °C was added triphosgene (735 g, 2.48 mol) portion wise and the mixture was stirred at same temperature for 45 min. The reaction was quenched cautiously into ice cold water (10 L) with vigorous stirring. After the effervescence stopped, the reaction mass was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, rinsed with water (1 L) and dried under vacuum to afford 5- amino-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 70%) as a yellow solid. ¾ NMR (400 MHz, DMSO- d) d: 12.46 (s, 1H), 8.05 - 7.98 (m, 3H), 7.65 (s, 1H), 7.50 - 7.44 (m, 3H), 6.93 (s, 1H).

Step 4: To a suspension of 5-amino-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 0.88 mol) in DCM/MeOH 1:1 (2 L) under N2 atmosphere, CaCCh (88 g, 0.88 mol) followed by (CH3)3PhN ⁺ Bn (331 g, 0.88 mol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with small portions of MeOH/DCM (1 : 1) and dried under vacuum to afford 5-amino-8-bromo-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (160 g, 59%) as a light brown solid. ¾NMR (400 MHz, DMSO-i/d) d: 12.57 (s, 1H), 7.62 - 7.60 (m, 2H), 7.45 - 7.41 (m, 3H). ESI MS [M+H] ⁺ for CiiHsBrNsO, calcd 306.0 found 306.0.

Table 1 contains additional intermediates that were made following Route A from the appropriate reagents. Table 1. Characterization data for intermediate lb

Route B: Preparation of 5-amino-8-bromo-7-phenyl-2-IT4-(trifluorc>rnethvDisoxazol -3- yl1methyl1-ri.2.41triazolor4.3-c1pyrimidin-3-one

To a solution of (5-(trifluoromethyl)oxazol-4-yl)methanol (cas #1823360-08, from Enamine) (0.710 g, 4.25 mmol), triethylamine (1.594 ml, 11.43 mmol) in DCM (5 mL) at 0 °C, methanesulfonyl chloride (0.381 ml, 4.90 mmol), was added and the resulting reaction mixture was stirred at rt for 40 min. Reaction mixture was then partitioned between DCM and water (5 mL each). Organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was combined with 5-amino-8-bromo-7-phenyl- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1 g, 3.27 mmol), potassium carbonate (1.354 g, 9.80 mmol) and DMSO (10 mL). The resulting reaction mixture was stirred at 50 °C for 2 hrs. The crude reaction mixture was cooled to rt, ice was added and the resulting mixture was stireed at rt for 10 min, then was set aside for 1 h. Solid was collected by filtration, washed with water and MTBE, dried under vacumn to afford 5-amino-8-bromo-7-phenyl-2-((5-(trifluoromethyl)oxazol- 4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.450 g, 98 %) as a brown solid. No further purification was used. ¾ NMR (500 MHz, DMSO-de) d: 5.14 (2H, s), 7.38 - 7.49 (3H, m), 7.61 (2H, br dd), 8.76 (1H, s). ESI MS [M+H] ⁺ for CieHioBrFsNeCE, calcd 456.0 found 456.1. Table 2 contains additional intermediates that were made following Route B from the appropriate reagents.

Table 2. Characterization data for intermediate 2b-2v

Route C: Preparation of 5-amino-8-bromo-2-r(3-methyltetrahvdrofuran-2- 7- phenyl-ri.2.41triazolor4.3-clpyrimidin-3-one

Step 1: Diiodine (887 mg, 3.49 mmol) was added to 3-methylpent-4-en-l-ol (350 mg, 3.49 mmol) in acetonitrile (11 mL) under nitrogen. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with saturated aqueous Na2S2Cb solution (20 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated to afford 2-(iodomethyl)-3-methyl- tetrahydrofuran as a yellow oil. This oil was used directly for Step 2 without further purification.

Step 2: 5-amino-8-bromo-7-phenyl-2H-[l,2,4]triazolo[4,3-c]pyrimidin- 3-one (1.070 g, 3.49 mmol) and above yellow oil was mixed with K2CO3 (483 mg, 3.49 mmol) in DMF (11.00 mL). The mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with saturated brine (50 mL), extracted with EtOAc (3 x 75 mL), the organic layer was dried over anhydrous Na2S04, filtered and evaporated to afford yellow oil. The crude product was purified by flash chromatography on silica using 0 to 20% MeOH in DCM to afford the title compound (0.162 g,

11.47 %) as a yellow oil. ESI MS [M+2] ⁺ for CivHisBrNsCL, calcd 404.1 found 405.9.

Route D: Preparation of 5-amino-8-bromo-2 difluorotetrahvdrofuran-2-yl jmethyll- 7-phenyl-rL2.41triazolor4.3-clpyrimidin-3-one

Step 1: A solution of diethylaminosulfur trifluoride (147 pL, 1.11 mmol) in DCM (1 mL) was added dropwise to methyl 4-oxotetrahydrofuran-2-carboxylate (100 mg, 0.69 mmol) in DCM (1 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated aqueous NaHCCh (5 mL), the aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (50 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered and evaporated to afford methyl 4,4-difluorotetrahydrofuran-2-carboxylate (0.100 g, 87 %) as a yellow oil. This oil was used directly for the next step without further purification. 'H NMR (DMSO- e, 400 MHz) d 2.52 - 2.66 (m, 1H), 2.72 - 2.92 (m, 1H), 3.69 (s, 3H), 3.98 - 4.10 (m, 2H), 4.83 (dd, J = 5.8, 9.0 Hz, 1H).

Step 2: Lithium aluminum hydride (1.0 M in THF, 1.8 mL, 1.81 mmol) was added dropwise to a solution of methyl 4,4-difluorotetrahydrofuran-2-carboxylate (100 mg, 0.60 mmol) in THF (2 mL) at -60 °C over a period of 2 minutes under nitrogen. The resulting mixture was then stirred at rt for 3 h. The reaction mixture was quenched sequentially with water (0.09 mL), 1M NaOH (0.112 mL) and water (0.09 mL).The mixture was filtered through a pad of celite. The filtrate was partitioned between EtOAc and water. The organic phase was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford (4,4- diflu orotetrahydrofuran-2-yl)m ethanol (0.070 g, 84 %) as a yellow oil. This oil was used directly for the next step without further purification. 'H NMR (DMSO-r/r,, 400 MHz) 52.17 - 2.29 (m, 1H), 2.36 - 2.47 (m, 1H), 3.75 - 3.89 (m, 1H), 3.95 - 4.08 (m, 1H), 4.13 (ddt, J = 4.5, 7.0, 8.7 Hz, 1H), 4.35 (t, J = 5.2 Hz, 1H), 4.88 (t, J = 5.7 Hz, 1H).

Step 3: MsCl (260 pL, 3.33 mmol) was added dropwise to a solution of (4,4- difluorotetrahydrofuran-2-yl)methanol (307 mg, 2.22 mmol) and Et3N (929 pL, 6.66 mmol) in DCM (10 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at it for 2 h. The reaction mixture was diluted with EtOAc (5 mL) and washed sequentially with water (2 mL x 2). The organic layer was separated, dried over Na2SC>4, filtered and evaporated to afford crude mesylate intermediate. This intermediate was combined with K2CO3 (921 mg, 6.66 mmol), 5-amino-8-bromo-7-phenyl-2H-[l,2,4]triazolo[4,3-c]pyrimidin- 3-one (680 mg, 2.22 mmol) and DMSO (10.00 mL) at rt under nitrogen. The resulting mixture was stirred at 60 °C for 1 h. The reaction mixture was then diluted with EtOAc (30 mL) and washed sequentially with water (5 mL x 2) and brine (10 mL x 1). The organic layer was separated, dried over anhydrous Na2S04, filtered and evaporated. The residue was purified by flash chromatography on silica using 0 to 6% MeOH in DCM to afford the title compound (0.210 g, 22.18 %) as a yellow solid. 1HNMR (DMSO-4, 400 MHz) d 2.30 - 2.47 (m, 1H), 2.65 (tt, J = 8.5, 16.2 Hz, 1H), 3.79 - 4.18 (m, 4H), 4.52 (qd, J = 4.6, 7.3 Hz, 1H), 7.46 (pd, J = 1.7, 4.7, 5.7 Hz, 3H), 7.56 - 7.67 (m, 2H), 7.69 - 8.85 (m, 2H). ESI MS [M+H] ⁺ for CieHMBrFiNsCL, calcd 426.0 found 426.2.

Table 3 contains additional intermediates that were made following Route C or Route D from the appropriate reagents.

Table 3. Characterization data for intermediate 3b-3d Table 4: Examples 1-1 to 5-1

Example 1-1: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[5- (trifluoromethyl)oxazol-4-yl] methyl]- [1,2, 4]triazolo [4,3-c] pyrimidin-3-one l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri din-2(lH)-one (0.403 g,

1.71 mmol), 5-amino-8-bromo-7-phenyl-2-((5-(trifluoromethyl)oxazol-4-yl) methyl)- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.650 g, 1.43 mmol), PdCl2(dtbpf) (0.093 g, 0.14 mmol), triethylamine (0.697 ml, 5.00 mmol) were combined with 1,4-dioxane (4 ml) and EhO (2 ml). The mixture was flashed under N2 for 5 min, was then sealed and stirred at 92 °C (oil bath temperature) for 10 hrs. The resulting mixture was cooled to rt, filtered through celite. The filtrate was combined and was concentrated under reduced pressure to give a brown residue. The residue was purified by flash chromatography on 40 g silica gel column with 0-6% MeOH/DCM to afford crude product along with minor impurities as a brown solid. This solid was triturated with acetone to yield a pale yellow solid. This solid was then sonicated with 5 mL of DI water for 15 min, stirrted at 45 °C for 1 h. The resulting solid was collected by filtration to afford the title compound (0.453 g, 65.6 %) as an off-white solid. 1HNMR (600 MHz, DMSO- is) 5.10 (2H, s), 6.23 (1H, d), 6.99 (1H, dd), 7.32 (3H, dd), 7.37 - 7.42 (2H, m), 7.56 (1H, d), 8.73 (1H, s). ESI MS [M+H] ⁺ for C22H16F3N7O3, calcd 484.1 found 484.2.

Example 1-2: 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl- 2-((5- (trifluoromethyl)thiazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example (86 mg, 62.4 %) as a brown solid. ¾ NMR (500 MHz, DMSO- e) 3.30 (3H, s), 5.27 (2H, s), 6.23 (1H, d), 7.00 (1H, dd), 7.23 - 7.43 (6H, m), 7.53 (1H, d), 7.57 - 8.42 (2H, m), 9.34 (1H, s). ESI MS [M+H]+ for C22H16F3N7O2S, calcd 500.1 found 500.3.

Example 1-3: 5-amino-2-((3-(difluoromethyl)pyridin-2-yl)methyl)-8-(l-meth yl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (97.0 mg, 57 %) as an off-white solid. 1H NMR (500 MHz, DMSO-4) 3.28 (3H, s), 5.33 (2H, s), 6.23 (1H, d), 7.02 (1H, dd), 7.23 - 7.46 (6H, m), 7.47 - 7.57 (2H, m), 8.07 (1H, br d), 8.65 (1H, br d). ESI MS [M+H] ⁺ for C24H19F2N7O2, calcd 476.1 found 476.3.

Example 1-4: 5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-phenyl-8-(pyridaz in-4-yl)- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (68.0 mg, 62.0 %) as a yellow solid. ¾NMR (400 MHz, DMSO- e) d 5.24 (d, J = 1.7 Hz, 2H), 7.23 - 7.40 (m,

5H), 7.41 - 7.53 (m, 2H), 7.76 (ddd, J = 1.3, 8.4, 10.0 Hz, 1H), 7.90 (s, 1H), 8.37 (dt, J = 1.5, 4.7 Hz, 1H), 8.70 (s, 1H), 8.79 (dd, J = 1.2, 2.4 Hz, 1H), 9.07 (dd, J = 1.3, 5.4 Hz, 1H). ESI MS [M+H] ⁺ for C21H15FN8O, calcd 415.1 found 415.1. Example 1-5: 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5-met hyloxazol-4- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (1.294 g, 64.7 %) as a light yellow solid. ¾ NMR (500 MHz, DMSO-d) 2.36 (3H, s), 3.32 (3H, br s), 4.88 (2H, s), 6.25 (1H, d), 7.03 (1H, dd), 7.23 - 7.43 (5H, m), 7.55 (1H, s), 8.16 (1H, s). ESI MS [M+H] ⁺ for C22H19N7O3, calcd 430.2 found 430.2.

Example 1-6: 5-amino-2-((5-(difluoromethyl)oxazol-4-yl)methyl)-8-(l-methy l-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (71.0 mg, 18.42 %) as a white solid. ¾ NMR (500 MHz, DMSO- e) 3.32 (3H, br s), 5.11 (2H, s), 6.23 (1H, d), 6.99 (1H, dd), 7.23 - 7.64 (7H, m), 8.58 (1H, s). ESI MS [M+H] ⁺ for C22H17F2N7O3, calcd 466.1 found 466.3. Example 1-7: 5-[5-amino-2-[[3-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl - [l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-lH-pyridin-2-one

The title compound was prepared in a similar fashion to Example 1-1 (0.034 g, 10.61 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) 3.28 (3H, br s), 5.24 (2H, br s), 6.24 (1H, br d), 7.04 (1H, br d), 7.31 (3H, br d), 7.38 (2H, br s), 7.46 (1H, br dd), 7.50 (1H, br s), 7.76 (1H, br t), 8.37 (1H, br d). ESI MS [M+H] ⁺ for C23H18FN7O2, calcd 444.1 found 444.2.

Example 1-8: 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl- 2-((4- (trifluoromethyl)oxazol-5-yl)methyl)-[l,2,4]triazolo[4,3-c]p yrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (160 mg, 84 %) as a cream solid. ¾ NMR (500 MHz, DMSO- e) 3.32 - 3.32 (3H, m), 5.28 (2H, s), 6.24 (1H, br d), 6.99 (1H, br d), 7.29 - 7.44 (5H, m), 7.55 (1H, br s), 8.67 (1H, s). ESI MS [M+H] ⁺ for C22H16F3N7O3, calcd 484.1 found 484.3. Example 1-9: 5-amino-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-8-(pyridaz in-4-yl)- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (56.0 mg, 37.4 %) as a yellow solid. ¹ HNMR (500 MHz, DMSO- e) 5.14 (2H, s), 7.25 - 7.39 (5H, m), 7.42 - 7.52 (2H, m), 7.68 - 7.77 (1H, m), 8.53 (1H, br s), 8.80 (1H, br d), 9.08 (1H, dd). ESI MS [M+H] ⁺ for C22H16CIN7O, calcd 415.1 found 415.1.

Example 1-10: 5-amino-2-((5-methyloxazol-4-yl)methyl)-7-phenyl-8-(pyridazi n-4-yl)- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (16.00 mg, 16.03 %) as a yellow solid. ¾ NMR (DMSO-4, 400 MHz) d 2.35 (3H, s), 4.87 (2H, s), 7.21 - 7.38 (5H, m), 7.48 (1H, dd, J=2.4, 5.4 Hz), 7.80 (1H, s), 8.15 (1H, s), 8.61 (1H, s), 8.80 (1H, dd,

J= 1.3, 2.4 Hz), 9.10 (1H, dd, J=1.3, 5.4 Hz). ESI MS [M+H] ⁺ for C20H16N8O2, calcd 400.1 found 400.1. Example 1-11: 5-amino-2-((5-methyloxazol-4-yl)methyl)-8-(6-oxo-l,6-dihydro pyridin-3-yl)- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (17.00 mg, 13.68 %) as an off-white solid. ¾ NMR (500 MHz, DMSO- e) 3.30 (3H, s), 4.88 (2H, s), 6.18 (1H, d), 6.97 - 7.10 (1H, m), 7.17 (1H, br s), 7.25 - 7.45 (6H, m), 8.16 (1H, s), 11.51 - 11.64 (1H, m). ESI MS [M+H]+ for C21H17N7O3, calcd 416.1 found 416.2.

Example 1-12: 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(l-methyl-6-oxo-l ,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (75 mg, 39.0 %) as a creamy solid. ¾NMR (500 MHz, DMSO- e) 3.29 (3H, s), 5.14 (2H, s), 6.25 (1H, d), 7.06 (1H, dd), 7.28 - 7.35 (3H, m), 7.36 - 7.41 (2H, m), 7.45 (1H, dd), 7.52 (1H, d), 7.73 (1H, td), 8.53 (1H, d). ESI MS [M+H] ⁺ for C23H18FN7O2, calcd 444.1 found 444.2. Example 1-13: 5-amino-8-(l-ethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5-meth yloxazol-4- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (51.0 mg, 33.0 %) as a light yellow solid. ¾ NMR (500 MHz, DMSO-d) 0.97 (3H, t), 2.36 (3H, s), 3.74 (2H, q), 4.88 (2H, s), 6.28 (1H, d), 7.14 (1H, dd), 7.25 - 7.43 (6H, m), 8.16 (1H, s). ESI MS [M+H] ⁺ for C23H21N7O3, calcd 444.1 found 444.2.

Example 1-14: 5-[5-amino-7-(4-fluorophenyl)-2-[(5-methoxy-2-pyridyl)methyl ]- [l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one

The title compound was prepared in a similar fashion to Example 1-12 (0.035 g, 52.1 %) as a white solid. ¹ HNMR (500 MHz, DMSO- e) 2.51 - 2.52 (3H, m), 2.73 - 2.84 (2H, m), 3.35 (3H, s), 4.07 (2H, t), 6.27 (1H, d), 7.06 (1H, dd), 7.22 - 7.45 (5H, m), 7.60 (1H, d), 7.72 - 8.61 (1H, m)ESI MS [M+H]+ for C24H20FN7O2, calcd 445.1 found 445.2. Example 1-15: 5-amino-7-phenyl-8-(pyridazin-4-yl)-2-((5-(trifluoromethyl)o xazol-4- yl)methyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (82 mg, 45.6 %). ¾NMR (500 MHz, DMSO-d) 5.09 (2H, s), 7.16 - 7.38 (5H, m), 7.47 (1H, dd), 8.70 (1H, s), 8.79 (1H, s), 9.07 (1H, d). ESI MS [M+H] ⁺ for C20H13F3N8O2, calcd 455.1 found 455.6.

Example 1-16: 5-amino-2-((5-cyclopropyloxazol-4-yl)methyl)-8-(l-methyl-6-o xo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (27.5 mg, 43.0 %) as a pale yellow solid. ¾ NMR (400 MHz, DMSO- e) d 0.85 (dt, J = 3.0, 5.3 Hz, 2H), 0.95 (dt, J = 3.2, 8.4 Hz, 2H), 2.13 (ddd, J = 5.0, 8.5, 13.4 Hz, 1H), 3.32 (s, 3H), 4.93 (s, 2H), 6.24 (d, J = 9.4 Hz, 1H), 7.02 (dd, J = 2.6, 9.3 Hz, 1H), 7.31 (p, J = 3.6 Hz, 3H), 7.38 (dd, J = 3.0, 6.8 Hz, 2H), 7.55 (d, J = 2.6 Hz, 1H), 8.09 (s, 3H). ESI MS [M+H] ⁺ for C22H19N7O2, calcd 456.2 found 456.1. Example 1-17: 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl- 2-(3,3,3- trifluoropropyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (37.0 mg, 19.21 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) 2.71 - 2.88 (2H, m), 3.35 (3H, s), 4.07 (2H, t), 6.27 (1H, d), 7.06 (1H, dd), 7.32 (3H, dd), 7.36 - 7.41 (2H, m), 7.60 (1H, d). ESI MS [M+H] ⁺ for C20H17F3N6O2, calcd 431.1 found 431.1.

Example 1-18: 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5-met hylisoxazol-3- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (72.0 mg, 33.6 %) as a yellow solid. 1HNMR (500 MHz, DMSO-4) 2.38 (3H, s), 3.32 (3H, s), 5.07 (2H, s), 6.23 (1H, d), 6.27 (1H, d), 7.06 (1H, dd), 7.22 - 7.44 (5H, m), 7.55 (1H, d). ESI MS [M+H] ⁺ for C22H19N7O3, calcd 430.2 found 430.1. Example 1-19: (R)-5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phe nyl-2- ((tetrahydrofuran-2-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimid in-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (66.0 mg, 30.8 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) 1.57 - 1.71 (1H, m), 1.75 - 1.90 (2H, m), 1.92 - 2.03 (1H, m), 3.33 - 3.33 (3H, m), 3.63 (1H, q), 3.70 - 3.80 (2H, m), 3.87 (1H, br dd), 4.18 (1H, quin), 6.27 (1H, d), 7.07 (1H, dd), 7.32 (3H, br d), 7.35 - 7.42 (2H, m), 7.59 (1H, s). ESI MS [M+H] ⁺ for C22H22N6O3, calcd 419.2 found 419.2.

Example 1-20: 5-amino-2-((5-(difluoromethyl)pyridin-2-yl)methyl)-7-phenyl- 8-(pyridazin- 4-yl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (51.0 mg, 29.0 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) 5.22 (2H, s), 6.99 - 7.41 (6H, m), 7.45 - 7.59 (2H, m), 8.01 (1H, br d), 8.68 - 8.86 (2H, m), 9.07 (1H, dd). ESI MS [M+H] ⁺ for C22H16F2N8O, calcd 447.1 found 447.1. Example 1-21 : 5-amino-8-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(( 5- methyloxazol-4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyr imidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (99 mg, 67.1 %) as a brown solid. ¾ NMR (500 MHz, DMSO- e) 0.43 (2H, br d), 0.87 (2H, br d), 2.36 (3H, s), 4.88 (2H, s), 6.24 (1H, d), 7.07 (1H, dd), 7.21 (1H, d), 7.30 - 7.36 (5H, m), 8.17 (1H, s). ESI MS [M+H] ⁺ for C22H18N8O, calcd 456.2 found 456.3.

Example 1-22: 5-amino-8-(6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-2-((5- (trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]p yrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-19 (34.0 mg, 16.49 %) as an off-white solid. ¾ NMR (500 MHz, DMSO- e) 5.11 (2H, s), 6.18 (1H, br d), 6.90 - 7.21 (2H, m), 7.24 - 8.42 (7H, m), 8.73 (1H, s), 11.55 (1H, br s). ESI MS [M+H] ⁺ for C21H14F3N7O3, calcd 470.1 found 470.3. Example 1-23: 5-amino-8-(l-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3-yl) -2-((5- methyloxazol-4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyr imidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (31.0 mg, 26.7 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) 2.36 (3H, s), 4.88 (2H, s), 6.39 (1H, d), 7.14 (1H, dd), 7.31 - 7.43 (5H, m), 7.56 (1H, d), 7.63 - 7.99 (3H, m), 8.16 (1H, s). ESI MS [M+H] ⁺ for C22H17F2N7O3, calcd 466.1 found 466.2.

Example 1-24: 5-amino-2-((4-(difluoromethyl)oxazol-5-yl)methyl)-8-(l-methy l-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (66.0 mg, 60.8 %) as a white solid. ¾NMR (400 MHz, DMSO- e) d 3.32 (s, 3H), 5.32 (s, 2H), 6.23 (d, J = 9.2 Hz, 1H), 6.91 - 7.25 (m, 2H), 7.29-7.33 (m, 3H), 7.34-7.39 (m, 2H), 7.56 (d, J = 2.5 Hz, 1H), 8.54 (s, 1H). ESI MS [M+H] ⁺ for C22H17F2N7O3, calcd 466.1 found 466.2. Example 1-25: (R)-5-amino-7-phenyl-8-(pyridazin-4-yl)-2-((tetrahydrofuran- 2-yl)methyl)- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (24.53 mg, 30.7 %) as a yellow solid. ¹ HNMR (400 MHz, DMSO- e) d 1.66 (ddt, J = 6.3, 8.2, 12.1 Hz, 1H), 1.74 - 1.91 (m, 2H), 1.96 (dddd, J = 5.6, 7.0, 8.6, 12.0 Hz, 1H), 3.62 (td, J = 6.1, 7.8 Hz, 1H), 3.70 - 3.80 (m, 2H), 3.87 (dd, J = 7.3, 14.1 Hz, 1H), 4.11 - 4.21 (m, 1H), 7.21 - 7.40 (m, 5H), 7.54 (dd, J = 2.4, 5.4 Hz, 1H), 7.81 (s, 1H), 8.62 (s, 1H), 8.83 (dd, J = 1.2, 2.4 Hz, 1H), 9.11 (dd, J = 1.2, 5.4 Hz, 1H). ESI MS [M+H] ⁺ for C20H19N7O2, calcd 390.1 found 390.2.

Example 1-26: 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(6-methylpyridazi n-4-yl)-7- phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (37.0 mg, 27.6 %) as a brown solid. ¾ NMR (500 MHz, DMSO- e) 2.49 (3H, s), 5.15 (2H, s), 7.26 - 7.38 (6H, m), 7.45 (1H, dd), 7.73 (1H, td), 8.53 (1H, d), 8.59 - 8.69 (1H, m). ESI MS [M+H] ⁺ for C22H17FN8O, calcd 429.2 found 429.3. Example 1-27 : 5-amino-8-(l-ethyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-2 -((5- (trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]p yrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (36.0 mg, 41.2 %) as a yellow solid. ¾ NMR (300 MHz, DMSO- e) d 0.96 (t, J = 7.2 Hz, 3H), 3.73 (q, J = 7.2 Hz, 2H), 5.09 (s, 2H), 6.24 (d, J = 9.3 Hz, 1H), 7.08 (dd, J = 9.3 Hz, 1H), 7.21 - 7.48 (m, 6H), 8.73 (s, 1H). ESI MS [M+H] ⁺ for C23H18F3N7O3, calcd 498.1 found 498.2.

Example 1-28: 5-amino-2-[(4-methyloxazol-5-yl)methyl]-8-(l-methyl-6-oxo-3- pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (41.0 mg, 31.9 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) 2.17 (3H, s), 3.03 (3H, s), 5.09 (2H, s), 6.26 (1H, br d), 7.03 (1H, dd), 7.24 - 7.40 (5H, m), 7.56 (1H, br s), 8.18 - 8.29 (1H, m). ESI MS [M+H] ⁺ for C22H19N7O3, calcd 430.1 found 430.1. Example 1-29: 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(6-oxo-l,6-dihydr opyridin-3-yl)- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (58.0 mg, 14.02 %) as a light brown solid. ¾ NMR (500 MHz, DMSO- e) 5.14 (2H, s), 6.17 (1H, br d), 7.05 (1H, br d), 7.16 (1H, br s), 7.25 - 7.47 (6H, m), 7.73 (1H, br t), 8.53 (1H, br s), 11.52 (1H, br s). ESI MS [M+H] ⁺ for C22H16FN7O2 calcd 430.1 found 430.1.

Example 1-30: 5-amino-8-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)- 2-((5- methyloxazol-4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyr imidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (33.0 mg, 24.66 %) as a light brown solid. ¾ NMR (500 MHz, DMSO- e) 2.36 (3H, s), 3.39 (3H, s), 4.88 (2H, s), 7.05 (1H, dd), 7.24 - 7.45 (6H, m), 8.16 (1H, s). ESI MS [M+H] ⁺ for C22H18FN7O3 calcd 448.1 found 448.2. Example 1-31 : 2-(5-(5-amino-2-((5-methyloxazol-4-yl)methyl)-3-oxo-7-phenyl -2, 3-dihydro- [l,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-oxopyridin-l(2H)-yl) acetonitrile

The title compound was prepared in a similar fashion to Example 1-1 (72.0 mg, 53.0 %) as a yellow solid. ¾NMR (500 MHz, DMSO-d6) 2.37 (3H, s), 4.87 (2H, s), 4.94 (2H, s), 6.40 (1H, d), 7.16 (1H, dd), 7.25 - 7.50 (7H, m), 7.63 (1H, d), 8.15 (1H, s). ESI MS [M+H] ⁺ for C23H18N8O3 calcd 455.2 found 455.3.

Example 1-32: (R)-5-amino-8-(6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-2- ((tetrahydrofuran-2-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimid in-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (64.0 mg, 30.9 %) as a light yellow solid. ¾ NMR (500 MHz, DMSO-d) 1.62 - 1.72 (1H, m), 1.76 - 1.92 (2H, m), 1.92 - 2.02 (1H, m), 3.60 - 3.68 (1H, m), 3.71 - 3.80 (2H, m), 3.87 (1H, br dd), 4.08 - 4.20 (1H, m), 6.20 (1H, br d), 7.06 - 7.49 (8H, m), 11.55 (1H, br dd). ESI MS [M+H] ⁺ for C21H20N6O3 calcd 405.2 found 405.1. Example 1-33: 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(l-(oxa zol-4- yl)ethyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (0.035 g, 23.03 %) as a light brown solid. ¾ NMR (500 MHz, DICHLOROMETHANE-ife) 1.81 (3H, br d), 3.41 (3H, s), 5.57 (1H, br d), 6.34 (1H, br d), 7.07 (1H, br d), 7.34 (4H, br d), 7.42 (2H, br d), 7.68 (1H, s), 7.88 (1H, s). ESI MS [M+H] ⁺ for C22H19N7O3 calcd 430.2 found 430.3.

Example 1-34: 2-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-amino-7-phenyl-8 -(pyridazin-4- yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (0.078 g, 27.9 %) as a light yellow solid. ¾ NMR (500 MHz, DMSO-d) 1.45 (2H, dd), 1.77 (2H, br d), 3.54 (2H, s), 4.16 (2H, s), 4.44 (1H, s), 7.22 - 7.40 (5H, m), 7.51 (1H, dd), 8.84 (1H, s), 9.11 (1H, d). ESI MS [M+H] ⁺ for C21H19N7O2 calcd 402.2 found 402.3. Example 1-35: 2-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-amino-8-(l-methy l-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (0.112 g, 34.9 %) as a light yellow solid. ¾NMR (500 MHz, DMSO-d) 1.45 (2H, br d), 1.77 (2H, br d), 3.30 (3H, br s), 3.54 (2H, s), 4.16 (2H, s), 4.45 (1H, s), 6.27 (1H, d), 7.05 (1H, dd), 7.32 (3H, br d), 7.39 (2H, br d), 7.57 (1H, s). ESI MS [M+H] ⁺ for C23H22N6O3 calcd 431.2 found 431.3.

Example 1-37 : 5-amino-8-(6-methoxypyridazin-4-yl)-2-((5-methyloxazol-4-yl) methyl)-7- phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (12.00 mg, 22.37 %) as a yellow solid. ¾ NMR (DMSO-4, 400 MHz) d 2.36 (3H, s), 3.87 (3H, s), 4.88 (2H, s), 6.57 (1H, d, J=1.2 Hz), 7.37 (4H, m),7.73 (1H, s), 7.93 (1H, d, J=l.l Hz), 8.16 (1H, s), 8.62 (1H, s). ESI MS [M+H] ⁺ for C21H18N8O3 calcd 431.1 found 431.2. Example 1-38: 5-amino-2-((5-(difluoromethyl)pyridin-2-yl)methyl)-8-(l-meth yl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (57.0 mg, 29.8 %) as a yellow solid. ¹ HNMR (500 MHz, DMSO- e) 3.29 (3H, s), 5.22 (2H, s), 6.25 (1H, d), 7.03 - 7.43 (7H, m), 7.46 - 7.58 (2H, m), 8.01 (1H, br d), 8.74 (1H, s). ESI MS [M+H] ⁺ for C24H19F2N7O2 calcd 476.1 found 476.1.

Example 1-39: 5-amino-2-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-8-( l-methyl-6- oxo-l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (26.0 mg, 49.0 %) as a creamy solid. ¾NMR (500 MHz, DMSO- e) 1.31 - 1.40 (6H, s), 3.26 - 3.29 (3H, s), 5.05 - 5.14 (2H, s), 5.16 - 5.19 (1H, s), 6.18 - 6.26 (1H, d), 6.99 - 7.05 (1H, d), 7.05 - 7.12 (1H, d), 7.25 - 7.34 (3H, m), 7.35 - 7.41 (2H, m), 7.48 - 7.51 (1H, s), 7.52 - 7.56 (1H, d), 7.71 - 7.75 (1H, t). ESI MS [M+H] ⁺ for C24H19F2N7O2 calcd 484.2 found 484.2. Example 1-40: 5-amino-8-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5 -methyloxazol- 4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)- one

The title compound was prepared in a similar fashion to Example 1-1 (31.0 mg, 21.09 %) as a yellow solid. 1HNMR (500 MHz, DMSO-d6) 1.87 (3H, s), 2.36 (3H, s), 4.88 (2H, s), 6.98 (1H, dd), 7.19 - 7.44 (5H, m), 8.16 (1H, s). ESI MS [M+H] ⁺ for C23H21N7O3 calcd 444.2 found 444.2.

Example 1-41: (R)-5-amino-8-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-7 -phenyl-2- ((tetrahydrofuran-2-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimid in-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (54.0 mg, 48.7 %) as a brown solid. ¾ NMR (500 MHz, DICHLOROMETHANE-ife) 1.69 - 1.79 (2H, m), 1.87 - 1.99 (2H, m), 2.01 (3H, s), 2.04 - 2.12 (1H, m), 3.43 (3H, s), 3.73 - 3.80 (1H, m), 3.84 (1H, dd), 3.88 - 3.94 (1H, m), 4.00 (1H, dd), 4.28 - 4.40 (1H, m), 5.33 - 5.40 (2H, m), 7.01 (1H, d), 7.19 (1H, d), 7.27 - 7.36 (3H, m), 7.39 - 7.45 (2H, m). ESI MS [M+H] ⁺ for C23H24N6O3 calcd 433.2 found 433.3. Example 1-42: 2-(5-(5-amino-3-oxo-7-phenyl-2-((5-(trifluoromethyl)oxazol-4 -yl)methyl)- 2,3-dihydr 0- [1 ,2,4] triazolo [4,3-c] pyrimidin-8-yl)-2-oxopyridin- 1 (2H)-yl)acetonitrile

The title compound was prepared in a similar fashion to Example 1-1 (82 mg, 48.9 %) as an off-white solid. 1H NMR (500 MHz, DMSO-4) 4.91 (2H, s), 5.10 (2H, s), 6.38 (1H, d), 7.17 (1H, dd), 7.25 - 7.43 (5H, m), 7.59 (1H, d), 8.72 (1H, s). ESI MS [M+H] ⁺ for C23H15F3N8O3 calcd 509.0 found 509.1.

Example 1-43: 5-amino-8-(l-isopropyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5- methyloxazol- 4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)- one

The title compound was prepared in a similar fashion to Example 1-1 (43.0 mg, 31.4 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) 0.97 (6H, d), 2.35 (3H, s), 4.83 - 5.00 (2H, m), 6.30 (1H, d), 7.20 (1H, dd), 7.26 - 7.40 (7H, m), 8.17 (1H, s). ESI MS [M+H] ⁺ for C24H23N7O3 calcd 458.2 found 458.2. Example 1-44: 5-amino-2-((5-methyloxazol-4-yl)methyl)-8-(6-oxo-l-(2,2,2-tr ifluoroethyl)- l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyri midin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (8.00 mg, 12.91 %) as a white solid. ¾NMR (300 MHz, DMSO) d 2.33 (s, 3H), 4.71 (q, J = 9.2 Hz, 2H), 4.85 (s, 2H), 6.40 (d, J = 9.5 Hz, 1H), 7.19 (d, 9.5 Hz, 1H), 7.24 - 7.36 (m, 5H), 7.41 (d, J = 2.5 Hz, 1H), 8.15 (s, 1H). ESI MS [M+H] ⁺ for C23H18F3N7O3 calcd 498.1 found 498.2.

Example 1-45: 5-amino-2-((l-methyl-5-(trifluoromethyl)-lH-imidazol-4-yl)me thyl)-8-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazo lo[4,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (64.0 mg, 50.3 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) 3.03 (3H, br s), 3.33 (3H, br s), 5.14 (2H, s), 6.19 (1H, d), 6.90 (1H, dd), 7.28 - 7.34 (4H, m), 7.37 - 7.42 (2H, m), 7.59 (1H, d), 7.85 (1H, s). ESI MS [M+H] ⁺ for C23H19F3N8O2 calcd 497.2 found 497.3. Example 1-46: 5-amino-8-(6-oxo-l-(2,2,2-trifluoroethyl)-l,6-dihydropyridin -3-yl)-7-phenyl- 2-((5-(trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4 ,3-c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (58.0 mg, 53.2 %) as a white solid. ¾NMR (300 MHz, DMSO- e) d 4.72 (q, J = 9.0 Hz, 2H), 5.07 (s, 2H), 6.36 (d, J = 9.6 Hz, 1H), 7.14 (d, J = 9.6 Hz, 1H), 7.18 - 7.39 (m, 5H), 7.43 (s, 1H), 8.72 (s, 1H). ESI MS [M+H] ⁺ for C23H15F6N7O3 calcd 552.1 found 552.2.

Example 1-47 : 5-amino-7-(4-fluorophenyl)-2-((5-methyloxazol-4-yl)methyl)-8 -(6-oxo-l,6- dihydropyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-o ne

The title compound was prepared in a similar fashion to Example 1-1 (16.00 mg, 15.48 %) as a light brown solid. ¾ NMR (500 MHz, DMSO- e) 3.33 - 3.34 (3H, s), 4.88 (2H, s), 6.21 (1H, d), 7.05 (1H, dd), 7.11 - 7.27 (3H, m), 7.42 (2H, dd), 11.58 (1H, br s). ESI MS [M+H] ⁺ for C21H16FN7O3 calcd 434.1 found 434.1. Example 1-48: 5-amino-7-(4-fluorophenyl)-2-((5-fluoropyridin-2-yl)methyl)- 8-(6-oxo-l,6- dihydropyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-o ne

The title compound was prepared in a similar fashion to Example 1-1 (75 mg, 40.3 %) as a grey solid. ¾NMR (500 MHz, DMSO- e) 5.14 (2H, s), 6.20 (1H, d), 7.05 (1H, dd), 7.12 - 7.22 (3H, m), 7.37 - 7.52 (3H, m), 7.73 (1H, td), 8.52 (1H, d), 11.53 (1H, br s). ESI MS [M+H] ⁺ for C22H15F2N7O2 calcd 448.1 found 448.1.

Example 1-49: 5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-l,6-dihydropyri din-3-yl)-2- ((5-methyloxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (165 mg, 30.9 %) as an off-white solid. ¾NMR (500 MHz, DMSO- e) 2.36 (3H, s), 3.32 - 3.34 (3H, m), 4.88 (2H, s), 6.28 (1H, br d), 7.04 (1H, br d), 7.16 (2H, br t), 7.43 (2H, br t), 7.58 (1H, br s), 8.16 (1H, s). ESI MS [M+H] ⁺ for C22H18FN7O3 calcd 448.1 found 448.2.

Example 1-50: (R)-5-amino-7-(4-fluorophenyl)-8-(6-oxo-l,6-dihydropyridin-3 -yl)-2- ((tetrahydrofuran-2-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimid in-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (87 mg, 28.0 %) as a yellow solid. ¾ NMR (500 MHz, DMSO- e) 1.62 - 1.72 (1H, m), 1.76 - 1.92 (2H, m), 1.93 - 2.02 (1H, m), 3.63 (1H, q), 3.72 - 3.81 (2H, m), 3.84 - 3.91 (1H, m), 4.11 - 4.22 (1H, m), 6.24 (1H, br d), 7.04 - 7.28 (4H, m), 7.43 (2H, br t), 11.59 (1H, br s). ESI MS [M+H] ⁺ for C21H19FN6O3 calcd 423.2 found 423.1.

Example 1-51 : 5-amino-7-(4-fluorophenyl)-2-((5-fluoropyridin-2-yl)methyl)- 8-(pyridazin-4- yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one The title compound was prepared in a similar fashion to Example 1-1 (0.047 g, 29.4 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) 5.14 (2H, s), 7.16 (2H, brt), 7.30 - 7.36 (2H, m), 7.40 - 7.54 (2H, m), 7.73 (1H, td), 8.52 (1H, d), 8.84 (1H, d), 9.10 (1H, d). ESI MS [M+H] ⁺ for C21H14F2N8O calcd 433.1 found 433.2.

Example 1-52: 5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-l,6-dihydropyri din-3-yl)-2- ((5-(trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4,3 -c]pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (0.101 g, 73.3 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) 3.32 (3H, br s), 5.10 (2H, s), 6.26 (1H, d), 7.00 (1H, dd), 7.16 (2H, brt), 7.44 (2H, br dd), 7.57 (1H, d), 8.72 (1H, s). ESI MS [M+H] ⁺ for C22H15F4N7O3 calcd 502.1 found 502.1.

Example 1-53: 5-amino-7-(4-fluorophenyl)-2-((5-methylisoxazol-3-yl)methyl) -8-(6-oxo-l,6- dihydropyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-o ne

The title compound was prepared in a similar fashion to Example 1-1 (15.00 mg, 14.51 %) as a grey solid. ¾NMR (500 MHz, DMSO-4) 2.38 (3H, s), 5.06 (1H, s), 6.10 - 6.38 (2H, m), 7.07 (1H, dd), 7.12 - 7.22 (4H, m), 7.43 (2H, br dd), 11.56 (1H, br s). ESI MS [M+H] ⁺ for C21H16FN7O3 calcd 434.1 found 434.2.

Example 1-54: (R)-5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-l,6-dihydro pyridin-3-yl)- 2-((tetrahydrofuran-2-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrim idin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (61.0 mg, 28.5 %) as a grey solid. ¾NMR (500 MHz, DMSO- e) 1.66 (1H, br dd), 1.74 - 1.91 (2H, m), 1.91 - 2.03

(1H, m), 3.36 (3H, br s), 3.58 - 3.68 (1H, m), 3.69 - 3.81 (2H, m), 3.87 (1H, br dd), 4.17 (1H, br s), 6.30 (1H, br d), 7.07 (1H, br d), 7.17 (2H, br t), 7.44 (2H, br s), 7.61 (1H, br s). ESI MS [M+H] ⁺ for C22H21FN6O3 calcd 437.2 found 437.2.

Example 1-55: 5-amino-7-(4-fluorophenyl)-2-((5-fluoropyridin-2-yl)methyl)- 8-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin -3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (0.121 g, 56.8 %) as a pale yellow solid. ¾ NMR (500 MHz, DMSO- e) 3.31 (3H, s), 5.14 (2H, s), 6.28 (1H, d), 7.06 (1H, dd), 7.17 (2H, t), 7.41 - 7.48 (3H, m), 7.55 (1H, d), 7.73 (1H, td), 8.53 (1H, d). ESI MS [M+H] ⁺ for C23H17F2N7O2 calcd 462.1 found 462.3.

Example 1-56: 5-amino-7-(4-fluorophenyl)-8-(5-methyl-6-oxo-l,6-dihydropyri din-3-yl)-2- (3,3,3-trifluoropropyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (32.0 mg, 14.99 %) as an off-white solid. ¾NMR (500 MHz, DMSO- e) 1.87 (3H, s), 2.75 (2H, dt), 4.07 (2H, t), 7.04 (m, 2H), 7.16 (2H, t), 7.42 (2H, dd), 11.29 - 11.61 (1H, m) ESI MS [M+H] ⁺ for C20H16F4N6O2 calcd 449.1 found 449.2.

Example 1-57 : 5-amino-7-(4-fluorophenyl)-8-(5-methyl-6-oxo-l,6-dihydropyri din-3-yl)-2- (3,3,3-trifluoropropyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 {32.0 mg, 14.99 %) as an off-white solid. ¾ NMR (500 MHz, DMSO- e) 1H NMR (500 MHz, DMSO-d6) 5.10 (2H, s), 7.15 (2H, t), 7.33 (2H, dd), 7.46 (1H, dd), 8.73 (1H, s), 8.84 (1H, s), 9.10 (1H, d). ESI MS [M+H] ⁺ for C20H16F4N6O2 calcd 473.1 found 473.3.

Example 1-58: 5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-l,6-dihydropyri din-3-yl)-2- ((5-methylisoxazol-3-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimi din-3(2H)-one The title compound was prepared in a similar fashion to Example 1-1 (87 mg, 40.8 %) as a yellow solid. ¾ NMR (500 MHz, DMSO- e) 2.38 (3H, s), 3.34 (3H, s), 5.06 (2H, s), 6.22 (1H, s), 6.29 (1H, d), 7.06 (1H, br d), 7.17 (2H, br t), 7.39 - 7.49 (2H, m), 7.58 (1H, s). ESI MS [M+H] ⁺ for C22H18FN703 calcd 448.1 found 448.1.

Example 1-59: 5-amino-7-(4-fluorophenyl)-8-(5-methyl-6-oxo-l,6-dihydropyri din-3-yl)-2- ((5-methyloxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (44.0 mg, 27.5 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) 1.85 (3H, s), 2.36 (3H, s), 4.88 (2H, s), 7.00 (2H, s), 7.11 - 7.23 (2H, m), 7.41 (1H, dd), 8.15 (1H, s), 11.48 (1H, br s). ESI MS [M+H] ⁺ for C22H18FN7O3 calcd 448.1 found 448.1.

Example 1-60: (R)-5-amino-7-(4-fluorophenyl)-8-(pyridazin-4-yl)-2-((tetrah ydrofuran-2- yl)methyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (8.00 mg, 6.17 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) 1.57 - 1.72 (1H, m), 1.78 - 1.89 (2H, m), 1.95 (1H, br d), 3.63 (1H, br d), 3.75 (2H, br d), 3.82 - 3.95 (1H, m), 4.16 (1H, br d), 7.16 (2H, br s), 7.33 (2H, br s), 7.53 (1H, br d), 8.88 (1H, br s), 9.14 (1H, br d). ESI MS [M+H] ⁺ for C20H18FN7O2 calcd 408.2 found 408.3.

Example 1-61 : 5-amino-8-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-7-(4- fluorophenyl)- 2-((5-methyloxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimi din-3(2H)-one

The title compound was prepared in a similar fashion to Example 1-1 (46.0 mg, 38.3 %) as an off-white solid. ¾NMR (500 MHz, DMSO- e) 1.89 (3H, s), 2.35 (3H, s), 3.34 (3H, br s), 4.87 (2H, s), 6.97 - 7.03 (1H, m), 7.15 (2H, t), 7.35 - 7.50 (3H, m), 8.15 (1H, s). ESI MS [M+H] ⁺ for C23H20FN7O3 calcd 462.2 found 462.2.

Example 1-62: 5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-8- (l-methyl-6- oxo-3-pyridyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (120.0 mg, 56.3 %) as an off-white solid. ¹ HNMR (500 MHz, DMSO- e) d 3.30 (3H, s), 5.10 - 5.38 (2H, m), 6.22 - 6.30 (1H, m), 7.04 (1H, dd), 7.16 (2H, t), 7.38 - 7.49 (3H, m), 7.53 (1H, d), 7.76 (1H, ddd), 8.32 - 8.41 (1H, m). ESI MS [M+2] ⁺ for C23H17F2N7O2 calcd 463.1 found 463.4.

Example 1-63: 5-amino-2-[(3,5-difluoro-2-pyridyl)methyl]-8-(l-methyl-6-oxo -3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (87.0 mg, 54.5 %) as an off-white solid. ¾NMR (500 MHz, DMSO- e) d 3.29 (3H, s), 5.22 (2H, s), 6.24 (1H, d), 7.04 (1H, dd), 7.32 (3H, br dd), 7.35 - 7.43 (2H, m), 7.51 (1H, d), 7.97 - 8.03 (1H, m), 8.48 (1H, d). ESI MS [M+H] ⁺ for C23H17F2N7O2 calcd 462.1 found 462.3. Example 1-64: 5-amino-7-phenyl-8-pyridazin-4-yl-2-[[(2R)-tetrahydrofuran-2 -yl]methyl]- [l,2,4]triazolo [4,3-c] pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (20.0 mg, 36.4 %) as a yellow solid. ¹ HNMR (500 MHz, DMSO- e) d 1.65 (dq, J = 6.9, 13.3 Hz, 1H), 1.90 - 2.03 (m, 1H), 2.64 (dd, J = 7.0, 13.9 Hz, 1H), 3.51 (dd, J = 5.4, 8.8 Hz, 1H), 3.57 - 3.72 (m, 2H), 3.77 (ddd, J = 4.4, 7.5, 13.6 Hz, 3H), 7.20 - 7.41 (m, 5H), 7.54 (dd, J = 2.4, 5.4 Hz, 1H), 8.60 (s, 1H), 8.83 (s, 1H), 9.11 (d, J = 5.4 Hz, 1H). ESI MS [M+H] ⁺ for C20H19N7O2 calcd 390.2 found 390.1.

Example 1-65: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[(2R)-tetra hydrofuran-2- yl] methyl]- [1,2, 4]triazolo [4,3-c] pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (35.8 mg, 59.3 %) as a yellow solid. ¾NMR (400 MHz, DMSO- e) d 1.65 (dq, J = 6.8, 13.2 Hz, 1H), 1.89 - 2.03 (m, 1H), 2.66 (h, J = 6.8 Hz, 1H), 3.33 (s, 3H), 3.51 (dd, J = 5.4, 8.7 Hz, 1H), 3.62 (q, J = 7.6 Hz, 1H), 3.69 (dd, J = 6.9, 8.7 Hz, 1H), 3.77 (ddd, J = 4.6, 7.5, 13.8 Hz, 3H), 6.27 (d, J = 9.3 Hz,

1H), 7.06 (dd, J = 2.6, 9.3 Hz, 1H), 7.31 (dd, J = 2.1, 5.1 Hz, 3H), 7.39 (dd, J = 2.9, 6.7 Hz, 2H), 7.57 (d, J = 2.6 Hz, 1H), 7.99 (d, J = 70.6 Hz, 2H). ESI MS [M+H] ⁺ for C22H22N6O3 calcd 419.2 found 419.1. Example 1-66: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[rel-(lR)-l- oxazol-4- ylethyl]- [l,2,4]triazolo [4,3-c] pyrimidin-3-one

OR Enantiomer

The title compound was prepared in a similar fashion to Example 1-1, followed by chiral SFC separation (chiralpak AS column 4.6 mm x 100 mm, 5pm; mobile phase A: 100% C02, mobile phase B: MeOH; 4.0 mL/min, 20% B over 6 min; Rt: 2.12) (10.0 mg, 6.58 %) as an off- white solid. ¹ HNMR (400 MHz, DMSO- e) d 1.81 (3H, br d), 3.41 (3H, s), 5.57 (1H, br d), 6.34 (1H, br d), 7.07 (1H, br d), 7.34 (4H, br d), 7.42 (2H, br d), 7.68 (1H, s), 7.88 (1H, s). ESI MS [M+H] ⁺ for C22H19N7O3 calcd 430.2 found 430.3.

Example 1-67: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[rel-(lS)-l- oxazol-4- ylethyl]- [l,2,4]triazolo [4,3-c] pyrimidin-3-one

OR Enantiomer

The title compound was prepared in a similar fashion to Example 1-1 followed by chiral SFC separation (chiralpak AS column 4.6 mm x 100 mm, 5pm; mobile phase A: 100% C02, mobile phase B: MeOH; 4.0 mL/min, 20% B over 6 min; Rt: 2.61), resulting in (10.0 mg, 6.58 %) a yellow solid. ¾ NMR (400 MHz, DMSO-4) d 1.81 (3H, br d), 3.41 (3H, s), 5.57 (1H, br d), 6.34 (1H, br d), 7.07 (1H, br d), 7.34 (4H, br d), 7.42 (2H, br d), 7.68 (1H, s), 7.88 (1H, s). ESI MS [M+H] ⁺ for C22H19N7O3 calcd 419.2 found 430.3. Example 1-68: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S,3S )-3- methyltetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyr imidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3a, followed by chiral HPLC separation (Column: CHIRALPAK IC, 2*25cm, 5um; Mobile Phase A: Hex:DCM=l:l(10mMNH3-MEOH), Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient:50 B to 50 B in 21 min; 254/220 nm; RTE9.418), resulting in (28.0 mg, 33.7 %) a white solid. ¹ HNMR (400 MHz, DMSO- e) d 1.00 (d, J = 6.4 Hz, 3H), 1.36 - 1.64 (m, 1H), 1.90-2.04( m, 2H), 3.30 (s, 3H), 3.68 (q, J = 4.4, 5.2 Hz, 3H), 3.78 - 3.94 (m, 2H), 6.26 (d, J = 9.2 Hz, 1H), 7.05 (dd, J = 2.4, 9.2 Hz, 1H), 7.22 - 7.33 (m, 3H), 7.33 - 7.41 (m, 2H), 7.55 (d, J = 2.4 Hz, 1H), 7.82-8.15(m, 1H). ESI MS [M+H] ⁺ for C23H24N6O3 calcd 433.5 found 433.2.

Example 1-69: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R,3R )-3- methyltetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyr imidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3a, followed by chiral HPLC separation (Column: CHIRALPAK IC, 2*25cm,5um; Mobile Phase A: Hex:DCM=l:l(10mMNH ₃ -MEOH), Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient:50 B to 50 B in 21 min; 254/220 nm; RT: 14.013), resulting in (25.0 mg, 30.1 %) a white solid. ¾NMR (400 MHz, DMSO- e) d 1.00 (d, J = 6.4 Hz, 3H), 1.36 - 1.64 (m, 1H), 1.90-2.04( m, 2H), 3.30 (s, 3H), 3.68 (q, J = 4.4, 5.2 Hz, 3H), 3.78 - 3.94 (m, 2H), 6.26 (d, J = 9.2 Hz, 1H), 7.05 (dd, J = 2.4, 9.2 Hz, 1H), 7.22 - 7.33 (m, 3H), 7.33 - 7.41 (m, 2H), 7.55 (d, J = 2.4 Hz, 1H), 7.82-8.15(m, 1H). ESI MS [M+H] ⁺ for C23H24N6O3 calcd 433.5 found 433.2.

Example 1-70: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R,3R )-3- (trifluoromethyl)tetrahydrofuran-2-yl] methyl]- [1,2, 4]triazolo [4,3-c] pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3b, followed by chiral HPLC separation (CHIRAL ART Cellulose-SB column, 2*25cm, 5um; Mobile Phase A: Hex:DCM=3 : lQOmM ME-MeOH), Mobile Phase B: IP A; Flow rate: 20 mL/min; Gradient:50 B to 50 B in 8 min; 254/220 nm; RT: 5.025), resulting in (8.0 mg, 20 %) a yellow solid. ¾ NMR (400 MHz, DMSO- e) d 1.80-2.08 (m, 1H), 2.13 - 2.36 (m, 1H), 3.13 - 3.30 (m, 1H), 3.32 (s, 3H), 3.67-3.82 (m, 1H), 3.82 - 3.95 (m, 2H), 3.96-4.11 (m, 1H), 4.22 - 4.39 (m, 1H), 6.27 (d, J = 9.3 Hz, 1H), 7.06 (dd, J = 2.6, 9.3 Hz, 1H), 7.22-7.35 (m, 3H), 7.5- 7.44 (m, 2H), 7.57 (d, J = 2.4 Hz, 1H). ESI MS [M+H] ⁺ for C23H21F3N6O3 calcd 487.1 found 487.1. Example 1-71: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S,3S )-3- (trifluoromethyl)tetrahydrofuran-2-yl] methyl]- [1,2, 4]triazolo [4,3-c] pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3b, followed by chiral HPLC separation (CHIRAL ART Cellulose-SB column, 2*25cm,5um; Mobile Phase A: Hex:DCM=3 : lQOmM ME-MeOH), Mobile Phase B: IP A; Flow rate: 20 mL/min; Gradient:50 B to 50 B in 8 min; 254/220 nm; RT:6.071), resulting in (16.0 mg, 40 %) a yellow solid. ¾ NMR (400 MHz, DMSO- e) d 1.80-2.08 (m, 1H), 2.13 - 2.36 (m, 1H), 3.13 - 3.30 (m, 1H), 3.32 (s, 3H), 3.67-3.82 (m, 1H), 3.82 - 3.95 (m, 2H), 3.96-4.11 (m, 1H), 4.22 - 4.39 (m, 1H), 6.27 (d, J = 9.3 Hz, 1H), 7.06 (dd, J = 2.6, 9.3 Hz, 1H), 7.22-7.35 (m, 3H), 7.5- 7.44 (m, 2H), 7.57 (d, J = 2.4 Hz, 1H). ESI MS [M+H] ⁺ for C23H21F3N6O3 calcd 487.1 found 487.1.

Example 1-72: 5-amino-2-[(4,4-difluorotetrahydrofuran-2-yl)methyl]-8-(l-me thyl-6-oxo-3- pyridyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3c (90.0 mg, 42.2 %) as a yellow solid. ¾ NMR (400 MHz, DMSO-d) d 2.29 - 2.45 (m, 1H), 2.55 - 2.71 (m, 1H), 3.33 (s, 3H), 3.80 - 3.98 (m, 2H), 4.00 - 4.12 (m, 2H), 4.44 - 4.53 (m, 1H), 6.27 (d, J = 9.4 Hz, 1H), 7.06 (dd, J = 2.6, 9.4 Hz, 1H), 7.31 (dd, J = 2.1, 5.1 Hz, 3H), 7.35 - 7.43 (m, 2H), 7.58 (d, J = 2.5 Hz, 1H). ESI MS [M+H] ⁺ for C22H20F2N6O3 calcd 455.4 found 455.1.

Example 1-73: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R)-4 ,4- difluorotetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]p yrimidin-3-one

The title compound was prepared from Example 1-72 after chiral HPLC separation (Column: CHIRALPAK IA, 2*25cm, 5um; Mobile Phase A: MTBE (0.5% 2M ME-MeOH), Mobile Phase B: MeOH; Flow rate:20 mL/min; Gradient: 10 B to 10 B in 20 min; 220/254 nm; RT:11.531) (33.2 mg, 15.6%) as a solid. ¾ NMR (400 MHz, DMSO- e) d 2.28 - 2.45 (m, 1H), 2.56 - 2.71 (m, 1H), 3.33 (s, 3H), 3.80 - 3.98 (m, 2H), 3.99 - 4.12 (m, 2H), 4.44 - 4.54 (m, 1H), 6.27 (d, J = 9.3 Hz, 1H), 7.06 (dd, J = 2.6, 9.4 Hz, 1H), 7.23 - 7.35 (m, 3H), 7.39 (td, J = 3.3, 5.2, 5.9 Hz, 2H), 7.58 (d, J = 2.6 Hz, 1H),7.93 (s, 2H). ESI MS [M+H] ⁺ for C22H20F2N6O3 calcd 455.4 found 455.2.

Example 1-74: 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S)-4 ,4- difluorotetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]p yrimidin-3-one

The title compound was prepared from Example 1-72 after chiral HPLC separation (Column: CHIRALPAK IA, 2*25cm, 5um; Mobile Phase A: MTBE (0.5% 2M ME-MeOH), Mobile Phase B: MeOH; Flow rate:20 mL/min; Gradient: 10 B to 10 B in 20 min; 220/254 nm; RT:15.121) (34.4 mg, 16.1%) as a solid. ¹ HNMR (400 MHz, DMSO- e) d 2.28 - 2.45 (m, 1H), 2.56 - 2.71 (m, 1H), 3.33 (s, 3H), 3.80 - 3.98 (m, 2H), 3.99 - 4.12 (m, 2H), 4.44 - 4.54 (m, 1H), 6.27 (d, J = 9.3 Hz, 1H), 7.06 (dd, J = 2.6, 9.4 Hz, 1H), 7.23 - 7.35 (m, 3H), 7.39 (td, J = 3.3, 5.2, 5.9 Hz, 2H), 7.58 (d, J = 2.6 Hz, 1H),7.93 (s, 2H). ESI MS [M+H] ⁺ for C22H20F2N6O3 calcd 455.4 found 455.1.

Example 1-75: 5-amino-7-phenyl-8-pyridazin-4-yl-2-[[rel-(2R)-3,3- difluorotetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]p yrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3d, followed by chiral HPLC separation (Column: CHIRALPAK IC, 2*25cm, 5um; Mobile Phase A: Hex:DCM=3 : 1 (0.5% 2M ME-MeOH), Mobile Phase B: EtOH; Flow rate:20 mL/min; Gradient: 30 B to 30 B in 24 min; 220/254 nm; RT:11.477), that resulted in (15.4 mg, 12.8%) a yellow solid. ¾ NMR (400 MHz, DMSO- e) d 2.46 (d, J = 6.9 Hz, 1H), 2.52 - 2.60 (m, 1H), 3.89 (dt, J = 7.8, 9.1 Hz, 1H), 4.04 (ddd, J = 6.0, 8.0, 16.0 Hz, 3H), 4.25 (tt, J = 6.2, 12.1 Hz,

1H), 7.20 - 7.42 (m, 5H), 7.54 (dd, J = 2.4, 5.4 Hz, 1H), 8.64 (s, 1H), 8.84 (dd, J = 1.3, 2.4 Hz, 1H), 9.11 (dd, J = 1.2, 5.4 Hz, 1H). ESI MS [M+H] ⁺ for C20H17F2N7O2 calcd 426.1 found 426.1.

Example 1-76: 5-amino-7-phenyl-8-pyridazin-4-yl-2-[[rel-(2S)-3,3-difluorot etrahydrofuran- 2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 3d, followed by chiral HPLC separation (Column: CHIRALPAK IC, 2*25cm, 5um; Mobile Phase A: Hex:DCM=3 : 1 (0.5% 2M ME-MeOH), Mobile Phase B: EtOH; Flow rate:20 mL/min; Gradient: 30 B to 30 B in 24 min; 220/254 nm; RT:17.59), that resulted in (14.1 mg, 11.8%) a yellow solid. ¾ NMR (400 MHz, DMSO- e) d 2.46 (d, J = 6.9 Hz, 1H), 2.52 - 2.60 (m, 1H), 3.89 (dt, J = 7.8, 9.1 Hz, 1H), 4.04 (ddd, J = 6.0, 8.0, 16.0 Hz, 3H), 4.25 (tt, J = 6.2, 12.1 Hz,

1H), 7.20 - 7.42 (m, 5H), 7.54 (dd, J = 2.4, 5.4 Hz, 1H), 8.64 (s, 1H), 8.84 (dd, J = 1.3, 2.4 Hz, 1H), 9.11 (dd, J = 1.2, 5.4 Hz, 1H). ESI MS [M+H] ⁺ for C20H17F2N7O2 calcd 426.1 found 426.1.

Example 2-1 : 5-amino-2-((5-methylisoxazol-3-yl)methyl)-8-(6-oxo-l,6-dihyd ropyridin-3-yl)- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

Stepl: 5-amino-8-bromo-2-((5-methylisoxazol-3-yl)methyl)-7-phenyl-[ l,2,4]triazolo[4,3- c]pyrimidin-3(2H)-one (213 mg, 0.53 mmol) , 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (212 mg, 0.90 mmol), PdCl2(dtbpf) (27.7 mg, 0.04 mmol), triethylamine (0.259 mL, 1.86 mmol), dioxane (1.0 mL) and H2O (0.5 ml) were added and the resulting mixture was purged with nitrogen gas and then was stirred at 88 °C for 5 hrs. Solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel column using 0-40% EtO Ac/hexanes to afford the title compound (200 mg, 87.7%) as an off-white solid. ESI MS [M+H] ⁺ for C22H19N7O3 calcd 430.2 found 430.2.

Step2: 5-amino-2-((5-methylisoxazol-3-yl)methyl)-8-(6-oxo-l,6-dihyd ropyridin-3-yl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

5-amino-8-(6-methoxypyridin-3-yl)-2-((5-methylisoxazol-3- yl)methyl)-7-phenyl- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.47 mmol) was combined with HBr (33 % in acetic acid) (1.9 ml, 11.64 mmol) at rt. The mixture was stirred at 70 °C for 14 hrs. The resulting mixture was cooled to rt, EtO Ac (5 mL) was added and the solid was collected by filtration. The collected solid was sonicated with saturated sodium bicarbonate solution (5 mL) for 10 min. To this mixture, MeOH (10 mL) was added and the slurry was sonicated for 30 min and the resulting solid was collected by filtration. The collected solid was washed with water (2 mL), MeOH (5 mL) and MTBE (5 mL) to afford the title compound (110 mg, 56.9 %) as a white solid. ¾NMR (500 MHz, DMSO-4) 2.38 (3H, s), 5.06 (2H, s), 6.14 (1H, d), 6.21 (1H, s), 7.03 (1H, dd), 7.20 (1H, d), 7.29 - 7.44 (5H, m). ESI MS [M+H] ⁺ for C21H17N7O3 calcd 416.1 found 416.2. Example 2-2: 5-amino-8-(5-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3-yl) -2-(3- fluoropropyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H) -one

The title compound was prepared in a similar fashion to Example 2-1 (42.0 mg, 16.55 %) as a light yellow solid. ¾NMR (500 MHz, DMSO-d) 1.89 - 2.17 (2H, m), 3.91 (2H, t), 4.29 - 4.66 (2H, m), 6.57 - 6.92 (1H, m), 7.30 - 7.46 (7H, m), 12.10 (1H, br s). ESI MS [M+H] ⁺ for C20H17F3N6O2 calcd 431.0 found 431.2.

Example 2-3: 5-amino-2-((5-(difluoromethyl)pyridin-2-yl)methyl)-8-(6-oxo- l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one

The title compound was prepared in a similar fashion to Example 2-1 (65.0 mg, 31.5 %) as an off-white solid. ¾NMR (500 MHz, DMSO- e) 5.22 (2H, s), 6.17 (1H, d), 7.13 - 7.28 (2H, m), 7.30 - 7.36 (3H, m), 7.39 (2H, dd), 7.50 (1H, d), 8.01 (1H, br d), 11.52 (1H, br s). ESI MS [M+H] ⁺ for C23H17F2N7O2 calcd 462.1 found 462.1. Example 3-1: tert-butyl (S)-2-((5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3 -oxo- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)methyl)mor pholine-4-carboxylate

Stepl: l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (106 mg, 0.16 mmol) was combined with TEA (1.1 mL, 8.17 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2(lH)-one (768 mg, 3.27 mmol) and l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (768 mg, 3.27 mmol), dioxane (5 mL) and water (0.500 mL). The mixture was purged with nitrogen and was stirred at 80 °C for 4 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash silica chromatography with 0 to 10% MeOH in DCM to afford 5-amino-8-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidi n-3(2H)-one (0.440 g, 81 %) as a yellow solid. ESI MS [M+H] ⁺ for C17H14N6O2 calcd 334.1 found 335.1.

Step2: Mesyl Chloride (35.0 mΐ, 0.45 mmol) was added dropwise to a solution of tert- butyl (ri)-2-(hydroxymethyl)morpholine-4-carboxylate (78 mg, 0.36 mmol) and Et3N (125 mΐ, 0.90 mmol) in DCM (1 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 2 hrs. The reaction mixture was then diluted with EtOAc (5 mL), and washed with water (2 mL x 2). The organic layer was separated and was dried over anhydrous Na2SC>4, concentrated to afford crude mesylate intermediate. This intremediate was combined with K2CCh (124 mg, 0.90 mmol), 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.30 mmol) and DMSO (1.0 mL). The resulting mixture was stirred at 55°C under nitrogen for 2 hrs, then diluted with EtOAc (10 mL), and was washed with water (5 mL x 2). The organic layer was separated, dried over anhydrous Na2S04 and was concentrated. The residue was purified by flash silica chromatography with 0 to 8% MeOH in DCM to afford the title compound (0.021 g, 13.12 %) as a pale yellow solid. ¾ NMR (400 MHz, DMSO- e) d 1.39 (s, 9H), 2.76 (s, 1H), 2.91 (s, 1H), 3.05 - 3.20 (m, 1H), 3.38 - 3.55 (m, 3H), 3.66 (d, J = 17.1 Hz, 2H), 3.74 - 4.07 (m, 4H), 6.26 (d, J = 9.4 Hz, 1H), 7.06 (d, J = 9.3 Hz, 1H), 7.18 - 7.49 (m, 5H), 7.58 (s, 1H), 8.12 (d, J = 100.1 Hz, 2H). ESI MS [M+H] ⁺ for C27H31N7O5 calcd 534.2 found 534.2.

Example 4-1 : 5-amino-8-(6-(hydroxymethyl)pyridazin-4-yl)-2-((5-methyloxaz ol-4- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one

Stepl: Et3N (0.115 mL, 0.82 mmol) was added to 5-amino-8-bromo-2-((5-methyloxazol- 4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)- one (110 mg, 0.27 mmol), 3-(((tert- butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridazine (1.1 g, 3.14 mmol)(crude) and l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (17.87 mg, 0.03 mmol) in 1,4-dioxane (6 mL) and water (2 mL) at rt under nitrogen. The resulting mixture was stirred at 80 °C for 3 hours. Solvents were removed under reduced pressure. The residue was purified by preparative TLC (DCM: MeOH = 20: 1, Rf = 0.7) to afford 5-amino-8- (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridazin-4-yl)-2-( (5-methyloxazol-4-yl)methyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (80 mg, 67.8 %) as a red solid. ¾NMR (400 MHz, DMSO- e) d 8.75 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.83 - 7.68 (m, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.39 - 7.16 (m, 6H), 4.86 (d, J = 2.9 Hz, 4H), 2.33 (s, 3H), 0.84 (s, 9H). ESI MS [M+H] ⁺ for C27H32N8O3S1 calcd 545.2 found 545.4

Step2: Potassium fluoride (32.0 mg, 0.55 mmol) was added to 5-amino-8-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridazin-4-yl)-2-((5-methylox azol-4-yl)methyl)-7-phenyl- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg, 0.11 mmol) in MeOH (2 mL) at rt under nitrogen. The resulting mixture was stirred at 60 °C for 3 hrs. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (31.1 mg, 65.5 %) as a yellow solid. ¾ NMR (400 MHz, DMSO-d6) d 8.60 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.39 - 7.22 (m, 4H), 5.56 (t, J = 5.7 Hz, 1H), 4.87 (s, 2H), 4.68 (d, J = 5.7 Hz, 2H), 2.36 (s, 3H). ESI MS [M+H] ⁺ for CiiHisNeCb calcd 431.2 found 431.3.

Example 4-2: 5-amino-8-(6-(hydroxymethyl)pyridazin-4-yl)-7-phenyl-2-((5- (trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]p yrimidin-3(2H)-one

The title compound was prepared in a similar fashion to Example 4-1 (65.0 mg, 31.5 %) as an off-white solid. ¾NMR (400 MHz, DMSO- e) d 8.72 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.38 - 7.23 (m, 5H), 5.52 (t, J = 5.7 Hz, 1H), 5.12 - 5.07 (m, 2H), 4.65 (d, J = 5.4 Hz, 2H). ESI MS [M+H] ⁺ for C21H15F3N8O3 calcd 485.1 found 485.2.

Example 5-1: 5-amino-8-[6-(difluoromethyl)pyridazin-4-yl]-2-[(5-fluoro-2- pyridyl)methyl]- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

Stepl: Manganese(IV) oxide (23.47 mg, 0.27 mmol) was added to 5-amino-2-((5- fluoropyridin-2-yl)methyl)-8-(6-(hydroxymethyl)pyridazin-4-y l)-7-phenyl-[l,2,4]triazolo[4,3- c]pyrimidin-3(2H)-one (30 mg, 0.07 mmol) in DCM (10 mL) at 0°C under nitrogen. The resulting mixture was stirred at 80 °C for 2 hrs. The mixture was filtered through Celite. The solvent was removed under reduced pressure to afford 5-[5-amino-2-[(5-fluoro-2- pyridyl)methyl]-3-oxo-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimid in-8-yl]pyridazine-3-carbaldehyde (40.0 mg, 134 %) as a yellow oil. No further purification was used. ¾ NMR (400 MHz, DMSO- de) d 8.52 (dd, J = 5.7, 2.9 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.74 (td, J = 8.7, 3.0 Hz, 1H), 7.66 - 7.53 (m, 1H), 7.46 (dd, J = 8.7, 4.6 Hz, 1H), 7.41 - 7.23 (m, 6H), 5.14 (d, J = 13.7 Hz, 2H). ESI MS [M+H] ⁺ for C22H15FN8O2 calcd 443.1 found 443.3.

Step2: DAST (0.031 mL, 0.24 mmol) was added dropwise to 5-(5-amino-2-((5- fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[l,2,4 ]triazolo[4,3-c]pyrimidin-8- yl)pyridazine-3-carbaldehyde (30 mg, 0.07 mmol) in DCM (1 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 1 hr. The reaction mixture was quenched with water. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (2.250 mg, 7.14 %) as a yellow solid. ¾NMR (400 MHz, DMSO-d) d 8.95 (s, 1H), 8.46 (d, J = 2.9 Hz, 1H), 7.79 - 7.58 (m, 2H),

7.49 - 6.90 (m, 7H), 5.11 (s, 2H). ESI MS [M+H] ⁺ for C22H15F3N8O calcd 465.1 found 465.1.

Example 5-2: 5-amino-2-[(3-fluoro-2-pyridyl)methyl]-8-(l-methyl-6-oxo-pyr idazin-3-yl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (0.070 g, 32.7 %) as a yellow solid. ¾NMR (500 MHz, DMSO- e) d 3.43 (3H, s), 5.23 (2H, d), 6.84 (1H, d), 7.24 (1H, d), 7.33 (5H, s), 7.45 (1H, dt), 7.76 (1H, ddd), 8.33 - 8.44 (1H, m). ESI MS [M+H] ⁺ for C22H17FN8O2 calcd 445.1 found 444.7. Example 5-3: 5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-8- (l-methyl-6- oxo-pyridazin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one

The title compound was prepared in a similar fashion to Example 1-1 (0.045 g, 42 %) as a yellow solid. ¾ NMR (500 MHz, DMSO- e) 3.46 (3H, s), 4.42 (2H, d), 6.93 (1H, d), 7.20 (2H, t), 7.34 - 7.52 (5H, m), 7.64 - 7.78 (1H, m), 8.06 - 8.27 (1H, m), 8.34 (1H, br d). ESI MS [M+H] ⁺ for C17H12F2N6 calcd 447.4 found 447.3.

Example 6: cAMP Accumulation Inhibition Assay pIRES_neo3 expression vectors were generated for human A2AR (UniProt P29274) or human A2BR (UniProt P29275) modified with an N-terminal preprolactin signal peptide to aid functional expression. 6 pg of plasmid was transfected into CHO-K1 cells using PEI transfection agent, and single cell clones were selected over 22-45 days in the presence of 0.5 mg/mL G418 (Sigma, G8168). Selected single cell clones were cultured in Ham’s F12 medium supplemented with 0.5 mg/mL G418. Cells were harvested to a seeding density of 1.5 x 10 ⁵ cells/mL in Ham’s F12 media in the absence of G418, supplemented with 0.2 U/mL adenosine deaminase (Sigma, 52544) and 40 pL/well seeded into 384 well plates. Following overnight incubation (18 h), the monolayer was washed 3X with PBS to remove adenosine deaminase. Cells were incubated in 40 pM Rolipram (Sigma) prepared in Stimulation Buffer (CisBio) for 10 minutes at room temperature before addition of a concentration response of test antagonist using an Echo acoustic dispenser. Following 30 minutes incubation under tissue culture conditions, adenosine (Sigma, A9251) was added to a final concentration of 5 pM for 30 minutes under tissue culture conditions. cAMP was quantified using the cAMP Gs HiRange HTRF kit (CisBio) following manufacturer’s instructions. Example 7: CB1 Binding Assay

Cell membrane homogenates (5 pg protein) are incubated for 30 min at 22°C with 2 nM [3H]CP 55940 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgC12, 2.5 mM EDTA and 0.3% BSA. Nonspecific binding is determined in the presence of 10 mM WIN 55212-2.

Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with an 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 are dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).

The results are expressed as a percent inhibition of the control radioligand specific binding.

The standard reference compound is CP 55940 which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.

Example 8: CB1 functional antagonism assay (cAMP in CHO cells)

The cells are suspended in HBSS buffer (Invitrogen) complemented with 20 mM HEPES (pH 7.4), then distributed in microplates at a density of 5.10 ³ cells/well and preincubated for 5 min at room temperature in the presence of either of the following: HBSS (stimulated control), the reference antagonist AM 281 at 3 mM (basal control) or various concentrations (ICso determination), or the test compounds.

Thereafter, the reference agonist CP 55940 and the adenylyl cyclase activator NKH 477 are added at respective final concentrations of 3 nM and 3 pM. For basal control measurements, CP 55940 is omitted from the wells containing 3 pM AM 281. Following 20 min incubation at 37°C, the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti -cAMP antibody labeled with europium cryptate) are added.

After 60 min at room temperature, the fluorescence transfer is measured at lec=337 nm and lah=620 and 665 nm using a microplate reader (Rubystar, BMG). The cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).

The results are expressed as a percent inhibition of the control response to 3 nM CP

55940. The standard reference antagonist is AM 281, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its ICso value is calculated.

Table 5: Activity of examples vs. A2aR, A2bR, and/or CB1 receptors

Other embodiments are within the scope of the following claims.