WO2021156439A1 - Triazole compounds as adenosine receptor antagonists - Google Patents

Abstract

Described herein are triazole compounds of Formula (I): and pharmaceutically acceptable salts thereof. Methods of making and using compounds of Formula (I) are also described. Compounds of Formula (I) and pharmaceutically acceptable salts thereof can be useful as adenosine receptor antagonists, for example in the treatment of diseases or conditions mediated by the adenosine receptor, such as cancer, movement disorders, or attention disorders.

Description

TRIAZOLE COMPOUNDS AS ADENOSINE RECEPTOR ANTAGONISTS

This application claims priority to provisional U.S. application no. 62/970,855 filed 06 February 2020, the contents of which is hereby incorporated by reference.

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 2019/222677 discloses fused pyrimidine derivatives as A2A / A2B inhibitors. International patent application WO 2018/184590 discloses [l,2,4]triazolo[l,5- cjpyrimidine derivatives as A2a receptor inhibitors. Other compounds are described in, for example, WO 2018/166493; WO 2020/010197; and WO 2020/052631.

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, wherein: ring A is:

R¹ is H, Ci-6alkyl, or C3-6cycloalkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR^a, halo and cyano; each R², independently, is halo, cyano, Ci-3alkyl, -0-Ci-3alkyl, -CCkR³, or -NR⁷R⁸; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR^a, halo, and cyano;

R³ is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R^a, and -OR^a;

R⁴ is -CR^xR^y-R⁵;

R⁵ is Ci-3alkyl wherein alkyl is optionally substituted with one or more substituents independently selected from -OR^a, halo, and cyano; wherein R⁵ is optionally substituted with from one to four groups R⁶; or R⁵ 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 R⁵ is optionally replaced by -C(=0)-; wherein R⁵ is optionally substituted with from one to four groups R⁶; each R⁶, independently, is H, halo, cyano, Ci-6alkyl, or -0-Ci-6alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo, cyano, -R^a, and -OR^a; each R⁷ and each R⁸, 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;

R^x is H or -OH;

R^y is H; or R^x and R^y together are =0; and each k, independently, is 0, 1, or 2.

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

In another aspect, 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 is provided.

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.

Other features, objects, and advantages will be apparent from the description and drawings, 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:

R¹ is H, Ci-₆alkyl, or C3-₆cycloalkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR^a, halo and cyano; each R², independently, is halo, cyano, Ci-3alkyl, -0-Ci-₃alkyl, -C02R^a, or -NR⁷R⁸; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR^a, halo, and cyano;

R³ is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R^a, and -OR^a;

R⁴ is -CR^xR^y-R⁵;

R⁵ is Ci-₃alkyl wherein alkyl is optionally substituted with one or more substituents independently selected from -OR^a, halo, and cyano; wherein R⁵ is optionally substituted with from one to four groups R⁶; or R⁵ 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 R⁵ is optionally replaced by -C(=0)-; wherein R⁵ is optionally substituted with from one to four groups R⁶; each R⁶, independently, is H, halo, cyano, Ci-₆alkyl, or -0-Ci-₆alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo, cyano, -R^a, and -OR^a; each R⁷ and each R⁸, 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;

R^x is H or -OH;

R^y is H; or R^x and R^y together are =0; and each k, independently, is 0, 1, or 2. In some embodiments, R¹ can be H, -CH3, or -CH2CN. Each R², independently, can be H or -CH3. R³ can be phenyl or phenyl substituted by halo.

In some embodiments, both R^x and R^y can be H.

In some embodiments, R⁵ can be Ci-3alkyl.

In some embodiments, R⁵ can be heterocyclyl. When R⁵ is heterocyclyl, R⁵ can be tetrahydrofuranyl, pyrrolidinyl, morpholinyl, or piperidyl.

In some embodiments, R⁵ can be heteroaryl. When R⁵ is heteroaryl, R⁵ can be pyridyl, pyrimidinyl, or oxazolyl.

In some embodiments, R⁵ can substituted with from one to three groups R⁶, wherein each R⁶, independently, is halo, Ci-6alkyl, or -0-Ci-6alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo. Each R⁶, independently, can be halo, methyl, difluoromethyl, trifluoromethyl, or methoxy.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; and R³ can be phenyl or phenyl substituted by halo.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; R³ can be phenyl or phenyl substituted by halo; and R⁵ can be Ci-3alkyl.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; R³ can be phenyl or phenyl substituted by halo; and R⁵ can be heterocyclyl.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; R³ can be phenyl or phenyl substituted by halo; and R⁵ can be heteroaryl.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; R³ can be phenyl or phenyl substituted by halo; R⁵ can be Ci-3alkyl; and R⁵ can substituted with from one to three groups R⁶, wherein each R⁶, independently, is halo.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; R³ can be phenyl or phenyl substituted by halo; R⁵ can be heterocyclyl; and R⁵ can substituted with from one to three groups R⁶, wherein each R⁶, independently, is halo or Ci-3alkyl, wherein alkyl is optionally substituted with one or more substituents independently selected from halo.

In some embodiments, R¹ can be H, -CEE, or -CEECN; each R², independently, can be H or -CEE; R³ can be phenyl or phenyl substituted by halo; R⁵ can be heteroaryl; and R⁵ can substituted with from one to three groups R⁶, wherein each R⁶, independently, is halo or Ci-3alkyl, wherein alkyl is optionally substituted with one or more substituents independently selected from halo.

In some embodiments, ring A is

R¹ is H or -CH3; each R², independently, is H; R³ is phenyl or 4-fluorophenyl; R⁵ is pyridyl substituted by halo, Ci-₃alkyl, or -0-Ci-₃alkyl; wherein alkyl is optionally substituted with one to three substituents independently selected from halo.

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

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be for use for the treatment of a disease or condition mediated by the adenosine receptor. The disease or condition mediated by the adenosine receptor can be cancer, e.g., 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 “ΆL/V'” i_n formulas herein denotes the point of attachment between different groups.

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

In some embodiments, the compound of Formula (I) can be selected from the group consisting of:

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

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

5-[5-amino-2-[[3-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

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

5-[5-amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-lH-pyridin-2-one;

2-[(3-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

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;

2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

5-[5-amino-2-[(5-chloro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one;

5-[5-amino-2-[(5-fluoropyrimidin-4-yl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin- 8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-2-[(5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one;

5-[5-amino-2-[(5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-one; 5-[5-amino-2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one;

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

5-[5-amino-2-[(3-fluoro-5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-one;

5-[5-amino-2-[(5-methyl-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one;

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

5-[5-amino-2-[[4-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-lH-pyridin-2-one;

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

5-[5-amino-7-phenyl-2-(pyrimidin-4-ylmethyl)-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l- methyl-pyridin-2-one;

5-[5-amino-2-[[4-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

2-[5-[5-amino-2-[(3-fluoro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin- 8-yl]-2-oxo- 1 -pyridyljacetonitrile;

5-[5-amino-7-phenyl-2-[[5-(trifluoromethyl)oxazol-4-yl]methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

7-phenyl-8-pyridazin-4-yl-2-(tetrahydrofuran-2-ylmethyl)-[ 1 ,2,4]triazolo[ 1,5- c]pyrimidin-5-amine;

7-phenyl-8-pyridazin-4-yl-2-[[rel-(2S)-tetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

7-phenyl-8-pyridazin-4-yl-2-[[rel-(2R)-tetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine; 2-[[5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-2- yl]methyl]pyridine-3-carbonitrile;

5-[5-amino-2-[(3-chloro-5-fluoro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

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

7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

5-[5-amino-7-phenyl-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l- methyl-pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-

8-yl]-lH-pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-

8-yl]-3-methyl-lH-pyridin-2-one;

5-[5-amino-7-phenyl-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-lH- pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin- 8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(pynOlidin-l-ylmethyl)-[l,2,4]triazolo[l,5-c]pyrimidin-

8-yl]-3-methyl-lH-pyridin-2-one;

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

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

5-[5-amino-2-(3-fluoropyridine-2-carbonyl)-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-one;

5-[5-amino-2-[(3-fluoro-2-pyridyl)-hydroxy-methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-7-phenyl-2-[rel-(R)-(3-fluoro-2-pyridyl)-hydroxy-methyl]- [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one; 5-[5-amino-7-phenyl-2-[rel-(S)-(3-fluoro-2-pyridyl)-hydroxy-methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-2-[hydroxy-(5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-2-[(3-chloro-2-pyridyl)methyl]-7-(4-fluorophenyl)-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

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

5 - [5 -amino-7-(4-fluorophenyl)-2- [rel-(R)-(3 -fluoro-2-pyridyl)-hydroxy -methyl] - [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one; and

5-[5-amino-7-(4-fluorophenyl)-2-[rel-(S)-(3-fluoro-2-pyridyl)-hydroxy-methyl]- [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one.

In some embodiments, the compound of Formula (I) is 5-[5-amino-2-[(3-fluoro-2- pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one or 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-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 (e.g., a receptor for a compound other than adenosine). 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 some embodiments, 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.

In some embodiments, 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.

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 are dual A2aR/A2bR antagonists.

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 /i-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 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 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).

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

Scheme 1 illustrates the preparation of compounds of Formula (II) and the 6-sub stituted- 4,5-dihalo-2-aminopyrimidine compounds of Formula (III):

Scheme 1

Scheme 2 illustrates the preparation of compounds of Formula (V) and (VI) form the compounds of Formula (III) and (IV):

Scheme 2

Scheme 3 illustrates an alternative route, from the compound of Formula (III), via intermediate compound of Formula (VII), to compounds of Formula (V):

Scheme 3

Compounds of Formula (VI) can be transformed into compounds of Formula (I) according to Scheme 4:

Scheme 4

4

H 2

(VI) (I)

Optionally, a compound of Formula (I) can be further modified, for example, to form a different compound of Formula (I). EXAMPLES

General Experimental Conditions

'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-¹H 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 Spi™ 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 BIO VIA Draw/19.1 from Dassault Systemes.

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=1 mL of TFA in 1000 mL ofMilli-Q Water; Solvent B=1 mL 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 ImE (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 = FLO, 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 H2O, 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 H2O, B- MeCN, Column: YMC Actus Triart C8 (20 mm x 250 mm) 5 pm. 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 mmxlOO mm. Gradient [time (min)/solvent B (%)] :0.0/l 0, 20/95, 23/95, 24/10, 26/10.

Synthesis routes:

Route A: Preparation of 4-chloro-6-(4-fluorophenvD-5-iodo-pyrimidin-2-amine

Step 1 : 4,6-dichloropyrimidin-2-amine (20 g, 121.96 mmol) was combined with (4- fluorophenyl)boronic acid (14.22 g, 101.63 mmol), 1,1'- bis(diphenylphosphino)fenOcenedichloropalladium (II) dichloromethane adduct (8.30 g, 10.16 mmol), K2CO3 (28.1 g, 203.27 mmol), 1,4-dioxane (1500 mL) and water (250 mL). The resulting mixture was purged with nitrogen for 10 min and was stirred at rt for 24 hours. The reaction mixture was diluted with EtOAc (1 L). The organic phase was separatedand was washed sequentially with water (500 mL x 2) and saturated brine (500 mL). The organic layer was then dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The redisue was triturated with MTBE:DCM=20:1. The resulting solid was collected by filtration and was dried under vacuum to afford 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine (18.00 g, 79 %) as a yellow solid. ¾NMR (DMSO-de, 400 MHz) d 7.18 (2H, s), 7.27 (1H, d, J=1.5 Hz), 7.29 - 7.38 (2H, m), 8.13 - 8.21 (2H, m). ESI MS [M+H]⁺ for C10H7CIFN3, calcd 224.0 found 224.0.

Step 2: NIS (10.06 g, 44.72 mmol) was combined with 4-chloro-6-(4- fluorophenyl)pyrimidin-2-amine (5 g, 22.36 mmol) and acetic acid (100 mL). The resulting solution was stirred at rt for 4 hours. Solvent was removed under reduced pressure. The mixture was basified with saturated NaHCCh aqueous solution. The resulting mixture was diluted with EtOAc (500 mL), and washed sequentially with water (200 mL x2) and saturated brine (200 mL xl). The organic layer was separated, dried over anhydrous Na2S04. Solid was fitered off and the filtrate was concentrated under reduced pressure to afford crude product. The crude product was purified by flash chromatography on silica with 0 to 25% EtOAc in petroleum ether to afford the title compound (3.10 g, 39.7 %) as a white solid. ¾ NMR (DMSO-d6, 400 MHz) d 7.25 - 7.34 (4H, m), 7.56 (2H, dd, J=5.1, 7.9 Hz). ESI MS [M+H]⁺ for CioHeCIFINi, calcd 348.9 found 349.9.

Route B: Preparation of 4-chloro-5-iodo-6-phenyl-pyrimidin-2-amine

Step 1: Pd(PPh3)4 (5.86 g, 8.00 mmol) was combined with 4,6-dichloropyrimidin-2- amine (19.69 g, 120.07 mmol), phenylboronic acid (12.2 g, 121.93 mmol), K2CO3 (27.7 g,

200.11 mmol), 1,4-dioxane (1500 mL) and water (270 mL) at it under nitrogen. The resulting mixture was stirred at rt for 23 hours. 1.2 L of water was added, the resulting solid was filtered off. The filtrate was concentrtaed under reduced pressure. The remaining mixture was extracted with EtOAc ( 3x). The combined organic phases were concentrated to give a residue. This residue was triturated with PE:EtOAc (10:1) to afford 4-chloro-6-phenylpyrimidin-2-amine (13.00 g, 63.2 %) as a light brown solid. ¾ NMR (400 MHz, DMSO-De) d 7.19 (s, 2H), 7.26 (s, 1H), 7.44 - 7.59 (m, 3H), 8.06 - 8.17 (m, 2H). ESI MS [M+H]⁺ for CioHsCINs, calcd 205.0 found 206.0.

Step 2: NIS (2.188 g, 9.73 mmol) was added to 4-chloro-6-phenylpyrimidin-2-amine (1 g, 4.86 mmol) in acetonitrile (10 mL) under air. The resulting solution was stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc and saturated sodium thiosulfate aqueous solution. The aqueous layer was extracted with EtOAc 2 x 50 mL.The crude product was purified by flash chromatography on silica with 0 to 30% PE in EtOAc to afford the title compound (1.2 g, 74.4 %) as a yellow solid. ¾ NMR (400 MHz, DMSO- e) d 7.33 (s, 2H), 7.47 (dq, J = 3.5, 7.2 Hz, 5H). ESI MS [M+H]⁺ for C10H7CIIN3, calcd 331.9 found 331.7.

Route C: Preparation of 5-bromo-4-chloro-6-phenyl-pyrimidin-2-amine

intermediate 3

NBS (5.19 g, 29.18 mmol) was added to 4-chloro-6-phenylpyrimidin-2-amine (3 g, 14.59 mmol) in MeCN (50 mL) under air. The resulting mixture was stirred at 80 °C for 14 hours. The reaction mixture was concentrated and diluted with EtOAc (400 mL), and washed sequentially with water (300 mL x2) and saturated brine (300 mL). The organic layer was dried over Na2S04, filtered and concentrated to afford crude product. The crude product was purified by flash chromatography on silica with 0 to 20% EtOAc in petroleum ether to afford the title compound (2.80 g, 67.5 %) as a yellow solid. ¹HNMR (DMSO- e, 400 MHz) d 7.38 (2H, s), 7.46 - 7.50 (3H, m), 7.53 - 7.65 (2H, m).

Route D: Preparation of 2-(3-fluoropyri din-2 -vOacetohydrazide

intermediate 4a

Step 1: Copper(I) oxide (0.650 g, 4.55 mmol) was added to 2-bromo-3-fluoropyridine (4 g, 22.73 mmol), diethyl malonate (7.28 g, 45.46 mmol), 2-pyridine-4-carboxylic acid (1.119 g, 9.09 mmol) and CS2CO3 (22.22 g, 68.19 mmol) in 1,4-dioxane (80 mL) at rt under nitrogen. The resulting mixture was stirred at 130 °C for 18 hours. The mixture was filtered through celite, washed with DCM. The filtrate was concentrated. The residue was purified by flash chromatography on silica with 0 to 30% EtOAc in PE to afford ethyl 2-(3-fluoropyridin-2- yl)acetate (2.50 g, 60.0 %) as a yellow oil. ¾ NMR (300 MHz, DMSO- e) d 8.37 (dt, J = 4.7,

1.6 Hz, 1H), 7.72 (ddd, J = 9.8, 8.4, 1.4 Hz, 1H), 7.57 - 7.37 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.91 (d, J = 2.4 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H). ESI MS [M+H]⁺ for C9H10FNO2, calcd 184.2 found 184.2.

Step 2: Hydrazine hydrate (1.37 g, 27.30 mmol) was added to ethyl 2-(3-fluoropyridin-2- yl)acetate (2.5 g, 13.65 mmol) in MeOH (50 mL) at rt under nitrogen. The resulting mixture was stirred at rt for 16 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with MTBE:DCM(3:1, 40 mL).The precipitate was collected by filtration, washed with MTBE (20 mL) and dried under vacuum to afford the title compound (2.0 g, 87 %) as a white solid. No further purification was used. 'H NMR (300 MHz, DMSO-r/r,) d 9.25 (s, 1H), 8.33 (dt, J = 4.7, 1.6 Hz, 1H), 7.66 (ddd, J = 9.9, 8.3, 1.4 Hz, 1H), 7.37 (dt, J = 8.6, 4.4 Hz, 1H), 3.62 (d, J = 2.4 Hz, 2H). ESI MS [M+H]⁺ for CvHsFNsO, calcd 170.1 found 170.0.

Table 1 contains additional intermediates that were made following Route D from the appropriate reagents. Table 1. Characterization data for intermediates 4b-4m

Route E: Preparation of 2-(5-methyloxazol-4-v0acetohvdrazide

intremediate 5

Step 1: 2-(5-Methyloxazol-4-yl)acetic acid (250 mg, 1.77 mmol) was combined with DCM (10 mL), the mixture was cooled to 0 °C, and (diazomethyl)trimethylsilane (2.0 M in Et20) (2.66 ml, 5.31 mmol) was added dropwise under N2. The resulting mixture was stirred at rt for 14 hours. The mixture was then concentrated under reduced pressure and the residue was purified by flash chromatography on silica with 0-60% EtOAc to afford methyl 2-(5- methyloxazol-4-yl)acetate as a pale yellow oil (163 mg, 59 %). ¾NMK (500 MHz, DICHLOROMETHANE-d₂) 2.31 (3H, s), 3.52 (2H, s), 3.72 (3H, s), 7.73 (1H, s).

Step 2: Methyl 2-(5-methyloxazol-4-yl)acetate (340 mg, 2.19 mmol), hydrazine monohydrate (0.213 ml, 4.38 mmol) were combined with MeOH (5 mL). The mixture was stirred at rt for 14 hours. The crude reaction mixture was concentrated under reduced pressure to give a light yellow solid. This solid was triturated with MTBE to afford the title compound as a beige colored solid. No further purification was used. ¾ NMR (500 MHz, DICHLOROMETHANE-ife) 2.33 (3H, br d), 3.42 (2H, br d), 3.62 - 4.31 (1H, m), 7.79 (1H, br d).

Route F: Preparation of 2-G(3-fluoro-2-pyridvOmethvP-8-iodo-7-phenyl-

intermediate 6a

Step 1: KOtBu (1M in THF, 3.0 mL, 3.0 mmol) was added dropwise to 4-chloro-5-iodo- 6-phenylpyrimidin-2-amine (500 mg, 1.51 mmol) and 2-(3-fluoropyridin-2-yl)acetohydrazide (306 mg, 1.81 mmol) in DMSO (5 mL) at 0°C over a period of 3 minutes under nitrogen. The resulting mixture was stirred at rt for 3 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with saturated brine (20 mL x3). The organic layer was dried over anhydrous Na2SC>4, concentrated to afford crude product. The crude product was purified by flash chromatography on silica with 0 to 7% MeOH in DCM to afford N'-(2- amino-5-iodo-6-phenylpyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)acetohydrazide (400 mg, 57.1 %) as a yellow solid. ¾NMR (300 MHz, DMSO- e) d 10.15 (s, 1H), 8.37 (dt, J = 4.8, 1.5 Hz, 1H), 8.29 (d, J = 24.3 Hz, 1H), 7.70 (ddd, J = 9.8, 8.3, 1.3 Hz, 1H), 7.40 (q, J = 4.2 Hz, 6H), 6.40 (s, 2H), 3.83 (d, J = 2.3 Hz, 2H). ESI MS [M+H]⁺ for CivHwFINeO, calcd 465.2 found 465.1.

Step 2: Trimethyl silyl (Z)-N-(trimethylsilyl)acetimidate (10.5 ml, 43.08 mmol) was added to N'-(2-amino-5-iodo-6-phenylpyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)acetohydrazide (400 mg, 0.86 mmol) at rt under nitrogen. The resulting mixture was stirred in a sealed pressure tube at 160 °C for 1 hour. The solvent was removed under reduced pressure to give a brown residue. MeOH- water (1 :3, 20 mL) was added to the above residue, followed by sonication.

Solid was gradually formed and was collected by filtration, washed with water and MTBE to give the title compound (400 mg, 104 %) as a pale yellow solid. ¾ NMR (400 MHz, DMSO- is) d 8.36 (dt, J = 4.7, 1.5 Hz, 1H), 8.03 (s, 2H), 7.74 (ddd, J = 9.9, 8.4, 1.4 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.50 - 7.38 (m, 4H), 4.44 (d, J = 2.1 Hz, 2H). ESI MS [M+H]⁺ for CivHiiFINe, calcd 447.0 found 447.2.

Table 2 contains additional intermediates that were made following Route F from the appropriate reagents.

Table 2: Characterization data for intermediates 6b-6p

Route G: Preparation of 8-bromo-2-r(3-fluoro-2-pyridvDmethvH-7-phenyl- ri.2.41triazolori.5-c1pyrimidin-5-amine

Step 1: K2CO3 (194 mg, 1.41 mmol) was added to 5-bromo-4-chloro-6-phenylpyrimidin- 2-amine (200 mg, 0.70 mmol) and 2-(pyrimidin-4-yl)acetohydrazide (160 mg, 1.05 mmol) in n- butanol (3 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered through celite. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica with 0 to 10% MeOH in DCM to afford N'-(2-amino-5-bromo-6-phenylpyrimidin-4-yl)-2-(pyrimidin-4-yl)acetohydrazide (180 mg, 64.0 %) as a yellow solid. ESI MS [M+H]⁺ for CieHuBrNvO calcd 399.0 found 400.2.

Step 2: N'-(2-amino-5-bromo-6-phenylpyrimidin-4-yl)-2-(pyrimidin-4-yl)acetohydrazide (170 mg, 0.42 mmol) was added to trimethyl silyl N-(trimethylsilyl)acetimidate (864 mg, 4.25 mmol) under air. The resulting mixture was stirred at 160 °C for 30 minutes. The crude product was purified by flash chromatography on silica with 0 to 10% MeOH in DCM to afford the title compound (90 mg, 55.4 %) as a yellow solid. ESI MS [M+H]⁺ for Ci6Hi2BrN7, calcd 382.0 found 382.0. Route H: Preparation of 8-bromo-7-phenyl-2-rr5-(trifluoromethvDoxazol-4-yl1methyl1- ri.2.41triazolori.5-c1pyrimidin-5-amine

Step 1: Hydrazine hydrate (158 mg, 3.16 mmol) was added to 5-bromo-4-chloro-6- phenylpyrimidin-2-amine (300 mg, 1.05 mmol) in ethanol (20 mL) at rt under nitrogen. The resulting mixture was stirred at 60 °C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash C18 chromatography on silica with 0-30% MeCN in water to afford 5-bromo-4-hydrazinyl-6-phenylpyrimidin-2-amine (200 mg, 67.7 %) as a pale yellow solid. ¾ NMR (400 MHz, DMSO- e) d 4.50 (s, 2H), 6.36 (s, 2H), 7.41 (dtd, J = 1.8, 4.4, 6.6 Hz, 3H), 7.46 - 7.51 (m, 2H), 7.99 (s, 1H). ESI MS [M+H]⁺ for CioHioBrNs calcd 280.0 found 280.2.

Step 2: DIPEA (269 pL, 1.54 mmol) was added to 5-bromo-4-hydrazinyl-6- phenylpyrimidin-2-amine (172 mg, 0.62 mmol), 2-(5-(trifluoromethyl)oxazol-4-yl)acetic acid (100 mg, 0.51 mmol, prepared according to WO 2016096115) and HATU (292 mg, 0.77 mmol) in DMF (5 mL) at rt under nitrogen. The resulting mixture was stirred at rt for 4 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford N'-(2-amino-5-bromo-6-phenylpyrimidin-4-yl)-2-(5- (trifluoromethyl)oxazol-4-yl)acetohydrazide (0.200 g, 85 %) as a yellow solid. 'H NMR (400 MHz, DMSO- e) d 3.69 (s, 2H), 6.38 (s, 1H), 7.43 (d, J = 5.3 Hz, 3H), 7.50 (d, J = 6.4 Hz, 2H), 7.95 (s, 1H), 8.67 (d, J = 18.8 Hz, 2H), 10.12 (s, 1H). ESI MS [M+H]⁺ for CieHiiBrFsNeCE calcd 457.0 found 457.1.

Step 3: Trimethyl silyl (E)-N-(trimethylsilyl)acetimidate (845 mg, 4.16 mmol) was added to N'-(2-amino-5-bromo-6-phenylpyrimidin-4-yl)-2-(5-(trifluoromethyl)oxazol-4- yl)acetohydrazide (190 mg, 0.42 mmol) at rt under nitrogen. The resulting mixture was stirred at 160 °C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica with 0 to 3% MeOH in DCM to afford the title compound (0.050 g, 27.4 %) as a yellow oil. ¾ NMR (400 MHz, DMSO- e) d 4.32 (s, 2H), 7.48 (d, J = 6.7 Hz, 3H), 7.66 (dd, J = 2.1, 7.4 Hz, 2H), 8.10 (s, 2H), 8.71 (s, 1H). ESI MS [M+H]⁺ for CieHioBrFsNeO calcd 439.0 found 439.0.

Route I: Preparation of 2-r2-oxo-5-(4A5.5-tetramethyl-E3.2-dioxaborolan-2-vD-l- pyridyllacetonitrile

Step 1: 2-chloroacetonitrile (1.432 g, 18.97 mmol) was added to K2CO3 (4.77 g, 34.48 mmol) and 5-bromo-lH-pyridin-2-one (3 g, 17.24 mmol) in DMF (30 mL) under air. The resulting mixture was stirred at rt for 14 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed sequentially with water (150 mL 2) and saturated brine (150 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated to afford crude product. The crude product was purified by flash chromatography on silica with 0 to 70% EtOAc in petroleum ether to afford 2-(5-bromo-2-oxo-l-pyridyl)acetonitrile (2.30 g, 62.6 %) as a yellow solid. ¾ NMR (DMSO-de, 400 MHz) d 4.95 (2H, s), 6.49 (1H, d, J=9.8 Hz), 7.62 (1H, dd,

J=2.8, 9.8 Hz), 8.08 - 8.14 (1H, m). ESI MS [M+H]⁺ for CvHsBr^O, calcd 213.0 found 213.1.

Step 2: PdCl2(dppf) (137 mg, 0.19 mmol) was added to potassium acetate (369 mg, 3.76 mmol), bis(pinacolato)diboron (715 mg, 2.82 mmol) and 2-(5-bromo-2-oxo-l- pyridyl)acetonitrile (400 mg, 1.88 mmol) in 1,4-dioxane (5 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 14 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was directly used in next step without further purification. ESI MS [M+H]⁺ for C13H17BN2O3, calcd 261.1 found 261.3. Table 3. Examples 1-1 to 4-9

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

Et3N (0.375 mL, 2.69 mmol) was added to 2-((3-fluoropyridin-2-yl)methyl)-8-iodo-7- phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-5-amine (400 mg, 0.90 mmol), l-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (316 mg, 1.34 mmol) and l,l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (58.4 mg, 0.09 mmol) in 1,4-dioxane (6 mL) and water (2 mL) at rt. The mixture was purged with N2 and was stirred at 80 °C for 8 hours. The crude reaction mixture was cooled to rt, filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica with 0 to 6% MeOH in DCM to afford the desired product along with minor impurities as a brown solid. The brown solid was triturated with acetone to afford the title compound (238 mg, 61.4 %) as an off- white solid. ¾NMR (600 MHz, DMSO- e) 3.32 (3H, s), 4.42 (2H, d), 6.25 (1H, d), 7.10 (1H, dd), 7.30 - 7.36 (2H, m), 7.30 - 7.35 (1H, m), 7.34 - 7.37 (1H, m), 7.39 (1H, dt), 7.41 - 7.46 (1H, m), 7.63 (1H, d), 7.71 (1H, ddd), 7.95 (2H, br s), 8.33 (1H, dt). ESI MS [M+H]⁺ for C23H18FN7O, calcd 428.1 found 428.1. Example 1-2: 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-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 1-1 (0.053 g, 55.2 %) as a pale yellow solid. ¾ NMR (DMSO- e, 400 MHz) d 3.34 (3H, s), 4.41 (2H, s), 6.28 (1H, d, J=9.4 Hz), 7.11 (1H, dd, J=2.4, 9.7 Hz), 7.19 (2H, t, J=8.6 Hz), 7.40 (1H, dt, J=4.5, 8.7 Hz), 7.48 (2H, dd, J=5.7, 8.3 Hz), 7.65 (1H, d, J=2.5 Hz), 7.71 (1H, t, J=9.2 Hz), 7.96 (2H, s), 8.30 - 8.36 (1H, m). ESI MS [M+H]⁺ for C23H17F2N7O, calcd 446.1 found 446.1.

Example 1-3: 5-[5-amino-2-[[3-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl- [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 1-1 (40.0 mg, 41.6 %). ¾NMR (DMSO-4, 300 MHz) d 3.32 (3H, s), 4.52 (2H, s), 6.21 (1H, d, J=9.4 Hz), 7.03 (1H, dd, J=2.6, 9.3 Hz), 7.25 - 7.50 (6H, m), 7.49 - 7.75 (2H, m), 7.95 - 8.07 (3H, m), 8.55 - 8.63 (1H, m). ESI MS [M+H]⁺ for C24H19F2N7O, calcd 460.2 found 460.2. Example 1-4: 5-[5-amino-2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-[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 1-1 (35.0 mg, 18.27 %) as a light brown solid. ¾ NMR (500 MHz, DMSO-i/6) 3.34 (3H, s), 4.38 (2H, s), 6.26 (1H, d), 7.12 (1H, dd), 7.29 - 7.40 (3H, m), 7.41 - 7.52 (3H, m), 7.62 - 7.73 (2H, m), 7.98 (2H, br s), 8.46 (1H, d). ESI MS [M+H]⁺ for C23H18FN7O, calcd 428.1 found 428.2.

Example 1-5: 5-[5-amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)methyl]- [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 1-4 (0.039 g, 27.5 %) as a white solid using intermediate 6b and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one. ¾NMR (400 MHz, DMSO-d) d 4.37 (s, 2H), 6.22 (d, J = 9.5 Hz, 1H), 7.11 - 7.24 (m, 3H), 7.29 (d, J = 2.6 Hz, 1H), 7.47 (qd, J = 3.4, 6.1 Hz, 3H), 7.67 (td, J = 3.0, 8.7 Hz, 1H), 7.97 (s, 2H), 8.46 (d, J = 3.0 Hz, 1H), 11.59 (s, 1H). ESI MS [M+H]⁺ for C22H15F2N7O, calcd 432.1 found 432.1. Example 1-6: 2-[(3-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c] pyrimidin-5-amine

The title compound was prepared in a similar fashion to Example 1-4 (13.00 mg, 14.56 %) as a yellow solid using intermediate 6a and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridazine. ¾ NMR (DMSO- e, 400 MHz) d 4.43 (2H, d, J=2.0 Hz), 7.28 - 7.44 (6H, m), 7.56 (1H, dd, J=2.4, 5.4 Hz), 7.71 (1H, ddd, J=1.4, 8.3, 9.9 Hz), 8.33 (3H, dt, J=1.6, 4.7 Hz), 8.91 (1H, dd, J= 1.3, 2.4 Hz), 9.10 (1H, dd, J=1.3, 5.4 Hz). ESI MS [M+H]⁺ for CiiHisFNsO, calcd 399.1 found 399.2.

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 1-3 (14.00 mg, 16.70 %) as a light yellow solid. ¾ NMR (400 MHz, DMSO- e) d 11.56 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.95 (s, 2H), 7.67 - 7.20 (m, 8H), 7.14 (dd, J = 9.4, 2.7 Hz, 1H), 6.19 (d, J = 9.4 Hz, 1H), 4.53 (s, 2H). ESI MS [M+H]⁺ for C23H17F2N7O, calcd 446.1 found 446.2. Example 1-8: 2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c] pyrimidin-5-amine

(1H, d). ESI MS [M+H]⁺ for CiiHisFNs, calcd 399.1 found 399.3.

Example 1-9: 5-[5-amino-2-[(5-chloro-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 1-7 (52.0 mg, 60.7 %) as a brown solid. ¾ NMR (300 MHz, DMSO- e) d 4.35 (s, 2H), 6.18 (d, J = 9.5 Hz, 1H), 7.12 (d, J = 9.5 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.30-7.38 (m, 3H), 7.39-7.45 (m, 3H), 7.80-7.90 (m, 1H), 7.95 (s, 2H), 8.50 (d, J = 2.6 Hz, 1H), 11.56 (s, 1H). ESI MS [M+H]⁺ for C22H16CIN7O, calcd 430.1 found 430.3. Example 1-10: 5-[5-amino-2-[(5-fluoropyrimidin-4-yl)methyl]-7-phenyl-[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 1-1 (10.20 mg, 16.43 %) as a white solid. ¾ NMR (400 MHz, DMSO- e) d 3.33 (s, 3H), 4.48 (s, 2H), 6.25 (d, J = 9.4 Hz, 1H), 7.10 (dd, J = 2.6, 9.4 Hz, 1H), 7.29 - 7.39 (m, 3H), 7.39 - 7.48 (m, 2H), 7.64 (d, J = 2.5 Hz, 1H), 7.99 (s, 2H), 8.87 (d, J = 2.0 Hz, 1H), 8.97 (d, J = 3.0 Hz, 1H). ESI MS [M+H]⁺ for C22H17FN8O, calcd 429.1 found 429.1.

Example 1-11: 5-[5-amino-2-[(5-methoxy-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 (37.1 mg, 13.33 %) as a white solid. ¾ NMR (300 MHz, DMSO-i/6) d 11.56 (s, 1H), 8.17 (s, 1H), 7.95 (s, 2H), 7.43 -7.41 (m, 2H), 7.35 - 7.31 (m, 5H), 7.15 (s, 1H), 7.12 (dd, J = 9.4, 2.6 Hz, 1H), 6.19 (d, J = 9.5 Hz, 1H), 4.28 (s, 2H), 3.79 (s, 3H). ESI MS [M+H]⁺ for C23H19N7O2, calcd 426.4 found 426.1. Example 1-12: 5-[5-amino-2-[(5-methoxy-2-pyridyl)methyl]-7-phenyl-[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 1-11 (65.0 mg, 45.2 %) as a white solid. ¾NMR (DMSO- e, 400 MHz) d 3.34 (3H, s), 3.79 (3H, s), 4.29 (2H, s), 6.26 (1H, d, J=9.3 Hz), 7.11 (1H, dd, J=2.6, 9.4 Hz), 7.27 - 7.40 (5H, m), 7.44 (2H, dd, J=2.3, 7.5 Hz), 7.64 (1H, d, J=2.6 Hz), 7.99 (2H, s), 8.17 (1H, dd, J=l.l, 2.7 Hz). ESI MS [M+H]⁺ for C24H21N7O2, calcd 440.2 found 440.1.

Example 1-13: 5-[5-amino-2-[(5-fluoro-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 1-4 (187 mg, 74.8 %) as an off-white solid. ¾NMR (500 MHz, DMSO- e) 4.37 (2H, s), 6.20 (1H, d), 7.15 (1H, dd), 7.27 (1H, s), 7.35 (3H, br d), 7.40 - 7.50 (3H, m), 7.61 - 7.75 (1H, m), 7.95 (2H, br s), 8.46 (1H, d), 11.57 (1H, br s). ESI MS [M+H]⁺ for C22H16FN7O, calcd 414.1 found 414.3. 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. ¾NMR (DMSO- e, 400 MHz) d 3.36 (3H, s), 3.79 (3H, d, J=1.4 Hz), 4.29 (2H, s), 6.29 (1H, d, J=9.3 Hz), 7.08 - 7.15 (1H, m), 7.19 (2H, t, J=8.7 Hz), 7.33 (2H, d, J=3.7 Hz), 7.48 (2H, t, J=7.0 Hz), 7.66 (1H, s), 7.98 (2H, s), 8.17 (1H, d, J=2.3 Hz). ESI MS [M+H]⁺ for C24H20FN7O2, calcd 458.2 found 458.2.

Example 1-15: 5-[5-amino-2-[(3-fluoro-5-methoxy-2-pyridyl)methyl]-7-phenyl- [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 (0.065 g, 47.6 %) as a pale yellow solid. ¾ NMR (400 MHz, DMSO- e) d 3.33 (s, 3H), 3.83 (s, 3H), 4.32 (d, J = 2.1 Hz, 2H), 6.25 (d, J = 9.4 Hz, 1H), 7.10 (dd, J = 2.6, 9.3 Hz, 1H), 7.29 - 7.38 (m, 3H), 7.39 - 7.47 (m, 3H), 7.63 (d, J = 2.5 Hz, 1H), 7.93 (s, 2H), 8.09 (dd, J = 1.0, 2.5 Hz, 1H). ESI MS [M+H]⁺ for C24H20FN7O2, calcd 458.2 found 458.1. Example 1-16: 5-[5-amino-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[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 1-1 (14.00 mg, 18.30 %) as a light brown solid. ¾ NMR (500 MHz, DICHLOROMETHANE-ife) 2.34 - 2.45 (3H, m), 3.42 - 3.52 (3H, m), 4.12 (2H, s), 6.38 (1H, d), 6.48 (2H, br s), 7.14 (1H, dd), 7.38 (3H, br d), 7.46 - 7.56 (3H, m), 7.74 (1H, s). ESI MS [M+H]⁺ for C22H19N7O2, calcd 414.2 found 414.3.

Example 1-17: 5-[5-amino-2-[(5-methyl-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 1-4 (22.00 mg, 23.76 %) as a white solid. ¾ NMR (Methanol-^, 300 MHz) d 2.34 (3H, s), 4.38 (2H, s), 6.42 (1H, d, J=9.3 Hz), 7.36 (5H, dd, J=4.1, 7.5 Hz), 7.42 (1H, d, J=2.4 Hz), 7.48 (2H, dd, J=3.0, 6.9 Hz), 7.64 (1H, d, J=7.7 Hz), 8.31 (1H, s). ESI MS [M+H]⁺ for C23H19N7O, calcd 410.2 found 410.2. Example 1-18: 5-[5-amino-2-[(3-chloro-5-fluoro-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 1-13 (15.00 mg, 16.10 %) as a white solid. ¾ NMR (DMSO- e, 300 MHz) d 4.47 (2H, s), 6.17 (1H, d, J=9.4 Hz), 7.11 (1H, dd, J=2.6, 9.4 Hz), 7.25 (1H, s), 7.33 (3H, dd, J=2.0, 5.1 Hz), 7.41 (2H, dd, J=3.0, 6.6 Hz), 7.91 (2H, s), 8.12 (1H, dd, J=2.6, 8.5 Hz), 8.51 (1H, d, J=2.6 Hz),l 1.55(1H, s). ESI MS [M+H]⁺ for C22H15CIFN7O, calcd 448.1 found 448.1.

Example 1-19: 5-[5-amino-2-[[4-(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 1-7 (25.00 mg, 16.78 %) as a white solid. ¾ NMR (DMSO- e, 300 MHz) d 4.44 (2H, s), 6.18 (1H, d, J=9.5 Hz), 6.84 - 7.27 (3H, m), 7.33 (3H, dd, J=2.1, 5.2 Hz), 7.42 (3H, dd, J=3.0, 7.5 Hz), 7.55 (1H, s), 7.97 (2H, s), 8.63 (1H, d, J=5.1 Hz), 11.55 (1H, s). ESI MS [M+H]⁺ for C23H17F2N7O, calcd 446.1 found 446.2. Example 1-20: 5-[5-amino-2-[(3-chloro-2-pyridyl)methyl]-7-phenyl-[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 1-1 (6.00 mg, 60.0 %) as a pale yellow solid. ¾ NMR (DMSO-i/6, 400 MHz) d 3.32 (3H, s), 4.50 (2H, s), 6.25 (1H, d, J=9.4 Hz), 7.09 (1H, dd, J=2.6, 9.3 Hz), 7.31 - 7.40 (4H, m), 7.44 (2H, dd, J=2.3, 7.5 Hz), 7.64 (1H, d, J=2.5 Hz), 7.95 (3H, dd, J=1.5, 8.1 Hz), 8.44 (1H, dd, J=1.5, 4.7 Hz). ESI MS [M+H]⁺ for C23H18CIN7O, calcd 444.1 found 444.1.

Example 1-21: 5-[5-amino-7-phenyl-2-(pyrimidin-4-ylmethyl)-[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 1-1 (18.00 mg, 18.63 %) as a white solid. ¾ NMR (DMSO- e, 400 MHz) d 3.34 (3H, s), 4.39 (2H, s), 6.26 (1H, d, J=9.3 Hz), 7.11 (1H, dd, J=2.6, 9.3 Hz), 7.29 - 7.44 (3H, m), 7.44 (2H, dd, J=2.4, 7.4 Hz), 7.54 (1H, dd, J=1.4, 5.2 Hz), 7.65 (1H, d, J=2.5 Hz), 7.99 - 8.04 (2H, m), 8.73 (1H, d, J=5.2 Hz), 9.09 (1H, d, J=1.4 Hz). ESI MS [M+H]⁺ for CiiHisNsO, calcd 411.2 found 411.1. Example 1-22: 5-[5-amino-2-[[4-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl- [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 1-19 (42.0 mg, 36.4 %) as a white solid. ¹HNMR (DMSO- e, 300 MHz) d 3.31 (3H, s), 4.44 (2H, s), 6.23 (1H, d, J=9.3 Hz), 6.82 - 7.11 (2H, m), 7.29 - 7.44 (3H, m), 7.43 (3H, t, J=3.9 Hz), 7.56 - 7.68 (2H, m), 8.00 (2H, s), 8.63 (1H, d, J=5.1 Hz). ESI MS [M+H]⁺ for C24H19F2N7O, calcd 460.2 found 460.2.

Example 1-23 : 2-[5- [5-amino-2- [(3-fluoro-2-pyridyl)methyl]-7-phenyl- [1,2,4] triazolo [1 ,5- c]pyrimidin-8-yl]-2-oxo-l-pyridyl]acetonitrile

The title compound was prepared in a similar fashion to Example 1-1 using intermediate 9 (50.0 mg, 17.61 %) as a brown solid. ¹HNMR (DMSO- e, 300 MHz) d 4.40 (2H, d, J=2.1 Hz), 4.92 (2H, s), 6.38 (1H, d, J=9.5 Hz), 7.19 - 7.28 (1H, m), 7.28 - 7.46 (6H, m), 7.63 - 7.76 (2H, m), 8.01 (2H, s), 8.32 (1H, dt, J=1.5, 4.7 Hz). ESI MS [M+H]⁺ for C24H17FN8O, calcd 453.2 found 453.2. Example 1-24: 5-[5-amino-7-phenyl-2-[[5-(trifluoromethyl)oxazol-4-yl]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 1-16 using intermediate 8 (0.016 g, 38.4 %) as a white solid. ¾NMR (400 MHz, DMSO- e) d 3.31 (s, 3H), 4.29 (s, 2H), 6.24 (d, J = 9.4 Hz, 1H), 7.07 (dd, J = 2.5, 9.4 Hz, 1H), 7.35 (dd, J = 1.9, 5.3 Hz, 3H), 7.44 (dd, J = 2.8, 6.6 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.97 (s, 1H), 8.68 (s, 1H). ESI MS [M+H]⁺ for C22H16F3N7O2, calcd 468.1 found 468.2.

Example 1-25: 7-phenyl-8-(pyridazin-4-yl)-2-((tetrahydrofuran-2-yl)methyl)- [l,2,4]triazolo[l,5-c]pyrimidin-5-amine

The title compound was prepared in a similar fashion to Example 1-8 using intermediate 6p (0.022 g, 44.0 %) as an off-white solid. ¾NMR (400 MHz, DMSO- e) d 1.64 (ddt, J = 6.9,

8.7, 12.0 Hz, 1H), 1.74 - 1.94 (m, 2H), 1.95 - 2.12 (m, 1H), 2.99 (qd, J = 6.7, 14.2 Hz, 2H), 3.60

(td, J = 6.3, 7.8 Hz, 1H), 3.77 (td, J = 6.0, 7.7 Hz, 1H), 4.29 (p, J = 6.7 Hz, 1H), 7.27 - 7.43 (m, 5H), 7.62 (dd, J = 2.4, 5.4 Hz, 1H), 8.25 (d, J = 46.6 Hz, 2H), 8.96 (dd, J = 1.2, 2.3 Hz, 1H), 9.14 (dd, J = 1.3, 5.4 Hz, 1H). ESI MS [M+H]⁺ for C20H19N7O, calcd 374.2 found 374.1. Example 1-26: 7-phenyl-8-pyridazin-4-yl-2-[[rel-(2S)-tetrahydrofuran-2-yl]methyl]- [l,2,4]triazolo[l,5-c]pyrimidin-5-amine

OR Enantiomer

The title compound was prepared from Example 1-25 and was purified by preparative SFC (Column: LUX 5um Cellulose-2, 2.12*25 cm; Mobile Phase A:C02, Mobile Phase B:ACN:MEOH=2:l (0.1 % NH3 as modifier); Flow rate: 40 mL/min; Gradient: 45% B; 220 nm; RT1:13.38; Injection Volumn:1.5 ml; Number Of Runs:8;) as an off-white solid (13.85 mg, 5.54%). ¹H MR (400 MHz, DMSO- e) d 1.64 (ddt, J = 6.9, 8.7, 12.0 Hz, 1H), 1.74 - 1.94 (m, 2H), 1.95 - 2.12 (m, 1H), 2.99 (qd, J = 6.7, 14.2 Hz, 2H), 3.60 (td, J = 6.3, 7.8 Hz, 1H), 3.77 (td, J = 6.0, 7.7 Hz, 1H), 4.29 (p, J = 6.7 Hz, 1H), 7.27 - 7.43 (m, 5H), 7.62 (dd, J = 2.4, 5.4 Hz, 1H), 8.25 (d, J = 46.6 Hz, 2H), 8.96 (dd, J = 1.2, 2.3 Hz, 1H), 9.14 (dd, J = 1.3, 5.4 Hz, 1H). ESI MS [M+H]⁺ for C20H19N7O, calcd 374.2 found 374.1.

Example 1-27: 7-phenyl-8-pyridazin-4-yl-2-[[rel-(2R)-tetrahydrofuran-2-yl]methyl]- [l,2,4]triazolo[l,5-c]pyrimidin-5-amine

OR Enantiomer

The title compound was prepared from Example 1-25 and was purified by preparative SFC (Column: LUX 5um Cellulose-2, 2.12*25 cm; Mobile Phase A:C02, Mobile Phase B:ACN:MEOH=2:l (0.1 % NH3 as modifier); Flow rate: 40 mL/min; Gradient: 45% B; 220 nm; RT2:15.54; Injection Volumn:1.5 ml; Number Of Runs:8;) as an off-white solid (16.80 mg, 6.72%). ¾NMR (400 MHz, DMSO- e) d 1.64 (ddt, J = 6.9, 8.7, 12.0 Hz, 1H), 1.74 - 1.94 (m, 2H), 1.95 - 2.12 (m, 1H), 2.99 (qd, J = 6.7, 14.2 Hz, 2H), 3.60 (td, J = 6.3, 7.8 Hz, 1H), 3.77 (td, J = 6.0, 7.7 Hz, 1H), 4.29 (p, J = 6.7 Hz, 1H), 7.27 - 7.43 (m, 5H), 7.62 (dd, J = 2.4, 5.4 Hz, 1H), 8.25 (d, J = 46.6 Hz, 2H), 8.96 (dd, J = 1.2, 2.3 Hz, 1H), 9.14 (dd, J = 1.3, 5.4 Hz, 1H). ESI MS [M+H]⁺ for C20H19N7O, calcd 374.2 found 374.1.

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

Step 1: DMAP (2.5 mg, 0.02 mmol) was added to Et3N (85 mΐ, 0.61 mmol), (Boc)20 (100 mg, 0.45 mmol) and 5-[5-amino-2-[(3-chloro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-l-methyl-pyridin-2-one (90 mg, 0.20 mmol) in THF (2 mL) under air. The resulting solution was stirred at rt for 2 hrs. The reaction mixture was diluted with EtOAc (10 mL), and washed sequentially with water (5 mL x2) and saturated brine (5 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and evaporated to dryness. The residue was purified by preparative TLC (MeOH: DCM = 1: 10) to afford tert-butyl (tert-butoxycarbonyl)(2- ((3-chloropyridin-2-yl)methyl)-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl- [l,2,4]triazolo[l,5-c]pyrimidin-5-yl)carbamate (0.110 g, 84 %) as a brown solid.

Step 2: Nickel(II) chloride hexahydrate (1.107 mg, 4.66 pmol) was added to DMAP (9.5 mg, 0.08 mmol), zinc (1.015 mg, 0.02 mmol), zinc cyanide (7.29 mg, 0.06 mmol), dppf (2.152 mg, 3.88 pmol) and tert-butyl (tert-butoxycarbonyl)(2-((3-chloropyridin-2-yl)methyl)-8-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-5-yl)carbamate (50 mg, 0.08 mmol) in acetonitrile (1 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 14 hrs. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (MeOH: DCM = 1 : 15) to afford crude bis hoc protected product. The crude product was purified by reverse phase preparative HPLC under acidic condition to afford the title compound (0.015 g, 44.5 %) as a white solid. ¾NMR (400 MHz, DMSO-d) d 3.34 (3H, s), 4.60 (2H, s), 6.23 (1H, d, J=9.3 Hz), 7.06 (1H, dd, J=2.6, 9.3 Hz), 7.34 (3H, t, J=3.4 Hz), 7.41 - 7.48 (2H, m), 7.53 (1H, dd, J=4.9, 7.9 Hz), 7.69 (1H, d, J=2.7 Hz), 7.97 (2H, s), 8.31 - 8.38 (1H, m), 8.75 (1H, d, J=4.9 Hz). ESI MS [M+H]⁺ for C24H18N8O, calcd 435.2 found 435.1.

Example 1-29: 5-[5-amino-2-[(3-chloro-5-fluoro-2-pyridyl)methyl]-7-phenyl- [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 1-1 (0.015 g, 50 %) as a white solid. ¾ NMR (400 MHz, DMSO- e) d 3.33 (3H, s), 4.49 (2H, s), 6.25 (1H, d, J=9.4 Hz), 7.09 (1H, dd, J=2.6, 9.4 Hz), 7.30 - 7.40 (3H, m), 7.44 (2H, dd, J=2.4, 7.4 Hz), 7.65 (1H, d, J=2.6 Hz), 7.93 (2H, s), 8.13 (1H, dd, J=2.6, 8.5 Hz), 8.52 (1H, d, J=2.6 Hz). ESI MS [M+H]⁺ for C23H17CIFN7O, calcd 462.1 found 462.1.

Example 1-30: 2-[[5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-2-yl]methyl]-5-fluoro-pyridine-3-carbonitrile

The title compound was prepared in a similar fashion to Example 1-28 using 5-[5-amino- 2-[(3-chloro-5-fluoro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l- methyl-pyridin-2-one as the starting material (0.030 g, 30.6 %) as a white solid. ¾NMK (400 MHz, DMSO- e) d 3.35 (3H, s), 4.59 (2H, s), 6.24 (1H, d, J=9.3 Hz), 7.06 (1H, dd, J=2.6, 9.3 Hz), 7.35 (3H, dd, J=2.0, 5.1 Hz), 7.44 (2H, dq, J=3.1, 5.3 Hz), 7.70 (1H, d, J=2.6 Hz), 7.97 (2H, s), 8.49 (1H, dd, J=2.9, 8.5 Hz), 8.82 (1H, d, J=2.9 Hz). ESI MS [M+H]⁺ for C24H17FN8O, calcd 452.1 found 453.2.

Example 1-31: 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(pyridazin-4-yl)- [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-5-amine

The title compound was prepared in a similar fashion to Example 1-8 (0.030 g, 33.4 %) as a white solid. ¾NMR (DMSO- e, 300 MHz) d 4.43 (2H, d, J=2.1 Hz), 6.97 - 7.26 (2H, m), 7.40 (3H, ddd, J=2.9, 5.3, 8.8 Hz), 7.57 (1H, dd, J=2.4, 5.4 Hz), 7.72 (1H, ddd, J=1.4, 8.3, 9.9 Hz), 8.34 (3H, dt, J=1.6, 4.7 Hz), 8.97 (1H, dd, J=1.2, 2.4 Hz), 9.13 (1H, dd, J=1.3, 5.4 Hz). ESI MS [M+H]⁺ for C21H14F2N8, calcd 417.1 found 417.2.

Route J: Preparation of 8-iodo-7-phenyl-2-(3.3.3-trifluoropropyO-rE2.41triazolorE5- c1pyrimidin-5-amine

Step

Step 1: Ethyl 4,4,4-trifluorobutanoate (lOg, 58.78 mmol) in MeOH (53 ml) was added hydrazine monohydrate (5.70 mL, 117.56 mmol) The reaction was stirred at rt for 14 hours. To the reaction mixture was added toluene, and the resulting mixure was concentrated under reduced pressure. To the residue was added hexanes, and the mixture was concentrated under reduced pressure to afford 4,4,4-trifluorobutanehydrazide as a pale yellow solid (8.92 g, 97 %). No further purification was used. ¹H MR (500 MHz, DMSO-de) 2.21 - 2.32 (2H, m), 2.47 - 2.55 (2H, m), 3.92 - 4.36 (2H, brs), 9.00 - 9.28 (NH, brs).

Step 2: 4,4,4-trifluorobutanehydrazide (3.59 g, 23.00 mmol) and 4,6-dichloropyrimidin- 2-amine (3.77 g, 23 mmol) in DMSO (45 mL) was added with potassium tert-butoxide (1.0 M in THF, 46.0 ml, 46.00 mmol) dropwise at 0°C. The resulting mixture was stirred at rt for 2h. The crude reaction solution was partitioned between EtOAc and H2O. The organic phase was separated and the aqueous phase was extracted with EtOAc (3x). The combined organic phases were combined with acetic acid (1.3 mL, 23.00 mmol). The resulting solid was collected by filtration. The filtrate was concentrated under reduced pressure to give a solid. The combined solid was washed with water, dried under vaccum to afford N'-(2-amino-6-chloropyrimidin-4- yl)-4,4,4-trifluorobutanehydrazide as an off-white solid (5.26 g, 81 %). ¹HNMR (500 MHz, DMSO-de) 2.41 - 2.47 (2H, m), 2.52 - 2.58 (2H, m), 5.66 - 5.88 (1H, s), 6.46 - 6.82 (2H, brs), 8.77 - 9.16 (1H, br), 9.75 - 10.14 (1H, brs).

Step 3: N'-(2-amino-6-chloropyrimidin-4-yl)-4,4,4-trifluorobutanehydrazide (4.28 g,

15.09 mmol) in Bis(trimethylsilyl)acetamide (30 mL) was heated at 160°C in microwave for 30 min. The mixture was concentrated under reduced pressure. To the residue was added MeOH (12 mL) and the resulting mixture was stirred at 0°C. Concentrated HC1 (1 ml, 6N) was added dropwise to this mixture. The mixture was stirred at 0 °C for 30 min. Solvent was removed under reduced pressure and the residue was basified with saturated aqueous NaHCCb solution (30 mL). Solid was collected by filtration, triturated with MeOH, washed with H2O, dried under vaccum to afford 7-chloro-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-5-amine as a yellow solid (2.200 g, 54.9 %). ¾NMR (500 MHz, DMSO-d6) 2.68 - 2.88 (2H, m), 2.98 - 3.14 (2H, m), 6.89 - 7.10 (1H, m), 8.01 - 8.78 (2H, m).

Step 4: 7-chloro-2-(3,3,3-trifhioropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-5-amine (398 mg, 1.5mmol), (4-fluorophenyl)boronic acid (315 mg, 2.25 mmol), potassium carbonate (622 mg, 4.50 mmol), and SPhosPdG3 (58.5 mg, 0.08 mmol) were combined with 1,4-dioxan (7.5 mL) and H2O (2.5 mL). The mixture was purged with N2. The crude reaction mixture was stirred in a microwave at 150°C for 30 min. The crude mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica with 0- 50% EtOAc in hexanes to afford 7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine as a white solid (332 mg, 68.0 %). ¾NMR (500 MHz, DICHLOROMETHANE-ife) 2.61 - 2.83 (2H, m), 3.11 - 3.28 (2H, m), 5.77 - 6.05 (2H, br), 7.05 - 7.26 (2H, t), 7.31 - 7.47 (1H, s), 8.00 - 8.14 (2H, t).

Step 5: 7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-5- amine (277 mg, 0.85 mmol) and N-iodosuccinimide (383 mg, 1.70 mmol) in CH3CN (4.2 mL) was heated at 80 °C for 20 min. Solvent was removed under reduced pressure and the residue was partitioned between saturated aqeous Na2S2Ch solution and diethyl ether. The organic phase was separated, dried over anhydrous MgSCri, concentrated under reduced pressure to afford the title compound as a pale yellow solid (345 mg, 90 %). ¾ NMR (500 MHz, DICHLOROMETHANE-ife) 2.73 - 2.83 (2H, m), 3.16 - 3.24 (2H, m), 5.80 - 5.92 (2H, br), 7.13 - 7.22 (3H, m), 7.65 - 7.74 (2H, m). Table 4 contains additional intermediates that were made following Route J from the appropriate reagents.

Table 4. Characterization data for intermediates lOb-llb

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

l-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (49.1 mg, 0.40 mmol), 8- iodo-7-phenyl-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-5-amine (50 mg, 0.13 mmol), potassium carbonate (55.6 mg, 0.40 mmol), SPhosPdG3 (5.23 mg, 6.71 pmol) were combined with 1,4-dioxan (1 mL) and H2O (0.3 mL). The mixture was purged with N2 and was heated in a microwave at 150°C for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography first on normal phase silica with 0- 10% Methanol in DCM, then on reverse phase silica with 20-60% CTbCN in H2O to afford the title compound as a solid (11.00 mg, 19.79 %). ¾NMR (500 MHz, DMSO- e) 2.75 - 2.90 (2H, m), 3.03 - 3.13 (2H, m), 3.34 - 3.39 (3H, s), 6.24 - 6.32 (1H, d), 7.07 - 7.15 (1H, d), 7.29 - 7.40 (3H, m), 7.40 - 7.50 (2H, m), 7.63 - 7.74 (1H, s), 7.91 - 8.09 (2H, br). ESI MS [M+H]⁺ for C20H17F3N6O, calcd 415.1 found 415.4.

Example 2-2: 5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[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 2-1 (95 mg, 44.5 %) as a solid. ¾NMR (500 MHz, DMSO-d) 2.71 - 2.88 (2H, m), 3.05 - 3.11 (2H, m), 6.21 - 6.28 (1H, d), 7.13 - 7.17 (1H, d), 7.17 - 7.23 (2H, t), 7.27 - 7.32 (1H, d), 7.40 - 7.57 (2H, t), 7.87 - 8.10 (2H, br), 11.51 - 11.75 (1H, s). ESI MS [M+H]⁺ for C19H14F4N6O, calcd 419.1 found 419.6.

Example 2-3: 5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-3-methyl-lH-pyridin-2-one

The title compound was prepared in a similar fashion to Example 2-1 (12.00 mg, 13.64 %) as a solid. ¾NMR (500 MHz, METHANOL-^) 1.98 - 2.09 (3H, s), 2.71 - 2.87 (2H, m), 3.09 - 3.20 (2H, m), 6.97 - 7.14 (2H, t), 7.20 - 7.27 (1H, s), 7.28 - 7.36 (1H, s), 7.48 - 7.58 (2H, t). ESI MS [M+H]⁺ for C20H16F4N6O calcd 433.1 found 433.2.

Example 2-4: 5-[5-amino-7-phenyl-2-(3,3,3-trifluoropropyl)-[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 2-1 (19.00 mg, 23.73 %) as a solid. ¹HNMR (500 MHz, DMSO-4) 2.75 - 2.86 (2H, m), 3.04 - 3.14 (2H, m), 6.18 - 6.27 (1H, d), 7.11 - 7.19 (1H, d), 7.25 - 7.30 (1H, s), 7.30 - 7.39 (3H, m), 7.40 - 7.46 (2H, m), 7.87 - 8.04 (2H, br). 11.32-11.76 (1H, s). ESI MS [M+H]⁺ for C19H15F3N6O calcd 401.1 found 401.2.

Example 2-5: 5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[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 2-1 (9.10 mg, 15.69 %) as a solid. ¾NMR (500 MHz, DMSO- e) 2.74 - 2.88 (2H, m), 3.03 - 3.12 (2H, m), 3.35 - 3.43 (3H, s), 6.27 - 6.34 (1H, d), 7.07 - 7.15 (1H, d), 7.16 - 7.24 (2H, m), 7.45 - 7.53 (2H, m), 7.67 - 7.74 (1H, s), 7.95 - 8.09 (2H, br). ESI MS [M+H]⁺ for C20H16F4N6O calcd 433.1 found 433.2. Route K: Preparation of 7-(4-fluorophenvD-8-(6-methoxy-3-pyridvD-2-(pynOlidin-l- ylmethvD-rL2.41triazolorL5-clpyrimidin-5-amine

intermediate 12a

Step 1: Ethyl 2-((tert-butyldimethylsilyl)oxy)acetate (7.34 g, 33.61 mmol) in ethanol (30 ml) was added with hydrazine hydrate (3.3 mL, 67.23 mmol), and the reaction was stirred at 80°C for 4 hours. Solvent was removed under reduced pressure and the residue was combined with toluene (10 mL). The resulting mixture was concentrated under reduced pressure to afford 2-((tert-butyldimethylsilyl)oxy)acetohydrazide (6.65 g, 97 %) as a solid. No further purificaiton was used. ¾NMR (500 MHz, DMSO-de) -0.15 - 0.20 (6H, s), 0.71 - 1.02 (9H, s), 3.89 - 4.11 (2H, s), 4.09 - 4.37 (2H, br), 8.49 - 8.95 (1H, br).

Step 2: 2-((tert-butyldimethylsilyl)oxy)acetohydrazide (2.103 g, 10.29 mmol) and 5- bromo-4,6-dichloropyrimidin-2-amine (2.5 g, 10.29 mmol) in DMSO (15.80 mL) were added with potassium tert-butoxide (1.0 M in THF, 24 mL, 24 mmol) dropwise at 0°C. The resulting mixture was stirred at rt for 30 min. After the reaction completed, acetic acid (1.374 mL, 24.00 mmol) was added dropwise, follwed by H2O (20 mL) and CH2CI2 (30 mL). The solid was filtered off and the organic phase was concentrated under reduced pressure to afford N'-(2- amino-5-bromo-6-chloropyrimidin-4-yl)-2-((tert-butyldimethylsilyl)oxy)acetohydrazide (2.2 g, 52.0 %) as a solid. ¹H NMR (500 MHz, DMSO-de) 0.06 - 0.13 (6H, s), 0.84 - 1.00 (9H, m), 4.01 - 4.25 (2H, m), 6.54 - 6.91 (2H, m), 8.66 - 8.95 (1H, m), 9.46 - 9.70 (1H, m).

Step 3: N'-(2-amino-5-bromo-6-chloropyrimidin-4-yl)-2-((tert- butyldimethylsilyl)oxy)acetohydrazide (2.17 g, 5.28 mmol) in bis(trimethylsilyl)acetamide (5.28 mL) was stirred at 150 °C for 2 h. Solvent was removed under reduced pressure and to the residue was added TBAF (1.0 M in THF, 15.85 mL, 15.85 mmol). The mixture was stirred at rt for 1 h. After reaction completed, H2O was added. Solid was collected by filtration, triturated with EtOAc and dried under vacuum to afford (5-amino-8-bromo-7-chloro-[l,2,4]triazolo[l,5- c]pyrimidin-2-yl)methanol (0.700 g, 47.6 %) as a solid. ¾ NMR (500 MHz, DMSO- is) 4.56 - 4.65 (2H, t), 5.53 - 5.64 (1H, d), 8.25 - 8.64 (2H, br).

Step 4: 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.879 g, 1.98 mmol), (5-amino-8-bromo-7-chloro-[l,2,4]triazolo[l,5-c]pyrimidin-2-yl)methanol (0.605 g, 2.17 mmol), potassium carbonate (0.901 g, 6.52 mmol), and PdCl2(dtbpf) (0.152 g,

0.22 mmol) were combined with 1,4-dioxane (11 mL) and H2O (3.6 mL). The mixture was purged with N2 and heated in microwave at 130 °C for 1 h. The crude reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure. The residue was first purified by flash chromatography on normal phase silica with 0-10% MeOH in CH2CI2), then purified by flash chromatography on reverse phase silica with 10-100% CH3CN in H2O to afford (5-amino-7-chloro-8-(6-methoxy-5-methylpyridin-3-yl)-[l,2,4]triazolo[l,5-c]pyrimidin-2- yl)methanol (0.316 g, 45.4 %) as a solid. ¾NMR (500 MHz, METHANOL-^) 2.24 - 2.29 (3H, s), 3.98 - 4.04 (3H, s), 7.31 - 7.41 (1H, s), 8.15 - 8.28 (1H, s), 8.68 - 8.81 (1H, s).

Step 5: (4-fluorophenyl)boronic acid (0.414 g, 2.96 mmol), (5-amino-7-chloro-8-(6- methoxy-5-methylpyridin-3-yl)-[l,2,4]triazolo[l,5-c]pyrimidin-2-yl)methanol (0.316 g, 0.99 mmol), potassium carbonate (0.408 g, 2.96 mmol), and SPhosPdG3 (0.038 g, 0.05 mmol) were combined with 1,4-dioxane (7.4 mL) and H2O (2.5 mL). The mixture was purged with N2 and heated in microwave at 130 °C for 30 min. The crude reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure. The residue was first purified by flash chromatography on normal phase silica with 0-10% methanol in CH2CI2 to afford (5- amino-7-(4-fluorophenyl)-8-(6-methoxy-5-methylpyridin-3-yl)-[l,2,4]triazolo[l,5-c]pyrimidin- 2-yl)methanol (0.261 g, 69.6 %) as a solid. ESI MS [M+H]⁺ for C19H17FN6O2 calcd 381.4 found 381.2. Step 6: To (5-amino-7-(4-fluorophenyl)-8-(6-methoxy-5-methylpyridin-3-yl)-

[1.2.4]triazolo[l,5-c]pyrimidin-2-yl)methanol (24 mg, 0.06 mmol) in CH2CI2 (0.63 mL) was added Dess-Martin periodinane (29.4 mg, 0.07 mmol) and the reaction mixture was stirred at rt for 30 min. A drop of H2O was added followed by addition of another equivalent of Dess-Martin periodinane. The mixture was then stirred at rt for 1 h. The crude reaction was diluted with CH2CI2 and washed sequentially with saturated aqueous Na2S2Cb solution and saturated NaHCCb solution. The organic phase was separated, dried over anhydrous MgSCri, concentrated to 5-amino-7-(4-fluorophenyl)-8-(6-methoxy-5-methylpyridin-3-yl)-[l,2,4]triazolo[l,5- c]pyrimidine-2-carbaldehyde as an oil. The crude material was used directly in the next step without further purification. ESI MS [M+H]⁺ for C19H15FN6O2 calcd 379.1 found 379.1.

Step 7: 5-amino-7-(4-fluorophenyl)-8-(6-methoxy-5-methylpyridin-3-yl)-

[1.2.4]triazolo[l,5-c]pyrimidine-2-carbaldehyde (45.4 mg, 0.12 mmol) and pyrrolidine (17.07 mg, 0.24 mmol) in CH2CI2 (1.2 mL) was added to sodium triacetoxyborohydride (50.9 mg, 0.24 mmol), and the mixture was stirred at rt for 30 min. Solvent was removed and the residue was purified by flash chromatography on silica with 0-10% MeOH (with 1% NELOH) in CH2CI2) to afford the title compound (27.0 mg, 51.9 %). ¾ NMR (500 MHz, CHLOROFORM- ) 1.88 - 1.93 (4H, m), 2.16 (3H, s), 2.80 (4H, br s), 3.96 (3H, s), 4.02 (2H, s), 6.06 (2H, br s), 6.99 (1H, t), 7.35 - 7.45 (3H, m), 7.93 (1H, d). ESI MS [M+H]⁺ for C23H24FN7O calcd 434.2 found 434.3.

Table 5 contains additional intermediates that were made following Route K from the appropriate reagents.

Table 5: Characterization Data for Intermediates 12b-12c

Example 3-1: 5-[5-amino-7-(4-fluorophenyl)-2-(pyrrolidin-l-ylmethyl)-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-3-methyl-lH-pyridin-2-one

7-(4-fluorophenyl)-8-(6-methoxy-5-methylpyridin-3-yl)-2-(pyrrolidin-l-ylmethyl)- [l,2,4]triazolo[l,5-c]pyrimidin-5-amine (27 mg, 0.06 mmol) in CH3CN (0.6 mL) was added TMSC1 (31.8 pL, 0.25 mmol), followed by sodium iodide (37.3 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 30 min and was then stirred at 65 °C for 20 min. After reaction completed, volatiles were removed under reduced pressure and the residue was partitioned between diluted aqueous NH4OH solution and CH2CI2. The organic phase was separated, dried over anhydrous MgSCri, concentrated under reduced pressure. The residue was purified by flash chromatography on reverse phase Cl 8 silica with 10-100% CH3CN in H2O with 0.1% TFA as modifier to afford the title compound (3.60 mg, 10.58 %) as a solid. ¾ NMR (500 MHz, METHANOL-^) 2.02 - 2.07 (3H, m), 2.07 - 2.34 (6H, m), 3.66 - 3.89 (2H, m), 4.70 - 4.76 (2H, m), 7.03 - 7.18 (2H, m), 7.23 - 7.32 (1H, m), 7.34 - 7.40 (1H, m), 7.52 - 7.65 (2H, m). ESI MS [M+H]⁺ for C22H22FN7O calcd 420.2 found 420.3. Example 3-2: 5-[5-amino-7-(4-fluorophenyl)-2-(morpholinomethyl)-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-3-methyl-lH-pyridin-2-one

The title compound was prepared in a similar fashion to Example 3-1 using intermediate 12b (29.0 mg, 74.8 %) as solid. ¾NMR (500 MHz, METHANOL-^) 2.00 - 2.09 (3H, s), 3.39 - 3.73 (4H, m), 3.77 - 4.15 (4H, m), 4.64 - 4.72 (2H, s), 7.06 - 7.17 (2H, t), 7.20 - 7.29 (1H, s),

7.32 - 7.42 (1H, s), 7.48 - 7.62 (2H, t). ESI MS [M+H]⁺ for C22H22FN7O2 calcd 436.2 found 436.3.

Example 3-3: 5-[5-amino-7-(4-fluorophenyl)-2-(l-piperidylmethyl)-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-3-methyl-lH-pyridin-2-one

The title compound was prepared in a similar fashion to Example 3-1 using intermediate 12c (32.0 mg, 49.4 %) as solid. ¾ NMR (500 MHz, METHANOL-^) 1.47 - 1.60 (1H, m), 1.74 - 1.92 (2H, m), 1.94 - 2.02 (2H, s), 2.02 - 2.06 (3H, m), 3.06 - 3.22 (2H, m), 3.62 - 3.75 (2H, m), 4.51 - 4.64 (2H, s), 7.03 - 7.16 (2H, t), 7.21 - 7.28 (1H, s), 7.32 - 7.40 (1H, s), 7.50 - 7.59 (2H, t). ESI MS [M+H]⁺ for C23H24FN7O calcd 434.2 found 434.2.

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

Selenium dioxide (44.1 mg, 0.40 mmol) was added to : 5-[5-amino-2-[(3-fluoro-2- pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one (85 mg, 0.20 mmol) in ethyl acetate (5 mL) under air. The resulting mixture was stirred at 80 °C for 14 h. The solvent was removed under reduced pressure. The residue was purified by flash silica chromatography with 0 to 10% MeOH in DCM to afford the title compound (0.080 g, 91 %) as a yellow solid. ¾ NMR (DMSO- e, 400 MHz) d 3.36 (3H, s), 6.28 (1H, d, J=9.3 Hz), 7.13 (1H, dd, J=2.6, 9.4 Hz), 7.37 (3H, dd, J=2.0, 5.1 Hz), 7.48 (2H, dd, J=2.9, 6.9 Hz), 7.71 (1H, d, J=2.6 Hz), 7.81 (1H, dt, J=4.4, 8.7 Hz), 8.03 (1H, ddd, J=1.3, 8.6, 10.1 Hz), 8.25 (2H, s), 8.59 (1H, dt, J= 1.5, 4.6 Hz). ESI MS [M+H]⁺ for C23H16FN7O2 calcd 444.1 found 444.2.

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

NaBH4 (24.00 mg, 0.63 mmol) was added to 5-[5-amino-2-(3-fluoropyridine-2- carbonyl)-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one (70 mg, 0.16 mmol) in MeOH (3 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 2 hrs. The reaction mixture was quenched with 2M HC1 and neutralised with saturated NaHC03 solution, extracted with EtOAc (3 x 100 mL), the organic layer was dried over anhydrous Na2S04, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC to afford the title compound (0.035 g, 49.8 %) as a white solid. 'H NMR (DMSO- e, 400 MHz) d 6.20 (1H, d, J=5.8 Hz), 6.25 (1H, d, J=9.4 Hz), 6.30 (1H, d, J=6.6 Hz), 7.10 (1H, dd, J=2.6, 9.4 Hz), 7.31 - 7.44 (3H, m), 7.40 - 7.51 (3H, m), 7.62 (1H, d, J=2.5 Hz), 7.73 (1H, ddd, J=1.4, 8.4, 10.0 Hz), 7.97 (2H, s), 8.38 (1H, dt, J=1.5, 4.7 Hz). ESI MS [M+H]+ for C23H21FN7O2 calcd 444.1 found 444.2.

Example 4-3: 5-[5-amino-7-phenyl-2-[rel-(R)-(3-fluoro-2-pyridyl)-hydroxy-methyl]-

[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one

OR Enantiomer

The title compound was prepared from Example 4-2 and was purified by preparative SFC (CHIRAL ART Cellulose-SB, 2*25cm, 5um; Mobile Phase A:Hex:DCM=3 : 1(0.1%TFA)-HPLC, Mobile Phase B :IP A— HPLC; Flow rate:20 mL/min; Gradient: 50 B to 50 B in 15 min; 254/220 nm; RT:5.654; Injection Volumn:2 ml; Number Of Runs: 1) (0.008 g, 26.9 %) as a white solid. 1H NMR (DMSO-d6, 400 MHz) d 3.32 (3H, s), 6.11 - 6.33 (2H, m), 7.10 (1H, dd, J=2.6, 9.4 Hz), 7.30 - 7.40 (3H, m), 7.40 - 7.52 (3H, m), 7.62 (1H, d, J=2.5 Hz), 7.73 (1H, ddd, J=1.4, 8.4, 10.0 Hz), 7.97 (2H, s), 8.38 (1H, dt, J=1.5, 4.7 Hz). ESI MS [M+H]⁺ for C23H21FN7O2 calcd 444.1 found 444.4.

Example 4-4: 5-[5-amino-7-phenyl-2-[rel-(S)-(3-fluoro-2-pyridyl)-hydroxy-methyl]-

[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one

OR Enantiomer

The title compound was prepared from Example 4-2 and was purified by preparative SFC (CHIRAL ART Cellulose-SB, 2*25cm, 5um; Mobile Phase A:Hex:DCM=3 : 1(0.1%TFA)~HPLC, Mobile Phase B PA--HPLC; Flow rate:20 mL/min; Gradient: 50 B to 50 B in 15 min; 254/220 nm; RT:12.196; Injection Volumn:2 ml; Number Of Runs:l) (0.010 g, 33.7 %) as a white solid. ¾NMR (DMSO- e, 400 MHz) d 3.32 (3H, s), 6.11 - 6.33 (2H, m), 7.10 (1H, dd, J=2.6, 9.4 Hz), 7.30 - 7.40 (3H, m), 7.40 - 7.52 (3H, m), 7.62 (1H, d, J=2.5 Hz), 7.73 (1H, ddd, J=1.4, 8.4, 10.0 Hz), 7.97 (2H, s), 8.38 (1H, dt, J=1.5, 4.7 Hz). ESI MS [M+H]⁺ for C23H18FN7O2 calcd 444.1 found 444.4.

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

The title compound was prepared in a similar fashion as Example 4-2 (0.015 g, 29.9 %) as a white solid. ¾NMR (DMSO- e, 400 MHz) d 3.33 (3H, s),3.81 (3H, s), 5.91 (1H, d, J=3.2 Hz), 6.27 (1H, d, J=9.3 Hz), 6.31 (1H, s), 7.11 (1H, dd, J=2.6, 9.3 Hz), 7.30 - 7.39 (2H, m), 7.39 - 7.46 (3H, m), 7.61 (1H, d, J=2.6 Hz), 7.67 (1H, d, J=8.7 Hz), 7.96 - 8.01 (2H, m), 8.14 (1H, d, J=2.9 Hz). ESI MS [M+H]⁺ for C24H21N7O3 calcd 456.2 found 456.2.

Example 4-6: 5-[5-amino-2-[(3-chloro-2-pyridyl)methyl]-7-(4-fluorophenyl)- [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 1-1 (40 mg, 18 %) as a pale yellow solid. ¾NMR (DMSO- e, 400 MHz) d 3.34 (3H, s), 4.50 (2H, s), 6.28 (1H, d, J=9.3 Hz), 7.06-7.14 (1H, m, J=2.6, 9.4 Hz), 7.14 - 7.25 (2H, m), 7.32-7.40 (1H, m, J=4.7, 8.1 Hz), 7.44 - 7.53 (2H, m), 7.67 (1H, d, J=2.5 Hz), 7.91-7.98 (1H, m, J=1.5, 8.1 Hz), 8.40-8.46 (1H, m, J= 1.5, 4.7 Hz). ESI MS [M+H]+ for C23H17CIFN7O, calcd 462.1 found 462.0.

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

The title compound was prepared in a similar fashion to Example 1-2 (45 mg, 42.1%) as a white solid. ¾ NMR (DMSO- e, 500 MHz) d 3.46 (2H, s), 4.42 (2H, d), 6.93 (1H, d), 7.20 (2H, t), 7.34 - 7.52 (4H, m), 7.64 - 7.78 (1H, m), 8.06 - 8.27 (1H, m), 8.34 (1H, br d). ESI MS [M+H]+ for C22H16F2N8O, calcd 447.1 found 447.0. Example 4-8: 5-[5-amino-7-(4-fluorophenyl)-2-[rel-(R)-(3-fluoro-2-pyridyl)-hydroxy- methyl]-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one

OR Enantiomer

The title compound was prepared in a similar fashion to Example 4-3 (199 mg, 28.3%) as a white solid. ¾ NMR (DMSO- e, 500 MHz) d 3.34 (4H, s), 6.20 (1H, s), 6.28 (2H, d), 7.11 (1H, dd), 7.20 (2H, t), 7.44 - 7.53 (3H, m), 7.65 (1H, d), 7.69 - 7.77 (1H, m), 7.98 (2H, br s), 8.38 (1H, d). ESI MS [M+2] for C23H17F2N7O2, calcd 463.4 found 463.4.

Example 4-9: 5-[5-amino-7-(4-fluorophenyl)-2-[rel-(S)-(3-fluoro-2-pyridyl)-hydroxy- methyl]-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one

OR Enantiomer

The title compound was prepared in a similar fashion to Example 4-3 (173 mg, 24.6%) as a white solid. ¹HNMR (DMS04, 500 MHz) d 3.34 (4H, s), 6.20 (1H, s), 6.28 (2H, d), 7.11 (1H, dd), 7.20 (2H, t), 7.44 - 7.53 (3H, m), 7.65 (1H, d), 7.69 - 7.77 (1H, m), 7.98 (2H, br s), 8.38 (1H, d). ESI MS [M+2] for C23H17F2N7O2, calcd 463.4 found 463.4.

Example 5: 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 10⁵ 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.

Other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: ring A is:

R¹ is H, Ci-6alkyl, or C3-6cycloalkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR^a, halo and cyano; each R², independently, is halo, cyano, Ci-3alkyl, -0-Ci-3alkyl, -C02R^a, or -NR⁷R⁸; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR^a, halo, and cyano;

R³ is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R^a, and -OR^a;

R⁴ is -CR^xR^y-R⁵;

R⁵ is Ci-3alkyl wherein alkyl is optionally substituted with one or more substituents independently selected from -OR^a, halo, and cyano; wherein R⁵ is optionally substituted with from one to four groups R⁶; or R⁵ 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 R⁵ is optionally replaced by -C(=0)-; wherein R⁵ is optionally substituted with from one to four groups R⁶; each R⁶, independently, is H, halo, cyano, Ci-6alkyl, or -0-Ci-6alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo, cyano, -R^a, and -OR^a; each R⁷ and each R⁸, 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;

R^x is H or -OH;

R^y is H; or R^x and R^y together are =0; and each k, independently, is 0, 1, or 2.

2. The compound of claim 1, wherein: R¹ is H, -CH3, or -CH2CN.

3. The compound of any one of claims 1 to 2, wherein: each R², independently, is H or -CH3.

4. The compound of any one of claims 1 to 3, wherein: R³ is phenyl or phenyl substituted by halo.

5. The compound of any one of claims 1 to 4, wherein: R⁵ is Ci-₃alkyl.

6. The compound of any one of claims 1 to 4, wherein: R⁵ is heterocyclyl.

7. The compound of claim 6, wherein R⁵ is tetrahydrofuranyl, pyrrolidinyl, morpholinyl, or piperidyl.

8. The compound of any one of claims 1 to 4, wherein: R⁵ is heteroaryl.

9. The compound of claim 8, wherein: R⁵ is pyridyl, pyrimidinyl, or oxazolyl.

10. The compound of any one of claims 1 to 9, wherein R⁵ is substituted with from one to three groups R⁶, wherein each R⁶, independently, is halo, Ci-₆alkyl, or -0-Ci-₆alkyl; wherein alkyl is optionally substituted with one or more substituents independently selected from halo.

11. The compound of claim 10, wherein: each R⁶, independently, is halo, methyl, difluoromethyl, trifluoromethyl, or methoxy.

12. The compound of claim 1, wherein the compound is selected from the group consisting of:

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

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

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

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

5-[5-amino-7-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-lH-pyridin-2-one;

2-[(3-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

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;

2-[(5-fluoro-2-pyridyl)methyl]-7-phenyl-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

5-[5-amino-2-[(5-chloro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one;

5-[5-amino-2-[(5-fluoropyrimidin-4-yl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin- 8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-2-[(5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one; 5-[5-amino-2-[(5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-one;

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

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;

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

5-[5-amino-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-one;

5-[5-amino-2-[(5-methyl-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-lH-pyridin-2-one;

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

5-[5-amino-2-[[4-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-lH-pyridin-2-one;

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

5-[5-amino-7-phenyl-2-(pyrimidin-4-ylmethyl)-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l- methyl-pyridin-2-one;

5-[5-amino-2-[[4-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-l-methyl-pyridin-2-one;

2-[5-[5-amino-2-[(3-fluoro-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin- 8-yl]-2-oxo- 1 -pyridyljacetonitrile;

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

7-phenyl-8-pyridazin-4-yl-2-(tetrahydrofuran-2-ylmethyl)-[ 1 ,2,4]triazolo[ 1,5- c]pyrimidin-5-amine;

7-phenyl-8-pyridazin-4-yl-2-[[rel-(2S)-tetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine; 7-phenyl-8-pyridazin-4-yl-2-[[rel-(2R)-tetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

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

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

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

7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-8-pyridazin-4-yl-[l,2,4]triazolo[l,5- c]pyrimidin-5-amine;

5-[5-amino-7-phenyl-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l- methyl-pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-

8-yl]-lH-pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-

8-yl]-3-methyl-lH-pyridin-2-one;

5-[5-amino-7-phenyl-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-lH- pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[l,2,4]triazolo[l,5-c]pyrimidin- 8-yl]- 1 -methyl-pyridin-2-one;

5-[5-amino-7-(4-fluorophenyl)-2-(pynOlidin-l-ylmethyl)-[l,2,4]triazolo[l,5-c]pyrimidin-

8-yl]-3-methyl-lH-pyridin-2-one;

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

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

5-[5-amino-2-(3-fluoropyridine-2-carbonyl)-7-phenyl-[l,2,4]triazolo[l,5-c]pyrimidin-8- yl]-l-methyl-pyridin-2-one;

5-[5-amino-2-[(3-fluoro-2-pyridyl)-hydroxy-methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-l-methyl-pyridin-2-one; 5-[5-amino-7-phenyl-2-[rel-(R)-(3-fluoro-2-pyridyl)-hydroxy-methyl]- [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one;

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

5-[5-amino-2-[hydroxy-(5-methoxy-2-pyridyl)methyl]-7-phenyl-[l,2,4]triazolo[l,5- c]pyrimidin-8-yl]-l-methyl-pyridin-2-one;

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

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

5 - [5 -amino-7-(4-fluorophenyl)-2- [rel-(R)-(3 -fluoro-2-pyridyl)-hydroxy -methyl] - [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one; and

5-[5-amino-7-(4-fluorophenyl)-2-[rel-(S)-(3-fluoro-2-pyridyl)-hydroxy-methyl]- [ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-8-yl]- 1 -methyl-pyridin-2-one.

13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

14. Use of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition mediated by the adenosine receptor.

15. The use of claim 14, wherein 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.