Triazolopyrimidines as A2A / A2B inhibitors

Abstract

The present application provides compounds of formula (I): which modulate the activity of adenosine receptors, such as A2A and A2B receptors, and are useful for treating diseases associated with adenosine receptor activity, including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. TIFF2022545923000117.tif30164(I), or a pharmaceutically acceptable salt or stereoisomer thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 891,685, filed Aug. 26, 2019, which is incorporated by reference in its entirety.

[0002] The present invention provides triazolopyrimidine compounds that modulate the activity of adenosine receptors, e.g., subtypes A2A and A2B, and are useful for treating diseases associated with adenosine receptor activity, including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. [Background technology]

[0003] Adenosine is an extracellular signaling molecule that can regulate immune responses through many types of immune cells. Adenosine was first recognized as a physiological regulator of coronary vascular tone by Drury and Szent-Gyorgyu (Sachdeva, S. and Gupta, M. Saudi Pharmaceutical Journal, 2013, 21, 245-253), but it was not until 1970 that Sattin and Rall showed that adenosine regulates cell function through the occupation of specific receptors on the cell surface (Sattin, A., and Rall, TW, 1970. Mol. Pharmacol. 6, 13-23; Hasko', G., at al., 2007, Pharmacol. Ther. 113, 264-275).

[0004] Adenosine plays an important role in various other physiological functions. It participates in the synthesis of nucleic acids when linked to three phosphate groups; it forms ATP, an essential component of the cellular energy system. Adenosine can be generated by enzymatic degradation of extracellular ATP or can also be released from injured neurons and glial cells by crossing damaged cell membranes (Tautenhahn, M. et al. Neuropharmacology, 2012, 62, 1756-1766). Adenosine exerts various pharmacological actions in both the peripheral and central nervous systems through its action on specific receptors localized on the cell membrane (Matsumoto, T. et al. Pharmacol. Res., 2012, 65, 81-90). Alternative pathways for extracellular adenosine generation have been described. These pathways include the production of adenosine from nicotinamide dinucleotide (NAD) rather than ATP through the concerted action of CD38, CD203a, and CD73. CD73-independent production of adenosine can also occur through other phosphates such as alkaline phosphatase or prostate-specific phosphatase.

[0005] There are four known subtypes of adenosine receptors in humans, including A1, A2A, A2B, and A3 receptors. A1 and A2A are high affinity receptors, while A2B and A3 are low affinity receptors. Adenosine and its agonists can act through one or more of these receptors to modulate the activity of adenylate cyclase, an enzyme that contributes to increasing cyclic AMP (cAMP). Different receptors have different stimulatory and inhibitory effects on this enzyme. Increased intracellular concentrations of cAMP can suppress the activity of immune and inflammatory cells (Livingston, M. et al., Inflamm. Res., 2004, 53, 171-178).

[0006] A2A adenosine receptors can signal in the periphery and CNS with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases (Carlsson, J. et al., J. Med. Chem., 2010, 53, 3748-3755). In most cell types, A2A subtypes inhibit intracellular calcium levels, while A2B increases them. A2A receptors generally appear to inhibit inflammatory responses from immune cells (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

[0007] A2B receptors are highly expressed in the gastrointestinal tract, bladder, lungs and on mast cells (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). A2B receptors are structurally closely related to A2A receptors and can activate adenylate cyclase, but are functionally distinct. It has been hypothesized that this subtype may utilize signaling systems other than adenylate cyclase (Livingston, M. et al., Inflamm. Res., 2004, 53, 171-178). Of all adenosine receptors, A2B adenosine receptors are low affinity receptors that remain inactive under physiological conditions and are thought to be activated as a result of increased extracellular adenosine levels (Ryzhov, S. et al. Neoplasia, 2008, 10, 987-995). Activation of the A2B adenosine receptor can stimulate adenylate cyclase and phospholipase C through activation of Gs and Gq proteins, respectively. Coupling to mitogen-activated protein kinases has also been described (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

[0008] In the immune system, the involvement of adenosine signaling may be an important control mechanism that protects tissues against excessive immune responses. Adenosine can down-regulate immune responses through many types of immune cells, including T cells, natural killer cells, macrophages, dendritic cells, mast cells, and myeloid-derived suppressor cells (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29, 7-16).

[0009] In tumors, this pathway is hijacked by the tumor microenvironment, hindering the immune system's antitumor capabilities and promoting cancer progression. In the tumor microenvironment, adenosine is mainly generated from extracellular ATP by CD39 and CD73. Multiple cell types can generate adenosine by expressing CD39 and CD73. This is the case for tumor cells, effector T cells, regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), endothelial cells, cancer-associated fibroblasts (CAFs), and mesenchymal stromal / stem cells (MSCs). Hypoxia, inflammation, and other immunosuppressive signaling in the tumor microenvironment can induce the expression of CD39, CD73, and subsequent adenosine production. As a result, adenosine levels in solid tumors are abnormally high compared to normal physiological conditions.

[0010] A2A is primarily expressed on lymphoid-derived cells, including effector T cells, regulatory T cells, and natural killer cells. Blockade of the A2A receptor can inhibit downstream immunosuppressive signals that temporarily inactivate T cells. A2B receptors are primarily expressed on monocyte-derived cells, including dendritic cells, tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), and mesenchymal stromal / stem cells (MSCs). Blockade of the A2B receptor in preclinical models can suppress tumor growth, inhibit metastasis, and increase tumor antigen presentation.

[0011] Regarding the safety profile of ADORA2A / ADORA2B (A2A / A2B) blockade, all A2A and A2B receptor knockout mice were viable and fertile without growth abnormalities (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29, 7-16). A2A knockout mice showed increased levels of proinflammatory cytokines only upon challenge with LPS, and no evidence of inflammation at baseline (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). A2B knockout mice showed normal platelet, red blood cell, and white blood cell counts, but naive A2B knockout mice showed increased inflammation at baseline (TNF-alpha, IL-6) (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). Excessive production of TNF-alpha and IL-6 was detected after LPS treatment. A2B knockout mice also showed increased vascular adhesion molecules that mediate inflammation and leukocyte adhesion / rolling; enhanced mast cell activation; increased susceptibility to IgE-mediated anaphylaxis, and increased vascular leakage and neutrophil influx under hypoxia (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857).

[0012] In summary, there is a need to develop novel adenosine receptor selective ligands, for example for subtypes A2A and A2B, for the treatment of diseases such as cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. This application relates to this need and more. Summary of the Invention

[0013] The present invention relates in particular to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the components are defined herein.

[0014] The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0015] The present invention further provides a method of inhibiting activity of an adenosine receptor, comprising contacting the receptor with a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0016] The present invention further provides a method for treating a disease or disorder associated with abnormal expression of adenosine receptors, comprising administering to said patient a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0017] The present invention further provides a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in any of the methods described herein.

[0018] The invention further provides the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] compound The present invention relates in particular to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 2 is selected from LW and L-W'-Z; L is for C 1-3 Alkyl, -C 1-3 Alkyl-O-, -OC 1-3 Alkyl-, -C 1-3 Alkyl-NH-, -NH-C 1-3 Alkyl-, -NH-C 1-3 Alkyl-NH- and -N(C 1-3 alkyl)-; W is cyano, halogen, and C 1-3 is a 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 groups each independently selected from alkyl; W' is phenyl or 5-6 membered heteroaryl, and each phenyl or 5-6 membered heteroaryl of W' is selected from the group consisting of cyano, halogen, and C 1-3 optionally substituted with 1, 2, or 3 groups each independently selected from alkyl; Z is phenyl or 5- to 6-membered heteroaryl, and each phenyl or 5- to 6-membered heteroaryl in Z is selected from the group consisting of cyano, halogen, C 1-3 Alkyl, amine, and C 1-3 optionally substituted with 1, 2, or 3 groups each independently selected from alkoxy; Cy 1 is selected from cyanophenyl and cyanofluorophenyl; Cy 2 is C 1-3 Alkyl, C 1-3 Alkoxy, NH 2 , NH(C 1-3 Alkyl) and N(C 1-3 Alkyl) 2 and Cy is a 5- to 6-membered heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from 2 ring-forming carbon atoms of are optionally substituted by oxo.

[0020] In some embodiments, R 2 is LW.

[0021] In some embodiments, R 2 is L-W'-Z.

[0022] In some embodiments, L is -CH 2 -, -NH-CH 2 -, -O-CH 2 -, -NH-, -CH 2 -O-, -NH-CH(CH 3 )- and -NH-C(CH3 ) 2 - is selected.

[0023] In some embodiments, W is pyridinyl optionally substituted with 1 or 2 groups each independently selected from methyl, fluoro, and cyano.

[0024] In some embodiments, W' is selected from tetrazolyl and phenyl, wherein the phenyl is optionally substituted with fluoro.

[0025] In some embodiments, Z is selected from phenyl, pyridinyl, pyrazolyl, thiazolyl, pyrimidinyl, and pyrazinyl, each of which is optionally substituted with 1 or 2 groups independently selected from cyano, halogen, methyl, amino, and methoxy.

[0026] In some embodiments, Cy 1 is 3-cyanophenyl optionally substituted with fluoro.

[0027] In some embodiments, Cy 2 is selected from pyrimidinyl, 1-methyl-6-oxo-1,6-dihydropyridinyl, 1-methyl-6-oxo-1,6-dihydropyridazinyl, pyridinyl, dimethylaminopyridinyl, aminopyridinyl, 1-ethyl-6-oxo-1,6-dihydropyridinyl, methylpyridinyl, dimethylpyridinyl, and methoxymethylpyridinyl.

[0028] In some embodiments, the compound of formula (I) is 3-(5-amino-2-((5-(3-aminophenyl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methylpyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methoxypyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrazin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-(dimethylamino)pyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(2-fluoro-6-(pyridin-4-yl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-(2-(2-aminopyridin-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(pyridin-2-ylamino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(3-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((pyridin-2-yloxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 3-(5-amino-2-((1-(pyridin-2-yl)ethyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((2-(pyridin-2-yl)propan-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(pyrimidin-4-yl)-2-((5-(pyrimidin-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-3-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-4-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; or a pharma- ceutically acceptable salt thereof.

[0029] In some embodiments, the compound of formula (I) is 3-(5-amino-2-((5-(3-aminophenyl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methylpyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methoxypyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrazin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-(dimethylamino)pyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(2-fluoro-6-(pyridin-4-yl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-(2-(2-aminopyridin-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(pyridin-2-ylamino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((pyridin-2-yloxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(pyrimidin-4-yl)-2-((5-(pyrimidin-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-3-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-4-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, the compound is the (S)-enantiomer of one of the aforementioned compounds, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is the (R)-enantiomer of one of the aforementioned compounds, or a pharma- ceutically acceptable salt thereof.

[0031] It is further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0032] At various points in this specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R'') n -NR(CR'R'') n -and-(CR'R'') n Both NR-- and NR-- are included. Where a structure clearly requires a linking group, the Markush variable recited for that group is understood to be the linking group.

[0033] The term "n-membered" (n is an integer) typically refers to the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0034] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substitution may be at any chemically available position. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It is understood that substitution at a given atom is limited by the valence of the atom.

[0035] As used herein, the phrase "each 'variable' is independently selected from" has substantially the same meaning as "at each occurrence, the 'variable' is selected from."

[0036] Through definition, "C n-m " refers to a range inclusive of the endpoints, where n and m are integers indicating the number of carbons. Examples include 1~3 , C 1~4 , C 1~6 etc.

[0037] As used herein, the term "C" used alone or in combination with other terms means n~mThe term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be linear or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0038] As used herein, the term "C" used alone or in combination with other terms means n~m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0039] As used herein, the term "amino" refers to a group of the formula -NH 2 Refers to the group.

[0040] As used herein, "halo" or "halogen" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0041] As used herein, "heteroaryl" refers to a monocyclic aromatic heterocycle having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-membered heteroaryl ring. In some embodiments, the heteroaryl is a 6-membered heteroaryl ring. In some embodiments, the heteroaryl group has 1-4 ring-forming heteroatoms, 1-3 ring-forming heteroatoms, 1-2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. Exemplary heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, dihydropyridine, dihydropyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, triazine.

[0042] In certain places, definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings can be bonded to any ring member, provided that the valence of the atom is not exceeded. For example, the azetidine ring can be bonded at any position of the ring, while the pyridin-3-yl ring is bonded at the 3-position.

[0043] As used herein, the term "oxo" refers to an oxygen atom (i.e., =O) as a divalent substituent which forms a carbonyl group (e.g., C=O or C(O)) when attached to carbon, or a nitroso, sulfinyl, or sulfonyl group when attached to a nitrogen or sulfur heteroatom.

[0044] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent is independently selected at each occurrence from an applicable list.

[0045] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separate isomeric forms. In some embodiments, the compounds have the (R)-configuration. In some embodiments, the compounds have the (S)-configuration. The formulas provided herein (e.g., formulas (I), (II), etc.) include stereoisomers of the compounds.

[0046] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using chiral resolving acids that are optically active salt-forming organic acids. Resolving agents suitable for fractional recrystallization are optically active acids such as, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D- and L-forms of various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereoisomerically pure forms (e.g., S and R forms, or diastereomerically pure forms) of α-methylbenzylamine, stereoisomerically pure forms of 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0047] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0048] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond, with the associated migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium, or may be sterically fixed in one form by appropriate substitution.

[0049] All compounds and their pharma- ceutically acceptable salts may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0050] In some embodiments, preparation of compounds may involve the addition of acids or bases, for example to affect catalysis of a desired reaction or the formation of salt forms, such as acid addition salts.

[0051] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched for the compounds provided herein. Substantial separation can include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds provided herein, or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0052] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0053] The phrase "pharmacologically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0054] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an acid or base moiety present therein into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acid moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of the compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, with the solvent generally being preferably a non-aqueous medium such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN). Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference.

[0055] synthesis As will be appreciated by those of skill in the art, the compounds provided herein (including salts and stereoisomers thereof) may be prepared using known organic synthesis techniques, or may be synthesized according to any of a number of possible synthetic routes.

[0056] Scheme 1 [ka] Compounds of formula 1-9 can be synthesized via the synthetic route outlined in Scheme 1. Starting material 1-1 can first be converted to reagent 1-2 (wherein M is a boronic acid, boronic ester, or appropriately substituted metal [e.g., M is B(OR)), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). 2 , Sn(alkyl) 3 , or Zn-Hal) to give compound 1-3. Then, nucleophilic aromatic substitution (S N Reaction of 1-6 with N,O-bis(trimethylsilyl)acetamide at elevated temperature provides compound 1-5, which undergoes a cyclization reaction to generate bicyclic compound 1-6. Halogenation of 1-6 with a suitable reagent such as N-bromosuccinimide (NBS) provides compound 1-7. The final product 1-9 can be prepared by a cross-coupling reaction between compound 1-7 and a derivative of formula 1-8 using a procedure similar to that described for the preparation of compound 1-3 from starting material 1-1. At various stages during this synthetic process, R 2 The group may be further functionalized.

[0057] Scheme 2 [ka] Compounds of formula 2-4 may be synthesized via the synthetic route outlined in Scheme 2. The advanced intermediate 2-1 (which may be prepared using the synthetic procedures as outlined in Scheme 1) first undergoes a halogenation reaction (using a suitable reagent such as thionyl chloride) to produce compound 2-2 (Hal is a halide such as F, Cl, Br, or I). Compound 2-2 then undergoes a nucleophilic substitution reaction (S N 2) can be subjected to afford compound 2-4.

[0058] Scheme 3 [ka] Compounds of formula 3-6 can be synthesized via the synthetic route outlined in Scheme 3. The advanced intermediate 3-1 (which can be prepared using the synthetic procedures as outlined in Scheme 1) can first be converted to reagent 3-2 (wherein M is a boronic acid, boronic ester or appropriately substituted metal [e.g., M is B(OR)), under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). 2 , Sn(alkyl) 3 , or Zn-Hal] to produce compound 3-3. Bromination reaction (NBS) of 3-3 produces compound 3-4. Compound 3-4 can then be subjected to a cross-coupling reaction with reagent 3-5 to provide compound 3-6, using a procedure similar to that described for the preparation of compound 3-3 from 3-1.

[0059] Scheme 4 [ka] Compounds of formula 4-10 can be synthesized via the synthetic route outlined in Scheme 4. Selective nucleophilic aromatic substitution (S NAr) reaction provides compound 4-3. Compound 4-3 can then be cyclized to intermediate 4-4 via a suitable chemical transformation, such as a two-step process using O-ethylcarbonyl isothiocyanatidate and hydroxylamine hydrochloride. 4-4 can be reacted with a reagent of formula 4-5 (where M is a boronic acid, boronic ester or appropriately substituted metal [e.g., M is B(OR)) under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst) to afford compound 4-3. 2 , Sn(alkyl) 3 , or Zn-Hal) to generate intermediate 4-6. The amino group of 4-6 can then be functionalized using a suitable chemical transformation, such as Buchwald-Hartwig coupling conditions in the presence of a palladium catalyst (e.g., chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) and a base (e.g., sodium tert-butoxide), or reductive amination conditions (e.g., in the presence of a suitable hydride source) to provide 4-7. Halogenation of 4-7 using a suitable reagent, such as N-bromosuccinimide (NBS), gives compound 4-8. Cross-coupling reaction of 4-8 with a derivative of formula 4-9, followed by removal of the protecting group, using a procedure similar to that described for the preparation of compound 4-6 from compound 4-4, provides product 4-10.

[0060] Scheme 5 [ka] Compounds of formula 5-7 can be synthesized via the synthetic route outlined in Scheme 5. The amino group of 5-1 (which can be prepared via the synthetic route outlined in Scheme 4) can first be converted to a halogen using a suitable chemical transformation such as the Sandmeyer reaction (e.g., in the presence of a suitable oxidizing agent such as isobutylnitrile and a suitable halogen source) to provide 5-2. Nucleophilic aromatic substitution (S N Ar) reaction provides compound 5-4. Halogenation of 5-4 using a suitable reagent such as N-bromosuccinimide (NBS) gives compound 5-5. Cross-coupling reaction of 5-5 with a derivative of formula 5-6, followed by removal of the protecting group, provides product 5-7.

[0061] How to use The compounds of the present disclosure may modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors. Thus, the compounds, salts or stereoisomers described herein may be used in a method of inhibiting adenosine receptors (e.g., A2A and / or A2B receptors) by contacting the receptor with any one or more of the compounds, salts, or compositions described herein. In some embodiments, the compounds or salts may be used in a method of inhibiting the activity of adenosine receptors in an individual / patient in need thereof by administering an effective amount of a compound or salt described herein. In some embodiments, modulating is inhibiting. In some embodiments, contacting is in vivo. In some embodiments, contacting is ex vivo or in vitro.

[0062] The compounds or salts described herein can be selective. By "selective" it is meant that the compound binds to or inhibits adenosine receptors with higher affinity or potency, respectively, compared to at least one other receptor, kinase, etc. The compounds of the present disclosure can also be dual antagonists (i.e., inhibitors) of adenosine receptors, for example, A2A and A2B adenosine receptors.

[0063] Another aspect of the present disclosure relates to a method of treating an adenosine receptor-associated disease or disorder in an individual (e.g., a patient) by administering a therapeutically effective amount or dose of one or more compounds of the present disclosure or a pharmaceutical composition thereof to the individual in need of such treatment. The adenosine receptor-associated disease or disorder may include any disease, disorder, or condition directly or indirectly associated with the expression or activity of an adenosine receptor, including overexpression and / or abnormal activity levels.

[0064] The compounds of the present disclosure are useful for treating diseases associated with adenosine receptor activity, including, for example, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, immune dysregulation diseases, central nervous system diseases, and diabetes.

[0065] Based on the potential role of adenosine, e.g., A2A, A2B receptors in multiple immune suppression mechanisms, developing inhibitors can promote the immune system to suppress tumor progression.Adenosine receptor inhibitors can be used alone or in combination with other therapies to treat bladder cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC), lung metastasis), melanoma (e.g., metastatic melanoma), breast cancer, cervical cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer, uterine cancer, head and neck cancer, and renal cell carcinoma (Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857). zhttps: / / globenewswire.com / news-release / 2017 / 04 / 04 / 954192 / 0 / en / Corvus-Pharmaceuticals-Announces-Interim-Results-from-Ongoing-Phase-1-1b-Study-Demonstrating-Safety-and-Clinical-Activity-of-Lead-Checkpoint-Inhibitor-CPI-444-in-Patients-with-Adva.html;Cekic C.et al.,J Immunol,2012,188:198-205;Iannone,R.et al.,Am.J.Cancer Res.2014,4:172-181(Study shows that blockade of both A2A and CD73 enhances antitumor activity of anti-CTLA-4 mAb therapy in B16F10 mouse melanoma model);Iannone,R.et See also, Beavis PA., et al., Neoplasia, 2013, 15:1400-1410 and Beavis PA., et al., Proc Natl Acad Sci.USA, 2013, 110:14711-14716 (study shows that blocking A2A and CD73 reduced metastasis in 4T1 breast tumor model with high CD73 expression). In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the colon cancer is colorectal cancer (CRC).

[0066] In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, squamous cell carcinoma of the head and neck, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant nerve sheath tumor, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[0067] In some embodiments, the disease or disorder is mesothelioma or adenocarcinoma. In some embodiments, the disease or disorder is mesothelioma. In some embodiments, the disease or disorder is adenocarcinoma.

[0068] MDSCs (myeloid-derived suppressor cells) are a heterogeneous group of immune cells from myeloid lineage (a family of cells derived from bone marrow stem cells). MDSCs proliferate strongly as a result of altered hematopoiesis in pathological conditions such as chronic infection and cancer. MDSCs are distinct from other myeloid cell types in that they have potent immunosuppressive activity rather than immunostimulatory properties. As with other myeloid cells, MDSCs interact with and regulate the function of other immune cell types, including T cells, dendritic cells, macrophages, and natural killer cells. In some embodiments, the compounds, etc. described herein can be used in methods related to cancer tissues (e.g., tumors) with high infiltration of MDSCs, including solid tumors with high basal levels of macrophage and / or MDSC infiltration.

[0069] In some embodiments, the disease or disorder is head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colon cancer, melanoma, ovarian cancer, bladder cancer, renal cell carcinoma, liver cancer, or hepatocellular carcinoma.

[0070] In some embodiments, compounds of the present disclosure may be used to treat pulmonary inflammation, including bleomycin-induced pulmonary fibrosis and injuries associated with adenosine deaminase deficiency (Baraldi, et al., Chem. Rev., 2008, 108, 238-263).

[0071] In some embodiments, the compounds of the present disclosure can be used as therapeutic agents for inflammatory diseases such as allergic reactions (e.g., A2B adenosine receptor-dependent allergic reactions) and other adenosine receptor-dependent immune reactions. Additional inflammatory diseases that can be treated by the compounds of the present disclosure include respiratory disorders, sepsis, reperfusion injury, and thrombosis.

[0072] In some embodiments, the compounds of the present disclosure can be used as therapeutic agents for cardiovascular diseases such as coronary artery disease (myocardial infarction, angina, heart failure), cerebrovascular disease (stroke, transient ischemic attack), peripheral arterial disease, and aortic atherosclerosis and aneurysm. Atherosclerosis is the underlying etiological factor in many types of cardiovascular diseases. Atherosclerosis begins as fatty streaks in adolescence, which progress to plaques in adulthood, eventually resulting in thrombotic events that cause occlusion of blood vessels, resulting in clinically significant morbidity and mortality. Antagonists against A2B and A2A adenosine receptors can be beneficial in preventing the formation of atherosclerotic plaques (Eisenstein, A. et al., J. Cell Physiol., 2015, 230(12), 2891-2897).

[0073] In some embodiments, compounds of the present disclosure may be used as treatments for disorders of motor activity; deficiencies caused by degeneration of the striatonigral dopamine system; and Parkinson's disease; some of the motivational symptoms of depression (Collins, LE et al. Pharmacol. Biochem. Behav., 2012, 100, 498-505.).

[0074] In some embodiments, the compounds of the present disclosure may be used as therapeutic agents for diabetes and related disorders, such as insulin resistance. Diabetes is characterized by the expression of the A2B adenosine receptor (A2BR), which stimulates the production of adenosine and IL-6 and CRP production, insulin resistance, and A 2B Affects the relationship between single nucleotide polymorphisms in the R gene (ADORA2B SNPs) and inflammatory markers. Increased A2BR signaling in diabetes may increase insulin resistance in part by recruiting proinflammatory mediators. Selective A2BR blockers may be useful to treat insulin resistance (Figler, RA et al. Diabetes, 2011, 60(2), 669-679).

[0075] It is believed that the compounds provided herein, e.g., compounds of formula (I), or any of its embodiments, may have a sufficient pharmacological profile and promising biopharmaceutical properties, e.g., toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that the determination of suitable biopharmaceutical properties, e.g., the determination of inhibition of a particular target or channel to determine cytotoxicity or potential toxicity in cells, is within the knowledge of one of ordinary skill in the art.

[0076] The terms "individual" or "patient", used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0077] The phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or drug response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician.

[0078] As used herein, the term "treating" or "treatment" refers to (1) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting a symptom or symptom of the disease, condition, or disorder (i.e., halting further progression of the symptom and / or symptom); and (2) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting a symptom or symptom of the disease, condition, or disorder (i.e., reversing the symptom and / or symptom), e.g., reducing the severity of the disease.

[0079] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may have a predisposition to a disease, condition, or disorder, but who has not yet experienced or exhibited the pathology or symptoms of the disease.

[0080] Combination therapy I. Immune checkpoint therapy In some embodiments, the dual inhibitors of A2A and A2B provided herein may be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer as described herein. In one embodiment, the combination with one or more immune checkpoint inhibitors as described herein may be used for the treatment of melanoma. The compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of the disclosure provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0081] In some embodiments, the dual A2A and A2B inhibitors provided herein may be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, OX40, GITR, and CD137 (also known as 4-1BB).

[0082] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0083] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics, e.g., 4-1BB (e.g., urelumab or utomirumab).

[0084] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0085] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1 / PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.

[0086] In some embodiments, the inhibitor is INCB086550.

[0087] In some embodiments, the inhibitor is MCLA-145.

[0088] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0089] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0090] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0091] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0092] In some embodiments, the inhibitor of immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178.In some embodiments, the OX40L fusion protein is MEDI6383.

[0093] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0094] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, tumor-specific antigens (e.g., CD70), or TGFβ receptor.

[0095] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors.In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0096] As provided throughout, the additional compounds, inhibitors, agents, etc. may be combined with the present compounds in a single or consecutive dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0097] II. Cancer Therapy Cancer cell growth and survival can be affected by multiple signaling pathways. Therefore, combinations of different enzyme / protein / receptor inhibitors that exhibit different selectivity in the targets that they modulate the activity of are useful for treating such conditions. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the chance of drug resistance developing in a cell population and / or reduce the toxicity of the treatment.

[0098] The compounds of the present disclosure can be used in combination with one or more other enzyme / protein / receptor inhibitors or one or more therapies for the treatment of diseases such as cancer. Examples of diseases and indications treatable with combination therapy include those described herein.

[0099] The compounds of the present disclosure may be used in combination with one or more additional pharmaceutical agents, such as, for example, chemotherapeutic agents, tumor immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, and FAK kinase inhibitors. The one or more additional pharmaceutical agents may be administered to the patient simultaneously or sequentially.

[0100] For example, the compounds as disclosed herein can be combined with inhibitors of one or more of the following kinases for the treatment of cancer and other diseases or disorders described herein: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PD GFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Non-limiting examples of inhibitors that may be combined with the compounds of the present disclosure for the treatment of cancer and other diseases and disorders described herein include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or INCB39110), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors (e.g., ribavirinib ... inhibitors, PI3K-delta inhibitors (e.g., INCB50797 and INCB50465), Pim inhibitors, CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), histone deacetylase inhibitors (HDACs), such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as INCB54329 and INCB57643), and adenosine receptor antagonists, or combinations thereof.

[0101] Examples of antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (trade name Avastin, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), Rituxan (anti-CD20), and antibodies against c-MET.

[0102] One or more of the following agents may be used in combination with the compounds of the present disclosure, which are presented as a non-limiting list: cytostatics, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778,123, BMS214662, Iressa™ (gefitinib), Tarceva™ (erlotinib), antibodies against EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, cyclophosphamide ... Lormetine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Oxaliplatin, Leucovirin, Eloxatin (Oxaliplatin), Pentostatin, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17. Alpha-.- Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megstrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin (trademark) Tuzumab), Bexar™ (tositumomab), Velcade™ (bortezomib), Zevalin™ (ibritumomab tiuxetan), Trisenox™ (arsenic trioxide), Xeloda™ (capecitabine), vinorelbine, porfimer, Erbitux™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, Relosol, Fu Rubestrant, Exemestane, Ifosfomide, Rituximab, C225 (Cetuximab), Campath (Alemtuzumab), Clofarabine, Cladribine, Afidicolone, Rituxan, Sunitinib, Dasatinib, Tezacitabine, Sml1, Fludarabine, Pentostatin, Triapine, Didox, Trimidox, Amidox, 3-AP, and MDL-101,731.

[0103] The compounds of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery.Examples of immunotherapy include cytokine treatment (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, adoptive T cell transfer, Toll receptor agonists, STING agonists, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, etc.The compounds can be administered in combination with one or more anti-cancer agents, such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, bortezomib, intravenous busulfan, oral busulfan, calcitidine, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, Rulotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, i Interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,Olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, rucaparib, streptozocin, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib, talazoparib, and zoledronate.

[0104] Additional examples of chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0105] Examples of Bcr-Abl inhibitors include imatinib mesylate (Gleevec™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other examples of suitable Bcr-Abl inhibitors include the genera and species of compounds disclosed in U.S. Patent No. 5,521,184, WO04 / 005281, and U.S. Serial No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0106] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tanzutinib, PLX3397 and ASP2215, and pharmaceutically acceptable salts thereof.Other suitable Flt-3 inhibitors include compounds as disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0107] Exemplary and suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary and suitable RAF inhibitors include compounds as disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0108] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharma- ceutically acceptable salts thereof. Other examples of suitable FAK inhibitors include compounds such as those disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharma- ceutically acceptable salts thereof.

[0109] In some embodiments, compounds of the present disclosure may be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0110] In some embodiments, the compounds of the present disclosure may be used in combination with chemotherapeutic agents in the treatment of cancer and may improve the response to the treatment compared to the response to the chemotherapeutic agent alone without exacerbating its toxic effects. In some embodiments, the compounds of the present disclosure may be used in combination with chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan and prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).Additive or synergistic effects are desirable outcomes of combining a PI3K inhibitor of the present disclosure with an additional agent.

[0111] In some embodiments, compounds of the present disclosure can be used in combination with inhibitors of JAK or PI3Kδ.

[0112] The agents may be combined with the compound in a single or consecutive dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0113] The compounds of the present disclosure may be used in combination with one or more other inhibitors or one or more therapies to treat infectious diseases. Examples of infectious diseases include viral, bacterial, fungal, or parasitic infections.

[0114] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure, where the dexamethasone is administered intermittently rather than continuously.

[0115] The compounds of formula (I) or any formula described herein, any of the claims and compounds described herein, or salts thereof, may be combined with another immunogen, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0116] The compounds of formula (I) or any formula described herein, any of the claims and compounds described herein, or salts thereof, may be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the compounds of the present disclosure may be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the compounds of formula (I) or any formula described herein, any of the claims and compounds described herein, or salts thereof, may be combined with dendritic cell immunization to activate a potent anti-tumor response.

[0117] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor expressing effector cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate the host's immune responsiveness.

[0118] In some further embodiments, the combination of the disclosed compounds and other therapeutic agents can be administered to a patient before, during, and / or after bone marrow or stem cell transplantation. The disclosed compounds can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0119] The compounds of formula (I) or any of the formulas described herein, any of the claims and compounds described herein, or their salts, can be used in combination with vaccines to stimulate immune responses against pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful include those for which there is currently no effective vaccine, or for which conventional vaccines are not completely effective. These include, but are not limited to, HIV, hepatitis (types A, B, and C), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, and Pseudomonas Aeruginosa.

[0120] Viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, infectious virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0121] Pathogenic bacteria causing infections treatable by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme burgdorferi.

[0122] Pathogenic fungi causing infections treatable by the methods of the present disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum. Examples of pathogenic parasites causing infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0123] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard texts. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference in its entirety as if set forth herein.

[0124] Pharmaceutical Preparations and Dosage Forms When used as a pharmaceutical, the compounds of the present disclosure may be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including delivery to mucous membranes, including transdermal, epidermal, ocular and intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0125] The present disclosure also includes pharmaceutical compositions that contain the compounds of the present disclosure or pharma- ceutically acceptable salts thereof as active ingredients in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. In making compositions of the present disclosure, the active ingredients are typically mixed with excipients, diluted by excipients, or enclosed in such carriers, for example, in the form of capsules, sachets, paper or other containers. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0126] When preparing formulation, active compound can be pulverized to obtain suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be pulverized to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by pulverization to provide substantially uniform distribution in formulation, for example, about 40 mesh.

[0127] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain particle sizes suitable for tableting and other types of formulations.Finely divided (nanoparticulate) preparations of the compounds of the present disclosure can be prepared by processes known in the art.See, for example, International Application No. WO2002 / 000196.

[0128] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; and flavoring agents.The composition of the present disclosure may be formulated to provide quick, sustained, or delayed release of active ingredient after administration to a patient by using methods known in the art.

[0129] The compositions may be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0130] In some embodiments, compositions of the present disclosure contain from about 5 to about 50 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing from about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of active ingredient.

[0131] In some embodiments, the compositions of the present disclosure contain from about 50 to about 500 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing from about 50 to about 100, from about 100 to about 150, from about 150 to about 200, from about 200 to about 250, from about 250 to about 300, from about 350 to about 400, or from about 450 to about 500 mg of active ingredient.

[0132] In some embodiments, the compositions of the present disclosure contain about 500 to about 1000 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of active ingredient.

[0133] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

[0134] The active compound can be effective over a wide dosage range and is generally administered in a pharmacologic effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's condition, etc.

[0135] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When referring to these preformulation compositions as homogeneous, the active ingredient is typically evenly dispersed throughout the composition, and the composition can be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation composition is then divided into unit dosage forms of the type described above, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0136] The tablet or pill of the present disclosure can be coated or otherwise compounded to provide a dosage form that provides the advantage of long-term action.For example, the tablet or pill can comprise an inner dose and an outer dose component, the latter being in the form of an envelope on the former.The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release.Various materials can be utilized as such enteric layer or coating, including materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0137] Liquid forms for oral or injectable administration into which the compounds and compositions of the present disclosure may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0138] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by using inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0139] Topical formulations may include one or more conventional carriers. In some embodiments, ointments may include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of creams may be based on glycerol and water in combination with one or more other ingredients, such as, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other ingredients, such as, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations include at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the present disclosure. Topical formulations may be suitably packaged in 100 g tubes, optionally accompanied by instructions for treating a selected indication, such as, for example, psoriasis or other skin conditions.

[0140] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated, as well as the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and general health of the patient.

[0141] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged or lyophilized for use as is, although lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formulation of pharmaceutical salts.

[0142] The therapeutic dosage of the compounds of the present disclosure may vary according to, for example, the particular application for which the treatment is to be performed, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in a pharmaceutical composition may vary depending on many factors, including the dosage amount, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present disclosure may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosages range from about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0143] The compositions of the present disclosure may further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0144] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure that may be useful in both in vitro and in vivo assays, as well as imaging techniques, for localizing and quantifying A2A and / or A2B receptors in tissue samples, including humans, and for identifying A2A and / or A2B antagonists by inhibitory binding of the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure may also be useful to produce differentiated ADME (absorption, distribution, metabolism, and excretion). Thus, the present disclosure includes adenosine receptor (e.g., A2A and / or A2B) assays that include such labeled or substituted compounds.

[0145] The present disclosure further includes compounds of the present disclosure that are isotopically labeled. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced by a deuterium atom (e.g., C 1-6 One or more hydrogen atoms of an alkyl group may be -CH 3 Ga-CD 3 (Optionally, the alkyl group may be replaced with a deuterium atom such that the alkyl group is replaced with a deuterium atom such that the alkyl group is replaced with a deuterium atom.) In some embodiments, the alkyl group in any of the disclosed formulas, for example, formula (I), may be perdeuterated.

[0146] One or more constituent atoms of the compounds provided herein may be replaced or substituted with natural or non-natural abundance isotopes of the atoms. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds provided herein may be replaced or substituted with a deuterium atom (e.g., C 1-6 One or more hydrogen atoms of an alkyl group may be -CH 3 Ga-CD 3 (can be replaced with deuterium atoms so as to be replaced with deuterium atoms). In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound can be replaced or substituted with deuterium atoms.

[0147] In some embodiments, any “alkyl,” “alkenyl,” “alkynyl,” “aryl,” “phenyl,” “cycloalkyl,” “heterocycloalkyl,” or “heteroaryl” substituent as described herein or “—C 1-6 Alkyl-, "alkylene," "alkenylene," and "alkynylene" linking groups each have one, two, three, four, five, six, seven, or eight hydrogen atoms bonded to a carbon atom optionally replaced by a deuterium atom.

[0148] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey, Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0149] Substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, due to greater metabolic stability, and therefore may be preferred in some cases (see, e.g., A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0150] The radionuclide that is incorporated into the radiolabeled compound will depend on the particular application of that radiolabeled compound. For example, for in vitro adenosine receptor labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S may be useful. For radioimaging applications, 11 C. 18 F, 125 I,123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br may be useful.

[0151] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0152] The present disclosure may further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure.Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods that are applicable to the compounds of the present disclosure.

[0153] The labeled compounds of the present disclosure can be used in screening assays to identify / evaluate compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to an adenosine receptor by monitoring its concentration change when it contacts an adenosine receptor through tracking of the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) that is known to bind to an adenosine receptor. Thus, the ability of a test compound to compete with a standard compound for binding to an adenosine receptor directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, to evaluate the competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored, thereby ascertaining the relative binding affinity of the test compound.

[0154] kit The present disclosure also includes pharmaceutical kits useful for treating or preventing, for example, adenosine receptor-related diseases or disorders (e.g., cancer, inflammatory diseases, cardiovascular diseases, or neurodegenerative diseases, etc.), which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be apparent to one of skill in the art, such kits can optionally further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharma-ceutically acceptable carriers, additional containers, etc. Instructions indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components, either as an insert or label, can also be included in the kit.

[0155] The present invention will be described in more detail by specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to essentially produce the same results.The compounds of the examples have been found to inhibit the activity of adenosine receptors (e.g., A2A and / or A2B) according to at least one assay described herein. EXAMPLES

[0156] Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass-directed preparative system. The basic equipment settings, protocols, and control software for the operation of these systems are described in detail in the literature (see, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004)). The isolated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire™ C 18 5 μm, 2.1×50 mm, buffer: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient from 2% to 80% B in 3 min at a flow rate of 2.0 mL / min.

[0157] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detection, as shown in the examples. Typical preparative reversed-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows: pH=2 purification: Waters Sunfire™ C eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile18 5μm, 30×100mm or Waters XBridge™ C 18 5 μm, 30×100 mm column; flow rate was 60 mL / min, and separation gradient was optimized for each compound using compound specific method optimization protocols as described in the literature (see, e.g., “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). pH=10 purification: Waters XBridge (trademark) C 18 5 μm, 30 × 100 mm column, mobile phase A: 0.1% NH in water 4 OH and mobile phase B: acetonitrile; the flow rate was 60 mL / min, and the separation gradient was optimized for each compound using a compound specific method optimization protocol as described in the literature (see, e.g., "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0158] Separation of the racemate into some enantiopure samples was carried out on a preparative scale by chiral-phase high performance liquid chromatography under the following conditions: Instrument: Agilent 1100 Prep HPLC; Column: Phenomenex Lux Cellulose-4, 21.2 x 250 mm, 5 μm; Eluting with an isocratic mobile phase of 45% EtOH in hexane at a flow rate of 20 mL / min.

[0159] Example 1. 3-(5-amino-2-((5-(3-aminophenyl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(2-amino-6-chloropyrimidin-4-yl)benzonitrile [ka] A mixture of 4,6-dichloropyrimidin-2-amine (2.5 g, 15.2 mmol), (3-cyanophenyl)boronic acid (2.02 g, 13.7 mmol), tetrakis(triphenylphosphine)palladium(0) (1.06 g, 0.92 mmol) and sodium carbonate (3.23 g, 30.5 mmol) in 1,4-dioxane (60 mL) and water (5 mL) was degassed with nitrogen, and the resulting mixture was then heated and stirred at 60 °C for 2 days. After cooling to room temperature (rt), the mixture was concentrated, diluted with water and extracted with DCM (30 mL x 3). The combined organic layers were washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The resulting residue was purified by flash chromatography on a silica gel column eluted with 8% EtOAc in dichloromethane to give the desired product. 11 H 8 ClN 4 (M+H) + LCMS calculated for: 231.0, found: 231.0.

[0160] Step 2: 3-(5-amino-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 2-Hydroxyacetohydrazide (2.34 g, 26.01 mmol) was added to a solution of 3-(2-amino-6-chloropyrimidin-4-yl)benzonitrile (4.00 g, 17.34 mmol) in ethanol (35 mL) at room temperature. After heating and stirring at reflux for 2 h, the reaction mixture was cooled to room temperature and concentrated. The resulting residue was taken up in N,O-bis(trimethylsilyl)acetamide (20 mL) and stirred at 120° C. for 7 h. The mixture was then cooled to room temperature, poured onto ice, and stirred at room temperature for 1 h. The resulting solid was collected by filtration and taken up in 20 mL of 1N HCl solution. The resulting mixture was stirred at room temperature for 1 h, filtered, and the aqueous layer was washed with saturated NaHCO 3 The mixture was neutralized by the addition of water. The resulting precipitate was collected by filtration and dried to give the desired product as a brown solid. 13 H 11 N 6 O(M+H) + LCMS calculated for: 267.1; found 267.1.

[0161] Step 3: 3-(5-amino-8-bromo-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a mixture of 3-(5-amino-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (1.0 g, 3.76 mmol) in DMF (12 mL) at -30 °C was added NBS (0.67 g, 3.76 mmol) in small portions. The reaction mixture was gradually warmed to 0 °C, resulting in a homogeneous solution. After stirring at 0 °C for 1 h, the reaction mixture was washed with saturated NaHCO 3 The solution was diluted and the desired product was collected by filtration and dried. 13 H 10 BrN 6 O(M+H) + LCMS calculated for: 345.0; found 345.0.

[0162] Step 4: 3-(5-amino-2-(hydroxymethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Tetrakis(triphenylphosphine)palladium(0) (0.067 g, 0.058 mmol) was added to a mixture of 4-(tributylstannyl)pyrimidine (0.321 g, 0.869 mmol), 3-(5-amino-8-bromo-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (0.20 g, 0.579 mmol), CsF (0.176 g, 1.159 mmol), and copper(I) iodide (0.022 g, 0.116 mmol) in 1,4-dioxane (5.0 mL). The reaction mixture was cooled to 5° C. for 1 hour and then cooled to 5° C. for 1 hour. 2 The mixture was purged with 0.5% CO and stirred at 80° C. for 7 h. The resulting mixture was cooled to room temperature, concentrated, and purified by flash column chromatography eluting with 0% to 10% methanol in DCM to give the product. 17 H 13 N 8 O(M+H) + LC-MS calculated for: 345.1; found 345.1.

[0163] Step 5: 3-(5-amino-2-(chloromethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a mixture of 3-(5-amino-2-(hydroxymethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (0.1 g, 0.290 mmol) in acetonitrile (10 ml) was added thionyl chloride (0.212 ml, 2.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 h, concentrated and purified by flash chromatography eluting with 0% to 5% methanol in DCM to give the product. 17 H12 ClN 8 (M+H) + LC-MS calculated for: 363.1; found 363.1.

[0164] Step 6: 3-(5-amino-2-((5-(3-aminophenyl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-amino-2-(chloromethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (10 mg, 0.028 mmol), 3-(1H-tetrazol-5-yl)aniline (8.9 mg, 0.055 mmol) and Cs in DMF (1 mL). 2 CO 3 A mixture of (20.7 mg, 0.064 mmol) was stirred at 100° C. for 10 min. The reaction mixture was then cooled to room temperature, diluted with methanol (4 mL) and purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 24 H 18 N 13 (M+H) + LCMS calculated for: 488.2; found 488.2.

[0165] Example 2. 3-(5-amino-2-((5-(6-methylpyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 5-(m-tolyl)-1H-tetrazole for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 24 H 18 N13 (M+H) + LCMS calculated for: 488.2; found 488.2.

[0166] Example 3. 3-(5-amino-2-((5-(6-methoxypyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 2-methoxy-6-(1H-tetrazol-5-yl)pyridine for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 24 H 18 N 13 O(M+H) + LCMS calculated for: 504.2; found 504.2.

[0167] Example 4. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-amino-2-(hydroxymethyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(5-amino-8-bromo-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.046 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (100 mg, 0.46 mmol), XPhos Pd G2 (35 mg, 47 μmol), and Na in 1,4-dioxane (5.0 mL) and water (1.0 mL). 2 CO 3 A mixture of (200 mg, 1.9 mmol) was flushed with nitrogen and sealed. The reaction mixture was stirred at 110° C. for 1 h. The resulting mixture was cooled to room temperature, concentrated, and purified by flash column chromatography eluting with 0% to 10% methanol in DCM to give the product. 19 H 16 N 7 O 2 (M+H) + LC-MS calculated for: m / z = 374.1; found 374.1.

[0168] Step 2: 3-(5-amino-2-(chloromethyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for step 5 of Example 1, substituting 3-(5-amino-2-(hydroxymethyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile for 3-(5-amino-2-(hydroxymethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile. 19 H 15 ClN 7 O(M+H) + LCMS calculated for: 392.1; found: 392.

[0169] Step 3: 3-(5-amino-2-(chloromethyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile This compound was prepared using a procedure similar to that described for Example 1, step 6, substituting 3-(5-amino-2-(chloromethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile for 3-(5-amino-2-(chloromethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 24 H 18 N 13 O(M+H) + LCMS calculated for: 504.2; Found 504.2

[0170] Example 5. 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting 5-(1H-pyrazol-1-yl)-1H-tetrazole for 2-(1H-tetrazol-5-yl)pyridine. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 23 H 18 N 13 O(M+H) + LCMS calculated for: 492.5; Found: 492.4.

[0171] Example 6. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting 4-(1H-tetrazol-5-yl)thiazole for 2-(1H-tetrazol-5-yl)pyridine. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 23 H 17 N 12 OS(M+H) + LCMS calculated for: 509.1; found: 509.2.

[0172] Example 7. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting 2-(1H-tetrazol-5-yl)pyrimidine for 2-(1H-tetrazol-5-yl)pyridine. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 24 H 18 N 13 O(M+H) + LCMS calculated for: 504.2; Found 504.2

[0173] Example 8. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrazin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting 2-(1H-tetrazol-5-yl)pyrazine for 2-(1H-tetrazol-5-yl)pyridine. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 24 H 18 N 13 O(M+H) + LCMS calculated for: 504.2; Found 504.2

[0174] Example 9. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 1. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the desired product as the TFA salt. 24 H 18 N 13 O(M+H) + LCMS calculated for: 504.2; Found 504.2

[0175] Example 10. 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting pyridin-4-ylboronic acid for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 1. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the desired product as a TFA salt. 24 H 17 N 12 (M+H) + LCMS calculated for: 473.2; found 473.2.

[0176] Example 11. 3-(5-amino-8-(2-(dimethylamino)pyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting (2-(dimethylamino)pyridin-4-yl)boronic acid for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 1. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the desired product as a TFA salt. 26 H 22 N 13 (M+H) + LCMS calculated for: 515.2; found 515.2.

[0177] Example 12. 3-(5-amino-8-(2-aminopyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 4, substituting (2-aminopyridin-4-yl)boronic acid for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 1. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the desired product as a TFA salt. 24 H 18 N 13 (M+H) + LCMS calculated for: 488.2; found 488.2.

[0178] Example 13. 3-(5-amino-2-(2-fluoro-6-(pyridin-4-yl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-amino-2-(2-bromo-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, step 2, substituting 2-(2-bromo-6-fluorophenyl)acetohydrazide for 2-hydroxyacetohydrazide. 19 H 13 BrFN 6 (M+H) +LCMS calculated for: 423.0; found 423.0.

[0179] Step 2: 3-(5-amino-8-bromo-2-(2-bromo-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] NBS (126 mg, 0.709 mmol) was added to a solution of 3-(5-amino-2-(2-bromo-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (300 mg, 0.709 mmol) in DMF (2.00 mL) at room temperature. After stirring at room temperature for 1 h, it was diluted with water and the resulting precipitate was collected by filtration. The brown solid was dissolved in DCM and purified by flash chromatography on a silica gel column eluting with 0-50% EtOAc in DCM to give the desired product. C 19 H 12 Br 2 N 6 (M+H) + LCMS calculated for: 501.0; found 501.0.

[0180] Step 3: 3-(5-amino-2-(2-fluoro-6-(pyridin-4-yl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile A mixture of 3-(5-amino-8-bromo-2-(2-bromo-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (30 mg, 0.060 mmol) and pyridin-4-ylboronic acid (8.8 mg, 0.072 mmol), XPhos Pd G2 (4.7 mg, 6.0 μmol), and sodium carbonate (13.0 mg, 0.123 mmol) in 1,4-dioxane (2.0 mL) and water (0.20 mL) was stirred at 100° C. for 3 h. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 29 H20 FN 8 (M+H) + LCMS calculated for: 499.2; Found 499.2

[0181] Example 14. 3-(5-amino-8-(2-aminopyridin-4-yl)-2-(2-(2-aminopyridin-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 13, substituting (2-aminopyridin-4-yl)boronic acid for pyridin-4-ylboronic acid in step 3. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 29 H 22 FN 10 (M+H) + LCMS calculated for: 529.2; found 529.3.

[0182] Example 15. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 6-Chloro-N 2 ,N 2 -Bis(4-methoxybenzyl)pyrimidine-2,4-diamine [ka] To a solution of 2,6-dichloropyrimidin-4-amine (5.0 g, 31 mmol) in 2-propanol (31 mL) was added N,N-diisopropylethylamine (6.4 ml, 37 mmol) and bis(4-methoxybenzyl)amine (7.9 g, 31 mmol). The resulting solution was stirred at 100° C. for 16 h, cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to yield the crude product, which was used in the next step without further purification. 20 H 22 ClN 4 O 2 (M+H) + LC-MS calculated for: 385.1; found 385.1.

[0183] Step 2: 7-Chloro-N 5 ,N 5 -Bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine-2,5-diamine [ka] O-Ethyl carboxamidoisothiocyanatidate (3.1 mL, 26 mmol) was dissolved in 6-chloro-N 2 ,N 2 To a solution of N,N-bis(4-methoxybenzyl)pyrimidine-2,4-diamine (1.0 g, 2.6 mmol) in 1,4-dioxane (5.0 mL) was added at room temperature. The reaction mixture was then stirred at 90° C. overnight, cooled to room temperature, and concentrated. The resulting material was dissolved in methanol (12 mL) and ethanol (12 mL) and N,N-diisopropylethylamine (0.91 mL, 5.2 mmol) was added, followed by hydroxylamine hydrochloride (0.54 g, 7.8 mmol). The reaction mixture was stirred at 45° C. for 2 hours, cooled to room temperature, and concentrated. The resulting material was taken up in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude material was then purified by silica gel chromatography eluting with 0% to 50% EtOAc in hexane to give the product. 21 H 22ClN 6 O 2 (M+H) + LC-MS calculated for: 425.1; found 425.2.

[0184] Step 3: 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (330 mg, 0.42 mmol) in 1,4-dioxane (8.8 mL) and water (1.8 mL) (3-cyanophenyl)boronic acid (460 mg, 3.2 mmol), 7-chloro-N 5 ,N 5 The mixture was added to a mixture of 1,2,4-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine-2,5-diamine (890 mg, 2.1 mmol) and sodium carbonate (890 mg, 8.4 mmol). 2 The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel chromatography eluting with 0% to 50% EtOAc in DCM to give the desired product. 28 H 26 N 7 O 2 (M+H) + LC-MS calculated for: 492.2; found 492.2.

[0185] Step 4: 3-(5-(bis(4-methoxybenzyl)amino)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (300 mg, 0.610 mmol), triethyl orthoformate (508 μl, 3.05 mmol), 3-methylpicolinaldehyde (148 mg, 1.221 mmol) were combined and EtOH (5 ml) was added. The suspension was heated at 120° C. overnight, then cooled to room temperature and diluted with DCM (2 ml). Sodium tetraborohydride (46.2 mg, 1.221 mmol) was carefully added to the solution. After stirring at room temperature for 1 h, the mixture was diluted with saturated aqueous NH 4 The mixture was carefully quenched with Cl, extracted with DCM and separated. The organic layer was diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was used in the next reaction without further purification. 35 H 33 N 8 O 2 (M+H) + LCMS calculated for: m / z=597.2; found 597.2.

[0186] Step 5: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of 3-(5-(bis(4-methoxybenzyl)amino)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (300 mg, 0.503 mmol) in DCM (1 ml) at room temperature was added NBS (89 mg, 0.503 mmol). The mixture was stirred at room temperature for 1 h and then saturated aqueous NaHCO 3 The mixture was quenched with and separated. The organic layer was 2 SO 4The mixture was dried at 40° C., filtered and evaporated. The residue was purified by column chromatography (10-50% AcOEt in hexanes) to give the desired product. 35 H 32 BrN 8 O 2 (M+H) + LCMS calculated for: m / z=675.2; observed 675.2.

[0187] Step 6: 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (30 mg, 0.044 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (20.88 mg, 0.089 mmol), Xphos-G2 (3.49 mg, 4.44 μmol), sodium carbonate (9.41 mg, 0.089 mmol) were combined. To the mixture was added 1,4-dioxane (1 ml) and water (0.100 ml). The mixture was heated to 100° C., stirred for 3 h, then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 min. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 22 N 9 O(M+H) + LCMS calculated for: m / z=464.2; observed 464.2.

[0188] Example 16. 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 15, substituting 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 26 H 24 N 9 O(M+H) + LCMS calculated for: m / z=478.2; found 478.2.

[0189] Example 17. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 15, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 21 N 10 O(M+H) +LCMS calculated for: m / z=465.2; observed 465.2.

[0190] Example 18. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-(bis(4-methoxybenzyl)amino)-2-iodo-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] CH of 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (Example 15, Step 3, 250 mg, 0.509 mmol) 2 Cl 2 To a solution of 3.00 ml of tert-butylnitrile (3 ml) was added HI (57% in water, 201 μl, 1.526 mmol). The mixture was heated to 60° C. and then tert-butylnitrile (134 μl, 1.017 mmol) was added. The reaction was heated at 60° C. for 20 min. After cooling to room temperature, 1N aqueous NH 4 OH solution was added and the mixture was cooled to CH 2 Cl 2 The combined organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10-50% AcOEt in hexanes) to give the desired product. 28 H 24 IN 6 O 2 (M+H) + LCMS calculated for: m / z=603.1; found 603.1.

[0191] Step 2: 3-(5-(bis(4-methoxybenzyl)amino)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(5-(bis(4-methoxybenzyl)amino)-2-iodo-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (250 mg, 0.415 mmol), (3-methylpyridin-2-yl)methanol (153 mg, 1.245 mmol) were combined and 1,4-dioxane (5 ml) was added. To the solution was added sodium hydride (60% in mineral oil, 41.5 mg, 1.037 mmol). The suspension was heated to 105° C. and stirred for 1 h, then cooled to room temperature and diluted with aqueous NH 4 The mixture was quenched with Cl, diluted with AcOEt and separated. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, separated and purified with N 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was used for the next reaction without further purification. 35 H 32 N 7 O 3 (M+H) + LCMS calculated for: m / z=598.2; found 598.2.

[0192] Step 3: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of 3-(5-(bis(4-methoxybenzyl)amino)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (292 mg, 0.488 mmol) (300 mg, 0.503 mmol) in DCM (5 ml) at room temperature was added NBS (87 mg, 0.488 mmol). The mixture was stirred at room temperature for 1 h and then saturated aqueous NaHCO 3 The mixture was quenched with and separated. The organic layer was 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was purified by column chromatography (10-50% AcOEt in hexanes) to give the desired product. 35 H 31 BrN 7 O 3 (M+H) + LCMS calculated for: m / z=676.2; observed 676.2.

[0193] Step 4: 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.030 mmol) (30 mg, 0.044 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (13.90 mg, 0.059 mmol), Xphos-G2 (2.326 mg, 2.96 μmol) and sodium carbonate (6.27 mg, 0.059 mmol) were combined. To the mixture was added 1,4-dioxane (1 ml) and water (0.100 ml). The mixture was heated to 100° C., stirred for 3 h and then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 min. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 21 N 8 O 2 (M+H) + LCMS calculated for: m / z=465.2; observed 465.2.

[0194] Example 19. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 18, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt.24 H 20 N 9 O 2 (M+H) + LCMS calculated for: m / z=466.2; observed 466.2.

[0195] Example 20. 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 18, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 25 H 21 N 8 O(M+H) + LCMS calculated for: m / z=449.2; found 449.2.

[0196] Example 21. 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 18, substituting 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H 23 N 8 O(M+H) + LCMS calculated for: m / z=463.2; observed 463.2.

[0197] Example 22. 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 18, substituting 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H 23 N 8 O 2 (M+H) + LCMS calculated for: m / z=479.2; observed 479.2.

[0198] Example 23. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] Step 1: 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] Chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.185 g, 0.235 mmol) was dissolved in 1,4-dioxane (13.08 ml) and water (2.62 ml) with (3-cyano-2-fluorophenyl)boronic acid (0.582 g, 3.53 mmol), 7-chloro-N 5 ,N 5 The mixture was added to a mixture of 1,2,4-bis(4-methoxybenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine-2,5-diamine (Example 15, Step 2, 1 g, 2.354 mmol), sodium carbonate (0.499 g, 4.71 mmol). 2 The mixture was purged with ethyl acetate and heated at 110° C. overnight. The mixture was diluted with AcOEt and water and separated. The organic layer was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 4°C, concentrated and purified by column chromatography (0-50% AcOEt in DCM). 28 H 25 FN 7 O 2 (M+H) + LCMS calculated for: m / z=510.2; found 510.2.

[0199] Step 2: 3-(5-(bis(4-methoxybenzyl)amino)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile (300 mg, 0.589 mmol) (300 mg, 0.610 mmol), triethyl orthoformate (490 μl, 2.94 mmol), 3-methylpicolinaldehyde (143 mg, 1.178 mmol) were combined and EtOH (5 ml) was added. The suspension was heated at 120° C. overnight. The mixture was then cooled to room temperature and diluted with DCM (2 ml). Sodium borohydride (46.2 mg, 1.221 mmol) was carefully added to the solution. After stirring at room temperature for 1 h, the mixture was diluted with aqueous NH 4 The mixture was carefully quenched with Cl, extracted with DCM and separated. The organic layer was diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was used in the next reaction without further purification. 35 H 32 FN 8 O 2 (M+H) + LCMS calculated for: m / z=615.2; observed 615.2.

[0200] Step 3: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] To a solution of 3-(5-(bis(4-methoxybenzyl)amino)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile (300 mg, 0.488 mmol) in DCM (5 ml) at room temperature was added NBS (87 mg, 0.488 mmol). The mixture was stirred at room temperature for 1 h and then saturated aqueous NaHCO 3 The mixture was quenched with and separated. The organic layer was 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was purified by column chromatography (10-50% AcOEt in hexanes) to give the desired product. 35 H 31 BrFN 8 O 2 (M+H) + LCMS calculated for: m / z=693.2; found 693.2.

[0201] Step 4: 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile (20 mg, 0.029 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (13.56 mg, 0.058 mmol), sodium carbonate (6.11 mg, 0.058 mmol) were combined. To the mixture was added 1,4-dioxane (1 ml) and water (0.100 ml). The mixture was heated to 100° C., stirred for 3 hours, and then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 minutes. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 21 FN 9 O(M+H) + LCMS calculated for: m / z=482.2; observed 482.2.

[0202] Example 24. 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 23, substituting 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 26 H 23 FN 9O(M+H) + LCMS calculated for: m / z=496.2; observed 496.2.

[0203] Example 25. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 23, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 20 FN 10 O(M+H) + LCMS calculated for: m / z=483.2; observed 483.2.

[0204] Example 26. 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 23, substituting 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H 23 FN 9 O(M+H) + LCMS calculated for: m / z=496.2; observed 496.2.

[0205] Example 27. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 2-(pyridin-2-yl)acetohydrazide [ka] Hydrazine (4.15 mL, 132 mmol) was added to a solution of methyl 2-(pyridin-2-yl)acetate (10 g, 66.2 mmol) in ethanol (66 mL) at room temperature. The mixture was heated at 85° C. for 4 h, stirred, and then cooled to room temperature. Upon standing, a white solid formed, which was collected by filtration and used in the next step without further purification. 7 H 10 N 3 O(M+H) + LCMS calculated for: 152.1, found: 152.0.

[0206] Step 2: 3-(5-amino-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 2-(Pyridin-2-yl)acetohydrazide (2.62 g, 17.34 mmol) was added to a solution of 3-(2-amino-6-chloropyrimidin-4-yl)benzonitrile (Example 1, Step 1, 4.00 g, 17.34 mmol) in ethanol (35 mL) at room temperature. After heating and stirring under reflux for 2 h, the reaction mixture was cooled to room temperature and concentrated. The resulting residue was taken up in N,O-bis(trimethylsilyl)acetamide (20 mL) and stirred at 120° C. for 7 h. The mixture was then cooled to room temperature, poured onto ice, and stirred at room temperature for 1 h. The resulting solid was collected by filtration and taken up in 20 mL of 1N HCl solution. The resulting mixture was stirred at room temperature for 1 h, filtered, and the aqueous layer was washed with saturated NaHCO 3 The mixture was neutralized by the addition of water. The resulting precipitate was collected by filtration and dried to give the desired product as a brown solid. 18 H 14 N 7 (M+H) + LCMS calculated for: 328.1; found 328.1.

[0207] Step 3: 3-(5-amino-8-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a mixture of 3-(5-amino-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (2 g, 6.11 mmol) in DMF (12 mL) at -30 °C was added NBS (1.09 g, 6.11 mmol) in small portions. The reaction mixture was gradually warmed to 0 °C, resulting in a homogeneous solution. After stirring at 0 °C for 1 h, the reaction mixture was washed with saturated NaHCO 3 The solution was diluted and the resulting solid was collected by filtration. The solid was then purified by flash chromatography on a silica gel column eluting with 0-10% MeOH in DCM to give the desired product. 18 H 13 BrN7 (M+H) + LCMS calculated for: 406.0; found 406.0.

[0208] Step 4: 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-amino-8-bromo-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (15 mg, 0.037 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (17.43 mg, 0.074 mmol), sodium carbonate (7.48 mg, 0.070 mmol) and Xphos-G2 (1.387 mg, 1.763 μmol) were combined. 1,4-Dioxane (1 ml) and water (0.100 ml) were added to the mixture. The mixture was heated to 100° C. and stirred for 3 h, then cooled to room temperature, diluted with acetonitrile and TFA, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 23 H 18 N 9 O(M+H) + LCMS calculated for: m / z=436.2; found 436.2.

[0209] Example 28. 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-(bis(4-methoxybenzyl)amino)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(5-(bis(4-methoxybenzyl)amino)-2-iodo-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (250 mg, 0.415 mmol), (3-fluoropyridin-2-yl)methanol (158 mg, 1.245 mmol) were combined and 1,4-dioxane (5 ml) was added. To the solution was added sodium hydride (60% in mineral oil, 41.5 mg, 1.037 mmol). The suspension was heated to 105° C. and stirred for 1 h, then cooled to room temperature and diluted with aqueous NH 4 The mixture was quenched with Cl, diluted with AcOEt and separated. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine, separated and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was used for the next reaction without further purification. 34 H 29 FN 7 O 3 (M+H) + LCMS calculated for: m / z=602.2; found 602.2.

[0210] Step 2: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of 3-(5-(bis(4-methoxybenzyl)amino)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (294 mg, 0.488 mmol) (300 mg, 0.503 mmol) in DCM (5 ml) at room temperature was added NBS (87 mg, 0.488 mmol). The mixture was stirred at room temperature for 1 h and then saturated aqueous NaHCO 3 The mixture was quenched with and separated. The organic layer was 2 SO 4The mixture was dried at 40° C., filtered and evaporated. The residue was purified by column chromatography (10-50% AcOEt in hexanes) to give the desired product. 34 H 28 BrFN 7 O 3 (M+H) + LCMS calculated for: m / z=680.2; found 680.2.

[0211] Step 3: 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (30 mg, 0.044 mmol), tetrakis (10.19 mg, 8.82 μmol), 4-(tributylstannyl)pyrimidine (24.41 mg, 0.066 mmol) were combined and 1,4-dioxane (1 ml) was added. The mixture was heated to 110° C., stirred for 3 hours, and then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 minutes. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the product as a TFA salt. C 22 H 15 FN 9 O(M+H) + LCMS calculated for: m / z=440.2; found 440.2.

[0212] Example 29. 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (12 mg, 0.018 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (8.29 mg, 0.035 mmol), sodium carbonate (3.74 mg, 0.035 mmol), and Xphos-G2 (1.387 mg, 1.763 μmol) were combined. To the mixture was added 1,4-dioxane (1 ml) and water (0.100 ml). The mixture was heated to 100° C., stirred for 3 h, and then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 min. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 24 H 18 FN 8 O 2 (M+H) + LCMS calculated for: m / z=469.2; found 469.2.

[0213] Example 30. 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 29, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 23 H17 FN 9 O 2 (M+H) + LCMS calculated for: m / z=470.2; found 470.2.

[0214] Example 31. 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 29, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 18 FN 8 O(M+H) + LCMS calculated for: m / z=453.2.

[0215] Example 32. 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 29, substituting 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 20 FN 8 O(M+H) + LCMS calculated for: m / z=467.2; observed 467.2.

[0216] Example 33. 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 29, substituting 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 20 FN 8 O 2 (M+H) + LCMS calculated for: m / z=483.2; observed 483.2.

[0217] Example 34. 3-(5-amino-2-(pyridin-2-ylamino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (Example 15, step 3, 200 mg, 0.407 mmol), 2-bromopyridine (79 μl, 0.814 mmol), sodium 2-methylpropan-2-olate (78 mg, 0.814 mmol), XPhos-G2 (64.0 mg, 0.081 mmol) were combined and t-BuOH (5 ml) was added. The mixture was heated at 70° C. overnight and then aqueous NH 4 The mixture was quenched with Cl solution, diluted with AcOEt and separated. The organic layer was washed with brine and 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was used for the next reaction without further purification. 33 H 29 N 8 O 2 (M+H) + LCMS calculated for: m / z=569.2; found 569.2.

[0218] Step 2: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of 3-(5-(bis(4-methoxybenzyl)amino)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (278 mg, 0.488 mmol) (300 mg, 0.503 mmol) in DCM (5 ml) at room temperature was added NBS (87 mg, 0.488 mmol). The mixture was stirred at room temperature for 1 h and then saturated aqueous NaHCO 3 The mixture was quenched with and separated. The organic layer was 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was purified by column chromatography (10-60% AcOEt in hexanes) to give the desired product. 33 H 28 BrN 8 O 2 (M+H) + LCMS calculated for: m / z=647.2; found 647.2.

[0219] Step 3: 3-(5-amino-2-(pyridin-2-ylamino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (30 mg, 0.046 mmol), tetrakis (10.71 mg, 9.27 μmol), 4-(tributylstannyl)pyrimidine (25.7 mg, 0.069 mmol) were combined and 1,4-dioxane (1 ml) was added. The mixture was heated to 110° C., stirred for 3 hours, and then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 minutes. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the product as a TFA salt. C 21 H 15 N 10 (M+H) + LCMS calculated for: m / z=407.2; observed 407.2.

[0220] Example 35. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.031 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (14.52 mg, 0.062 mmol), sodium carbonate (6.55 mg, 0.062 mmol), Xphos-G2 (2.430 mg, 3.09 μmol) are combined and 1,4-dioxane (1 ml) and water (0.100 ml) are added to the mixture. The mixture is heated at 100° C. for 3 hours and then evaporated. To the residue is added TFA (1 ml) and the mixture is heated at 120° C. for 20 minutes. After cooling to room temperature, the mixture is diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 23 H 18 N 9 O(M+H) + LCMS calculated for: m / z=436.2.

[0221] Example 36. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 35, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 22 H 17 N 10 O(M+H) + LCMS calculated for: m / z=437.2.

[0222] Example 37. 3-(5-amino-8-(3-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 35, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 23 H 18 N 9 (M+H) + LCMS calculated for: m / z=420.2.

[0223] Example 38. 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 35, using 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 20 N 9 (M+H) + LCMS calculated for: m / z=434.2.

[0224] Example 39. 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 35, substituting 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 20 N 9 O(M+H) + LCMS calculated for: m / z=450.2.

[0225] Example 40. 3-(5-amino-2-((6-methylpyridin-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 34, using 2-bromo-6-methylpyridine instead of 2-bromopyridine. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 22 H 17 N 10 (M+H) + LCMS calculated for: m / z=421.2; observed 421.2.

[0226] Example 41. 3-(5-amino-2-((pyridin-2-yloxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of 3-(5-amino-2-(hydroxymethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (Example 1, step 4, 15 mg, 0.044 mmol) and 2-fluoropyridine (0.011 ml, 0.131 mmol) in 1,4-dioxane (1 ml) was added sodium hydride (60% in mineral oil, 3.48 mg, 0.087 mmol). The mixture was heated at 60° C. and stirred for 3 h, then cooled to room temperature, diluted with acetonitrile and TFA, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 22 H 16 N 9 O(M+H) + LCMS calculated for: m / z=422.2; observed 422.2.

[0227] Example 42. 2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] Step 1: 2-((5-amino-7-(3-cyanophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] To a solution of 3-(5-amino-2-(hydroxymethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (Example 1, Step 2, 100 mg, 0.376 mmol) and 2-fluoronicotinonitrile (138 mg, 1.127 mmol) in 1,4-dioxane (5 ml) was added sodium hydride (60% in mineral oil, 30.0 mg, 0.751 mmol). The mixture was heated at 60° C. for 3 h, then cooled to room temperature and treated with aqueous NH 4 The mixture was quenched with Cl, diluted with DCM and separated. The organic layer was diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated. The residue was used for the next reaction without further purification. 19 H 13 N 8 O(M+H) + LCMS calculated for: m / z=369.2; found 369.2.

[0228] Step 2: 2-((5-amino-8-bromo-7-(3-cyanophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] To a suspension of 2-((5-amino-7-(3-cyanophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile (185 mg, 0.503 mmol) in DCM (1 ml) at room temperature was added NBS (89 mg, 0.503 mmol). The mixture was stirred at room temperature for 1 h. After cooling to room temperature, the mixture was diluted with saturated aqueous NaHCO 3 The mixture was quenched with ethyl acetate, diluted with DCM and separated. The organic layer was 2 SO 4The mixture was dried at 40° C., filtered and evaporated. The residue was purified by column chromatography (0-10% MeOH in DCM) to give the desired product. 19 H 12 BrN 8 O(M+H) + LCMS calculated for: m / z=447.0; observed 447.0.

[0229] Step 3: 2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile 2-((5-amino-8-bromo-7-(3-cyanophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile (15 mg, 0.034 mmol), tetrakis (7.75 mg, 6.71 μmol), 4-(tributylstannyl)pyrimidine (18.57 mg, 0.050 mmol) were combined and 1,4-dioxane (1 ml) was added. The mixture was heated at 110° C. for 3 h, then cooled to room temperature, quenched, diluted with TFA (0.5 ml), filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 23 H 15 N 10 O(M+H) + LCMS calculated for: m / z=447.2; observed 447.2.

[0230] Example 43. 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] 2-((5-(bis(4-methoxybenzyl)amino)-8-bromo-7-(3-cyanophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile (20 mg, 0.029 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (13.68 mg, 0.058 mmol), sodium carbonate (6.17 mg, 0.058 mmol), Xphos-G2 (2.289 mg, 2.91 μmol) were combined. 1,4-Dioxane (1 ml) and water (0.100 ml) were added and the mixture was heated to 100° C., stirred for 3 hours, then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 minutes. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 18 N 9 O 2 (M+H) + LCMS calculated for: m / z=476.2; observed 476.2.

[0231] Example 44. 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] This compound was prepared using a procedure similar to that described in Example 43, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 17 N 10O 2 (M+H) + LCMS calculated for: m / z=477.2; observed 477.2.

[0232] Example 45. 2-((5-amino-7-(3-cyanophenyl)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] This compound is prepared using a procedure similar to that described in Example 43, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 25 H 18 N 9 O(M+H) + LCMS calculated for: m / z=460.2.

[0233] Example 46. 2-((5-amino-7-(3-cyanophenyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] This compound was prepared using a procedure similar to that described in Example 43, substituting 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H20 N 9 O(M+H) + LCMS calculated for: m / z=474.2; observed 474.2.

[0234] Example 47. 2-((5-amino-7-(3-cyanophenyl)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile [ka] This compound was prepared using a procedure similar to that described in Example 43, substituting 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 26 H 20 N 9 O 2 (M+H) + LCMS calculated for: m / z=490.2; found 490.2.

[0235] Example 48. 3-(5-amino-2-((1-(pyridin-2-yl)ethyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-8-bromo-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (Example 15, Step 3, 330 mg, 0.66 mmol) in DMF (1.4 ml) is added NBS (120 mg, 0.66 mmol) slowly at 0° C. The reaction mixture is then stirred at room temperature for 30 minutes before adding water (10 mL). The resulting solid is collected by filtration and dried to give the desired product. 28 H 25 BrN 7 O 2 (M+H) + LC-MS calculated for: m / z = 570.1.

[0236] Step 2: 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] A mixture of 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-8-bromo-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (350 mg, 0.61 mmol), 4-(tributylstannyl)pyrimidine (0.21 ml, 0.67 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.060 mmol), copper(I) iodide (23 mg, 0.12 mmol) and cesium fluoride (180 mg, 1.2 mmol) in dioxane (4.7 ml) is heated and stirred at 140° C. for 30 min in a microwave reactor. The reaction mixture is then cooled to room temperature, filtered through a plug of Celite (washed with DCM) and concentrated. The resulting material is purified by silica gel column chromatography eluting with 0-20% MeOH / DCM to give the desired product. 32 H 28 N 9 O 2 (M+H) + LC-MS calculated for: m / z = 570.2.

[0237] Step 3: 3-(5-(bis(4-methoxybenzyl)amino)-2-bromo-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] To a solution of copper(II) bromide (91 mg, 0.407 mmol) and tert-butylnitrile (0.054 ml, 0.407 mmol) in acetonitrile (3 ml) under nitrogen at 50° C., 3-(2-amino-5-(bis(4-methoxybenzyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (100 mg, 0.203 mmol) in acetonitrile (3 ml) is added dropwise. The mixture is stirred at 50° C. for 2 h. After cooling to room temperature, 1N aqueous NH 4 OH solution (20 ml) was added and the mixture was diluted with CH 2 Cl 2 (20 ml) three times. The combined organic layers are dried over sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography eluting with 50-100% ethyl acetate / hexane to give the desired product. 32 H 26 BrN 8 O 2 (M+H) + LC-MS calculated for: m / z = 633.2.

[0238] Step 4: 3-(5-amino-2-((1-(pyridin-2-yl)ethyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-2-bromo-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (750 mg, 1.184 mmol), 1-(pyridin-2-yl)ethan-1-amine (289 mg, 2.368 mmol), sodium tert-butoxide (228 mg, 2.368 mmol) and (t-Bu)PhCPhos Pd G3 (92 mg, 0.118 mmol) are combined and 1,4-dioxane (10 ml) is added. The mixture is heated at 60° C. for 3 hours, then cooled to room temperature and evaporated. To the residue is added TFA (5 ml) and the mixture is heated at 120° C. for 20 minutes. After cooling to room temperature, the mixture is diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 23 H 19 N 10 (M+H) + LCMS calculated for: m / z=435.2.

[0239] Example 49. 3-(5-amino-2-((2-(pyridin-2-yl)propan-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 48, substituting 2-(pyridin-2-yl)propan-2-amine for 1-(pyridin-2-yl)ethan-1-amine. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 21 N 10 (M+H) + LCMS calculated for: m / z=449.2.

[0240] Example 50. 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 2-(1H-tetrazol-5-yl)pyridine for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 23 H 16 N 13 (M+H) + LCMS calculated for: 474.2; found 474.2

[0241] Example 51. 3-(5-amino-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 2-(1H-tetrazol-5-yl)pyrimidine for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 22 H 15 N 14 (M+H) + LCMS calculated for: 475.2; Found 475.2

[0242] Example 52. 3-(5-amino-8-(pyrimidin-4-yl)-2-((5-(pyrimidin-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 4-(1H-tetrazol-5-yl)pyrimidine for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 22 H 15 N 14 (M+H) + LCMS calculated for: 475.2; Found 475.2

[0243] Example 53. 3-(5-amino-2-((5-(pyridin-3-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 3-(1H-tetrazol-5-yl)pyridine for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 23 H 16 N 13 (M+H) + LCMS calculated for: 474.2; found 474.2

[0244] Example 54. 3-(5-amino-2-((5-(pyridin-4-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described for Example 1, substituting 4-(1H-tetrazol-5-yl)pyridine for 3-(1H-tetrazol-5-yl)aniline. The product was purified by preparative LC-MS (pH 2, acetonitrile / water with TFA) to give the product as a TFA salt. 23 H 16 N 13 (M+H) + LCMS calculated for: 474.2; found 474.2

[0245] Example 55. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 28, using (6-methylpyridin-2-yl)methanol instead of (3-fluoropyridin-2-yl)methanol in step 1. The product was purified by column chromatography (10-60% AcOEt in hexanes) to give the desired product. 35 H 31 BrN 7 O 3(M+H) + LCMS calculated for: m / z=676.2; observed 676.2.

[0246] Step 2: 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.030 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (6.95 mg, 0.030 mmol), sodium carbonate (6.27 mg, 0.059 mmol), and Xphos-G2 (2.326 mg, 2.96 μmol) were combined. To the mixture was added 1,4-dioxane (1 ml) and water (0.100 ml). The mixture was heated to 100° C., stirred for 3 h, and then evaporated. To the residue was added TFA (1 ml) and the mixture was heated at 120° C. for 20 min. It was then diluted with acetonitrile, filtered and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the product as a TFA salt. 25 H 21 N 8 O 2 (M+H) + LCMS calculated for: m / z=465.2; observed 465.2.

[0247] Example 56. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 55, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 2. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 20 N 9 O 2 (M+H) + LCMS calculated for: m / z=466.2.

[0248] Example 57. 3-(5-amino-2-((6-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 55, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in place of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 2. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 21 N 8 O(M+H) + LCMS calculated for: m / z=449.2; found 449.2.

[0249] Example 58. 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 55, using 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 2. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H 23 N 8 O(M+H) + LCMS calculated for: m / z=463.2; observed 463.2.

[0250] Example 59. 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 55, substituting 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one in step 2. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H 23 N 8 O 2 (M+H) + LCMS calculated for: m / z=479.2; observed 479.2.

[0251] Example 60. 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((3,6-dimethylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 28, using (3,6-dimethylpyridin-2-yl)methanol instead of (3-fluoropyridin-2-yl)methanol in step 1. The product is purified by column chromatography (10-60% AcOEt in hexanes) to give the desired product. 36 H 33 BrN 7 O 3 (M+H) + LCMS calculated for: m / z=690.2.

[0252] Step 2: 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.030 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (6.95 mg, 0.030 mmol), sodium carbonate (6.27 mg, 0.059 mmol), and Xphos-G2 (2.326 mg, 2.96 μmol) are combined. 1,4-Dioxane (1 ml) and water (0.100 ml) are added to the mixture. The mixture is heated to 100° C. and stirred for 3 h, then evaporated. To the residue is added TFA (1 ml) and the mixture is heated at 120° C. for 20 min. The mixture is then diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the product as a TFA salt. 26 H 23 N 8 O 2 (M+H) + LCMS calculated for: m / z=479.2.

[0253] Example 61. 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 60, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 2. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 25 H 22 N9 O 2 (M+H) + LCMS calculated for: m / z=480.2.

[0254] Example 62. 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 60, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in place of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in step 2. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 26 H 23 N 8 O(M+H) + LCMS calculated for: m / z=463.2.

[0255] Example 63. 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 60, using 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in step 2 instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 27 H 25 N 8 O(M+H) + LCMS calculated for: m / z=477.2.

[0256] Example 64. 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound is prepared using a procedure similar to that described in Example 60, using 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in step 2 instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material is purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 27 H 25 N 8 O 2 (M+H) + LCMS calculated for: m / z=493.2.

[0257] Example 65. 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] Step 1: 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 15, using 6-methylpicolinaldehyde instead of 3-methylpicolinaldehyde in step 4. The product was purified by column chromatography (10-60% AcOEt in hexanes) to give the desired product. 35 H 32 BrN 8 O 2 (M+H) + LCMS calculated for: m / z=675.2; observed 675.2.

[0258] Step 2: 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.030 mmol), tetrakis (6.84 mg, 5.92 μmol), 4-(tributylstannyl)pyrimidine (16.39 mg, 0.044 mmol) were combined. 1,4-dioxane (1 ml) was added to the mixture. The mixture was heated at 110° C. for 3 h and evaporated. TFA (1 ml) was added to the residue and the mixture was heated at 120° C. for 20 min, then diluted with acetonitrile, filtered, and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the product as a TFA salt. C 23 H 19 N 10 (M+H) +LCMS calculated for: m / z=435.2; observed 435.2.

[0259] Example 66. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] 3-(5-(bis(4-methoxybenzyl)amino)-8-bromo-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile (20 mg, 0.030 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (6.96 mg, 0.030 mmol), sodium carbonate (6.28 mg, 0.059 mmol), and Xphos-G2 (2.329 mg, 2.96 μmol) are combined. To the mixture is added 1,4-dioxane (1 ml) and water (0.100 ml). The mixture is heated at 100° C. for 3 hours and then evaporated. To the residue is added TFA (1 ml) and the mixture is heated at 120° C. for 20 min, then the mixture is diluted with acetonitrile, filtered and purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the product as a TFA salt. 25 H 22 N 9 O(M+H) + LCMS calculated for: m / z=464.2.

[0260] Example 67. 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 66, substituting 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 24 H 21 N 10 O(M+H) + LCMS calculated for: m / z=465.2; observed 465.2.

[0261] Example 68. 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 66, substituting 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 25 H 22 N 9 (M+H) + LCMS calculated for: m / z=448.2; observed 448.2.

[0262] Example 69. 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 66, substituting 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as a TFA salt. 26 H 24 N 9 (M+H) + LCMS calculated for: m / z=462.2; observed 462.2.

[0263] Example 70. 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile [ka] This compound was prepared using a procedure similar to that described in Example 66, substituting 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine for 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one. The final material was purified by preparative LC-MS (pH=2, MeCN / water with TFA) to give the desired product as the TFA salt. 26 H 24 N 9 O(M+H) + LCMS calculated for: m / z=478.2; found 478.2.

[0264] Example A. Adenosine A2A Receptor Cyclic AMP GS Assay Stably transfected HEK-293 cells expressing human adenosine A2A receptors (Perkin Elmer) are maintained in MEM medium with 10% FBS and 400 μg / ml Geneticin (Life Technologies). Geneticin is removed from the cultures 18-24 hours prior to the assay. cAMP accumulation in cells is measured using cisbio's cAMP-GS Dynamic Kit, which utilizes FRET (fluorescence resonance energy transfer) technology. Appropriate concentrations of compounds of the present disclosure are mixed with 10,000 cells / well in white 96-well half-area plates (Perkin Elmer) for 30 minutes at room temperature (RT) with gentle shaking. 4 nm of the agonist CGS21680 (R&D Technologies) is added to each well for 60 minutes at room temperature with gentle shaking. Detection reagents d2-labeled cAMP (receptor) and anti-cAMP cryptate (donor) are added to each well for 60 minutes at room temperature with gentle shaking. Plates were read on a Pherastar (BMG Labtech) and the fluorescence ratio 665 / 620 was calculated and the EC was calculated by curve fitting the percent of control versus the logarithm of compound concentration using GraphPad Prism. 50 Determine.

[0265] Example B. Adenosine A2B Receptor Cyclic AMP GS Assay Stably transfected HEK-293 cells expressing human adenosine A2B receptors (Perkin Elmer) were maintained in MEM medium with 10% FBS and 100 μg / ml Geneticin (Life Technologies). Geneticin was removed from the cultures 18-24 hours prior to the assay. Intracellular cAMP accumulation was measured using cisbio's cAMP-GS Dynamic Kit, which utilizes FRET (fluorescence resonance energy transfer) technology. Appropriate concentrations of compounds of the present disclosure were mixed with 10,000 cells / well in white 96-well half-area plates (Perkin Elmer) for 30 minutes at room temperature (RT) with gentle shaking. 12 nm of the agonist NECA (R&D Technologies) was added to each well for 60 minutes at room temperature with gentle shaking. Detection reagents d2-labeled cAMP (receptor) and anti-cAMP cryptate (donor) were added to each well for 60 minutes at room temperature with gentle shaking. Plates were read on a Pherastar (BMG Labtech) and the fluorescence ratio 665 / 620 was calculated and the EC was calculated by fitting a curve of the percentage of control versus the logarithm of the compound concentration using GraphPad Prism. 50 The EC obtained by this method was 50 The data are shown in Table 1.

[0266] Example C. A2A Tag-lite® HTRF Assay Assays were performed in a final volume of 10 μL in black low volume 384-well polystyrene plates (Greiner 784076-25). Test compounds were first serially diluted in DMSO and 100 nl was added to the plate wells before adding other reaction components. The final concentration of DMSO was 1%. Tag-lite® adenosine A2A labeled cells (CisBio C1TT1A2A) were diluted 1:5 in Tag-lite buffer (CisBio LABMED) and spun at 1200 g for 5 min. The pellet was resuspended in Tag-lite buffer in a volume 10.4 times the initial cell suspension volume and adenosine A2A receptor red antagonist fluorescent ligand (CisBio L0058RED) was added to a final concentration of 12.5 nM. 10ul of the cell and ligand mixture was added to the assay wells and incubated at room temperature for 45 minutes before reading on a PHERAstar FS plate reader (BMG Labtech) equipped with an HTRF337 / 620 / 665 optical module. Percent binding of fluorescent ligand was calculated; 100nM of A2A antagonist control ZM 241385 (Tocris1036) displaces 100% of the ligand and 1% DMSO displaces 0%. Data of % binding versus log of inhibitor concentration were fitted to a one-site competitive binding model (GraphPad Prism version 7.02) (ligand constant = 12.5nM and ligand Kd = 1.85nM). K obtained by this method was i The data are shown in Table 1.

[0267] Example D. A2B Filter Binding Assay The assay is carried out in a final volume of 550 μL in deep well polypropylene plates (Greiner 786201). Test compounds are first serially diluted in DMSO and then 5.5 ul is added to the plate wells before the addition of other reaction components. The final concentration of DMSO is 3%. HEK293 cell membranes overexpressing the human adenosine receptor A2B (Perkin Elmer ES-113-M400UA) are incubated with 50 mM HEPES pH 7.0, 5 mM MgCl 2, diluted to 40 μg / ml in 1 mM EDTA (assay buffer). [3H]8-Cyclopentyl-1,3-dipropylxanthine (Perkin Elmer NET974001MC) is diluted to 24.2 nM in assay buffer + 22% DMSO and then further diluted to 1 nM by addition to the diluted membranes. 545 μl of the membrane and ligand mixture is added to the assay wells and incubated at room temperature for 1 hour on a shaker. The membrane mixture is then filtered through a UniFilter GF / C filter plate (Perkin Elmer 6005174) and resuspended in 50 mM HEPES pH 6.5, 5 mM MgCl 2 Presoak in 1 mM EDTA, 0.5% BSA, and then 5 ml of ice-cold 50 mM HEPES pH 6.5, 5 mM MgCl. 2 , 1 mM EDTA, 0.2% BSA. 50 μl MicroScint™ cocktail (Perkin Elmer 6013621) is added and the plate is read on a Topcount NXT FS (Perkin Elmer). [3H] Percent binding of ligand is calculated, with 1000 nM LUF5834 (Tocris4603) control replacing 100% ligand and 3% DMSO replacing 0%. Data of % binding versus log inhibitor concentration are fitted to a one-site competitive binding model (GraphPad Prism version 7.02) with ligand constant = 2 nM and ligand Kd = 13 nM.

[0268] Example E. A1 and A3 SPA Binding Assays Both assays are performed in a final volume of 50 μL in white 384-well polystyrene plates (Greiner 781075). Inhibitors are first serially diluted in DMSO and 100 nL is added to plate wells before other reaction components are added. The final concentration of DMSO is 2%.

[0269] Wheat germ agglutinin-coated yttrium silicate SPA beads (Perkin Elmer RPNQ0023) and CHO-K1 cell membranes overexpressing each human adenosine receptor were incubated in 50 mM HEPES pH 7.0, 5 mM MgCl2 , 1 mM EDTA (assay buffer) for 2 hours at 4° C. on a rotary shaker. The beads are pelleted by centrifugation at 6000 g for 1 minute, then the supernatant with unbound membranes is discarded. The beads are resuspended to the original volume in assay buffer. The respective radioligand is diluted in assay buffer + 22% DMSO at 12.2 times the final concentration and then added to the SPA bead suspension. 50 μl of SPA bead reaction mixture is added to the assay wells and the plate is shaken at 600 rpm for 1 hour at room temperature. The beads are then allowed to settle for 1 hour before being read on a Topcount NXT FS (Perkin Elmer). The percent binding of the radiolabeled ligand is calculated, with controls at a Ki of >100× replacing 100% of the ligand and 2% DMSO replacing 0%. The data of % binding versus logarithm of inhibitor concentration are fitted to a one-site competitive binding model (GraphPad Prism version 7.02). The assay conditions are provided in the table below. [Table 1]

[0270] [Table 2-1] [Table 2-2]

[0271] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety. The present application also includes the following aspects. [Aspect 1] 3-(5-amino-2-((5-(3-aminophenyl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methylpyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methoxypyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrazin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-(dimethylamino)pyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(2-fluoro-6-(pyridin-4-yl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-(2-(2-aminopyridin-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(pyridin-2-ylamino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(3-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((pyridin-2-yloxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 3-(5-amino-2-((1-(pyridin-2-yl)ethyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((2-(pyridin-2-yl)propan-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(pyrimidin-4-yl)-2-((5-(pyrimidin-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-3-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-4-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; or a pharma- ceutically acceptable salt thereof. [Aspect 2] A pharmaceutical composition comprising a compound according to embodiment 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier. [Aspect 3] A method of inhibiting activity of an adenosine receptor comprising contacting said receptor with a compound of embodiment 1, or a pharma- ceutically acceptable salt thereof. [Aspect 4] A method of treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression of an A2A or A2B receptor, comprising administering to the patient a therapeutically effective amount of a compound of embodiment 1, or a pharma- ceutically acceptable salt thereof. [Aspect 5] The method of embodiment 4, wherein said disease or disorder is cancer, an inflammatory disease, a cardiovascular disease, or a neurodegenerative disease. [Aspect 6] The method of embodiment 5, wherein the cancer is bladder cancer, lung cancer, melanoma, breast cancer, cervical cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer, thyroid cancer, liver cancer, uterine cancer, head and neck cancer, or renal cell carcinoma. [Aspect 7] The method of embodiment 5, wherein the cancer is head and neck squamous cell carcinoma (HNSCC). [Aspect 8] The method of embodiment 5, wherein the cancer is non-small cell lung cancer (NSCLC). [Aspect 9] The method of embodiment 5, wherein the cancer is colon cancer. [Aspect 10] The method of embodiment 5, wherein the cancer is melanoma. [Aspect 11] The method of embodiment 5, wherein the cancer is ovarian cancer. [Aspect 12] The method of embodiment 5, wherein the cancer is bladder cancer. [Aspect 13] The method of embodiment 5, wherein the cancer is renal cell carcinoma. [Aspect 14] The method of embodiment 5, wherein the cancer is liver cancer. [Aspect 15] The method of embodiment 5, wherein the cancer is hepatocellular carcinoma. [Aspect 16] The method of embodiment 5, wherein the inflammatory disease is pneumonia. [Aspect 17] The method of embodiment 16, wherein the pneumonia is bleomycin-induced pulmonary fibrosis. [Aspect 18] The method of embodiment 5, wherein the inflammatory disease is an adenosine receptor dependent allergic reaction or an adenosine receptor immune reaction. [Aspect 19] The method of embodiment 18, wherein the adenosine receptor-dependent allergic response is A2B receptor-dependent. [Aspect 20] The method of embodiment 5, wherein the inflammatory disease is a respiratory disorder, sepsis, reperfusion injury, or thrombosis. [Aspect 21] The method of embodiment 5, wherein the cardiovascular disease is coronary artery disease, cerebrovascular disease, peripheral artery disease, atherosclerosis, or aneurysm. [Aspect 22] 22. The method of embodiment 21, wherein the coronary artery disease is myocardial infarction, angina pectoris, or heart failure. [Aspect 23] 22. The method of embodiment 21, wherein the cerebrovascular disease is stroke or transient ischemic attack. [Aspect 24] The method of embodiment 5, wherein the neurodegenerative disease is Parkinson's disease. [Aspect 25] The method of embodiment 4, wherein said disease or disorder is diabetes or insulin resistance. [Aspect 26] A method of treating or preventing atherosclerotic plaque formation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of embodiment 1, or a pharma- ceutically acceptable salt thereof.

Claims

1. 3-(5-amino-2-((5-(3-aminophenyl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methylpyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(6-methoxypyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((5-(pyrazin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-(dimethylamino)pyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(2-fluoro-6-(pyridin-4-yl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-aminopyridin-4-yl)-2-(2-(2-aminopyridin-4-yl)-6-fluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((3-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((3-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3-fluoropyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(pyridin-2-ylamino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(3-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((pyridin-2-yloxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 2-((5-amino-7-(3-cyanophenyl)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)nicotinonitrile; 3-(5-amino-2-((1-(pyridin-2-yl)ethyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((2-(pyridin-2-yl)propan-2-yl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyrimidin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(pyrimidin-4-yl)-2-((5-(pyrimidin-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-3-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((5-(pyridin-4-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((6-methylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-((6-methylpyridin-2-yl)methoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-((3,6-dimethylpyridin-2-yl)methoxy)-8-(2-methoxy-6-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-2-(((6-methylpyridin-2-yl)methyl)amino)-8-(3-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; 3-(5-amino-8-(2,6-dimethylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and 3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(((6-methylpyridin-2-yl)methyl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; or a pharma- ceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier.

3. A medicament for treating a disease or disorder in a patient, comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof, The disease or disorder is bladder cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, pancreatic cancer, prostate cancer, or head and neck cancer; Medicine.

4. The pharmaceutical composition described in claim 3, wherein the disease or disorder is head and neck cancer.

5. The pharmaceutical composition of claim 4, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

6. The pharmaceutical composition described in claim 3, wherein the disease or disorder is lung cancer.

7. The pharmaceutical composition according to claim 6, wherein the lung cancer is non-small cell lung cancer (NSCLC).

8. The pharmaceutical composition according to claim 3 , wherein the disease or disorder is colon cancer.

9. The pharmaceutical composition of claim 3, wherein the disease or disorder is prostate cancer.

10. The pharmaceutical described in claim 9, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

11. The pharmaceutical composition of claim 3 , wherein the disease or disorder is ovarian cancer.

12. The pharmaceutical composition of claim 3 , wherein the disease or disorder is bladder cancer.

13. The pharmaceutical composition of claim 3, wherein the disease or disorder is breast cancer.

14. The pharmaceutical composition of claim 3, wherein the disease or disorder is pancreatic cancer.

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