BR112015021164B1 - COMPOUND OF SUBSTITUTED XANTHINE AND ITS SALT - Google Patents

Abstract

SUBSTITUTED XANTHINES. The present invention relates to compounds, compositions and methods for inhibiting the TRPC5 ion channel and TRPC5 related disorders.

Description

PRIORITY CLAIM

[001] This order claims priority for U.S.S.N. 61/789,724, filed March 15, 2013, the contents of which are incorporated herein by reference.

BACKGROUND

[002] A variety of ion channel proteins exist to mediate ion flow across cell membranes. The function and correct expression of ion channel proteins are essential for the maintenance of cellular function, intracellular communication, and the like. Numerous diseases are the result of misregulation of aberrant calcium manipulation and membrane potential. Due to the central importance of ion channels in modulating membrane potential and ion flux in cells, the identification of agents that can promote or inhibit particular ion channels is of great interest as research tools and as possible therapeutic agents.

SUMMARY OF THE INVENTION

[003] The present invention provides methods of treating a TRPC5-mediated disorder in an individual, comprising administering to the individual a compound of formula I: or a pharmaceutically acceptable salt thereof, the constituent members of which are provided herein.

[004] The present invention also provides compounds of formula 1(a): or a pharmaceutically acceptable salt thereof, the constituent members of which are provided herein.

[005] The present invention also provides compounds of formula II: or a pharmaceutically acceptable salt thereof, which constituent members are provided herein.

[006] The present invention also provides compounds of formula III: or a pharmaceutically acceptable salt thereof, which constituent members are provided herein.

[007] The present invention also provides compositions comprising a compound of formula 1(a), II or III, and a pharmaceutically acceptable carrier.

[008] The present invention also provides methods of treating a TRPC5-mediated disorder in a subject, for example, a human, comprising administering to the subject a compound or composition of a compound of formula 1(a), II or Formula III, or a pharmaceutically acceptable salt thereof.

[009] The present invention provides methods, compounds, and compositions for treating conditions such as a neuropsychiatric disorder, a neurodegenerative disorder, nephropathy, and seizure disorder by modulating the activity of the transient receptor potential cation channel C subfamily, member 5 (TRPC5), which can exist in homomultimeric form, as well as, heteromultimeric form with other ion channels such as TRPCl or TRPC3 (i.e., TRPC5 - TRPC1 and TRPCl - TRPC3 - TRPC5). The compounds described herein modulate TRPC5 function by inhibiting TRPC5-mediated ion flux or by inhibiting TRPC5-mediated inward current, outward current, or both. Inhibition of a particular current is the ability to inhibit or reduce that current (eg inward and/or outward) in an in vitro or in vivo assay. Activation of a particular current is the ability to activate or increase that current (eg, inward and/or outward) in an in vitro or in vivo assay.

[0010] In one aspect, the invention relates to a method of treating a condition for which reduced TRPC5 activity can reduce the severity of the condition by administering a TRPC5 antagonist, such as a compound as described herein that inhibits TRPC5-mediated current and/or TRPC5-mediated ion flux. Described herein are compounds, which are TRPC5 antagonists that have a measured IC50 for TRPC5 inhibition of 10 nanomolar or less. In certain embodiments, compounds described herein that are TRPC5 antagonists inhibit one or both of TRPC5-mediated internal and external currents with an IC50 of 10 nanomolar or less. In certain embodiments, the compounds described herein inhibit at least 95% of TRPC5-mediated current or TRPC5-mediated ion flux when administered at 1 micromolar or less.

[0011] In another aspect, compounds described herein which are TRPC5 antagonists can be used to inhibit a TRPC5 function, for example, a TRPC5-mediated current and/or a TRPC5-mediated ion flux. In some embodiments, the compounds described herein can be used to inhibit. A current mediated by TRPC5 in vitro, for example, in cultured cells. In other embodiments, the compounds described herein can be used to inhibit a TRPC5-mediated current in vivo. In certain embodiments, the compounds described herein inhibit both an internal and an external TRPC5-mediated current.

[0012] Another aspect of the invention features a pharmaceutical preparation suitable for use in a human patient, or for veterinary use, comprising an effective amount of a compound described herein (or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt), and one or more pharmaceutically acceptable excipients. The invention also contemplates the use of the compounds described herein in the manufacture of a medicament or pharmaceutical preparation for treating or reducing the symptoms of any of the diseases or conditions provided in the specification. The compounds described herein can be used to treat a particular disease or condition, they can be formulated for administration through a routine appropriate for the particular disease or condition.

[0013] The compounds described herein can be administered alone or in combination with another therapeutic agent. For example, the compounds described herein can be administered together with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, anti-fungal agent, anti-viral agent, antiseptic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor.

[0014] The compounds described herein can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, sub arachnoidally, intraspinally, intrasternally, sublingually, or by inhalation.

[0015] In some embodiments, the compounds described herein can be administered topically.

[0016] In some embodiments, the compounds described herein can be administered orally.

[0017] In some embodiments, the compounds described herein can be administered parenterally.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a plot representing the immobility of MRI mice after administration of 0.5% methylcellulose (MC) (4000 CPS) orally, or Compound 260 at oral doses of 0.3, 1, 3, and 10 mg/kg one hour before testing, or desipramine by intraperitoneal injection of 30 mg/kg, 30 minutes before testing.

[0019] Figures 2A and 2B are plots representing activity in the Vogel Conflict Test Model for Wistar rats - Kyoto after administration of 0.5% methylcellulose (4000 CPS), or Compound 260 doses of 0,3,1, 3 and 10 mg/kg orally 1 hour before testing, or Midazolam 1 mg/kg by intraperitoneal injection, 30 minutes before testing.

[0020] Figures 3A - 3D are plots representing anxiolytic effects of Wistar - Kyoto rats employed in an elevated positive maze assay using Midazolam 1 mg/kg dose and methylcellulose 0.5% as positive and negative controls, respectively, as well as compound 260 at doses of 0.3, 1, 3 and 10 mg/kg. Figures 3A and 3B are plots representing % rat entries into the open branching portions of the maze. Figure 3C is a plot representing rat entries into the closed branch portion of the maze. Figure 3D is a plot representing the distance traveled (in centimeters) by the rats.

[0021] Figures 4A and 4B are line graphs depicting stimulatory effects on NMR mice following administration of phencyclidine (PCP) at 5 mg/kg subcutaneously delivered or with 0.5% methylcellulose (MC) (vehicle) delivered subcutaneously (Figure 4A), or with compound 260 at doses of 0.3, 1, 3, and 10 mg/kg in NMR mice ( Figure 4B).

DETAILED DESCRIPTION OF THE INVENTION

[0022] Cation channels such as TRPC5 modulate the flow of calcium and sodium ions across cell membranes. The influx of sodium and calcium leads to a depolarization of the cells. This increases the likelihood that voltage-gated ion channels will reach the required threshold for activation. As a result, activation of non-selective cation channels can increase electrical excitability and increase the frequency of voltage-gated events. Voltage-dependent events include, but are not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac muscle contraction, and skeletal muscle contraction.

[0023] Calcium influx caused by activation of non-selective cation channels such as TRPC5 also alters the intracellular free calcium concentration. Calcium is a ubiquitous second messenger molecule within the cell, and changes in intracellular calcium levels have profound effects on signal transduction and gene expression. Thus, activation of non-selective cation channels such as TRPC5 can lead to changes in gene expression and cellular phenotype. Gene expression events include, but are not limited to, production of mRNAs encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to hyperexcitability in that cell.

[0024] TRPC5 homomeric transient receptor potential (TRP) ion channels are Ca2+ permeable channels closed by signal transduction predominantly expressed in neurons. TRPC5 forms homomultimeric structures such as tetramers (ie TRPC5 homomultimers) and heteromultimeric structures such as tetramers (ie TRPC5 - TRPC1 heteromultimers). Unless expressly stated otherwise, when the term TRPC5 is used herein, for example when identifying a TRPC5 modulator such as a TRPC5 antagonist, the term TRPC5 is used generically to include either or both of a homomultimer or a heteromultimer of TRPC5 (e.g., TRPC5-TPRC1 or TRPC5-TRPC4 heteromultimer). Examples of TRPC5 in the literature include the following: Nature. January 3, 2008; 451(7174):69-72; Mol Pharmacol. January 2008; 73(1):42-9; J Biol Chem. November 16, 2007; 282(46):33868-78; Biochem Biophys Res Commun. January 11, 2008; 365(2):239-3045; J Biol Chem. November 3, 2006; 281(44):33487-96; Eur J Pharmacol. May 14, 2005"; 510(3):217-22; J Biol Chem. Feb 24, 2006; 281(8):4977-82; Biochem Soc Trans. Feb 2007; 35(Pt l):101-4; Handb Exp Pharmacol. 2007; (179):109-23; J Biol Chem. 2005 Mar.;280(12):10997-1006;J Physiol.January 2006 15;570(Pt2):219-35;and Nat Neurosci.(2003)6:837-45.

[0025] Modulation of TRPC5 protein function provides a means of modulating calcium homeostasis, sodium homeostasis, membrane polarization, and/or intracellular calcium levels, and compounds that can modulate TRPC5 function are useful in many aspects, including, but not limited to, maintaining calcium homeostasis, modulating intracellular calcium levels, modulating membrane polarization, and treating or preventing diseases, disorders, or conditions associated with homeostasis or disome ostasis.

[0026] In one aspect, the invention provides methods of treating a TRPC5-mediated disorder in an individual comprising administering to the individual a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0027] R1 is C1 - C6 alkyl, C2 - C6 alkenyl or C2 - C6 alkynyl, each of which is optionally substituted by 1 to 4 R5;

[0028] R2 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 -C6 haloalkyl, halo, C1 -C6 haloalkoxy, hydroxyl, C1 -C6 alkoxy, C3 -C7 cycloalkyloxy, C6 -C10 aryl, C6 -C10 aryloxy, C7 -C16 arylal alkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, - S -, - S - C1 - C6 alkyl, - S(O) -, - S(O)2 -, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, where each of C1 -C6 alkyl, C1 -C6 heteroalkyl, C2 -C6 alkenyl, C2-C6 alkynyl, C1 - C6 haloalkyl, C1 - C6 haloalkoxy, hydroxyl, C1 - C6 alkoxy, C3 - C7 cycloalkyloxy, C6 - C10 aryl, C6 - C10 aryloxy, C7 - C16 arylalkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, -S -, -S - C1 -C6 alkyl, -S(O)-, -S(O)2-, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1 to 3 R6;

[0029] R3 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C3 - C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkyl, or C1 -C6 alkoxy, each of which is optionally substituted with 1 to 4 R7;

[0030] R4 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl or C2 - C6 alkynyl, each of which is optionally substituted by 1 to 4 R8; R5, R6, R7, and R8 are each independently C1 - C6 alkyl, C1 - C6 heteroalkyl, halo, C1 - C6 haloalkyl, C1 - C6 haloalkoxy, hydroxyl, C1 - C6 alkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, cyano, nitro, amido, C1 -C6 alkylamido, C2 -C12 dialkylamido, - S-, - S(O)2 -, - C(O)O -, - C(O) -, - C(O)O - C1 - C6 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, heterocycloalkyl, or heteroaryl, wherein each of C1 -C6 alkyl, C1 -C6 heteroalkyl, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, hydroxyl, C1 -C 6 alkoxy, amino, C1 - C6alkylamino, C2 - C)2 dialkylamino, amido, C1 - C6 alkylamido, C2 - C12 dialkylamido, - S -, - S(O)2 -, - C(O)O -, - C(O) -, - C(O)O - C1 - C6 alkyl, C3 - C7 cycloalkyl, C6 - Cw aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R9; It is

[0031] each R9 is independently C1 -C6 alkyl, C1 -C6 heteroalkyl, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, heterocycloalkyl, C6 - C10 aryl, heteroaryl, C4 - C10 cycloalkylalkyl, heterocycloalkyl - C1 - C6 alkyl, C7 - C16 arylalkyl, heteroaryl - C1 - C6 alkyl, halo, hydroxyl, C1 - C6 alkoxy, C6 - C10 aryloxy, C7 - C16 arylalkoxy, C2 - C8 alkoxyalkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, C1 - C6 alkyl amino - C1 - C6 alkyl, C1 - C6 alkyl amino - C2 - C12 dialkyl, - S -, - S - C1 - C6 alkyl, -S(O)2 -C1 -C6 alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, -C(O)-C6-C10 aryl, -NHC(O)-C6-C10aryl, -C(O)NH-C6-Cw aryl, -C(O)OH, -C(O)O -CI -C6 alkyl, -C(O) -C -C6 alkyl a cyla, nitro, or cyano; to treat the individual that way.

[0032] In some embodiments, the TRPC5-mediated disorder is selected from the group consisting of: a neuropsychiatric disorder, a neurodegenerative disorder, nephropathy, and seizure disorder.

[0033] In some embodiments, R1 is C1 - C6 alkyl.

[0034] In some embodiments, R1 is C1 -C6 alkyl and R5 is independently C6 - C10 aryl or heteroaryl.

[0035] In some embodiments, R1 is C1-C6 alkyl and R5 is independently phenyl optionally substituted by 1 to 3 R9.

[0036] In some embodiments, R1 is C1-C6 alkyl and R5 is independently pyridyl, for example, 2-pyridyl, 3-pyridyl, or 4-pyridyl, optionally substituted with 1 to 3 R9.

[0037] In some embodiments, R2 is C6 - C10 aryl, C6 - C10 aryloxy or heteroaryloxy.

[0038] In some embodiments, R is C6 - C10 aryloxy.

[0039] In some embodiments, R is C1 - C6 alkoxy.

[0040] In some embodiments, R is C1 - C6 alkyl.

[0041] In some embodiments, R is C1 -C6 alkyl and R is independently C6 - C10 aryl or heteroaryl, optionally substituted with 1 to 3 R9.

[0042] In some embodiments, R2 is C1-C6 alkyl and R6 is independently phenyl, optionally substituted with 1 to 3 R9.

[0043] In some embodiments, R2 is either C1 - C6 alkylamino.

[0044] In some embodiments, R is -S(O) - or - S(O)2 -.

[0045] In some embodiments, R3 is C1 -C6 alkyl, C2 -C6 hydroxyalkyl, or C1 -C6 alkoxy.

[0046] In some embodiments, R3 is C2-C6 hydroxyalkyl, for example, hydroxypropyl.

[0047] In some embodiments, R is hydroxypropyl.

[0048] In some embodiments, R4 is C1 - C6 alkyl.

[0049] In some embodiments, R5 is independently C6 - C10 aryl, heteroaryl, C3 - C7 cycloalkyl, or heterocycloalkyl.

[0050] In some embodiments, R5 is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl.

[0051] In some embodiments, R5 is phenyl.

[0052] In some embodiments, R5 is pyridyl.

[0053] In some embodiments, R5 is thiazolyl.

[0054] In some embodiments, R9 is independently C1 -C6 alkyl, C1 -C6 alkoxy, halo, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, or heterocycloalkyl.

[0055] In some embodiments, R2 is C6-C10 aryl or C6-C10 aryloxy, and R6 is independently C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 or haloalkoxy.

[0056] In some embodiments, R2 is C6-C10 aryloxy and R6 is independently C1-C6 haloalkyl or C1-C6 or haloalkoxy.

[0057] In some embodiments, R2 is C6 - C10 aryloxy and R6 is -CF3 or -OCF3.

[0058] In another aspect, the invention provides compounds of formula T(a): or a pharmaceutically acceptable salt thereof, wherein:

[0059] R1 is C1 - C6 alkyl, C2 - C6 alkenyl or C2 - C6 alkynyl, each of which is optionally substituted by 1 to 4 R5;

[0060] R2 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 haloalkyl, halo, C1 - C6 haloalkoxy, hydroxyl, C1 - C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylal alkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, - S -, - S - C1 - C6 alkyl, - S(O) -, - S(O)2 -, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, where each of C1 -C6 alkyl, C1 -C6 heteroalkyl, C2 -C6 alkenyl, C2-C6 alkynyl, C1 - C6 haloalkyl, C1 - C6 haloalkoxy, hydroxyl, C1 - C6 alkoxy, C3 - C7 cycloalkyloxy, C6 - C10 aryl, C6 - C10 aryloxy, C7 - C16 arylalkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, -S -, -S - C1 -C6 alkyl, -S(O)-, -S(O)2-, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1 - 3 R6; R3 is C2 - C6 hydroxyalkyl or C1 - C6 heteroalkyl;

[0061] R4 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl or C2 - C6 alkynyl, each of which is optionally substituted by 1 to 4 R8;

[0062] R5, R6, R7, and R8 are each independently C1-C6 alkyl, C1-C6 heteroalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, cyano, nitro, amido, C1-C6 alkylamido, C2-C12 dial chylamido, -S-, -S(O)2 -, -C(O)O -, -C(O)-, -C(O)O - C1 - C6 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, heterocycloalkyl, or heteroaryl, each of C1 -C6 alkyl, C1 - C6 heteroalkyl, C1 - C6 haloalkyl, C1 - C6 haloalkoxy, hydroxyl, C 1 - C6 alkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, amido, C1 - C6 alkyl starch, C2-C12 dialkyl starch, -S-, -S(O)2-, -C(O)O-, -C(O)-, -C(O)O-C1 -C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, heterocycloalkyl, or heteroaryl ila is optionally substituted by 1 to 3 R9; It is

[0063] each R9 is independently C1 -C6 alkyl, C1 -C6 heteroalkyl, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, heterocycloalkyl, C6 - C10 aryl, heteroaryl, C4 - C10 cycloalkyl alkyl, heterocycloalkyl - C1 - C6 alkyl, C7 - C16 arylalkyl, heteroaryl - C1 - C6 alkyl , halo, hydroxyl, C1 - C6 alkoxy, C6 - C10 aryloxy, C7 - C16 arylalkoxy, C2 - C8 alkoxyalkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, C1 - C6 alkyl amino - C1 - C6 alkyl, C1 - C6 alkyl amino - C2 - C12 dialkyl, - S -, - S - C1 - C 6 alkyl, - S(O)2 - C1 - C6 alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, -C(O)-C6-C10 aryl, -NHC(O)-C6-Cw aryl, -C(O)NH-C6-C,O aryl, - C(O)OH, - C(O)O - CI - C6 alkyl, - C(O) - C - C6 alkyl acyl, nitro, or cyano.

[0064] In some embodiments, R1 is C1 - C6 alkyl and R5 is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl, e.g., phenyl, pyridyl, or thiazolyl.

[0065] In some embodiments, R1 is C1-C6 alkyl and R5 is independently phenyl optionally substituted by 1 to 3 R9.

[0066] In some embodiments, R1 is C1-C6 alkyl and R5 is independently pyridyl, for example, 2-pyridyl, 3-pyridyl, or 4-pyridyl, optionally substituted with 1 to 3 R9.

[0067] In some embodiments, R2 is C6-C10 aryl or C6-C10 aryloxy, and R6 is independently C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 or haloalkoxy.

[0068] In some embodiments, R2 is C1 -C6 alkyl and R6 is independently C6 - C10 aryl or heteroaryl, optionally substituted with 1 to 3 R9.

[0069] In some embodiments, R2 is C1-C6 alkyl and R6 is independently phenyl, optionally substituted with 1 to 3 R9.

[0070] In some embodiments, R3 is C2-C6 hydroxyalkyl, for example, hydroxypropyl.

[0071] In another aspect, the invention provides compounds of formula II: or a pharmaceutically acceptable salt thereof, wherein:

[0072] ring A is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl;

[0073] R2 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 haloalkyl, halo, C1 - C6 haloalkoxy, hydroxyl, C1 - C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylal alkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, - S -, - S - C1 - C6 alkyl, - S(O) -, - S(O)2 -, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, where each of C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - Cs alkenyl, C2 - C6 alkynyl, C1 - C6 haloalkyl, C1 - C6 haloalkoxy, hydroxyl, C1 - C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylalkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, - S -, - S - C1 -C6 alkyl, -S(O)-, -S(O)2-, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted by 1 to 3 R6;

[0074] R3 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C2 - C6 hydroxyalkyl, or C1 - C6 alkoxy, each of which is optionally substituted with 1 to 4 R7;

[0075] R4 is C1 - C6 alkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl or C2 - C6 alkynyl, each of which is optionally substituted by 1 to 4 R8;

[0076] R6, R7, and R8 are each independently C1-C6 alkyl, C1-C6 heteroalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6alkoxy, amino, C1-C6 alkylamino, C2-C12-10dialkylamino, cyano, nitro, amido, C1-C6 alkylamido, C2-C1 2 dialkylamido, - S -, - S(O)2 -, - C(O)O -, - C(O) -, - C(O)O - C - C6 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, heterocycloalkyl, or heteroaryl, where each of C1 - C6 alkyl, C1 - C6 heteroalkyl, C1 - C6 haloalkyl, C1 - C6 haloalkoxy, hydroxy Ila, C1 -C6 alkoxy, amino, C1 -C6 alkylamino, C2-C12 dialkylamino, amido, C1 - C6 alkylamido, C2 - C12 dialkylamido, - S -, - S(O)2 -, - C(O)O -, - C(O) -, - C(O)O - C1 - C6 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1 to 3 R9;

[0077] each R9 is independently C1 -C6 alkyl, C1 -C6 heteroalkyl, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, heterocycloalkyl, C6 - C10 aryl, heteroaryl, C4 - C10 cycloalkylalkyl, heterocycloalkyl - C1 - C6 alkyl, C7 - C16 arylalkyl, heteroaryl - C1 - C6 alkyl, halo, hydroxyl, C1 - C6 alkoxy, C6 - C10 aryloxy, C7 - C16 arylalkoxy, C2 - C8 alkoxyalkoxy, amino, C1 - C6 alkylamino, C2 - C12 dialkylamino, C1 - C6 alkyl amino - C1 - C6 alkyl, C1 - C6 alkyl amino - C2 - C12 dialkyl, - S -, - S - C1 - C6 alkyl, - S(O)2 - C1 - C6 alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, -C(O)-C6-C10 aryl, -NHC(O)-C6-Cw aryl, -C(O)NH-C6-Cw aryl, - C(O)OH, - C(O)O - C1 - C6 alkyl, - C(O) - Ci - C6 alkyl acyl a, nitro, or cyano;

[0078] each Ra is C1 - C6 alkyl, C1 - C6 haloalkyl, halo;

[0079] n is 1 or 2; It is

[0080] m is 1.2, or 3.

[0081] In some embodiments, the A ring is phenyl or thiazolyl.

[0082] In some embodiments, ring A is pyridyl, for example, 2 - pyridyl, 3 - pyridyl, or 4 - pyridyl.

[0083] In some embodiments, R2 is C1 -C6 alkyl and R6 is independently C6 - C10 aryl or heteroaryl, optionally substituted with 1 to 3 R9.

[0084] In some embodiments, R2 is C1-C6 alkyl and R6 is independently phenyl, optionally substituted with 1 to 3 R9.

[0085] In some embodiments, R is hydroxypropyl.

[0086] In another aspect, the invention provides the compound of formula III: or a pharmaceutically acceptable salt thereof, wherein:

[0087] R2 is C1 - C6 alkoxy or C6 - C10 aryloxy substituted by 1 to 3 R6;

[0088] R3 is C1-C6 heteroalkyl or C2-C6 hydroxyalkyl; R4 is C1-C6 alkyl;

[0089] R6 is independently C1 -C6 alkyl, halo, C1 -C6 haloalkyl, C1 -C6 haloalkoxy, or C1 -C6 alkoxy;

[0090] each Ra is C1 - C6 alkyl, C1 - C6 haloalkyl, halo; n is 1 or 2; It is

[0091] m is 1.2, or 3.

[0092] In some embodiments, R3 is hydroxypropyl.

[0093] In some embodiments, Ra is independently chloro, fluoro, or methyl.

[0094] In another aspect, the invention provides methods of treating a TRPC5-mediated disorder in a subject, the method comprising administering to the subject a compound or composition of any one of claims 23 to 33, to thereby treat the subject.

[0095] In some embodiments, the TRPC5-mediated disorder is selected from the group consisting of: a neuropsychiatric disorder, a neurodegenerative disorder, nephropathy, and seizure disorder.

[0096] In certain embodiments, exemplary compounds of the invention include those compounds described in Table A and in the examples.

DEFINITIONS

[0097] At various places in the present specification, substituents of compounds of the invention are described in groups or ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1 - 6 alkyl" is specifically intended to individually describe methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0098] For compounds of the invention in which a variable appears more than once, each variable may be a different portion selected from the Markush group defining the variable. For example, where the structure is described as having two R groups that are simultaneously present in the same compound; the two R groups can represent different selected portions of the Markush group defined for R.

[0099] It is also appreciated that certain aspects of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Unlike various aspects of the invention which are, for brevity, described in the context of a single embodiment, they may also be provided separately or in any suitable subcombination.

[00100] As used herein, "acyl" refers to the group (C1 - C6 alkyl) - C(O) -.

[00101] As used herein, "alkyl," alone or as part of another substituent, means, unless otherwise stated, a straight or branched chain, and may have an optionally designated number of carbon atoms (i.e., C1 - C6 means one to six carbons). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, homologues and isomers of, for example, n-pentyl, n-hexyl, and the like.

[00102] As used herein, "alkenyl" can be a straight or branched hydrocarbon chain, containing at least one double bond, and having from two to six carbon atoms (ie, C2-C6 alkenyl). ,4-dienyl, and the like.

[00103] As used here, "alcoxi" can be an alcoxi linear or branched alcoxi group having one to six carbon atoms (ie C1 - C6 alcoxi). Examples of alcoxi groups, but are not limited to, groups such as metoxi, etoxi, propyloloxi, butylóxi, isobutylóxi, terc - butylóxi, pentilóxi XI, or hexiloxi, and the like.

[00104] As used herein, "alkynyl" may be a straight or branched hydrocarbon chain, containing at least one triple bond, having from two to six carbon atoms (ie, C2 - C6 alkynyl). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[00105] As used herein, "amide" or "starch" refers to a chemical moiety with the formula - C(O)NRa - or - NRaC(O) - where Ra is H or C1 - C6 alkyl.

[00106] As used herein, "amino" or "amine" refers to a radical group -NH2.

[00107] As used herein, "alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl group each has 1 to 6 carbons.

[00108] As used herein, the term "dialkylamino" refers to a group of the formula -N(alkyl)2, wherein the two alkyl groups each independently have 1 to 6 carbons.

[00109] As used herein, "aryl" refers to a polyunsaturated, aromatic hydrocarbon moiety that may be a single ring or multiple rings (e.g., 1 to 2 rings) that are fused together or covalently bonded, having from six to twenty carbon atoms (i.e., C6 - C12 aryl). Non-limiting examples of aryl groups include phenyl, 1-naphthyline, 2-naphthyline, and 4-biphenyl.

[00110] As used herein, "arylalkyl” refers to an (aryl)alkyl- radical in which the aryl and alkyl moieties are as described herein.

[00111] As used herein, "aryloxy" refers to - O - (aryl), where the heteroaryl moiety is as defined herein.

[00112] As used herein, "arylalkoxy" refers to -O-(arylalkyl), wherein the heteroaryl moiety is as defined herein.

[00113] As used herein, "carboxyl" refers to a -(C=O)OH radical.

[00114] As used herein, "cyan" refers to a -CN radical.

[00115] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (ie, C3-C10 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl enyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.

[00116] As used herein, "C3 - C7 cycloalkyloxy" refers to - 0 - (C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl moiety is as defined herein.

[00117] As used herein, "halo" or "halogen," independently or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "halide" alone or as part of another substituent refers to a fluoride, chloride, bromide, or iodide atom.

[00118] As used herein, "haloalkyl" and "haloalkoxy" can include alkyl and alkoxy structures that are substituted by one or more halo groups or by combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine.

[00119] As used herein, "heteroalkyl" may include an optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given, for example, C1 - C6 heteroalkyl which refers to the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms. as "C3" heteroalkyl The connection to the rest of the molecule can be through either a heteroatom or a carbon in the heteroalkyl chain.

[00120] As used herein, "heteroaryl" refers to a 5- to 14-membered aromatic radical (e.g., C2 - Q3 heteroaryl) which includes one or more rings of heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic or bicyclic ring system. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl" by removing the hydrogen atom from the atom with the free valency are named by adding "-idene" to the name of the corresponding univalent radical, eg, a pyridyl group with two points of attachment is a pyridylene. A "heteroaromatic" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one of the skeletal ring atoms is a nitrogen atom. Polycyclic heteroaryl may be fused or unfused. The heteroatom in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quathermized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). 1a, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.

[00121] As used herein, "heteraryloxy" refers to -O- (heteroaryl), wherein the heteroaryl moiety is as defined herein.

[00122] As used herein, "heterocycloalkyl" may be a stable 3- to 18-membered non-aromatic ring radical comprising two to twenty carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. , isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2 -oxopiperidinyl, 2 -oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofur yl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like.

[00123] As used herein, "hydroxy” or "hydroxyl" refers to -OH.

[00124] As used herein, "hydroxyalkyl" refers to an alkyl group having 1 to 6 carbon atoms, which is substituted by a hydroxyl group, for example, hydroxypropyl.

[00125] As used here, "cyan" refers to -CN.

[00126] As used herein, "nitro" refers to -NO2. As used herein, "urea" refers to - NRa - C(O) - NRa2 or - NRa - C(O)NRa -, where Ra is H or C1 - C6 alkyl.

[00127] As used herein, "sulfonylurea" refers to -S(O)2 -NRa-C(O)-NRa- or -NRa-C(O)-NRa-SO2-, where Ra is H or C1-C6 alkyl.

[00128] As used herein, "sulfonamidyl" refers to -S(O)2 -NRa- or -NRa-S(O)2-, where Ra is H or C1-C6 alkyl.

[00129] The terms "antagonist" and "inhibitor" are used interchangeably to refer to an agent that decreases or suppresses a biological activity, such as to repress an activity of an ion channel, such as TRPC5. TRPC5 ion channels as described herein include homomultimeric and heteromultimeric structures (eg, homomultimeric TRPC5 and heteromeric TRPC5-TRPC1 or TRPC5-TRPC4). TRPC5 antagonists include inhibitors having any combination of the structural and/or functional properties described herein.

[00130] An "effective amount" of, for example, a TRPC5 antagonist, with respect to the object methods of inhibition or treatment, refers to an amount of the antagonist in a preparation that, when applied as part of a desired dosage regimen, produces a desired clinical or functional result. Without being bound by theory, an amount of a TRPC5 antagonist effective for use in the methods of the present invention includes an amount of a TRPC5 antagonist effective to reduce one or more in vitro or in vivo functions of a TRPC5 channel. Exemplary functions include, but are not limited to, membrane polarization (eg, an antagonist can promote hyperpolarization of a cell), ion flux, ion concentration in a cell, external current, and internal current. Compounds that antagonize TRPC5 function include compounds that antagonize a functional in vitro or in vivo activity of TRPC5. When a particular functional activity is only readily observable in an in vitro assay, the ability of a compound to inhibit TRPC5 function in that in vitro assay serves as a reasonable guarantee for that compound's activity. In certain embodiments, an effective amount is an amount sufficient to inhibit a TRPC5-mediated current and/or an amount sufficient to inhibit TRPC5-mediated ion flow.

[00131] TRPC5 antagonists for use in the methods of the present invention can be characterized according to their activity, or lack of activity, along one or more other ion channels. When other ion channels are referred to, the inhibition of the function of such other ion channels is defined similarly. For example, inhibition of one ion channel or one activity of one ion channel means that the antagonist inhibits one or more functional activities of the other ion channels. Such functions include the current mediated by the particular ion channel, ion flux, or membrane polarization.

[00132] The term "prevent" is art recognized, and when used in relation to a condition, such as a local recurrence, a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is well understood in the art, and includes administering a composition that reduces the frequency of, or delays the onset of, symptoms of a medical condition in an individual with respect to an individual not receiving the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, for example, by a statistically and/or clinically significant amount. Prevention of one includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population. Pain prevention includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by individuals in a treated population versus an untreated control population.

[00133] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted to the therapeutically active agents in the present invention. A common method for producing a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[00134] The term "small molecule" refers to a compound having a molecular weight of less than about 2500 amu, preferably less than about 2000 amu, even more preferably less than about 1500 amu, even more preferably less than about 1000 amu, or most preferably less than about 750 amu.

[00135] The terms "TRPC5", "TRPC5 protein", and "TRPC5 channel" are used interchangeably throughout the application. Unless expressly stated, the term TRPC5 includes homomultimeric structures (eg, homomultimeric TRPC5) and heteromultimeric structures (eg, TRPC5 - heteromultimeric TRPC1).

[00136] The term "oxidative metabolite" is intended to encompass compounds that are produced by metabolism of the parent compound under normal physiological conditions. Specifically, an oxidative metabolite is formed by oxidation of the parent compound during metabolism. For example, a thioether group can be oxidized to the corresponding sulfoxide or sulfone.

[00137] The term "solvate" as used herein, refers to a compound formed by solvation (eg, a compound formed by combining solvent molecules with solute molecules or ions).

[00138] The term "hydrate" as used herein, refers to a compound formed by the union of water with the parent compound.

[00139] The term "treat" includes prophylactic and/or therapeutic treatments. The term "prophylactic or therapeutic" treatment is art recognized and includes administering to the host one or more of the subject compositions. If they are administered before the clinical manifestation of the unwanted condition (e.g., disease or other unwanted condition of the host animal), then the treatment is prophylactic, (i.e., it protects the host against the development of the unwanted condition), if they are administered after the manifestation of the unwanted condition, the treatment is therapeutic, (i.e., they are intended to lessen, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[00140] The terms "compound" and "agent" are used interchangeably to refer to the inhibitors/antagonists of the invention. In certain embodiments, the compounds are small organic or inorganic molecules, for example, less than 7500 amu molecular size, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, or 600 amu. Such compounds can bind to and inhibit the function of TRPC5. In certain other embodiments, the compounds are nucleic acids, for example, TRPC5 antisense oligonucleotides or TRPC5 RNAi constructs. Such compounds can inhibit TRPC5 expression, thereby inhibiting TRPC5 activity. Other exemplary compounds that can act as inhibitors include ribozyme fragments and peptides.

[00141] Contemplated equivalents of the compounds described above include compounds that otherwise correspond to them, and that have the same general properties as them (e.g., the ability to antagonize TRPC5 activity), wherein one or more simple substituent variations are made that do not adversely affect the effectiveness of the compound. In general, the compound of the present invention can be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using easily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known per se but are not mentioned here.

[00142] For the purposes of this invention, the chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, back cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds that may be substituted or unsubstituted.

[00143] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise noted. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of how to prepare optically active forms of optically active starting materials are known in the art, such as by resolving 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 invention are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[00144] Resolution of racemic mixtures of compounds can be performed by any of numerous methods known in the art. An exemplary method includes fractional recrystallization using a "chiral resolving acid" which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the various optically active camphorsulfonic acids, such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[00145] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (eg dinitrobenzoylphenylglycine). Proper eluting solvent composition can be determined by one skilled in the art. Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.

[00146] The compounds of the invention may also include all isotopes of atoms occurring in the final or intermediate compounds. For example, the compound of the invention can be radiolabeled with radioactive isotopes, such as, for example, tritium (3H) or carbon-14 (14C). All isotopic variations whether radioactive or not, are intended to be within the scope of the present invention.

[00147] The compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are within the scope of the present invention. A compound of formula (I) can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[00148] The term "pharmaceutically acceptable salts" includes salts of a compound of the invention that are prepared with relatively non-toxic acids or bases or bases. Base addition salts can be obtained by contacting the neutral form of a compound of the invention with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. Acid addition salts can be obtained by contacting the neutral form of the compound of the invention with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively non-toxic organic acids such as acetic, trifluoroacetic, propionic, isobut iric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

[00149] Neutral forms of compounds of the invention are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

[00150] The term "sufficiently low pyrogen activity", with reference to a pharmaceutical preparation, refers to the preparation that does not contain a pyrogen in an amount that would lead to an adverse effect (eg, irritation, fever, inflammation, diarrhea, respiratory distress, endotoxic shock, etc.) in an individual to whom the preparation was administered. For example, the term is understood to encompass preparations that are free of, or substantially free of, an endotoxin such as, for example, lipopolysaccharide (LPS). Diseases, Disorders, or Conditions Related to TRPC5 Function

[00151] In certain embodiments, the invention provides methods and compositions for antagonizing a TRPC5 channel function in vitro or in vivo. Exemplary functions include, but are not limited to, TRPC5-mediated current. In certain embodiments, the invention provides methods for treating a disease or disorder or condition by administering compounds of the invention. In other embodiments, the compound of formula (I) selectively inhibits the level of expression and/or activity of a TRPC5 protein. In other words, in a certain embodiment, the compound of the invention inhibits the activity of a TRPC5 protein preferentially compared to the activity of one or more other ion channels. Treatment of anxiety and fear related disorders

[00152] In certain embodiments, the compound of the invention can be used to prevent or treat anxiety and fear related disorders (see, for example, Riccio et al. (2009) Cell 137:761 - 72 ). Examples of such disorders include post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, and separation anxiety. Memory, movement and mood disorders

[00153] A compound of the invention is also useful for the treatment of Parkinson's disease, epilepsy, memory disorders, stroke, seizure disorder, and mood disorders. Mood disorders include depression (eg, major depression, psychiatric depression, dysthymia, and postpartum depression) and bipolar disorder (eg, bipolar I, bipolar II, and cyclothymia). Memory disorders are conditions associated with any memory loss and can result from Alzheimer's disease, amnesia, aphasia, atherosclerosis, brain disorder or damage, brain tumor, chronic fatigue syndrome, Creutzfedt-Jacob disease, dissociative amnesia, depression, fugue amnesia, Huntington's disease, learning disorders, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wernicke-Kors syndrome akoff. Treatment of pain, Sensitivity to Pain and Touch, or Pain Related Diseases or Disorders

[00154] In certain embodiments, a compound of the invention is used to treat or ameliorate pain. Exemplary classes of pain that may be treated using a compound of formula (I) include, but are not limited to, nociceptive pain, inflammatory pain, and neuropathic pain. The pain can be chronic or acute.

[00155] A compound of the invention may be particularly useful in the treatment of pain associated with cancer, osteoarthritis, rheumatoid arthritis, postherpetic neuralgia, burns, and other indications detailed above. To further illustrate, additional exemplary indications for which a compound of the invention can be used include oral pain, pelvic pain, Fabry disease, complex regional pain syndrome, pancreatitis, and fibromyalgia syndrome.

[00156] A compound of the invention can also be used in connection with preventing or treating pain and touch sensitivity. Pain or sensitivity to pain and touch may be indicated in a variety of diseases, disorders or conditions including, but not limited to, breast pain from diabetic neuropathy, psoriasis, eczema, dermatitis, burns, postherpetic neuralgia (herpes zoster), nociceptive pain, peripheral neuropathic and central neuropathic pain, chronic pain, cancer and tumor pain, spinal cord injury, crush injury and trauma-induced pain, migraine, cerebrovascular and vascular pain, sickle cell disease pain ciformis, rheumatoid arthritis pain, musculoskeletal pain including treating signs and symptoms of osteoarthritis and rheumatoid arthritis, orofacial and facial pain, including dental disorder, temporomandibular, and cancer-related, low back or pelvic pain, pain related to surgical incision, inflammatory and non-inflammatory pain, visceral pain, psychogenic pain and inflammatory soft tissue pain, pain related to fibromyalgia, and reflex sympathetic dystrophy, and pain resulting from kidney stones or urinary tract infection.

[00157] The foregoing are simply examples of diseases and conditions that cause or lead to inflammation, lesions, ulcers, or other sources of oral pain. In other embodiments, oral pain is due to an injury to the mouth, jaw, lips, gums, or teeth. In other embodiments, oral pain is due to oral surgery, for example, cancer surgery, tooth extraction, or jaw reshaping. Other conditions that can lead to oral ulcers, and thereby oral pain, include, but are not limited to, chicken pox, herpes zoster, infectious mononucleosis, syphilis, tuberculosis, acute necrotizing gingivitis, and burning mouth syndrome.

[00158] Fibromyalgia (FMS; fibromyalgia syndrome) is a widespread musculoskeletal pain and fatigue disorder. Fibromyalgia is characterized by pain in muscles, ligaments, and tendons. The condition affects more women than men, and it occurs in people of all ages. Generally speaking, FMS is estimated to afflict 3 to 6% of the population. Patients have described the pain associated with fibromyalgia as deep, throbbing, sudden, and deep muscle pain. The pain sometimes includes an intense burning sensation. The pain and stiffness are often worse in the morning or after repetitive use of a particular muscle group.

[00159] Additionally, variable levels of fatigue ranging from mild to disabling are often associated with fibromyalgia. Other fibromyalgia symptoms include gastrointestinal symptoms. Irritable bowel syndrome and IBS-like symptoms such as constipation, diarrhea, frequent abdominal pain, abdominal gas, and nausea occur in approximately 40 to 70% of FMS patients. Acid reflux disease or gastroesophageal reflux disease (GERD) occurs at a similar frequency.

[00160] Complex regional pain syndrome (CRPS; also known as chronic regional pain syndrome) is a chronic pain condition. CRPS was first known as reflex sympathetic dystrophy (RSD). CRPS is a chronic, painful, and progressive neurological condition that affects the skin, muscles, joints, and bones. The syndrome usually develops in an injured limb, such as a broken leg or after surgery. However, many cases involve only a single injury, such as a strain, and sometimes no precipitating harmful event can be identified. CRPS involves intense, ongoing pain that is disproportionate to the severity of the injury. The pain gets worse, rather than better, over time.

[00161] Although CRPS can affect a variety of body regions, it most often affects the arms, legs, hands, or feet. Often the pain starts in one part of a limb but spreads over time to include the entire limb or even a different limb. Typical features include dramatic changes in the color and temperature of the skin over the affected limb or body part, accompanied by intense burning pain, skin tenderness, sweating, and swelling.

[00162] The compounds described herein can also be used to treat endometriosis and the pain associated therewith. Neurological or Neurodegenerative Diseases and Disorders

[00163] Neurodegenerative diseases and disorders include but are not limited to Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and other brain disorders caused by trauma or other insults including aging.

[00164] Mechanisms associated with calcium signaling can be altered in many neurodegenerative diseases and in disorders that result from brain damage. For example, fibroblasts or T-lymphocytes from AD patients consistently showed an increase in Ca2+ release from intracellular stores compared to controls (Ito et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91:534-538; Gibson et al. (1996) Biochem. Biophys. ACTA 1316:71-77; Etchenberrigaray et al (1998) Neurobiology of Disease, 5:37-45). Consistent with these observations, mutations in presenilin genes (PS1 or PS2) associated with familial AD (FAD) have been shown to increase InsP3-mediated Ca2+ release from internal stores (Guo et al. (1996) Neuro Report, 8:379-383; Leissring et al. (1999) J. Neurochemistry, 72,1061-1068; Leissring et al. (19) 99) J. Biol.Chem.274(46):32535-32538;Leissring et al.(2000) J.Cell Biol.149(4):793-797;Leissring et al.(2000) Proc.Natl.Acad.Sci.U.S.A.97(15):8590-8593). Furthermore, mutations in PS1 or PS2 associated with an increase in generation of amyloidogenic amyloid P-peptide in AD are reported to be associated with a decrease in intracellular calcium level ( Yoo et al. (2000) Neuron, 27(3):561-572 ).

[00165] Experimental traumatic brain damage has been shown to initiate massive disturbances in Ca2+ concentrations in the brain that may contribute to further neuronal damage. Intracellular Ca2+ can be elevated through many different ion channels. It has also been shown that Mockers channels can be beneficial in the treatment of neurological motor dysfunction when administered in the acute post-traumatic period (Cheney et al. (2000) J. Neurotrauma, 17(1):83-91).

convulsion

[00166] Excitotoxicity from a variety of sources leads to seizures. Commonly excess neuronal firing can lead to seizure activity. Compounds that reduce the hyperexcitability of relevant neuronal populations have significant potential in reducing seizure activity. Compounds of the invention that inhibit TRPC5 can reduce hyperexcitability and thereby reduce seizure activity.

Proteinuric Kidney Disease

[00167] TRPC5 is also expressed in the podocyte of the kidneys. It has also been proposed that there is an antagonistic regulation of actin and cell dynamics in podocytes by TRPC5 and TRPC6 (Tian et al., (2010) Science Signaling). Thus, TRPC5 inhibition may impact podocyte reaction to injury.

Combination Therapy

[00168] The present invention provides compounds of the invention for in vitro and in vivo use. The present invention also provides compositions and pharmaceutical compositions comprising a compound of formula (I) which inhibits TRPC5 activity. In certain embodiments, the compound of the invention is selective. In other words, in certain embodiments, the compound of the invention inhibits TRPC5 activity preferentially over the activity of other ion channels. In certain embodiments, the compound of formula (I) inhibits TRPC5 activity preferentially over TRPV1, TRPV2, TRPV3, TRPV4, TRPC3, TRPC6, TRPC7, TRPA1, and/or TRPM8 activity. For example, in certain embodiments, the compound of formula (I) inhibits the activity of TRPC5 and also inhibits the activity of one or more of TRPC4, TRPV1, TRPV2, TRPV3, TRPV4, TRPC3, TRPC6, TRPC7, TRPA1, and TRPM8.

[00169] A compound of the invention can be used alone or in combination with other pharmaceutically active agents. Examples of such other pharmaceutically active agents include, but are not limited to, antidepressants, antianxiety agents, antiepileptics, antiinflammatory agents (e.g., NSAIDS, bradykinin receptor antagonists, hormones and autacoids such as corticosteroids), or antimigraine agents. Certain agents belong to more than one category.

[00170] In certain embodiments, a compound of the invention is conjointly administered with an analgesic. Suitable analgesics include, but are not limited to, opioids, glucocorticosteroids, non-steroidal anti-inflammatory drugs, naphthylalkanones, oxicams, para-aminophenol derivatives, propionic acids, propionic acid derivatives, salicylates, fenamates, fenamate derivatives, pyrozoles, and pyrozole derivatives. Examples of such analgesic compounds include, but are not limited to, codeine, hydrocodone, hydromorphone, levorfarnol, morphine, oxycodone, oxymorphone, butorphanol, dezocine, nalbuphine, pentazocine, etodolac, indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, diclofenac, oxaprozin, aspirin, diflunisal, meclofenamic acid, mefanamic acid, prednisolone, and dexamethasone. Preferred analgesics are nonsteroidal anti-inflammatory drugs and opioids (preferably morphine).

[00171] In some embodiments, a compound of the invention can be administered in conjunction with a therapeutic whose administration causes pain. For example, a compound of the invention can be administered together with an anesthetic to reduce pain caused by administration of the anesthetic. A compound of the invention can also be administered together with a chemotherapeutic agent to reduce pain caused by administering the chemotherapeutic agent.

[00172] In certain embodiments, a compound of the invention is conjointly administered with a non-steroidal anti-inflammatory drug. Suitable non-steroidal anti-inflammatory compounds include, but are not limited to, piroxicam, diclofenac, etodolac, indomethacin, ketoralac, oxaprozin, tolmetin, naproxen, flubiprofen, fenoprofen, ketoprofen, ibuprofen, mefenamic acid, sulindac, apazone, phenylbutazone, aspirin, celecoxib and rofecoxib.

Pharmaceutical Compositions

[00173] While it is possible for a compound of the invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is combined with one or more pharmaceutically acceptable excipients or vehicles. The compound of the invention may be formulated for administration in any convenient manner for use in human or veterinary medicine. In certain embodiments, the compound of the invention can be a prodrug, for example, capable of being converted to an active compound in a physiological setting.

[00174] The phrase "pharmaceutically acceptable" is used here to refer to those compounds, materials, compositions, and/or dosage forms that fall within the scope of safe medical diagnosis, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00175] Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[00176] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[00177] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution delay agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[00178] Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the invention, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, germ, olive, castor oil and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.

[00179] Suspensions, in addition to the compound of the invention, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00180] Ointments, pastes, creams and gels may contain, in addition to the compound of the invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00181] Powders and sprays may contain, in addition to the compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[00182] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a compound of the invention that can be combined with a carrier material to produce a unit dosage form will vary depending on the host being treated, the particular mode of administration. The amount of a compound of the invention that can be combined with a carrier material to produce a unit dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of a compound of the invention, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to about 30 percent.

[00183] Tablets, and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may also be formulated to provide slow or controlled release of the active ingredient included herein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain pacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

[00184] Dosage forms for topical or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable vehicle, and with any preservatives, buffers, or propellants that may be required.

[00185] The formulations described here can be released through a device. Exemplary devices include, but are not limited to, a catheter, wire, stent, or other intraluminal device. Other exemplary delivery devices also include a plaster, bandage, mouthguard, or dental appliance. Transdermal patches have the added advantage of providing controlled release of a compound of the invention into the body. Such dosage forms can be made by dissolving or dispersing the compound of the invention in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled either by providing a rate controlling membrane or by dispersing the compound in a gel or polymer matrix.

[00186] Ophthalmic formulations, ophthalmic ointments, drops, solutions and the like are also contemplated as included within the scope of this invention.

[00187] In some cases, in order to prolong the effect of a drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor solubility in water. The rate of drug absorption then depends on its rate of dissolution, which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00188] Injectable deposit forms are made by forming microencapsulation matrices of the object compounds in biodegradable polymers, such as polylactide - polyglycolide. Depending on the drug to polymer ratio, and the nature of the particular polymer employed, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[00189] When a compound of the invention is administered as a pharmaceutical, to humans and animals, it can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the compound of the invention in combination with a pharmaceutically acceptable carrier.

[00190] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracardiacly, transtracheally, intraarticularly, intraspinally, inhalation.

Dosages

[00191] The actual dosage levels of the compound of the invention in the pharmaceutical compositions of this invention can be varied in order to obtain an amount of the active ingredient that is effective to obtain the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[00192] The dosage level selected will depend on a variety of factors, including the activity of the compound of the invention described herein employed, or the ester, salt or amide thereof, the routine of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts .

[00193] A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian may start doses of the compound of the invention in the pharmaceutical composition at lower levels than required in order to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.

[00194] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the smallest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention to a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. For example, the dose can be 0.1 -50, 0.1 -25, 0.5-10, 1 -10, or 5 -10 mg/kg. If desired, the effective daily dose of the compound of the invention can be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

Disease and Injury Models

[00195] A compound of the invention that antagonizes the function of TRPC5 may be useful in the prophylaxis and treatment of any of the foregoing injuries, diseases, disorders, or conditions. In addition to in vitro assays of the activity of the compound of the invention, its effectiveness can easily be tested in one or more animal models. By way of example, there are numerous well-known animal models. One or more suitable animal models (eg suitable for the particular indication) can be selected.

[00196] Fear-related behaviors can be assessed as described, for example, in Riccio et al. Pain behaviors can be studied using various agents or procedures to simulate pain resulting from injury, disease, or other conditions. Blackburn - Munro (2004) Trends in Pharmacological Sciences 25: 299-305 (see, for example, Table 1). Behavioral characteristics of challenged animals can then be observed. Compounds or procedures that can reduce pain in animals can be easily tested by observing the behavioral characteristics of animals challenged in the presence versus absence of the test compound(s) or procedure.

[00197] Exemplary behavioral tests used to study chronic pain include tests of spontaneous pain, allodynia, and hyperalgesia. ID To assess spontaneous pain, posture, gait, noxious cues (eg, paw licking, excessive grooming, excessive exploratory behavior, guarding the injured body part, and self-mutilation) can be observed. To measure evoked pain, behavioral responses can be examined following heat exposure (eg, thermal injury model).

[00198] Exemplary animal models of pain include, but are not limited to, Chung's model, carrageenan-induced hyperalgesia model, Freund's complete adjuvant-induced hyperalgesia model, thermal damage model, formalin model, and Bennett's model. Chung's model of neuropathic pain (without inflammation) involves binding one or more spinal nerves. Chung et al. (2004) Methods Mol Med 99: 35-45; Kim and Chung (1992) Pain 50: 355 - 363. Ligation of spinal nerves results in a variety of behavioral changes in animals including thermal hyperalgesia, cold allodynia, and constant pain. Compounds that antagonize TRPC5 can be administered to ligated animals to assess whether they lessen these ligation-induced behavioral changes compared to those observed in the absence of compound.

[00199] Useful anxiety and depression models include maternal separation model, the positive elevated maze model, the forced swim test, the tail suspension test, the light/dark preference model, the light-enhanced startle model, and the ultrasonic vocalization model.

[00200] Seizures models include, but are not limited to, maximal electric shock (MES), acoustic startle in susceptible animals (eg DBA mice), and chemically induced seizures (with proconvulsant compounds such as pilocarpine, pentalene tetrazol, kainic acid, N - methyl - D - aspartic acid).

[00201] Useful models of kidney function include LPS-induced proteinuria (waiting for a reference to others).

Examples Method A: Plaster Staple Experiments

[00202] Patch-clip experiments allow the detection of currents through the TRPC5 channel in the cell line described above. In normal whole-cell patch clamp recordings, a glass electrode is placed in contact with a single cell and a high-resistance (gigaohm) seal is established with the cell membrane. The membrane is then disrupted to obtain the whole-cell configuration, allowing control of the cell membrane voltage and measurement of currents flowing across the membrane, using the amplifier attached to the electrode and resulting in the replacement of cytoplasm with the pipette solution. A perfusion system allows control of the extracellular solution, including the addition of current blockers and activators. The current can be activated by including 1.4 uM free Ca2+ in the pipette solution (intracellular), and 80 uM LaCb in the extracellular solution.

[00203] TRPC5 cells were induced 20 - 48 hours, removed from growth plates, and reseeded at low density (to achieve good physical separation of a single cell) onto glass coverslips for measurement. In some cases, cells were grown at low density overnight on glass coverslips. Patch clip recordings were made in whole cell mode with a holding potential of -40 mV. Every 5 seconds, a voltage ramp was applied from -120 to +100 mV, 400 ms duration. Elicited currents were quantified at -80 mV and +80 mV. The internal solution consisted of 140 mM cesium aspartate, 10 mM HEDTA, 2 mM CaCl 2 , 2.27 mM MgCl 2 , and 10 mM HEPES, pH 7.2, with calculated 1,400 nM free Ca 2+ . The external solution consisted of 150 mM NaCl, 4.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 10 mM glucose, 1 mM EGTA, pH 7.4. On addition of LaCl3, TRPC5 current was induced only in cells expressing TRPC5 and not in parental HEK293 TREx cells. Removal of the LaCi3 stimulus causes most of the current to go away. Potential blockers were tested for their ability to block both internal and external currents in the continued presence of LaCi3.

[00204] IC50 of a compound of the invention was estimated by testing the compound at 5 uM and 500 nM. When 5 uM of a compound showed no blocking, IC50 was estimated as >10 uM. When 5 uM of a compound showed 50% or less blocking, a rough estimate of IC50 in the 5-10 uM range can be made. IC50 for a compound of Formula I or Formula II between 500 nM and 5 uM was similarly estimated.

[00205] A compound described herein can be tested for its ability to block both internal and external currents through the TRPC5 channel, for example, by an assay as described in Example 1. For example, the IC50 of a compound of the invention was estimated by testing the compound at 5 uM and 500 nM. When 5 uM of a compound showed no blocking, the IC50 was estimated as >10 uM. When 5 uM of a compound showed 50% or less blocking, a rough estimate of IC50 in the 5-10 uM range can be made. The IC50 for a compound of the invention between 500 nM and 5 uM was similarly estimated. Exemplary compounds are shown in Table B below. As shown in Table B, "A" refers to an IC50 < 100 nM. "B" refers to an IC50 between 100 nM and 500 nM. "C" refers to an IC50 between 500 nM and 1000 nM. "D" refers to an IC50 between 1 uM and 2 uM. "E" refers to an IC50 between 2 uM and 10 uM. "F" refers to agonist compounds. "ND" refers to compounds for which the IC50 has not been determined. Table B Copy the Table from pages 165 to 250 of the pdf (I couldn't insert it). Method B: High Performance Evaluation Test

[00206] The high-throughput assay relies on detecting the elevation in intracellular Ca concentration ([Ca2+]j) following channel activation in cells inducibly expressing the TRPC5 channel. Ca2+ elevation was quantified using fluorescent Ca2+ indicators that were loaded into cells and subsequently indicated [Ca2+]i Ca2+ influx following activation of the TRPC5 channel. Compounds that inhibit [Ca2+]i elevation were considered hits for another investigation.

[00207] The commercially available HEK293/TREx line (Invitrogen) was stably transfected with a TRPC5 construct and evaluated by conventional calcium imaging to discover TRPC5 expressing clones following stimulation with 1 ng/ml tetracycline. These cells were maintained in the manufacturer's recommended growth medium supplemented with 100 ng/ml hygromycin to promote retention of the TRPC5 construct. After growing to near confluence, cells were seeded at a density of ~35,000 cells/well in 384-well CellBind plates (Corning) in the presence of 1 ug/ml tetracycline, and allowed to grow for 20 to 30 hours. An almost confluent monolayer resulted. The cells were then loaded with pigment Ca: Fura - 2/AM or Fluo4/AM was added to the wells to a final concentration of 4 uM or 0.5 uM, respectively, and incubated for 80 minutes or 60 minutes, respectively, at room temperature. The supernatant was then removed from the cells by inverting the plates with a flick, and 25 ul of Hank's Balanced Salt Solution (HBSS; 0.185 g/l D-glucose, 0.9767 g/l MgSO4 (anhydrous), 0.4 g/l KCl, 0.06 g/l KH2PO4 (anhydrous), 0.35 g/l NaHCO3, 8.0 g/l of NaCl, and 0.04788 g/l of Na2 HPO4 (anhydrous; pH 7.4) were then added to each well. Following -0.5 hour charge recovery, cells were assayed using the Hamamatsu FDSS 6000 system, which allowed illumination alternately at 340 nm and 380 nm for Fura - 2 experiments, or at 485 nm for Fluo4 experiments. Frames were acquired at a rate of 0.2 Hz. During the assay, plates were continuously vortexed, with well pipette mixing after addition of each reagent.

[00208] For assay evaluation, 26 μl of a diluted compound stock (to 50 μM) was added to each well for 2 minutes after collection, from a short baseline (4 frames). 13 µl of Ringer's solution of Ca2+ elevated to 62 mM (4.17 ml of normal Ringer's (with 2mM Ca2+) plus 5.83 ml of isotonic calcium Ringer's (105 mM Ca2+; in this Ringer's all sodium has been replaced with calcium)) were then added to each well, obtaining a final concentration of 14 mM Ca2+ and 10 µM test compound. Data were collected for ~3 minutes following the addition of high Ca2+ Ringer, where fluorescent intensity (for Fluo4) and F340/F380 ratio (for Fura - 2) were proportional to [Ca2+]i. Negative controls consisted of HEK293/TREx TRPC5 cells exposed to high Ca2+ solution, but no compound. Positive control conditions consisted of adding 2-APB, a promiscuous blocker of TRPC5 and other channels, to columns 23 and 24 of the plates, to a final concentration of 200 µM. These controls defined an evaluation window, and "hits" were defined as those compounds that inhibit the fluorescence response by at least 40%. IC50 values were determined for compounds defined as "hits." Fluo4 cell-based fluorescence assay was used to determine intracellular Ca 2+ concentration in the presence of variant drug concentration. Final concentrations of compounds tested were 20 µM, 6.667 µM, 2.222 µM, 0.741 µM, 0.247 µM, 0.082 µM, and 0.027 µM. Compounds were tested in triplicate at all concentrations. Standard software was used to fit IC50 curves. Additionally or alternatively, efficacy can be plotted as the % inhibition in the presence (of a given concentration of compound) versus the absence of compound or compared to a control compound. For example, effectiveness can be plotted as the % inhibition of ion flux in the presence versus absence of compound. Exemplary compounds are shown in Table C below. As shown in Table C, "A" refers to an IC50 < 100 nM. "B" refers to an IC50 between 100 nM and 500 nM. "C" refers to an IC50 between 500 nM and 1000 nM. "D" refers to an IC50 between 101 µM and 2 µM. "E" refers to an IC50 between 2 µM and 10 µM. "F" refers to agonist compounds. "ND" refers to compounds in which the IC50 has not been determined. Method B: High Performance Evaluation Test

[00209] The high-throughput assay relies on detecting the elevation in intracellular Ca concentration ([Ca2+]j) following channel activation in cells inducibly expressing the TRPC5 channel. Ca2+ elevation was quantified using fluorescent Ca2+ indicators that were loaded into cells and subsequently indicated [Ca2+]i Ca2+ influx following activation of the TRPC5 channel. Compounds that inhibit [Ca2+]i elevation were considered hits for another investigation.

[00210] The commercially available HEK293/TREx line (Invitrogen) was stably transfected with a TRPC5 construct and evaluated by conventional calcium imaging to discover TRPC5 expressing clones following stimulation with 1 ng/ml tetracycline. These cells were maintained in the manufacturer's recommended growth medium supplemented with 100 ng/ml hygromycin to promote retention of the TRPC5 construct. After growing to near confluence, cells were seeded at a density of ~35,000 cells/well in 384-well CellBind plates (Corning) in the presence of 1 ug/ml tetracycline, and allowed to grow for 20 to 30 hours. An almost confluent monolayer resulted. The cells were then loaded with pigment Ca: Fura - 2/AM or Fluo4/AM was added to the wells to a final concentration of 4 uM or 0.5 uM, respectively, and incubated for 80 minutes or 60 minutes, respectively, at room temperature. The supernatant was then removed from the cells by inverting the plates with a flick, and 25 ul of Hank's Balanced Salt Solution (HBSS; 0.185 g/l D-glucose, 0.9767 g/l MgSO4 (anhydrous), 0.4 g/l KCl, 0.06 g/l KH2PO4 (anhydrous), 0.35 g/l NaHCO3, 8.0 g/l of NaCl, and 0.04788 g/l of Na2 HPO4 (anhydrous; pH 7.4) were then added to each well. Following -0.5 hour charge recovery, cells were assayed using the Hamamatsu FDSS 6000 system, which allowed illumination alternately at 340 nm and 380 nm for Fura - 2 experiments, or at 485 nm for Fluo4 experiments. Frames were acquired at a rate of 0.2 Hz. During the assay, plates were continuously vortexed, with well pipette mixing after addition of each reagent.

[00211] For assay evaluation, 26 μl of a diluted compound stock (to 50 μM) was added to each well for 2 minutes after collection, from a short baseline (4 frames). 13 µl of Ringer's solution of Ca2+ elevated to 62 mM (4.17 ml of normal Ringer's (with 2mM Ca2+) plus 5.83 ml of isotonic calcium Ringer's (105 mM Ca2+; in this Ringer's all sodium has been replaced with calcium)) were then added to each well, obtaining a final concentration of 14 mM Ca2+ and 10 µM test compound. Data were collected for ~3 minutes following the addition of high Ca2+ Ringer, where fluorescent intensity (for Fluo4) and F340/F380 ratio (for Fura - 2) were proportional to [Ca2+]i. Negative controls consisted of HEK293/TREx TRPC5 cells exposed to high Ca2+ solution, but no compound. Positive control conditions consisted of adding 2-APB, a promiscuous blocker of TRPC5 and other channels, to columns 23 and 24 of the plates, to a final concentration of 200 µM. These controls defined an evaluation window, and "hits" were defined as those compounds that inhibit the fluorescence response by at least 40%. IC50 values were determined for compounds defined as "hits." Fluo4 cell-based fluorescence assay was used to determine intracellular Ca 2+ concentration in the presence of variant drug concentration. Final concentrations of compounds tested were 20 µM, 6.667 µM, 2.222 µM, 0.741 µM, 0.247 µM, 0.082 µM, and 0.027 µM. Compounds were tested in triplicate at all concentrations. Standard software was used to fit IC50 curves.

[00212] Additionally or alternatively, efficacy can be plotted as the % inhibition in the presence (of a given concentration of compound) versus the absence of compound or compared to a control compound. For example, effectiveness can be plotted as the % inhibition of ion flux in the presence versus absence of compound. Exemplary compounds are shown in Table C below.

[00213] As shown in Table C, "A" refers to an IC50 < 100 nM. "B" refers to an IC50 between 100 nM and 500 nM. "C" refers to an IC50 between 500 nM and 1000 nM. "D" refers to an IC50 between 101 µM and 2 µM. "E" refers to an IC50 between 2 µM and 10 µM. "F" refers to agonist compounds. "ND" refers to compounds in which the IC50 has not been determined. Example 2: General Procedures

[00214] All reagents were purchased from commercial suppliers and used without further purification unless otherwise stated. THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, DCM was continuously refluxed and freshly distilled from CaH2 under nitrogen.

[00215] The reactions were monitored by TLC on silica gel plates (or percolated 60 HSGF254 plates (0.15-0.2 mm SiO2) or Baker-flex IB2 - F TLC plates), and visualized using UV light (254 nm or 365 nm) and/or staining with a DNP solution (12 g, 2,4-dinitrophenylhydrazine, 60 mL H2SO 4 concentrate, 80 ml of H2O, 200 ml of ethanol) and subsequent heating or monitored by means of LCMS.

[00216] Microwave reactions were performed with a Biotage Smith Synthesizer.

[00217] LCMS was performed on a SHIMADZU LCMS-2010EV instrument using one of two sets of conditions. LCMS conditions one: (Chromolith SpeedROD column, RP-18e, 50x4.6 mm, mobile phase: Solvent A: CH3CN/^O/HCOOH= 10/90/0.05, Solvent B: CH3CN/H2O/HCOOH=90/10/0.05, 0.8min @ 10% B, gradient 2.7 minutes (10 - 95% B), then 0.8min@95%B, flow rate: 3 mL/min, temperature: 40°C). LCMS conditions two: (Zorbax, 3.5 microns, C18 column 2.1 x 50 mm. Mobile phase: Solvent A: 0.1% formic acid / acetonitrile, Solvent B: 0.1% formic acid / water. Gradient: 5% to 95% B using a 5 minute or 8 minute run time).

[00218] Preparative HPLC was performed either on a SHIMADZU LC - 8A instrument. (Column: YMC Pack ODS-A (150*30mm, 10 μm)) or LC - 6AD (Column: Shim=Pack PREP - ODS - H (250*20mm, 10 μm)) with UV detection which was controlled by LC solution Chemstation software. H2O (0.1% HCOOH) and methanol (MeCN) as mobile phase at indicated flow rate.

[00219] Analytical HPLC was performed on a SHIMADZU LC-2010A instrument. (Chromolith SpeedROD, RP-18e, 50x4.6 mm, Mobile phase: Solvent A: CH3CN/H20/HC00H=10/90/0.05, Solvent B: CH3CN/H2O/HC00H=90/10/0.05, 0.8 min @ 10% B, 2.7 min gradient (10 - 95% B), Then 0.8 min@95%B, Flow rate: 3 mL/min, temperature: 40°C).

[00220] 1H NMR spectra were recorded on a Bruker Avance II 400 MHz instrument. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (5 = 0.000 ppm) and spectra were calibrated for the residual solvent signal of chloroform (8 = 7.26), Dimethyl sulfoxide (8 = 2.50), methanol (8 = 3.30). Data for 1H NMR spectra are reported as follows: chemical shift (multiplicity, number of hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad). Purine Numbering Preparation of intermediates Intermediate 1: 2 - (2 - (2 - chloroethoxy)ethoxy)tetrahydro - 2H - pyran

[00221] To a solution of 2-(2-chloroethoxy)ethanol (10 g, 0.071 mol) in DCM (150 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.2 g, 0.107 mol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 16 hours. It was split between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by silica gel chromatography, eluted with petroleum ether to give 2-(2-bromoethoxy)tetrahydro - 2H - pyran (11.9 g, 79.8% yield) as pale yellow oil. 1H NMR (CDCl3) δ 4.65 - 4.67 (t, 1H), 3.86 - 3.92 (m, 2H), 3.78 - .381 (m, 2H), 3.71 - 3.73 (t, 2H), 3.64 - 3.67 (t, 2H), 1.77 - 1.87 (m, 2H), 1.51 - 1.64 (m, 6H). Intermediate 2: 2 - (2 - bromoethoxy)tetrahydro - 2H - pyran

[00222] To a solution of 2-bromoethanol (15 g, 0.12 mol) in DCM (150 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.6 g, 0.126 mol) was added dropwise at 0°C. The mixture was stirred at room temperature for 4 h. It was split between DCM and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (50:1) to give 2 - (2 - bromoethoxy)tetrahydro - 2H - pyran (18.0 g, 72.0% yield) as a pale yellow oil. Intermediate 3: 2 - (3 - bromopropoxy)tetrahydro - 2H - pyran

[00223] To a solution of 3-bromopropan-1-ol (8 g, 57.9 mmol) in DCM (100 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (7.3 g, 86.9 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature overnight. It was split between DCM and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (50:1) to give 2 - (3 - bromopropoxy)tetrahydro - 2 H - pyran (8.9 g, 69.0% yield) as a pale yellow oil. Intermediate 4: 2 - (chloromethyl) - 5 - methylthiazole Step 1: (5 - methylthiazol - 2 - yl)methanol

[00224] To a solution of n - BuLi (8.4 ml, 13.48 mmol) in THF (30 ml) was added 2 - bromo - 5 - methylthiazole (2.0 g, 11.23 mmol) dropwise under a nitrogen atmosphere at -70°C; then it was stirred at this temperature for 1.5 h. DMF (1.3 ml, 16.85 mmol) was added dropwise under a nitrogen atmosphere at -70 °C. The resulting mixture was stirred at this temperature for 1 h., then the mixture was quenched with saturated aqueous ammonium chloride (5 mL), the mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. The yellow oil was dissolved in methanol (15 mL), sodium borohydride (512 mg, 13.48 mmol) was added portionwise under a nitrogen atmosphere at -60 °C. The mixture was stirred at this temperature for 1 h. The reaction mixture was quenched with acetone and concentrated. The residue was partitioned between ethyl acetate and water. The organic layers were dried over magnesium sulfate, filtered and concentrated, then purified by silica gel chromatography eluting with petroleum / ethyl acetate = 3:1 to provide thiazole - 2 -ylmethanol (1.3 g, 90.3%) as a brown oil. LCMS retention time 0.366 min; LCMS MH+ 130. Step 2: 2 - (chloromethyl) - 5 - methylthiazole

[00225] To a solution of (5-methylthiazol-2-yl)methanol (0.5 g, 3.87 mmol) in DCM (5 mL) was added thionyl chloride (0.19 mL, 2.6 mmol) at 0 °C, then the mixture was stirred at room temperature for 2 hours. The solvent was concentrated to give 2-(chloromethyl)-5-methylthiazole (570 mg) as a yellow oil which was used without purification. LCMS retention time 0.912 min; LCMS MH+148. Intermediate 5: 2 - (3 - (trifluoromethoxy)phenoxy)ethanol

[00226] To a solution of 3-(trifluoromethoxy)phenol (3 g, 16.8 mmol) in DMF (30 mL) was added 2-bromoethanol (3.16 g, 25.3 mmol), potassium carbonate (4.65 g, 33.7 mmol). The mixture was heated at 80 °C overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether and ethyl acetate (10:1) to give 2-(3-(trifluoromethoxy)phenoxy)ethanol (3.5g, 94.5% yield) as a yellow oil. 1H NMR (DMSO-d6) δ 7.28 - 7.30 (t, 1H), 6.81 -6.86 (m, 2H), 6.78 (s, 1H), 4.07 - 4.09 (t, 2H), 3.95 - 3.99 (m, 2H), 2.58 (t, 1H). Intermediate 6: 8 - bromo - 7 - ethyl - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 8-Bromo-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

[00227] To a solution of 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.4 g, 1.32 mmol, product of intermediate 16 step 2) in DMF (10 mL) was added iodoethane (0.25 g, 1.58 mmol) and potassium carbonate (0.27 g, 1.98 mmol ). The reaction was heated to 50 °C for 2 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over magnesium sulfate, filtered and concentrated to provide 8 - bromo - 7 - ethyl -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H)-dione (0.4 g, 91.7% yield) as a white solid. LCMS retention time 1.674 min; LCMS MH+ 331. Step 2: 8 - bromo - 7 - ethyl - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00228] To a solution of 8 - bromo - 7 - ethyl -1 - (3 - hydroxypropyl) - 3 - methyl-1H-purine-2,6(3H,7H)-dione (0.4 g, 1.2 mmol) in DCM (10 mL) was added PPTS (27 mg, 0.1 mmol); then dihydropyran (0.15 g, 1.8 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give 8 - bromo - 7 - ethyl - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H-purine-2,6(3H,7H)-dione (0.38g, 76.9% yield) as a white solid. LCMS retention time 1.871 min; 10 MH+ LCMS - THP331. Intermediate 7: 7 - (4 - chlorobenzyl) - 8 - mercapto - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione

[00229] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (400 mg, 0.781 mmol, intermediate 14) in DMF (10 mL) was added sodium sulfide nahydrate (375 mg, 1.563 mmol). The reaction was stirred at 85°C for 16 hours. The mixture was cooled, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 7 - (4 - chlorobenzyl) - 8 - mercapto - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) -dione (230 mg, 63.4%) as orange oil. LCMS retention time 1.517 min; LCMS MH+ - THP 381. Intermediate 8: 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1:8 - bromine - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00230] To a solution of 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (11.3 g, 6.8 mmol) in acetic acid (300 mL) was added sodium acetate (8.37 g, 13.6 mmol) followed by dropwise addition of bromine (13.04 g, 8.2 mmol) at 50 °C. After the addition, the mixture was stirred at 65°C for 3 hours. The mixture was cooled and poured into ice water (500 g), and the product precipitated. The suspension was filtered and the filter cake was washed with water twice and dried under vacuum to give 8 - bromo - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (16.1 g, 96.6% yield) as a pale yellow solid. LCMS retention time 0.541 min; LCMS MH+ 245. Step 2: 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 H - purine - 2,6(3H,7H) - dione

[00231] To a solution of 8 - bromo - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (8 g, 4.42 mmol) in DMF (200 mL) was added 1 - (bromomethyl) - 4 - chlorobenzene (10 g, 4.86 mmol) followed by potassium carbonate (9.16 g, 6.63 mmol). The resulting mixture was stirred at 45 °C for 2 h. The mixture was diluted with ethyl acetate (300 mL) and washed with brine (200 mL). The layers were separated and the organic suspension was filtered and the filter cake was washed with ice-cold ethanol, dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10.6 g, 64.9% yield) as a white solid. LCMS retention time 1.637 min; LCMS MH+ 369. Intermediate 9: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -

[00232] The title compound was prepared using the method of intermediate 12, step 2 to provide 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (1.97 g, 80.1% yield) as a white solid. LCMS retention time 1.724 min, LCMS MH+ 467. Intermediate 10: Step 1: 6 - amino - 3 - methylpyrimidine - 2,4(1H, 3H) - dione

[00233] To a solution of the 6-aminopyrimidine-2,4(1H, 3H)-dione (15 g, 118 mmol) in 1,1,1,3,3,3-hexamethyldisilazane (50 mL) was added ammonium sulfate (0.671 g, 5 mmol), then the resulting mixture was heated to reflux with stirring for 6 h. The mixture was concentrated to give a pale yellow solid. This solid was combined with acetonitrile (50 mL) and iodomethane (15 mL, 250 mmol) was added. The resulting mixture was stirred at 40°C for 16 hours. Then the mixture was concentrated, neutralized with saturated sodium bicarbonate to pH = 7, filtered, and the filter cake was washed with saline and ethanol, dried under vacuum to give 6 - amino - 3 - methylpyrimidine - 2,4(1H, 3H) - dione (7.1 g, 42.6% yield) as yellow solid. LCMS MET 142. Step 2: 6 - amino - 3 - methyl - 5 - nitrosopyrimidine - 2,4(1H, 3H) - dione

[00234] To a solution of 6 - amino - 3 - methylpyrimidine - 2,4(1H, 3H) -dione (6 g, 42.6 mmol) in acetic acid (50 mL) was added a solution of sodium nitrite (6.8 g, 98.6 mmol) in water (20 mL) dropwise, then the mixture was stirred at room temperature for 1 h. The mixture was filtered, the filter cake was washed with water and ethanol and dried under vacuum to provide 6 - amino - 3 - methyl - 5 - nitrosopyrimidine - 2,4(1H, 3H) - dione as a violet solid, which was used directly in the next step. Step 3: 5,6 - diamino - 3 - methylpyrimidine - 2,4(1H, 3H) - dione

[00235] To a solution of 6 - amino - 3 - methyl - 5 - nitrosopyrimidine - 2,4(1H, 3H) - dione in ammonium hydroxide (100 mL) was added sodium hydrosulfite (6.8 g, 39.1 mmol) in small portions at 70 °C, the mixture was stirred at 70 °C for 1 h. The mixture was concentrated and ice water was added. The suspension was filtered and the filter cake was washed with water and ethanol and dried under vacuum to give 5,6 - diamino - 3 - methylpyrimidine - 2,4(1H, 3H) - dione (2.0 g, 30.1% two-step production) as a yellow solid. LCMS MH+ 157. Step 4: 6 - amino - 5 - (4 - chlorobenzylamino) - 3 - methylpyrimidine - 2,4(1H, 3H) - dione

[00236] To a solution of 5,6 - diamino - 3 - methylpyrimidine - 2,4(1H, 3H) - dione (0.8 g, 5.13 mmol) in water (10 mL) and acetic acid (0.5 mL) was added 4-chlorobenzaldehyde (0.72 g, 5.14 mmol), the mixture was stirred at room temperature for 5 h. The mixture was cooled to 0 °C, sodium cyanoborohydride (0.3 g, 4.76 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and filtered, and the filter cake was washed with methanol, dried in vacuo to give 6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H, 3H)-dione (0.6 g, 42.9% yield) as yellow solid. LCMS MH+ 281. Step 5: 6 - amino - 5 - (4 - chlorobenzylamino) - 3 - methylpyrimidine - 2,4(1H, 3H) - dione

[00237] To a solution of 6 - amino - 5 - (4 - chlorobenzylamino) - 3 - methylpyrimidine - 2,4(1H, 3H) -dione (0.56 g, 2.0 mmol) in toluene (10 mL) was added trimethyl orthoformate (20 mL, 183 mmol), the mixture was stirred at 110 °C for 5 hours. Then the mixture was concentrated and filtered, the filter cake was washed with diethyl ether and dried under vacuum to give 6 - amino - 5 - (4 - 5-chlorobenzylamino) - 3 - methylpyrimidine-2,4(1H, 3H)-dione (0.5 g, 86.2% yield) as pale yellow solid. Mass Spec: 291 (M+H). Step 6: 8 - chloro - 7 - (4 - chlorobenzyl) -1 - methyl -1H - purine - 2,6(3H,7H) - dione

[00238] To a solution of 6 - amino - 5 - (4 - chlorobenzylamino) - 3 - methylpyrimidine-2,4(1H, 3H)-dione (0.5 g, 1.72mmol) in THF (20 ml) was added NCS (0.3 g, 2.26 mmol), the mixture was stirred at room temperature for 16 hours. Then the mixture was concentrated, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford product 8 - chloro - 7 - (4 - chlorobenzyl) -1 - methyl -1H - purine - 2,6(3H,7H) - dione (500 mg, 89.3% yield) as pale yellow solid. LCMS MH+ 325. Intermediate 11: 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethoxy)ethyl) -1 H - purine - 2,6(3H,7H) - dione

[00239] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.2 g, 0.54mmol, intermediate - 8) in DMF (3 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (169 mg, 0.81 mmol, intermediate 1 ), potassium carbonate (150 mg, 1.08 mmol) and a catalytic amount of TBAI. The mixture was stirred at 50°C overnight. It was divided between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product, which was washed with ethanol and dried under vacuum to give 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 1H - purine - 2,6(3H,7H)-dione (260 mg, 88.8 %) as a white solid. LCMS retention time 1.712 min, LCMS MH+-THP 459. Intermediate 12: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - 5 purine - 2,6(3H,7H) - dione Step 1: 8 - bromine - 3 - methyl - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00240] To a solution of 8 - bromo - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (3.5 g, 14.3 mmol, intermediate 8 step 1) in DMF (30 mL) was added potassium carbonate (3.9 g, 28.6 mmol). Then 2-(trimethylsilyl)ethoxymethyl chloride (2.37 g, 14.3 mmol) was added dropwise at 0 °C, and stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried in vacuo to give 8 - bromo - 3 - methyl - 7 -15((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) -dione (4.0 g, 74.9%) as a white solid. LCMS retention time 1.458 min, LCMS MH+ 377. Step 2: 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00241] To a solution of 8 - bromo - 3 - methyl - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (2.5 g, 6.65 mmol) in DMF (30 mL) were added 3-(trifluoromethoxy)phenol (1.78 g, 9.97 mmol) and potassium carbonate (3, 9 g, 28.6 mmol). It was heated at 80 °C overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried in vacuo to give 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) -dione (1.7 g, 54.3%) as a white solid. LCMS retention time 1.850 min, LCMS MH+ 473. Step 3: 3 - methyl -1 - (2 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethoxy)ethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2.6( 3H,7H) - dione

[00242] To a solution of 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (1.2 g, 2.54 mmol) in DMF (15 mL) was added 2 - (2 - (2 - chloroethoxy)ethoxy)tetraid ro - 2H - pyran (0.79 g, 3.82 mmol, intermediate 1), potassium carbonate (0.7 g, 5.08 mmol), TBAI (2 mg, 0.02 mmol). It was heated at 80°C overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product (1.6 g, 98.1%) as a yellow oil which was used without purification. LCMS retention time 2.179 min, LCMS MH+-THP 561. Step 4: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00243] To a solution of 3 - methyl -1 - (2 - (2 - (tetrahydro - 2H - pyran - 2 - yloxy)ethoxy)ethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (0.64 g, 1, 16 mmol,) in ethanol (15 mL) was added HCl (3 mL); then it was refluxed overnight. The solvent was concentrated to give a crude product which was purified by column chromatography to give 1 -(2-(2-hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (420 mg, 84% yield) as a white solid. LCMS retention time 1.209 min, LCMS MH+ 431. Intermediate 13: 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 1H - purine - 2,6(3H,7H) - dione To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine -2,6(3H,7H) -dione (2.0g, 5.4mmol, intermediate 8) in DMF (10ml) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.35g, 6.5mmol, intermediate 2), potassium carbonate ( 1.49 g, 10.8 mmol). The mixture was stirred at 50°C overnight. It was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried under vacuum to give 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 1H - purine - 2,6(3H,7H) -dione (2.10 g, 74.4 %) as a white solid. LCMS retention time 1.669 min LCMS MH+- THP 415. Intermediate 14: 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione

[00244] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.5 g, 1.35 mmol, intermediate 8) in DMF (5 mL) was added 2 - (3 - bromopropoxy)tetrahydro - 2H - pyran (0.45 g, 2.03 mmol, intermediate 3), potassium carbonate (0.37 g, 2.7 mmol). The mixture was stirred at 50 °C for 3 h; then it was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried under vacuum to give 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione (0.5 g, 72.2%) as a white solid. LCMS retention time 1.732 min, LCMS MH+-THP 429. Intermediate 15: 1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione Step 1: 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -157 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00245] To a solution of 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.0 g, 2.12 mmol, intermediate 12, step 2) in DMF (10 mL) was added 2 - (3 - bromopropoxy)tetraid ro - 2H - pyran (0.57 g, 2.54 mmol, intermediate 3) and potassium carbonate (0.88 g, 6.36 mmol). The reaction was heated to 50°C for 3 hours. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (1:3) to give 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)e toxy)methyl)-1H-purine-2,6(3H,7H)-dione (0.9 g, 70.0% yield) as a white solid. LCMS retention time 2.270 min, LCMS MH+- THP 531. Step 2: 1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00246] To a solution of 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (0.9 g, 1.5 mmol) in ethanol (10 mL) was HCl (2 mL) added, then refluxed overnight. The solvent was concentrated to give a crude product which was collected, washed with ethanol and dried in vacuo to give 1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.5 g, 80% yield) as a white solid. 1H NMR (DMSO-d6) δ 13.52 (br, 1H), 7.55 - 7.59 (t, 1H), 7.47 (s, 1H), 7.36 - 7.38 (d, 1H), 7.28 - 7.30 (d, 1H), 4.45 (br, 1H), 3.89 - 3.93 (t, 2 H), 3.39 - 3.43 (t, 2H), 3.42 (s, 3H), 1.66 - 1.69 (m, 2H). LCMS retention time 1.308 min, LCMSMH+ 401. Intermediate 16: 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 - yl)methyl) -1 H - purine - 2,6(3H,7H) - dione Step 1: 8 - bromo - 3 - methyl -1 - (3 - (tetrahydro - 2 H - pyran - 2 - yloxy)propyl) - 7 - ((2 (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00247] To a solution of 8 - bromo - 3 - methyl - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (4.0 g, 10.6 mmol, intermediate 12 step 1) in DMF (50 mL) was added 2-(3-bromopropoxy)tetrahydro - 2H - pyran (2, 6 g, 11.6 mmol, intermediate 3), potassium carbonate (2.4 g, 17.4 mmol). It was heated to 60 °C overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product (5.2 g, 94.5%) as a yellow oil which was used directly for the next step had LCMS MH+ 518. Step 2: 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00248] To a solution of 8 - bromo - 3 - methyl -1 - (3 - (tetrahydro - 2 H - pyran - 2 - yloxy)propyl) - 7 - ((2 (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H)-dione (4.2 g, 8.12 mmol) in ethanol (30 mL) was added HCl (6 mL). The mixture was refluxed overnight. The solvent was removed to give a crude product which was washed with ethanol and dried in vacuo to give 8 - bromo - 1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H)-dione (2.0 mg, 81.3% yield) as a white solid. LCMSMH+ 303. Step 3: 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 - yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00249] To a solution of 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.5 g, 51.65 mmol) in DMF (50 mL) was added 2 - (chloromethyl) - 5 - methylthiazole (0.27 g, 1.81 mmol, intermediate 4), potassium carbonate (0.3 4 g, 2.48 mmol) and TBAI (2 mg, 0.02 mmol). The mixture was heated at 60°C for 3 hours. The mixture was cooled; then partitioned between ethyl acetate and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The residue was purified by a column chromatography by ellicing with DCM/methanol (60: 1 to 30: 1) to supply 8 - bromine -1 - (3 - hydroxipropil) - 3 - methyl - 7 - (5 - methytiazol - 2 - il) methyl) - 1h - purine - 2.6 (3h, 7h) - diona (0.4 g, 58.4 %) as a yellow oil that was used without another purification. LCMS MH+ 416. Intermediate 17: 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-trifluoromethoxy)phenoxy)ethoxy)-1 H - purine - 2,6(3H,7H) - dione Step 1: 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00250] To a solution of 2-(3-(trifluoromethoxy)phenoxy)ethanol (0.64 g, 2.9 mmol, intermediate 5) in THF (15 mL) was added sodium hydride (0.23 g, 9.67 mmol) at 0 °C. It was stirred at 0 °C for 30 min, then 8 - bromo - 3 - methyl -1 - (3 - (tetrahydro - 2 H - pyran - 2 - yloxy)propyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) -dione (1.0 g, 1.93 mmol, intermediate 16 step 1) was added. The mixture was stirred 16 hours. The reaction was quenched with aq. (2 ml) at 0°C; then it was partitioned between ethyl acetate and water. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 2.144; LCMS MH+- THP 575. Step 2: 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) -1H - purine - 2,6(3H,7H) - dione

[00251] To a solution of 3 - methyl -1 - (3 - (tetrahydro - 2 H - pyran - 2 - yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (1.2 g, 1.8 2 mmol) in THF (15 mL) was added TBAF (3.7 mL, 3.64 mmol). The mixture was stirred at 80°C overnight. It was then cooled, divided between ethyl acetate and water. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether and ethyl acetate (2:1) to give 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine -2,6(3H,7H)-dione (900 mg, 93.7% yield) as a white solid. LCMS retention time 1.613; LCMS MH+ - THP 445. Intermediate 18: 7 - benzyl - 8 - chloro -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl)-3-((2-20 (trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione Step 1: 2 - amino - 7 - benzyl - 1H - purin - 6(7H) - one

[00252] To a solution of 2 - amino - 9 - ((2R,3S,4R,5S) - 3,4 - dihydroxy - 5 - (hydroxymethyl)tetrahydrofuran - 2 -yl) - 1H - purin - 6(9H) -one (14g, 49.47 mmol) in DMSO (50 mL) was added (bromomethyl)benzene (10 g, 59.36 mmol). The mixture was stirred at 50°C overnight. Then the mixture was cooled to room temperature and HCl (50 ml, 10% w/w) was added and the mixture was stirred at 70 °C for 2 h. The reaction was cooled to room temperature, filtered and the filter cake was washed with water and ethanol and dried under vacuum to give 2 - amino - 7 - benzyl - 1H - purin - 6(7H) - one (10 g, 74.2% yield) as a gray solid. LCMS retention time 0.529 min; LCMS MH+ 242. Step 2: 2 - amino - 7 - benzyl - 1H - purin - 6(7H) - one

[00253] To a solution of 2 - amino - 7 - benzyl - 1H - purin - 6(7H) - one (6.8 g, 28.33 mmol) in acetic acid (80 mL) and water (10 mL) was added a solution of sodium nitrite (1.95 g, 28.26 mmol) in water (10 mL) at 50 °C dropwise, the mixture was stirred at 50 °C for 1 hour. Then the mixture was cooled to room temperature and stirred for a further 1.5 hours. The mixture was filtered; then the filter cake was washed with water and ethanol, dried in vacuo to give 2 - amino - 7 - benzyl - 1H - purin - 6(7H) - one (6.5 g, 94.9% yield) as yellow solid. LCMS retention time 0.502 min; LCMS MH+243. Step 3: 7 - benzyl - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00254] To a solution of 2 - amino - 7 - benzyl - 1H - purin - 6(7H) - one (6.5 g, 26.86 mmol) in DMF (50 mL) was added potassium carbonate (5.6 g, 40.58 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (4.45 g, 27.08 mmol) at 0°C. The resulting mixture was stirred at 60°C for 16 hours. The mixture was diluted with water and filtered. The filter cake was washed with water twice, dried in vacuo to give 7-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (10.8 g, 100% yield) as yellow oil. LCMS retention time 1.523 min; LCMS MH+-58 315. Step 4: 7 - benzyl - 8 - chloro - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) -dione

[00255] To a solution of 7 - benzyl - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (6.0 g, 16.13 mmol) in DMF (50 mL) was added NCS (3.23 g, 24.19 mmol) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 7 - benzyl - 8 - chloro - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) -dione (5.1 g, 77.9% yield) as pale yellow oil. Product tlc [petroleum ether/ethyl acetate (15:1) iodine detection, Rf 0.6) Step 5: 7 - benzyl - 8 - chloro -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00256] To a solution of 7 - benzyl - 8 - chloro - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) -dione (5 g, 12.32 mmol) in DMF (30 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (3.60 g, 16.22 mmol, intermediate 14 step 1), followed by potassium carbonate (3.4 g, 24.64 mmol). The mixture was stirred at 65°C overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with saline, dry on magnesium sulfate, filtered and concentrated to provide 7 - benzil - 8 - chlorine -1 - (3 - (tetrahydro - 2h - piran - 2 - iloxi) propyl) - 3 - (2 - (trimethylsilil) etoxi) methyl) - 1h - Purina - 2.6 (3h) 93.3% of production) such as yellow oil. LCMS retention time 3.574 min; LCMS MNa+ 571. Intermediate 19: 1 - (4 - (bromomethyl)phenyl)ethanone

[00257] To a solution of 1-p-tolylethanone (600 mg, 4.47 mmol) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (955 mg, 5.37 mmol) and BPO (31 mg, 0.13 mmol). The mixture was refluxed for 3 h; then it was cooled, and filtered. The filtrate was concentrated to give 1-(4-(bromomethyl)phenyl)ethanone (683 mg, 71%) as a brown oil. LCMS MH+ 213. Intermediate 20: 2 - (3 - (4 - methyloxazol - 2 - yl)phenyl)acetic acid Step 1: 2-(3-(4-methyloxazol-2-yl)phenyl)acetonitrile

[00258] A solution of 3-(cyanomethyl)benzamide (200 mg, 1.25 mmol) in 1 - chloropropan - 2 - one (2 mL) was irradiated with microwave at 120 °C for 20 min in a sealed tube. The mixture was concentrated to provide the crude product (110 mg), which was directly used for the next step without purification. LCMSMH+ 199. Step 2: 2 - (3 - (4 - methyloxazol - 2 - yl)phenyl)acetic acid

[00259] To a solution of 2 - (3 - (4 - methyloxazol - 2 -yl)phenyl)acetonitrile (110 mg, 0.555 mmol) in 1,4-20dioxane (3 mL) was added 6N HCl (1 mL). Then the mixture was stirred at 80 °C for 2 h. The mixture was concentrated and purified by silica gel chromatography eluting with DCM/methanol (20:1) to give 2-(3-(4-methyloxazol-2-yl)phenyl)acetic acid (85 mg, 70.5%) as a yellow syrup. LCMS retention time 0.920 min, LCMS MH+ 218. Intermediate 21: 1-(4-chlorophenyl)ethyl methanesulfonate

[00260] The title compound was prepared using the method of intermediate 34 to provide 1-(4-chlorophenyl)ethyl methanesulfonate (258 mg, 23.6% yield) as a yellow oil, which was directly used for the next reaction without purification. Intermediate 22: 2-(bromomethyl)-5-methylthiazole

[00261] To a solution of 2,5-dimethylthiazole (200 mg, 1.77 mmol) in carbon tetrachloride (5 mL) was added NBS (377 mg, 2.12 mmol), followed by BPO (20 mg, 0.083 mmol). Then the mixture was heated to reflux for 4 hours with stirring. The mixture was cooled to room temperature and filtered, the filtrate was concentrated to give crude 2-(bromomethyl)-5-methylthiazole (260 mg, 76.9%) as a yellow oil, which was used without purification. Intermediate 23: 2 - (chloromethyl)thiazole Step 1: thiazol - 2 -ylmethanol

[00262] To a solution of n - BuLi (8.4 ml, 1.6 mol/1.13.4 mmol) in THF (30 ml) was added 2-bromothiazole (377 mg, 2.12 mmol) dropwise under nitrogen atmosphere at -70 °C, and the mixture was stirred at room temperature for 1 hour. Then DMF (1.4 ml, 18.3 mmol) was added to the solution dropwise under a nitrogen atmosphere at -70 °C. The resulting mixture was stirred at room temperature for 1 h. Then the mixture was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. The yellow oil was dissolved in methanol (15 ml), cooled to -60 °C, and sodium borohydride (463 mg, 12.2 mmol) was added portionwise under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched with acetone and concentrated. The residue was diluted with ethyl acetate and water, and the phases were separated. The organic layer was dried over sodium sulfate, filtered and concentrated, then purified by silica gel chromatography eluting with petroleum / ethyl acetate = 3:1 to provide thiazole - 2 -ylmethanol (230 mg, 16.4% yield) as brown oil. LCMS MH+ 116. Step 2: 2 - (chloromethyl)thiazole

[00263] To a solution of thiazol-2-ylmethanol (230 mg, 2.0 mmol) in DCM (5 mL) was added thionyl chloride (0.19 mL, 2.6 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and water, and the phases were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 2-(chloromethyl)thiazole (240 mg, crude), which was used without purification. Intermediate 24: 5 - (chloromethyl) - 2 - methylpyrimidine Step 1: (2 - methylpyrimidin - 5 - yl)methanol

[00264] To a solution of 2-methylpyrimidine-5-carboxylic acid (150 mg, 1.23 mmol) in ethanol (5 mL) was added sodium borohydride (93 mg, 2.46 mmol). The mixture was stirred at room temperature for 3 hours. It was quenched with aqueous HCl (2N, 2 mL), extracted with DCM, dried over sodium sulfate, filtered and concentrated to give the yellow oily product (2 - methylpyrimidin - 5 - yl)methanol (95 mg, 62.6%). LCMS MH+ 125. Step 2: 5 - (chloromethyl) - 2 - methylpyrimidine

[00265] A solution of (2-methylpyrimidin-5-yl)methanol (95 mg, 0.77 mmol) in thionyl chloride (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness and used without purification. LCMS MH+ 143. Intermediate 25: 3 - (4 - methyloxazol - 2 - yl)phenol Step 1:2-(3-methoxyphenyl)-4-methyloxazole

[00266] To a solution of 3-methoxybenzamide (1.5 g, 9.9 mmol) in toluene (15 mL) was added 1-chloropropan-2-one (1.37 g, 14.9 mmol), and the mixture was stirred at reflux for 16 hours. The mixture was cooled and concentrated to give the crude product, which was purified by silica gel chromatography eluting with ethyl acetate / petroleum ether (1:5) to give 2-(3-methoxyphenyl)-4-methyloxazole (1.21 g, 64.6% yield) as yellow syrup. LCMS MH+ 190. Step 2: 3 - (4 - methyloxazol - 2 - yl)phenol

[00267] A solution of 2 - (3 - methoxyphenyl) - 4 - methyloxazole (1.1 g, 5.79 mmol) in aqueous hydrogen bromide (10 mL, 48% weight/weight) was heated to 100 °C for 16 hours. The mixture was concentrated to give 153 - (4 - methyloxazol - 2 -yl)phenol (0.97 g, crude), which was used without purification. LCMS MH+ 176. Intermediate 26: 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - benzyl - 8 - chlorine -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione

[00268] A solution of 7 - benzyl - 8 - chloro -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (500 mg, 0.912 mmol, intermediate 18) in ethyl alcohol (20 mL) was Concentrated HCl (5 mL) is added. The mixture was stirred at 80°C overnight. Then the mixture was concentrated, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 7 - benzyl - 8 - chloro -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (280 mg, 91.9% yield) as yellow oil. LCMS retention time 1.710 min; LCMS MH+ 335. Step 2: 7 - benzyl - 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione

[00269] To a solution of 7 - benzyl - 8 - chloro -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (150 mg, 0.449 mmol) in DMF (5 mL) was added iodoethane (0.16 g, 0.13 mmol), followed by potassium carbonate (0.4 g, 2.90 mmol). The mixture was stirred at 40°C for 4 hours. The reaction was cooled and diluted with ethyl acetate. The organic phase was washed with water and brine; then it was dried over magnesium sulfate, filtered and concentrated to give 7-benzyl - 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (0.15 g, 92.3% yield) as yellow oil. LCMS retention time 1.296 min; LCMS MH+ 363. Step 3: 7 - benzyl - 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione

[00270] A solution of sodium (50 mg, 2.17 mmol) in ethyl alcohol (10 mL) was stirred at 40 °C under nitrogen until the sodium was consumed. Then 7 - benzyl - 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (150 mg, 0.414 mmol) was added at 0 °C and the mixture was stirred at 40 °C for 4 h. The mixture was quenched with ice water (15 mL) and concentrated. The aqueous residue was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 7 - benzyl - 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (120 mg, 77.9% yield) as yellow solid. LCMS retention time 1.488 min; LCMS MH+ 373. Step 4: 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione Caption of the figure above: ammonium formate

[00271] 7 - benzyl - 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (0.12 g, 0.323 mmol) was dissolved in ethanol (20 mL) and the mixture was degassed and recharged with nitrogen three times. Ammonium formate (0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added. The mixture was again degassed and recharged with nitrogen three times; then it was heated to 80 °C and stirred overnight. The mixture was cooled and filtered, and the filter cake was washed with methanol. The filtrate was concentrated to give 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (70 mg, 77.1% yield) as a white solid. LCMS retention time 0.413 min; LCMS MH+ 283. Intermediate 27: 3 - (morpholinomethyl)phenol

[00272] To a solution of 3-hydroxybenzaldehyde (1 g, 8.19 mmol) in methanol (15 mL) was added morpholine (1.42 g, 16.4 mmol). Then the mixture was stirred at room temperature for 1 hour. The mixture was cooled to -5 °C, and sodium borohydride (403 mg, 10.6 mmol) was added in small portions. The resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with dilute hydrochloric acid and concentrated. The aqueous solution was washed with ethyl acetate and then made basic by the addition of ammonium hydroxide. The basic aqueous suspension was extracted with ethyl acetate and this organic layer was dried and concentrated to give 3-(morpholinomethyl)phenol (0.76 g, 48.2%) as a white solid. LCMS retention time 0.871 min, LCMS MH+ 194. Intermediate 28a and 28b: 2 - chloro - 5 - hydroxybenzaldehyde (28a) and 4 - chloro - 3 - hydroxybenzaldehyde (28b)

[00273] To a solution of 3-hydroxybenzaldehyde (1 g, 10 mmol) in acetonitrile (50 mL) was added p-toluenesulfonic acid (3.4 g, 20 mmol) portionwise. The mixture was stirred at room temperature for 5 min, and NCS (1.33 g, 10 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with aqueous sodium thiosulfate, and diluted with ethyl acetate and saline. The organic layer was separated, dried, and concentrated to give the crude products which were purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (10:1 to 5:1) to give 2 - chloro - 5 - hydroxybehzaldehyde (340 mg, 21.7% yield intermediate 28a) as yellow solid; 1H NMR (CDCl3) 10.43 (s, 1H), 7.54 - 7.56 (d, 1H), 7.30 - 7.37 (m, 2H) and 4-chloro-3-hydroxybenzaldehyde (310 mg, 19.7% yield, intermediate 28b) as yellow solid. 1H NMR (CDCl3) δ 10.43 (s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.06 - 7.09 (dd, 1H). Intermediate 29: 4 - chlorine - 3 - (morpholinomethyl)phenol

[00274] To a solution of 2 - chloro - 5 - hydroxybenzaldehyde (200 mg, 1.27 mmol, intermediate 28a) and morpholine (280 mg, 3.21 mmol) in methanol (10 mL) was added 2 drops of acetic acid and the mixture was stirred at room temperature for 2 hours. To the mixture, sodium borohydride (97 mg, 2.56 mmol) was added and the resulting mixture was stirred at room temperature for 4 hours. The mixture was quenched with dilute hydrochloric acid and concentrated to provide the crude product. This crude material was purified by chromatography on silica gel eluting with petroleum ether / ethyl acetate (5:1 to 1:1) to provide 4 - chloro - 3 - (morpholinomethyl)phenol (150 mg, 51.8% yield) as a white solid. LCMS retention time 0.378; LCMS MH+ 228. Intermediate 30: 4 - chloro - 3 - (morpholinomethyl)phenol

[00275] The title compound was prepared using the method of intermediate 29 starting with intermediate 28b but using sodium triacetoxyborohydride as the reducing agent to provide 4 - chloro - 3 - (morpholinomethyl)phenol (190 mg, 68.1% yield) as yellow solid. LCMS retention time 0.347; LCMS MH+ 228. Intermediate 31: 3 - (chloromethyl) - 5-methylisoxazole Step 1: (5 - methylisoxazol - 3 - yl)methanol

[00276] To a solution of ethyl 5-methylisoxazole-3-carboxylate (500 mg, 3.22 mmol) in ethanol (8 mL) was added sodium borohydride (244 mg, 6.44 mmol) in portions at 0 °C. After the addition, the mixture was stirred at room temperature for 16 hours. The mixture was quenched with dilute hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give (5-methylisoxazol-3-yl)methanol (370 mg, 100% yield) as a yellow oil, which was used directly in the next reaction without purification. LCMS retention time 0.391 min; LCMS MH+ 114. Step 2: 3 - (chloromethyl) - 5 - methylisoxazole

[00277] To a solution of (5-methylisoxazol-3-yl)methanol (370 mg, 3.27 mmol) in DCM (5 mL) was added thionyl chloride (5 mL) dropwise. The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give 3-(chloromethyl) - 5 - methylisoxazole (350 mg, crude) as a brown oil, which was used without purification. LCMS retention time 0.768 min; LCMS MH+ 132. Intermediate 32: 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate Step 1: 2 - (2 - ethyl -1,3 - dioxolan - 2 - yl)methyl acetate

[00278] To a solution of methyl 3-oxopentanoate (3 g, 23.1 mmol) in toluene (30 mL) was added ethane-1,2-diol (3 mL, 70.2 mmol) and p-toluenesulfonic acid (500 mg, 2.91 mmol), the resulting mixture was stirred at 120 °C overnight. Then the mixture was concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over magnesium sulfate; then filtered and concentrated to afford methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1.7 g, 42.5%) as a yellow oil which was used without purification. tlc product [petroleum ether / ethyl acetate (15:1) developed with iodine, Rf 0.6] Step 2: 2 - (2 - ethyl -1,3 - dioxolan - 2 - yl)ethanol

[00279] To a solution of methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1 g, 5.75 mmol) in anhydrous THF (40 mL) was added LAH (900 mg, 23.7 mmol) at 0 °C under nitrogen atmosphere, the resulting mixture was stirred at 90 °C overnight. The mixture was cooled to room temperature, and ethyl acetate was added to the mixture. The resulting suspension was filtered and the filtrate was concentrated to dryness. The crude product was purified by chromatography on silica gel eluting with DCM / methanol (100:1 to 20:1) to give 2 - (2 - ethyl -1,3 - dioxolan-2-yl)ethanol (233 mg, 27.4%) as a yellow oil which was used without purification. Step 3: 2 - (2 - ethyl -1,3 - dioxolan - 2 - yl)ethyl methanesulfonate

[00280] To a solution of 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 1.59 mmol) and TEA (327 mg, 3.2 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.23 mL, 2.92 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (500 mg, 100%) as a yellow oil which was used without purification. tlc product [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.6] Intermediate 33: 4 - 3 - hydroxybutyl methylbenzenesulfonate

[00281] To a solution of butane -1,3-diol (1 g, 11.1 mmol), TEA (4.6 mL, 33.2 mmol) and DMAP (30 mg, 0.25 mmol) in DCM (20 mL) was added p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) at 15°C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3-hydroxybutyl 4-methylbenzenesulfonate (3 g, 100% yield) as a yellow oil, which was used without purification. tlc product [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.4] Intermediate 34: 2 - (2 - methoxyethoxy)ethyl methanesulfonate

[00282] To a solution of 2-(2-methoxyethoxy)ethanol (300 mg, 2.5 mmol) in DCM (5 mL) was added methanesulfonyl chloride (370 mg, - 2.6 mmol) dropwise at 0 °C. After stirring at this temperature for 5 min, TEA (505 mg, 5.0 mmol) was added. It was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a crude oily product, which was used without purification. Product [petroleum ether/ethyl acetate [1:1] developed with iodine, Rf 0.5] Intermediate 35: 3 - (3 - (trifluoromethoxy)phenoxy)propan -1 -ol

[00283] To a solution of 3-(trifluoromethoxy)phenol (0.3 g, 1.68 mmol) in DMF (10 mL) was added 3-bromopropan-1-ol (0.47 g, 3.37 mmol) and potassium carbonate (0.47 g, 3.37 mmol). The reaction was heated to 80°C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether and ethyl acetate (10:1) to give 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (0.32 g, 80.6 10% yield) as yellow oil. Intermediate 36: 3 - (2 - hydroxyethoxy)benzaldehyde

[00284] The title compound was prepared using the method of intermediate 5, except that the reaction was carried out at 140 °C to provide 3-(2-hydroxyethoxy)benzaldehyde (1.1 g, 73.4% yield) as a yellow oil which was used without purification. 1H NMR (DMSO-d6) δ 9.98 (s, 1H), 7.53 - 7.51 (m, 2H), 7.44 - 7.43 (m, 1H), 7.30 - 7.29 (m, 1H), 4.95 - 4.93 (t, 1H), 4.08 - 4.06 (t, 2H), 3.77 - 3.73 (q, 2H) Intermediate 37: 3 - (3 - (trifluoromethoxy)phenyl)propan -1 -ol Step 1: 3 - (3 - (trifluoromethoxy)phenyl)prop - 2 - in -1 -ol

[00285] To a solution of 1 - iodine - 3 - (trifluoromethoxy)benzene (0.5 g, 1.73 mmol) in toluene (10 mL) was added prop - 2 - in -1 -ol (0.15 g, 2.62 mmol) and morpholine (0.5 mL). Then cuprous iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) were added to the mixture under nitrogen. The reaction was heated to 80 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate / petroleum ether (1:6 to 1:3) to give 3-(3-(trifluoromethoxy)phenyl)prop - 2 - in -1 -ol (0.3g, 80.2%) as a yellow oil. LCMS retention time 51.552 min. Step 2: 3 - (3 - (trifluoromethoxy)phenyl)propan -1 -ol

[00286] To a solution of 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g, 1.39 mmol) in THF (10 10 mL) was added LAH (63 mg, 1.68 mmol) portionwise at 0°C. The reaction was stirred at 0°C for 3 hours. The reaction was carefully brought together by dropwise addition of ethyl acetate at 0°C and the mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate / petroleum ether (1:4 to 1:1) to give 3-(3-15(trifluoromethoxy)phenyl)propan-1-ol (0.26 g, 85.2%) as a yellow oil which was used without purification. 1H NMR (CD3OD) S 7.37 - 7.39 (d, 1H), 7.31 - 7.35 (m, 1H), 7.15 - 7.17 (d, 1H), 4.07 - 4.1L (t, 2H), 2.72 - 2.76 (1, 2H), 1.83 - 1.90 (m, 2H). Intermediate 38: 2 - (cyclohexyloxy)ethanol Step 1: 1,4 - dioxaspiro[4,5]decane(JF -0003 57-022)

[00287] To a solution of cyclohexanone (10 g, 0.102 mol) in ethylene glycol (50 mL) was added iodine (3.88 g, 15.3 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and extracted with saturated aqueous sodium thiosulfate. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (1:8) to give 1,4-dioxaspiro[4.5]decane (6.8 g, 46.9% yield) as a clear oil. 1H NMR (CDCl3) δ 3.93 (s, 4H), 1.58 - 1.59 (d,8H), 1.39 - 1.41 (m, 2H). Step 2: 2 - (cyclohexyloxy)ethanol

[00288] To the suspension of zirconium tetrachloride (10.65 g, 45.7 mmol) in THF (100 mL) was added sodium borohydride (4.3 g, 114.3 mmol) in small portions at room temperature. A solution of 1,4-dioxaspiro[4.5]decane (6.5 g, 45.7 mmol) in THF (20 mL) was added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction was carefully quenched with 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (3:2) to give 2-(cyclohexyloxy)ethanol (3.9 g, 59.2% yield) as pale yellow oil. 1H NMR (CDCl3) δ 3.68 - 3.70 (t, 2H), 3.53 - 3.56 (m, 2H), 3.27 - 3.29 (m, 1H), 2.54 (br, 1H), 1.89 - 1.93 (m, 2H), 1.70 - 1.73 (m, 152H), 1.51 - 1.54 (m, 1H), 1.17 - 1.28 (m, 5H). Intermediate 39: 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione Legend of the figure above: Aqueous NaOH Step 1: 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Caption of the figure above: aqueous NaOH

[00289] To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1 -methylpyrimidine - 2,4(1H, 3H) -dione (80 mg, 0.289 mmol, intermediate 59) in ethanol (2 mL) was added 2-(2-fluoro - 5 - (trifluoromethoxy)phenyl)acetic acid (68.8 mg, 0.289 mmol) followed by EDCI (66.5 mg, 0.347 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated. The residue was dissolved in ethanol (3 mL) and 1 mM sodium hydroxide (1 mL) was added. The resulting mixture was stirred at reflux for 3 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give a crude solid product, which was triturated with ethanol, collected and dried to give 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (67 mg, 48.4% yield) as a pale yellow solid. LCMS retention time 1.611 min; LCMS MH+ 479. Step 2: 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00290] To a solution of 8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (67 mg, 0.14 mmol) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (43.2 mg, 0.21 mmol) followed by carbon potassium act (38.7 mg, 0.28 mmol). The reaction was heated to 60°C for 3 hours. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give a crude product, which was purified by chromatography on silica gel eluting with DCM/methanol (60:1) to give 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (71.2 mg, 8 4.3% yield) as a white solid. LCMS retention time 2.375 min; LCMS MH+603. Step 3: 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00291] To a solution of 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H)-dione (71 mg, 0.118 mmol) in DCM (1 mL) was added TFA (0.3 mL) and trifluoromethanesulfonic acid (0 .2 mL). The reaction was stirred at room temperature for 16 hours. The mixture was concentrated and the residue partitioned between DCM and aqueous sodium bicarbonate. The organic layer was dried and concentrated to give 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H)-dione (39 mg, 68.4% yield) as a yellow syrup, which was used directly without purification. LCMS retention time 1.686 min; LCMS MH+ 483. Intermediate 40: (5 - methyloxazol - 2 - yl)methanol Step 1: 2 - (2 - hydroxypropylamino) - 2 - ethyl oxoacetate

[00292] To a solution of 1-aminopropan-2-ol (2 g, 26.6 mmol) and TEA (4.03 g, 39.9 mmol) in DCM (50 mL) was added ethyl 2-chloro-2-oxoacetate (4.36 g, 31.95 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM and extracted with brine. The organic layer was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (2:1) to give ethyl 2 - (2 - hydroxypropylamino) - 2-oxoacetate (2.19 g, 51% yield) as yellow syrup. LCMS retention time 0.348 min, LCMS MH+ 176. Step 2: Ethyl 2 - oxo - 2 - (2 - oxopropylamino)acetate

[00293] To a solution of ethyl 2-(2-hydroxypropylamino)-2-oxoacetate (2.1 g, 13 mmol) in DCM (30 mL) was added Dess-Martin periodinane (6.2 g, 14.6 mmol) in portions at 0 °C and the resulting mixture was stirred at room temperature for 16 hours. The reaction was diluted with DCM and extracted with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried and concentrated to give the crude product, which was purified by silica gel chromatography eluting with DCM/methanol (60:1) to give ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7g, 81.2% yield) as yellow syrup. LCMS retention time 0.392 min, LCMS MH+ 174. Step 3: 5 - methyloxazole - 2 - ethyl carboxylate

[00294] To a solution of ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7 g, 9.8 mmol) in toluene (10 mL) was added phosphorus oxychloride (2 mL). The mixture was heated to reflux for 3 hours. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (20 mL). This organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (4:1) to give ethyl 5-methyloxazole-2-carboxylate (0.68 g, 44.1% yield) as yellow syrup. 1H NMR (CDCl3) δ 6.97 (s, 1H), 4.44 - 4.49 (q, 2H), 2.43 (s, 3H), 1.42 - 1.46 (t, 2H). LCMS retention time 0.643 min; LCMS MH+ 156. Step 4: (5 - methyloxazol - 2 - yl)methanol

[00295] To a solution of ethyl 5-methyloxazole-2-carboxylate (0.68 g, 4.38 mmol) in anhydrous THF (10 mL) was added LAH (250 mg, 6.59 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with ethyl acetate and filtered. The filter cake was washed several times with ethyl acetate and the combined filtrate was concentrated to give the crude product which was purified by silica gel chromatography eluting with DCM/methanol (65:1) to give (5-methyloxazol-2-yl)methanol (0.33 g, 66.6% yield) as yellow syrup. LCMS retention time 0.328 min; LCMS MH+ 114. Intermediate 41: 5 - (chloromethyl)isoxazole

[00296] To a solution of isoxazole -5-carboxylic acid (1.0 g, 8.8 mmol) in THF (10 mL) was added borane-THF complex (26.4 mL, 26.4 mmol) at 0 °C. The reaction was stirred at room temperature until the substrate was consumed. The reaction was quenched with ethanol (5 mL) at 0 °C. The reaction mixture was partitioned between ethyl acetate and water. The combined organic phase was dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (2:1 to give isoxazole - 5 -ylmethanol (670 mg, 77.0% yield) as a pale yellow oil. LCMS retention time 50.329 min; LCMS MH+ 100.

[00297] Isoxazole - 5 - ylmethanol (50 mg, 0.5 mmol,) was dissolved in thionyl chloride (1 mL) at 0 °C. The reaction was stirred at room temperature until the substrate was consumed. The reaction was concentrated to provide 5-(chloromethyl)isoxazole as a brown solid which was used without purification. LCMS retention time 0.349 min; LCMS MH+ 118. Intermediate 42: (1-(hydroxymethyl)cyclopropyl)methyl methanesulfonate

[00298] To a solution of cyclopropane-1,1-diyldimethanol (0.1 g, 0.98 mmol) in DCM (5 mL) was added TEA (0.15 g, 1.44 mmol). Methanesulfonyl chloride (0.11 g, 0.98 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 2 h. The mixture was partitioned between DCM and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. Intermediate 43: 2 - (1 - hydroxycyclopentyl)ethyl methanesulfonate Step 1: 2 - (1 - hydroxycyclopentyl)tert -butyl acetate

[00299] To a solution of tert-butyl acetate (5.0 g, 42.8 mmol) in THF (20 mL) was added lithium diisopropylamide (21.4 mL, 42.8 mmol) at -60 °C. After stirring at -60 °C for 30 min, cyclopentanone (3.0 g, 35.7 mmol) was added at -60 °C. The reaction was stirred 1 h; then it was quenched with aqueous ammonium chloride (5 mL) at -60 °C and the mixture was warmed to room temperature. The reaction was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give tert-butyl 2-(1-hydroxycyclopentyl)acetate (5.0g, 70.1% yield) as a yellow oil. Step 2: 1 - (2 - hydroxyethyl)cyclopentanol

[00300] To a solution of tert-butyl 2-(1-hydroxycyclopentyl)acetate (0.5 g, 2.5 mmol) in THF (10 mL) was added lithium aluminum hydride (0.28 g, 7.5 mmol) portionwise at 0°C. The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (1:1) to give 1-(2-hydroxyethyl)cyclopentanol (0.33 g, 100%) as a yellow oil. Step 3: 2 - (1 - hydroxycyclopentyl)ethyl methanesulfonate

[00301] To a solution of 1-(2-hydroxyethyl)cyclopentanol (190 mg, 1.46 mmol) in dry dichloromethane (2 mL) was added methanesulfonyl chloride (200.3 mg, 1.75 mmol) dropwise at 0 °C, followed by TEA (295 mg, 2.92 mmol). Then the mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product (50mg, 31.1% yield), which was used without purification. Intermediate 44: 2-(1-hydroxycyclobutyl)ethyl methanesulfonate

[00302] The title product was prepared using the method of Intermediate 43. Intermediate 45: 4 - bromo - 2 - methylbutan - 2 - ole

[00303] To a solution of methyl 3-bromopropanoate (0.2 g, 1.2 mmol) in THF (5 mL) was added methyl magnesium bromide (2.4 mL, 2.4 mmol) at 0°C. The mixture was stirred at this temperature until the substrate was consumed based on tlc [petroleum ether/ethyl acetate (3:1); product Rf 0.3]. The reaction was quenched with ammonium chloride (2 mL) at 0 °C. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give 4 - bromo - 2 - methylbutan - 2 -ol (0.15 g, 75.1% yield) as a yellow oil. Intermediate 46: 1 - (2 - bromoethyl)cyclopropanol

[00304] To a solution of ethyl 3-bromopropanoate (0.5 g, 2.76 mmol) in THF (5 mL) was added titanium tetraisopropanolate (0.8 mL, 0.27 mmol) at 0 °C. Ethyl magnesium bromide (8.27 mL, 8.27 mmol) was added to the mixture at 0 °C. The reaction was stirred at this temperature 2 hours. The reaction was quenched with aqueous ammonium chloride (2 mL) at 0°C. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 1 - (2 - bromoethyl)cyclopropane (0.35 g, 77.7% yield) as a yellow oil. Intermediate 47: 7 - benzyl - 3 - ethyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - benzyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00305] To a solution of 7 - benzyl - 8 - chloro - 3 - ((2 - (trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-5dione (500 mg, 1.232 mmol, product of intermediate 18, step 4) in DMF (3 mL) was added 3 - (trifluoromethoxy)phenol (280 mg, 1.55 mmol), followed by potassium carbonate (400 mg, 2.90 mmol). The mixture was stirred at 80°C overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated to give 7 - benzyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H)-dione (0.59 g, 87.3% yield) as a brown oil. LCMS retention time 2.157 min; LCMS MH+ 549. Step 2: 7 - benzyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00306] To a solution of 7 - benzyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (0.59 g, 1.07 mmol) in ethanol (20 mL) was added concentrated HCl (2 mL). The reaction was stirred at 80°C for 16 hours. The reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated to give 7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (390 mg, 87.1% yield) as a yellow oil. LCMS retention time 1.543 min; LCMS MH+ 419. Step 3: 7 - benzyl - 3 - ethyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione

[00307] To a solution of 7 - benzyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (390 mg, 0.93 mmol) in DMF (3 mL) was added iodoethane (150 mg, 0.962 mmol), followed by potassium carbonate (350 mg, 2.54 mmol). The reaction was stirred at 40°C for 2 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated to give 7 - benzyl - 3 - ethyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (271 mg, 65.2% yield) as a yellow solid. LCMS retention time 1.765 min; LCMS MH+ 447. Step 4: 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione

[00308] 7 - benzyl - 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H)-dione (0.12 g, 0.323 mmol) was dissolved in ethanol (20 mL) and degassed and recharged with nitrogen three times. Ammonium formate (0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added and the mixture was again degassed and recharged with nitrogen three times. The reaction was stirred at 80 °C overnight. Then the mixture was cooled, filtered and the filter cake was washed with methanol. The filtrate was concentrated to provide 8-ethoxy-3-ethyl-1-(3-hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (70 mg, 77.1% yield) as a white solid. LCMS retention time 0.413 min; LCMS MH+ 283. Intermediate 48: 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: N - (6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 2,4 - dioxo -1,2,3,4 - tetrahydropyrimidin - 5 - yl) - 2 - (3 - (trifluoromethoxy)phenyl)acetamide

[00309] To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H, 3H)-dione (50 mg, 0.181 mmol, intermediate 59) in ethanol (3 ml) was added 2-(3-(trifluoromethoxy)phenyl)acetic acid (40 mg, 0.181 mmol) and EDCI (52 mg, 0.2 71 mmol) the mixture was stirred at room temperature for 2 h. The reaction was diluted with water, filtered and the solids were rinsed with water. The solid residue was dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give N - (6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 2,4 - dioxo -1,2,3,4 - tetrahydropyrimidin - 5 - yl) - 2 - (3 - (trifluoromethoxy)phenyl)acetamide (70 mg, 80.1%) as a pale gray solid. LCMS retention time 1.239 min; LCMS MH+ 479. Step 2: 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) - dione

[00310] To a solution of N - (6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 2,4 - dioxo -1,2,3,4 -tetrahydropyrimidin - 5 - yl) - 2 - (3 - (trifluoromethoxy)phenyl)acetamide (70 mg, 0.146 mmol) in ethanol (7 ml) was added 2N sodium hydroxide (1 ml). The reaction was stirred at 80°C for 3 hours. The reaction was quenched with aqueous ammonium chloride, filtered and the solids rinsed with water. The solid residue was dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) -dione (60 mg, 89.1%) as a light yellow solid. LCMS retention time 1.499 min; LCMS MH+ 461. Intermediate 49: 3-(5-methylthiazol-2-yl)propanoic acid Step 1: (E)-ethyl 3 - (5 - methylthiazol - 2 - yl)acrylate

[00311] To a solution of n-BuLi (4.2 ml, 6.74 mmol) in THF (15 ml) was added 2 - bromo - 5 - methylthiazole (1.0 g, 5.65 mmol) dropwise under nitrogen at -70°C. The reaction was stirred at this temperature for 1.5 h. DMF (0.65 ml, 8.43 mmol) was added dropwise at -70 °C. The reaction was maintained at this temperature for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and warmed to room temperature. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the intermediate aldehyde as a yellow oil which was used without purification.

[00312] To a suspension of sodium hydride (0.27 g, 6.78 mmol) in THF (10 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (1.52 g, 6.78 mmol) dropwise at 0 °C. After the reaction was stirred 30 min, a solution of the aldehyde in THF (3 mL) was added dropwise at 0 °C. The reaction was stirred at room temperature overnight. The mixture was quenched with saturated aqueous ammonium chloride (5 mL) and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil which was purified by column chromatography eluting with petroleum ether/ethyl acetate (4:1) to give (E)-ethyl 3-(5-methylthiazol-2-yl)acrylate (600 mg, 54.1% yield) as a pale yellow oil. LCMS retention time 1.410 min; LCMS MH+ 198. Step 2: Ethyl 3 - (5 - methylthiazol - 2 - yl)propanoate

[00313] To a solution of (E)-ethyl 3-(5-methylthiazol-2-yl)acrylate (200 mg, 1.01 mmol) in methanol (5 mL) was added 5% Pd/C (20 mg). The reaction was purged with nitrogen and then hydrogen and then stirred under a hydrogen atmosphere (balloon). The reaction was filtered. The filtrate was concentrated to give ethyl 3-(5-methylthiazol-2-yl)propanoate (200 mg, 99% yield) as a pale yellow oil. LCMS retention time 1.33 min; LCMS MH+ 200. Step 3: 3-(5-methylthiazol-2-yl)propanoic acid

[00314] To a solution of ethyl 3-(5-methylthiazol-2-yl)propanoate (0.2 g, 1 mmol) in THF/water (3 mL/3 mL) was added lithium hydroxide (61 mg, 1.5 mmol) portionwise at room temperature. The resulting mixture was stirred for 3 hours. The solvent was evaporated and the residue was acidified with conc. to adjust the pH to 1 - 2. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate and concentrated to give 3-(5-methylthiazol-2-yl)propanoic acid (0.17 g, 87.7% yield) as a colorless oil. LCMS retention time 0.436 min; LCMS MH+ 172. Intermediate 50: 2-(chloromethyl)-5-methylpyridine hydrochloride Step 1: 1 - 2,5 - dimethylpyridine oxide

[00315] To a solution of 2,5-dimethylpyridine (2.24 g, 21 mmol) in CHCl 3 (20 mL) was added MCPBA (4.31 g, 25 mmol) in portions over 30 min. The mixture was stirred at room temperature overnight. Calcium hydroxide (4g, 54 mmol) was added to quench the reaction and the mixture was stirred vigorously for 3 hours. The mixture was filtered through a Celita pad. The filtrate was concentrated and dried under vacuum to provide 2,5-dimethylpyridine 1-oxide (2.5g, 97.1% yield) as a white solid, which was used without purification. CMS retention time 0.442 min; LCMS MH+ 124. Step 2: (5 - methylpyridin - 2 - yl)methanol

[00316] 2,5-Dimethylpyridine 1-oxide (2.5g, 20.3mmol) was added to acetic anhydride (8.2mL) at 100 °C over a period of 30 min. Then the mixture was refluxed 1 hour. The mixture was cooled to room temperature and carefully quenched with ethanol (1 ml). The reaction mixture was concentrated. The residue was treated with 1N HCl (6 mL) and refluxed 1 h. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated to provide (5 - methylpyridin - 2 - yl) methanol (2g, 80.0% yield) as a pale yellow oil. LCMS MH+ 124. Step 3: 2-(chloromethyl)-5-methylpyridine hydrochloride

[00317] A solution of (5 - methylpyridin - 2 -yl)methanol in SOCl 2 (10 mL) was refluxed 30 min. The mixture was concentrated and dried in vacuo to provide 2-(chloromethyl)-5-methylpyridine hydrochloride (2.1g, 91.3% yield) as a white solid. LCMS MH+ 142. Intermediate 51: 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 1 - (4 - methoxybenzyl) - 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) - dione

[00318] To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (110 mg, 0.238 mmol, intermediate 48) in DMF (4 mL) was added 2-(chloromethyl)-5-methylpyridine (33.8 mg, 0.238 mmol, intermediate 50), followed by potassium carbonate (49.5 mg, 0.358 mmol). The reaction was stirred at 55 °C for 2 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a white solid product (120 mg, 88.8% yield) which was used without purification. LCMS MH+ 566. Step 2: 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione

[00319] To a solution of 1-(4-methoxybenzyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.212 mmol) in DCM (1.4 mL) was added triflic acid (0.7 mL) and TFA (0.7 mL). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography eluting with petroleum / ethyl acetate (10:1 to 1:1) to give 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2 ,6(3H,7H)-dione (60 mg, 63.5% yield) as white solid. LCMS MH+ 446. Intermediate 52: 4,4,4-trifluorobutyl methanesulfonate

[00320] To a solution of 4,4,4-trifluorobutan-1-ol (100mg, 83mmol) in dry DCM (2mL) was added methanesulfonyl chloride (107.3mg, 72mmol) followed by TEA (158mg, 216mmol) at 0°C. The reaction was stirred at room temperature for 1 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow oily product (50 mg, 31.1% yield), which was used without purification. tlc product [petroleum ether/ethyl acetate (3:1) Rf 0.4] Intermediate 53: 8 - amino - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 8 - azido - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione

[00321] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (0.28 g, 0.4 mmol, intermediate 14) in DMSO (10 mL) was added sodium azide (65 mg, 1mmol). The reaction was heated to 65 °C for 2.5 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1,800 min; LCMS MH+ - THP 390. Step 2: 8 - amino - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione

[00322] 8 - azido - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (0.19 g, 0.4 mmol) was dissolved in THF (5 mL) and 10% Pd/C (20 mg) was added. The reaction was jacketed in an atmosphere of hydrogen (balloon) and stirred overnight at room temperature. The mixture was filtered through celite, the filter cake was washed with methanol. The filtrate was concentrated in vacuo to provide 8 - amino - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione (0.2 g, 100% yield) as a white solid. LCMS retention time 1.324 min; LCMS MH+ - THP 364. Intermediate 54: Synthesis of 2 - (chloromethyl) - 4 - methylthiazole Step 1: Synthesis of (4 - methylthiazol - 2 - yl)methanol

[00323] To a solution of 4-methylthiazole (1.0 g, 10.1 mmol) in THF (30 mL) was added n - BuLi (7.56 mL, 13.48 mmol) dropwise under a nitrogen atmosphere at -60 °C. The reaction was stirred for 1 h; then DMF (1.4 mL, 18.2 mmol) was added dropwise while maintaining -60 °C. The resulting mixture was stirred at this temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil. This oil was dissolved in methanol (15 mL) and sodium borohydride (460 mg, 12.1 mmol) was added portionwise under a nitrogen atmosphere at 60 °C. The mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with acetone, warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:1) to give (4-methylthiazol-2-yl)methanol (1.3 g, 90.3%) as a brown oil. LCMS retention time 0.375 min; LCMS MH+ 130. Step 2: Synthesis of 2 - (chloromethyl) - 4 - methylthiazole

[00324] To a solution of (4-methylthiazol-2-yl)methanol (0.5 g, 3.87 mmol) in DCM (5 mL) was added thionyl chloride (0.19 mL, 2.6 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give 2-(chloromethyl)-4-methylthiazole (570 mg, crude) as a yellow oil, which was used without purification. LCMS retention time 0.895 min; LCMS 10 MH+ 148 Intermediate 55: 2 - (chloromethyl) - 5 - methylpyrazine

[00325] To a solution of 2,5-dimethylpyrazine (500 mg, 4.62 mmol) in carbon tetrachloride (7 mL) was added NCS (679 mg, 5.09 mmol) followed by BPO (20 mg) and the mixture was heated to 80 °C for 6 hours. The mixture was diluted with DCM and extracted with saturated aqueous sodium sulfite solution and brine. The organic layer was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (1:0 to 15:1) to give 2 - (chloromethyl) - 5 - methylpyrazine (133 mg, 20.19% yield) as yellow oil. LCMS retention time 0.557 min; LCMS MH+ 143. Intermediate 56: 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00326] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (150 mg, 0.405 mmol, Intermediate 8) in DMF (5 mL) was added 1 - (2 - bromoethyl)cyclopropanol (94 mg, 0.568 mmol) followed by potassium carbonate (84 mg , 0.609 mmol) and TBAI (catalytic amount). The resulting mixture was stirred at 50°C overnight. The reaction was diluted with ethyl acetate and washed with saline. The organic phase was dried and concentrated to give the crude product which was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (5:1 to 2:1) to give 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (150 mg, 81, 6% yield) as a pale yellow solid. LCMS retention time 1.523 min; LCMS MH+ 455. Intermediate 57: 1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 8 - bromine -1 - (3 - hydroxybutyl) - 3 - methyl - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H, 7H) - dione

[00327] To a solution of 8 - bromo - 3 - methyl - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (3 g, 8 mmol, product of Intermediate 12, step 1) in DMF (15 mL) was added 3-hydroxybutyl 4-methylbenzenesulfonate (2.3 g, 8 .8 mmol, Intermediate 33) followed by potassium carbonate (2.2 g, 16 mmol) and TBAI (catalytic amount). The resulting mixture was stirred at 80°C for 4 hours. The reaction was diluted with ethyl acetate and washed with saline. The organic phase was dried and concentrated to give 8 - bromo -1 - (3 - hydroxybutyl) - 3 - methyl - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine-2,6(3H,7H)-dione (3.5 g, 97.9% yield) as a yellow solid. LCMS retention time 1.428 min; LCMS MH+ 448. Step 3: 1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00328] To a solution of 8 - bromo -1 - (3 - hydroxybutyl) - 3 - methyl - 7 - ((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1 g, 2.2 mmol) in DNF (10 mL) was added 3 - (trifluoromethoxy)phenol (0.6 g, 3 mmol) followed by sodium carbonate potassium (0.6 g, 4.4 mmol). The reaction was stirred at 80 °C for 4 h. The mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried and concentrated to give 1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (1.1 g, 91.8% yield) as yellow syrup. LCMS retention time 2.036 min; LCMS MH+ 545. Step 3: Synthesis of 1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00329] To a solution of 1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (1.1 g, 2.02 mmol) in THF (5 mL) was added TBAF (5 mL, 1 mmol/L in THF) and the mixture was heated to reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with brine and saturated aqueous ammonium chloride; then it was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with DCM/methanol (45:1) to give (701 mg, 83.8% yield) as a white solid. LCMS retention time 1.372 min; LCMS MH+ 415. Intermediate 58: 1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00330] The title compound was prepared using the method of Intermediate 57 and purified by chromatography on silica gel eluting with petroleum ether/ethyl acetate (1:1) to afford 1 -(2-(1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (400) mg, 87.0% yield) as a white solid. LCMS retention time 1.457 min; LCMS MH+ 427. Intermediate 59: 5,6 - diamino - 3 - (4 - methoxybenzyl) -1 - methylpyrimidine - 2,4(1H, 3H)-dione Step 1: (E) - N' - (1 - (4 - methoxybenzyl) - 3 - methyl - 2,6 - dioxo -1,2,3,6 - tetrahydropyrimidin - 4 - yl) - N,N - dimethylformimidamide

[00331] To a solution of 6 - amino -1 - methylpyrimidine - 2,4(1H, 3H) - dione (13.1 g, 92.9 mmol) in DMF (200 mL) was added 1,1 - dimethoxy - N,N - dimethylmethanamine (13 mL, 97.9 mmol) and the mixture was stirred at 40 °C for 3 hours. Then 1-(chloromethyl)-4-methoxybenzene (15.05 mL, 111.5 mmol) was added followed by potassium carbonate (25.64 g, 0.186 mmol) and DMF (100 mL), the resulting mixture was stirred at 80 °C for 48 hours. The reaction was cooled and diluted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with methanol/DCM (1:80 to 1:20) to give (E) - N' - (1 - (4 - methoxybenzyl) - 3 - methyl - 2,6 - dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (7.8 g, 26.5% yield) as a yellow solid. LCMS retention time 1.023 min; LCMS MH+ 317. Step 2: 6 - amino - 3 - (4 - methoxybenzyl) -1 - methylpyrimidine - 2,4(1H, 3H) - dione

[00332] To a solution of (E)-N'-(1-(4-methoxybenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (7.8 g, 24.7 mmol) in methanol (90 mL) was added ammonium hydroxide (155 mL, 28% weight/weight) and the mixture was stirred at room temperature for 48 h. The reaction was concentrated to give the crude product which was purified by chromatography on silica gel eluting with methanol/DCM (1:15) to give 6 - amino - 3 - (4 - methoxybenzyl) -1 - methylpyrimidine - 2,4(1H, 3H) -dione (4.3g, 66.6%) as yellow solid. LCMS retention time 0.445 min; LCMS MH+ 262. Step 3: 6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 5 - nitrosopyrimidine - 2,4(1H, 3H) - dione

[00333] To a solution of 6 - amino - 3 - (4 - methoxybenzyl) -1 - methylpyrimidine-2,4(1H, 3 H)-dione (4.3 g, 16.45 mmol) in water (20 mL) and acetic acid (20 mL) was added sodium nitrite (3.4 g, 49.4 mmol) in small portions at 70 oC. After the addition, the mixture was stirred at 70 °C for 4 h. The reaction was cooled and concentrated. The solids were collected, washed with water and dried under vacuum to provide 6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 5 - nitrosopyrimidine - 2,4(1H, 3H) - dione (4.1 g, 85.9% yield) as a purplish solid. LCMS retention time 0.885 min; LCMS MH+ 291. Step 4: 5,6 - diamino - 3 - (4 - methoxybenzyl) -1 - methylpyrimidine - 2,4(1H, 3H) - dione

[00334] To a solution of 6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 5 - nitrosopyrimidine - 2,4(1H, 3 H) - dione (4.1 g, 14.1 mmol) in ammonium hydroxide (100 mL, 14 % weight/weight) was added sodium dithionite (4.9 g, 28.2 mmol) in small portions at 60 °C, and the mixture was stirred at this temperature for 4 hours. The reaction was cooled and diluted with water. The solids were collected, rinsed with water and dried under vacuum to provide 5,6 - diamino - 3 - (4 - methoxybenzyl) -1 - methylpyrimidine - 2,4(1H, 3H) - dione (3.5 g, 89.8% yield) as a pale yellow solid. LCMS retention time 0.404 min; LCMS MH+ 277. Intermediate 60: 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) -1H - purine - 2,6(3H,7H) - dione Step 1: Ethyl 3 - (3 - (trifluoromethoxy)phenoxy)propanoate

[00335] To a solution of ethyl 4-bromobutanoate (2 g, 10.26 mmol) in acetone (20 mL) was added 3-(trifluoromethoxy)phenol (1.52 g, 8.54 mmol), followed by potassium carbonate (3.5 g, 25.36 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (10:1 to 5:1) to give ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (2.3 g, 92.1% yield) as a colorless oil. Step 2: 3 - (3 - (trifluoromethoxy)phenoxy)propanoic acid

[00336] To a solution of ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (1.0 g, 3.42 mmol) in THF (8 mL) was added a solution of lithium hydroxide (164 mg, 6.83 mmol) in water (4 mL). The reaction was stirred at room temperature overnight. The reaction was neutralized with dilute HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 3-(3-(trifluoromethoxy)phenoxy)propanoic acid (0.9 g, 99.1% yield) as a colorless oil which was used without purification. Step 3: N - (6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 2,4 - dioxo -1,2,3,4 - tetrahydropyrimidin - 5 - yl) - 4 - (3 - (trifluoromethoxy)phenoxy)butanamide

[00337] To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H, 3H)-dione (100 mg, 0.362 mmol, Intermediate 59) in ethanol (3mL) were added 3-(3-(trifluoromethoxy)phenoxy)propanoic acid (96 mg, 0.364 mmol) and EDCI ( 105 mg, 0.546 mmol). The reaction was stirred at room temperature for 3 hours, then the mixture was diluted with water and the precipitate was collected by filtration and rinsed with water. The solids were then dissolved in ethyl acetate. This organic solution was dried over sodium sulfate and concentrated to provide N - (6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 2,4 - dioxo -1,2,3,4 -tetrahydropyrimidin - 5 -yl) - 4 - (3 - (trifluoromethoxy)phenoxy)butanamide (150 mg, 79.3%) as a yellow solid. LCMS retention time 1.422 min; LCMS MH+ 523. Step 4: 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00338] To a solution of N - (6 - amino - 3 - (4 - methoxybenzyl) -1 - methyl - 2,4 - dioxo -1,2,3,4 -tetrahydropyrimidin - 5 - yl) - 4 - (3 - (trifluoromethoxy)phenoxy)butanamide (150 mg, 0.287 mmol) in ethanol (7 mL) was added 2N NaOH (1 mL). The mixture was stirred at 80°C for 3 hours. The reaction was neutralized with saturated ammonium chloride and the product precipitated. The solids were collected and washed with water. The solids were dissolved in ethyl acetate, dried over sodium sulfate and concentrated to give 1-(4-methoxybenzyl)-3-methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) -dione (130 mg, 89.7%) as a pale yellow solid. LCMS retention time 1.635 min; LCMS MH+ 505. Intermediate 61: 8 - chloro - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 2 - amino - 7 - (4 - chlorobenzyl) - 1H - purin - 6(7H) - one

[00339] To a solution of 2 - amino - 9 - ((2R,3S,4R,5S) - 3,4 - dihydroxy - 5 - (hydroxymethyl)tetrahydrofuran - 2 -yl) -1H - purin - 6(9H) -one (14 g, 49.47 mmol) in DMSO (50 mL) was added 1 - chloro - 4 - (chloromethyl)benzene (10 g, 62.16 mmol). The reaction was stirred at 50 °C overnight. The mixture was cooled to room temperature and HCl (50 mL, 10% wt/wt) was added. The reaction was stirred at 70°C for 2 hours. The reaction was cooled and the precipitate was collected and washed with water and ethanol. The product was dried under vacuum to afford 2 - amino - 7 - (4 - chlorobenzyl) - 1H - purin - 6(7H) - one (10 g, 74.1% yield) as a gray solid. LCMS retention time 0.529 min; LCMS MH+ 276. Step 2: 7 - (4 - chlorobenzyl) - 1H - purine - 2,6(3H,7H) - dione

[00340] To a solution of 2 - amino - 7 - (4 - chlorobenzyl) - 1H - purin - 6(7H) - one (6.8 g, 24.7 mmol) in acetic acid (80 mL) and water (10 mL) was added a solution of sodium nitrite (3.4 g, 24.7 mmol) in water (10 mL) dropwise at 50 °C. The reaction was stirred at 50 °C for 1 h. The mixture was cooled to room temperature and stirred for an additional 1.5 h. The precipitate was collected, washed with water and ethanol, and dried in vacuo to give 7 - (4 - chlorobenzyl) - 1H - purine - 2,6(3H,7H) - dione (6.5 g, 95.3% yield) as a yellow solid. LCMS retention time 0.635 min; LCMS MH+ 277. Step 3 8 - chloro - 7 - (4 - chlorobenzyl) - 1H - purine - 2,6(3H,7H) - dione

[00341] To a solution of 7 - (4 - chlorobenzyl) - 1H - purine - 2,6(3H,7H) - dione (2.2 g, 7.97 mmol) in THF (30 mL) was added NCS (1.1 g, 8.27 mmol) at 0°C in portions. Then, the resulting mixture was stirred at room temperature until it became a clear solution. The reaction was immediately quenched with ice water and concentrated. The residue was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to provide a crude product. This material was purified by chromatography on silica gel eluting with DCM/methanol (50:1 to 20:1) to give 8 - chloro - 7 - (4 - chlorobenzyl) - 1H - purine - 2,6(3H,7H) - dione (450 mg, 18.2% yield) as a white solid. LCMS retention time 1.071; LCMS MH+-58 311. Step 4: 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00342] To a solution of 8 - chloro - 7 - (4 - chlorobenzyl) - 1H - purine - 2,6(3H,7H) -dione (450 mg, 1.45 mmol) in DMF (20 mL) was added potassium carbonate (0.4 g, 2.90 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 3.96 mmol) at 0 ° c. The resulting mixture was stirred at 60°C for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to provide the crude product. This material was purified by silica gel chromatography eluting with petroleum / ethyl acetate (3:1 to 1:1) to afford 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine-2,6(3H,7H)-dione (250 mg, 39.2% yield) as yellow oil. LCMS retention time 1.886; LCMS MH+-28 413. Step 5: 7 - benzyl -1 - (3 - (tert - butyldimethylsilyloxy)propyl) - 8 - chloro - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) - dione

[00343] To a solution of 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (250 mg, 0.568 mmol) in DMF (30 mL) was added (3-bromopropoxy)(tert-25butyl)dimethylsilane (0.2 g, 0 794 mmol), followed by potassium carbonate (160 mg, 1.13 mmol). The mixture was stirred at 70°C overnight. The reaction was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7 - benzyl -1 - (3 - (tert -butyldimethylsilyloxy)propyl) - 8 - chloro - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H -purine-2,6(3H,7H)-dione (340 mg, 97.4% yield) as a colorless oil. LCMS retention time 4.675 min; LCMS MH+ 613. Step 6: 8 - chloro - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione

[00344] To a solution of 7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-purine-2,6(3H,7H)-dione (340 mg, 0.56 mmol) in ethyl alcohol (20 mL) was added concentrated HCl (2 mL). The mixture was stirred at 80°C overnight. The reaction was concentrated, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 8 - chloro - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (180 mg, 87.5% yield) as a colorless oil. LCMS retention time 1.990 min; LCMS MH+ 369. Intermediate 62: 8 - bromo - 7 - (4 -fluorobenzyl) - 3 - methyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione Steps 1 and 2: 8 - bromo - 7 - (4 -fluorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00345] The title compound was prepared using the methods of Intermediate 8, step 2 and Intermediate 14 to afford 8 - bromo - 7 - (4 - fluorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H)-dione (26 g, 64.3% yield) as white solid. LCMS retention time 1.694 min; LC MSMH+ - THP 411. Step 3: 8 - bromo - 7 - (4 -fluorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00346] To a solution of 8 - bromo - 7 - (4 -fluorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (26 g, 52.5 mmol) in ethanol (500 mL) was added concentrated HCl (50 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to half its volume and the product precipitated. The solids were collected and washed with water and ethanol; then dried under vacuum to afford 8 - bromo - 7 - (4 - fluorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (18.1 g, 83.9% yield) as a white solid. LCMS retention time 1.243 min; LCMS MH+ 411. Intermediate 63: 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00347] The title compound was prepared using the method of Intermediate 62 to furnish 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (21 g, 93.1% yield) as white solid. LCMS retention time 1.375 min; LCMS MH+ 429. Intermediate 64: 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonyl chloride Step 1: 7 - (4 - chlorobenzyl) - 8 - mercapto - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00348] The title compound was prepared using the method of Intermediate 7 to furnish 7 - (4 - chlorobenzyl) - 8 - mercapto - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (710 mg, 81.5% yield) as yellow solid. LCMS retention time 0.973 min; LCMS MH+ 323. Step 2: 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purine - 8 - sulfonyl chloride

[00349] To a solution of 7 - (4 - chlorobenzyl) - 8 - mercapto - 3 - methyl-1H-purine-2,6(3H,7H)-dione (400 mg, 1.24 mmol) in concentrated sulfuric acid (5 mL) was added aqueous sodium hypochlorite solution (5 mL, 5% active chlorine) dropwise at 0 °C and the mixture was stirred at room temperature for 15 minutes . The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H-purine-8-sulfonyl chloride (230 mg, 47.6% yield) as brown solid, which was directly used immediately without purification.

[00350] The following Intermediates 65 to 71 were prepared using the method of Intermediate 5, Intermediate 65: 2 - (3,5 - bis(trifluoromethyl)phenoxy)ethanol

[00351] Light yellow oil, mg, 87.6% yield. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.4 Intermediate 66: 2 - (3 - chlorophenoxy)ethanol

[00352] Light yellow oil, 350 mg, 89.1% yield. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.4 Intermediate 67: 2 - (m -tolyloxy)ethanol

[00353] Light yellow oil, 357 mg, 91% yield. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.35 Intermediate 68: 2 - (3 - (trifluoromethyl)phenoxy)ethanol

[00354] Light yellow oil, 332 mg, 81.9% yield. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.4 Intermediate 69: 2 - (4 - (trifluoromethoxy)phenoxy)ethanol

[00355] Light yellow oil, 100 mg, 78.9% yield. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.4 Intermediate 70: 2 - (2 - (trifluoromethoxy)phenoxy)ethanol

[00356] Light yellow oil, 105 mg, 85% production. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.4 Intermediate 71: 2 - (4 - chloro - 3 - (trifluoromethyl)phenoxy)ethanol

[00357] Light yellow oil, 100 mg, 81% production. TLC petroleum ether / ethyl acetate (1:2), UV detection, Rf = 0.4 Intermediate 72: (2-hydroxycyclopentyl)methyl methanesulfonate Step 1: 2 - (hydroxymethyl)cyclopentanol

[00358] To a solution of ethyl 2-oxocyclopentanecarboxylate (1 g, 6.41 mmol) in anhydrous THF (40 mL) was added lithium bis(trimethylsilyl)amide (6.41 mL, 6.41 mmol, 1 mmol/L in THF) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 40 min. Then LAH (500 mg, 13.2 mmol) was added portionwise to the above solution at 0 °C. The reactin was stirred at 0 °C for 1 h. The mixture was quenched with ice water, filtered and the filter cake washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (30:1 to 10:1) to give 2-(hydroxymethyl)cyclopentanol (40 mg, 5.4%) as a yellow oil. 1H NMR (CDCl3) δ 4.03 - 4.05 (m, 1H), 3.76 - 3.80 (q, 1H), 3.54 - 3.59 (t, 1H), 1.57 - 2.01 (m, 7H). Step 2: (2-hydroxycyclopentyl)methyl methanesulfonate

[00359] The title compound was prepared using the method of Intermediate 42 to afford (2-hydroxycyclopentyl)methyl methanesulfonate (50 mg, 73.5% yield) as yellow oil. Intermediate 73: 1 - (3 - (benzyloxy)cyclobutyl) - 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione Step 1: Ethyl 4 - (3 - (3 - (benzyloxy)cyclobutyl)ureido) -1 - (4 - chlorobenzyl) -1H - imidazole - 5 - carboxylate

[00360] To a solution of 3-(benzyloxy)cyclobutanecarboxylic acid (442 mg, 2.14 mmol) in toluene (10 mL) was added diphenylphosphoryl azide (589 mg, 2.14 mmol) followed by TEA (216 mg, 2.14 mmol). The reaction was stirred at room temperature for 30 minutes. Ethyl 4-amino -1 - (4 - chlorobenzyl) - 1H - imidazole - 5 - carboxylate (300 mg, 1.07 mmol) was added to the mixture and the resulting mixture was stirred at 110 °C for 6 h. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (50:1) to give ethyl 4-(3-(3-(benzyloxy)cyclobutyl)ureido)-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate (310 mg, 59.9 g yield) as yellow solid. LCMS retention time 1.909 min; LCMS MH+ 483. Step 2: 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) -1H - purine - 2,6(3H,7H) - dione

[00361] To a solution of ethyl 4-(3-(3-(benzyloxy)cyclobutyl)ureido)-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate (310 mg, 0.64 mmol) in ethanol (50 mL) was added freshly prepared sodium ethoxide (87.4 mg, 1.28 mmol) and the reaction was heated to reflux for 4 h. The reaction was cooled and concentrated. The residue was partitioned between ethyl acetate and saline. The organic layer was dried and concentrated to give 1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl) - 1H - purine - 2,6(3H,7H) - dione (240 mg, 85.5% yield) as a yellow solid. LCMS retention time 1.764 min; LCMS MH+ 437. Step 3: 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) -1H - purine - 2,6(3H,7H) -dione

[00362] To a solution of 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (240 mg, 0.62 mmol) in DMF (5 mL) was added iodomethane (105.3 mg, 0.74 mmol) followed by potassium carbonate (128 mg, 0. 93 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give 1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (220 mg, 78.9% yield) as a yellow solid. LCMS retention time 1.914 min; LCMS MH+ 451. Step 4: 1 - (3 - (benzyloxy)cyclobutyl) - 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00363] To a solution of 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (220 mg, 0.49 mmol) in DMF (3 mL) was added NCS (71.7 mg, 0.54 mmol) in portions at 0 °C. The reaction was stirred at room temperature for 4 h. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried and concentrated to give a crude product, which was purified by chromatography on silica gel eluting with DCM/methanol (60:1) to give 1 - (3 - (benzyloxy)cyclobutyl) - 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (170 mg, 71.8% yield) as a yellow solid. LCMS retention time 2.079 min; LCMS MH+ 485. Intermediate 74: 3-hydroxycyclopentyl methanesulfonate

[00364] The title compound was prepared using the method of Intermediate 42 step 1 to provide 3-hydroxycyclopentyl methanesulfonate (100 mg, 89.1% yield) as a yellow oil which was used without characterization. Intermediate 75: Benzyl 3 - (methylsulfonyloxy)cyclobutanecarboxylate

[00365] The title compound was prepared using the method of Intermediate 42 to afford benzyl 3-(methylsulfonyloxy)cyclobutanecarboxylate (0.71 g, 79.8% yield) as a yellow solid which was used without characterization. Intermediate 76: 3 - (chloromethyl) - 5 -fluoropyridine Step 1 (5 -fluoropyridin - 3 -yl)methanol

[00366] To a solution of 5-fluoronicotinic acid (1.0 g, 7.09 mmol) in THF (10 mL) was added TEA (0.9 mL, 7.73 mmol), followed by ethyl chloroformate (0.6 mL, 7.73 mmol) at 0°C. The reaction was stirred at room temperature 2 h; then it was filtered. The residue was washed with a small amount of THF. The filtrate was cooled to 0 °C and sodium borohydride (0.67 g, 17.73 mmol) was added, followed by dropwise addition of water (5 mL). The reaction was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, and concentrated to give a crude product which was used purified by silica gel chromatography to give (5-fluoropyridin-3-yl)methanol (197 mg, 21.8% yield) as a colorless oil. LCMS retention time 0.375 min; LCMS MH+ 128. Step 2: 3-(chloromethyl)-5-fluoropyridine

[00367] To a solution of (5-fluoropyridin-3-yl)methanol (0.19 g, 1.50 mmol) in DCM (5 mL) was added thionyl chloride (0.19 mL, 2.6 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated and the residue was dried in vacuo to yield 3-(chloromethyl)-5-fluoropyridine (166 mg) which was used without characterization. Intermediate 77: 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00368] 8 - Bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (33.4 g, 90.4 mmol, Intermediate 8), potassium carbonate (25.0 g, 180.8 mmol) and TBAI (0.225 g) were combined in DMF (460 mL). To the mixture was added (3-bromopropoxy)(tert-butyl)dimethylsilane (25.17g, 99.4 mmol) and the reaction was heated at 100 °C for 4 h. The reaction was cooled to room temperature, diluted with water (1.2 L) and extracted with ethyl acetate (3 x 400 mL). The combined organic extracts were washed with 1N lithium chloride (2 x 500 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give a light golden oil. The oil was purified using 2 x 120 g silica gel columns eluted with 10% ethyl acetate/hexanes to yield 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 -chlorobenzyl) - 3 - methyl - 1H-purine-2,6(3H,7H)-dione (38.3 g, 78% yield) as a solid not quite white. LCMS retention time = 5.083 min and 99% purity, LCMS MH+ 543. 1H NMR (CDCl3) δ 7.29 - 7.34 (m, 4H), 5.50 (s, 2H), 4.08 (t, 2H, J=8 Hz), 3.70 (t, 2H, J=8 Hz), 3.53 (s , 3H), 1.83 - 1.90 (m, 2H), 0.86 (s, 109H), 0.02 (s, 6H). Intermediate 78: 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - allyl - 2 - amino - 1H - purine - 6(7H) - one

[00369] To a solution of 2 - amino - 9 - ((2R,3S,4R,5S) - 3,4 - dihydroxy - 5 - (hydroxymethyl)tetrahydrofuran - 2 -yl) -1H - purin - 6(9H) - one (50 g, 176.7 mmol) in DMSO (150 mL) was added allyl bromide (36 mL, 420 mmol), to The mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was cooled to 0 °C, concentrated HCl (100 mL) was added and the reaction was stirred at 70 °C for 4 h. The reaction was cooled to room temperature, poured into water (800 mL), and neutralized with 6N sodium hydroxide to pH 7-8. The solids that formed were collected and the filter cake was washed with water and ethanol, then dried under vacuum to provide 7 - allyl - 2 - amino - 1H - purin - 6(7H) - one (20 g, 59.2% yield) as a yellow solid. LCMS retention time 0.330 min; LCMS MH+ 192. Step 2: 7 - allyl - 1H=purine - 2,6(3H,7H) - dione

[00370] To a solution of 7 - allyl - 2 - amino - 1H - purin - 6(7H) - one (20 g, 104.7 mmol) in acetic acid (500 mL) and water (70 mL) was added a solution of sodium nitrite (30 g, 434.8 mmol) in water (70 mL) dropwise at 50 °C. The reaction was stirred at 50 °C for 1 h. The reaction was concentrated and poured into ice water. The solids that formed were filtered and the filter cake washed with water and ethanol, then dried under vacuum to afford 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 74.4% yield) as a yellow solid. LCMS retention time 0.555 min; LCMS MH+ 193. Step 3: 7 - allyl - 3 - ethyl - 1H - purine - 2,6(3H,7H) - dione

[00371] To a solution of 7-allyl-1H-purine-2,6(3H,7H)-dione (15 g, 78.13 mmol) in DMF (200 mL) was added potassium carbonate (23.7 g, 171.74 mmol), followed by dropwise addition of iodoethane (3.6 mL, 44.54 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum / ethyl acetate (6:1 to 3:1) to give 7 - allyl - 3 - ethyl - 1H - purine-2,6(3H,7H)-dione (7 g, 40.7% yield) as yellow solid. LCMS retention time 0.402 min; LCMS MH+ 221. Step 4: 7 - allyl - 8 - chloro - 3 - ethyl - 1H - purine - 2,6(3H,7H) - dione

[00372] To a solution of 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 31.82 mmol) in DMF (50 mL) was added NCS (5 g, 37.45 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 5 h under nitrogen. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7 - allyl - 8 - chloro - 3 - ethyl - 1H - purine - 2,6(3H,7H) - dione (11.8 g, ~50% pure) as a light yellow oil. LCMS retention time 0.764 min; LCMS MH+ 255. Step 5: 7 - allyl -1 - (3 - (tert -butyldimethylsilyloxy)propyl) - 8 - chloro - 3 - ethyl -1H - purine - 2,6(3H,7H) - dione

[00373] To a solution of 7 - allyl - 8 - chloro - 3 - ethyl - 1H - purine - 2,6(3H,7H) - dione (6.8 g, 26.77 mmol) in DMF (50 mL) was added (3 - bromopropoxy)(tert - butyl)dimethylsilane (8 g, 31.75 mmol), followed by potassium carbonate (5 g, 36.23 mmol ) and TBAI (5 mg, 0.014 mmol). The reaction was stirred at 60 °C overnight. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum / ethyl acetate (15:1 to 1:1) to give 7 - allyl -1 - (3 - (tert - butyldimethylsilyloxy)propyl) - 8 - chloro - 3 - ethyl - 1H - purine - 2,6(3H,7H) - dione (5.8 8 g, 51.6% yield) as a colorless oil. LCMS retention time 2.224 min; LCMS MH+ 427. Step 6: 7 - allyl - 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione

[00374] To a solution of 7 - allyl -1 - (3 - (tert - butyldimethylsilyloxy)propyl) - 8 - chloro - 3 - ethyl -1H - purine - 2,6(3H,7H) - dione (3.8 g, 8.92 mmol) in ethanol (20 mL) was added concentrated HCl (2 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give 7 - allyl - 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (3.8 g) as a yellow oil, which was used without purification. LCMS retention time 0.999 min; LCMS MH+ 313. Step 7: 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione FIGURE LEGEND: morpholine

[00375] To a solution of 7 - allyl - 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (3.8 g, 12.18 mmol) in THF (40 mL) and DMSO (10 mL) was added tetracis(triphenylphosphine)palladium(0) (800 mg, 0.693 mmol) and morpholine (5.4 mL, 62.07 mmol). The reaction was degassed and recharged with nitrogen 3 times. The reaction was stirred at room temperature overnight. The mixture was poured into water (20ml) and ethyl acetate (100ml). The solid precipitate was collected, washed with ethyl acetate, and dried under vacuum to provide 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (2.2 g, 66.4% yield) as a gray solid. LCMS retention time 0.404 min; LCMS MH+ 273. Step 8: 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione

[00376] To a solution of 8 - chloro - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine-2,6(3H,7H)-dione (2.2 g, 8.09 mmol) in DMF (10 mL) was added 1-(bromomethyl)-4-chlorobenzene (2.47 g, 12.11 mmol), followed by potassium carbonate (2.23 g, 16, 18 mmol) and TBAI (15 mg, 0.042 mmol). The reaction was stirred at 50 °C for 2 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum / ethyl acetate (5:1 to 1:2) to give 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ethyl - 1 -(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.3 g, 71.8 % production) as a white solid. LCMS retention time 1.485 min; LCMS MH+ 397. Intermediate 79: 3,3,3-trifluoropropyl methanesulfonate

[00377] To a solution of 3,3,3-trifluoropropan-1-ol (500 mg, 4.38 mmol) in DCM (10 mL) was added TEA (1.22 mL, 8.77 mmol) followed by dropwise addition of methanesulfonyl chloride (0.51 mL, 6.58 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM and the organic phase washed with brine, dried and concentrated to give the crude product which was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1) to give 3,3,3-trifluoropropyl methanesulfonate (490 mg, 58.2% yield) as pale yellow oil. TLC (petroleum ether/ethyl acetate = 3:1), Rf = 0.6. Intermediate 80: 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 - trifluoropropyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2 - (trimethylsilyl)ethoxy)methyl) -1H - purine - 2,6(3H,7H) -dione

[00378] To a solution of 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.06 mmol, Intermediate 12, step 2) in DMF (6 mL) was added 3,3,3-tri methanesulfonate fluoropropyl (305 mg, 1.59 mmol) followed by potassium carbonate (439 mg, 3.17 mmol). The reaction was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate and extracted with brine. The organic phase was dried and concentrated to give 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 - trifluoropropyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) -1 H - purine - 2,6(3H,7H) - dione (510 mg, 84.6% yield) as yellow syrup. LCMS retention time 2.275 min; LCMS MH+ 569. Step 2: 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 -trifluoropropyl) - 1H - purine - 2,6(3H,7H) - dione

[00379] The title compound was prepared as Intermediate 17, step 2 to afford 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione (228 mg, 56.3% yield) as white solid. LCMS retention time 1.626 min; LCMS MH+ 439. Intermediate 81: 8 - Bromine - 7 - isopentyl - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00380] 8 - Bromo - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (2.0 g, 8.16 mmol), diisopropylethylamine (2.13 mL, 12.24 mmol) and 1 - bromo - 3 - methylbutane (0.98 mL, 8.16 mmol) were combined in DMF (20 mL) and stirred at room temperature for 1 5 am. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 1N LiCl (2 x 100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford 8 - bromine - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (2.2 g, 78% yield) as a white solid. LCMS retention time = 2.654 min and 98% purity, LCMS MH+ 315. Intermediate 82: 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl - 7 - isopentyl - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00381] 8 - Bromo - 7 - isopentyl - 3 - methyl -1H - purine - 2,6(3H,7H) -dione (2.0 g, 6.35 mmol), (3-bromopropoxy)(tert-butyl)dimethylsilane (1.77 g, 6.98 mmol Intermediate 81), potassium carbonate (1.76 g, 12.70 mmol) and TB AI (0.020 g) were combined in DMF (45 mL) and stirred at room temperature for 6 h. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 1N LiCl (2 x 100 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a golden oil. The oil was purified using a 40 g silica gel flash column eluted with 10% ethyl acetate / hexanes to provide 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl - 7 - isopentyl - 3 - 10methyl - 1H - purine - 2,6(3H,7H) -dione (2.73 g, 88% yield) as a clear oil. LCMS retention = 5.271 minutes and 92% purity, LCMS MH+ = 489. Intermediate 83: 7 - Benzyl - 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00382] The title compound was prepared using the methods of Intermediates 81 and 82. Light golden oil, 15.5 g, 100% yield, LCMS retention time = 4.872 minutes and 96% purity, LCMS MH+ = 509. Examples Example 1: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00383] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (240 mg, 0.649 mmol, Intermediate 8) in dimethyl formamide (5 mL) was added 3 - (trifluoromethyl)phenol (105 mg, 0.649 mmol) followed by potassium carbonate (107 mg, 0.779 mmol). The resulting mixture was stirred at 80 °C for 6 h. The mixture was diluted with ethyl acetate (15 mL) and extracted with brine and saturated aqueous ammonium chloride solution. Then the organic phase was dried and concentrated to give a crude solid product which was collected and washed with ethanol to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (237 mg, 81.1% yield) as a white solid. 1H NMR (DMSO-d6) δ 11.24 (s, 1H), 7.77 (s, 1H), 7.69 - 7.71 (m, 3H), 7.43 (s, 4H), 5.42 (s, 2H), 3.22 (s, 3H). LCMS retention time 2.306 min; LCMS MH+ 451. Example 2: 7-(4-chlorobenzyl)-1-ethyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H - purine - 2,6(3H,7H) -dione

[00384] To a solution of 1 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.11 mmol, example 1) in DMF (1 mL) was added iodoethane (18.7 mg, 0.12 mmol) followed by potassium carbonate (23 mg, 0.16 mmol). Then the mixture was stirred at 50°C for 3 hours. The mixture was diluted with ethyl acetate and extracted with brine and saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give crude solid product which was collected and washed with ethanol to give 7 - (4 - chlorobenzyl) -1 - ethyl - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (15 mg, 26.7% yield) as white solid. 1H NMR (DMSO-d6) δ 7.77 (s, 1H), 7.69 - 7.73 (m, 3H), 7.43 (s, 4H), 5.46 (s, 2H), 3.91 - 3.93 (q, 2H), 3.29 (s, 3H), 1.11 - 1.14 (t, 3H). LCMS retention time 3.109 min; LCMS MH+ 479. Example 3: 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethyl)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl) - N - methylacetamide

[00385] The title compound was prepared using the method of example 2 except the catalytic amount of TBAI was added to give 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethyl)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl) - N - methylacetamide (36 mg, 62.1 % production) as a white solid. 1H NMR (DMSO - d6) δ 7.97 - 7.98 (m, 1H), 7.79 (s, 1H), 7.69 - 7.74 (m, 3H), 7.44 (s, 4H), 5.45 (s, 2H), 4.43 (s, 2H), 3.91 - 3.93 (q, 2H), 3.29 (s, 3H), 2.58 - 2.59 (d, 3H). LCMS retention time 2.547 min; LCMS MH+ 522. Example 4: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - ((5 - methylisoxazol - 3 - yl)methyl) - 8 - (3 -

[00386] The title compound was prepared using the method of example 2 except the catalytic amount of TBAI was added to give 7-(4-chlorobenzyl)-3-methyl-1-((5-methylisoxazol-3-yl)methyl)-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (29 mg, 39.9% yield) as white solid. 1H NMR (DMSO-d6) δ 7.79 (s, 1H), 7.69 - 7.73 (m, 3H), 7.44 (s, 4H), 6.12 (s, 1H), 5.45 (s, 2H), 5.07 (s, 1H), 3.30 (s, 3H), 2.35 (s, 3H). LCMS retention time 2.920 min; LCMS MH+ 546. Example 5: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00387] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (60 mg, 0.133 mmol, example 11) in DMF (1 mL) were added 2 - bromoethanol (16.5 mg, 0.133 mmol) and cesium carbonate (86.6 mg, 0.266 mmol). The resulting mixture was subjected to microwave irradiation at 120 °C for 20 min in a sealed tube. The mixture was diluted with ethyl acetate (5 mL) and extracted with saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give the crude product which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine-2,6(3H,7H)-dione (19 mg, 28.8% yield) as a white solid. 1H NMR (DMSO - d6) δ 7.76 (s, 1H), 7.69 - 7.71 (m, 3H), 7.43 (s, 4H), 5.45 (s, 2H), 4.77 - 4.78 (d, 1H), 3.95 - 3.98 (t, 2H), 3.51 - 3.54 (t, 2H) ), 3.28 (s, 3H). LCMS retention time 2.608 min; LCMS MH+ 495. Example 6: 7-(4-Chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride Step 1: 1 - (2 - bromoethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00388] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol, Intermediate 9) in DMF (3 mL) was added 1,2-dibromoethane (100 mg, 0.532 mmol), followed by carbonate of potassium (60 mg, 0.429 mmol). The mixture was stirred at 80°C overnight. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by recrystallisation from ethanol to give 1 - (2 - bromoethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (120 mg, 97.6% yield) as white solid. LCMS retention time 2.103 min; LCMS MH+ 573. Step 2: 7 - (4 - chlorobenzyl) -1 - (2 - (dimethylamino)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione hydrochloride

[00389] 1 - (2 - Bromoethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (120 mg, 0.0.210 mmol) was dissolved in dimethylamine (3 mL), then the mixture was heated to 100 °C in a sealed tube with stirring for the night. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative HPLC and lyophilized to give 7-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride (29 mg, 2 5.6% yield) as a white solid. 1H NMR (DMSO-d6) δ 9.67 (s, 1H), 7.64 - 7.60 (t, 1H), 7.47 - 7.41 (m, 6H), 7.36 - 7.34 (m, 1H), 5.46 (s, 2H), 4.23 - 4.21 (m, 2H), 3.37 - 3.34 (m, 2H), 3.31 (s, 3H), 2.87 - 2.86 (d, 6H). LCMS retention time 2.174 min; LCMS MH+ 538.

[00390] The following examples 7a to 7k were prepared using the method of example 6, step 1. Example 7a: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00391] The title compound was prepared using the method of example 6, step 1 and purified by preparative HPLC to provide 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (10 mg, 17.3% yield) as a white solid. 1H NMR (CD3OD) δ 7.57 - 7.53 (t, 1H), 7.46 - 7.44 (d, 2H), 7.37 - 7.33 (m, 4H), 7.26 - 7.24 (d, 1H), 5.49 (s, 2H), 4.13 - 4.09 (t, 1H), 3.64 - 3.60 (t, 2H), 3.42 (s, 3H), 1.89 - 1.86 (m, 2H). LCMS retention time 3.059 min; LCMS MH+ 525. 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl) - N,N - dimethylacetamide

[00392] The title compound was prepared with 2 - chloro - N,N - dimethylacetamide and purified by preparative HPLC to provide 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl) - N,N - dimethylacetamide ( 20 mg, 17.2% yield) as a white solid. 1H NMR (400 Hz, DMSO-d6) δ = 7.64 - 7.59 (t, 1 H), 7.55 (s, 1 H), 7.48 - 7.40 (m, 5 H), 7.35 - 7.33 (d, 1 H), 5.42 (s, 2 H), 4.69 (s, 2 H), 3.30 (s, 3 H), 3.07 (s, 3H), 2.84 (s, 3H). LCMS retention time 3.079 min; LCMS MH+ 552. Example 7c: 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione

[00393] The title compound was prepared with 1,1,1 -trifluoro - 3 - iodopropane to give 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 - trifluoropropyl) -1H - purine - 2,6(3H,7H) -dione (30 mg, 35.6% yield) as white solid. 1H NMR (DMSO - d6) δ 7.64 - 7.59 (t, 1H), 7.50 (s, 1H), 7.45 - 7.41 (m, 5H), 7.35 - 7.33 (d, 1H), 5.44 (s, 2H), 4.15 - 4.12 (t, 2H), 3.22 (s, 3H) ), 2.63-2.55 (m, 2H). LCMS retention time 3.575 min; LCMS MH+ 563.

[00394] The title compound was prepared using the method of example 58, step 1 except the reaction was facilitated by microwave irradiation at 120 °C for 45 min to provide 7 - (4 - chlorobenzyl) -1 - (4 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (10 mg , 8.9% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.58 (t, 1H), 7.49 (s, 1H), 7.44 - 7.42 (m, 5H), 7.38 - 7.32 (d, 1H), 5.44 (s, 2H), 4.41 (s, 1H), 3.89 - 3.86 (t, 2H) ), 3.39 - 3.34 (m, 2H), 3.29 (s, 3H), 1.61 - 1.54 (m, 2H), 1.45 - 1.38 (m, 2H). LCMS retention time 3.053 min; LCMS MH+ 539. Example 7e: 7 - (4 - chlorobenzyl) -1 - (5 - hydroxypentyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione

[00395] The title compound was prepared with 5 - bromopentan -1 -ol to give 7 - (4 - chlorobenzyl) -1 - (5 - hydroxypentyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (30 mg, 20.9% yield) as white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.58 (t, 1H), 7.49 (s, 1H), 7.44 - 7.42 (m, 5H), 7.34 - 7.32 (d, 1H), 5.44 (s, 2H), 4.40 - 3.78 (t, 1H), 3.88 - 3.84 (t, 2H), 3.40 - 3.36 (m, H), 3.29 (s, 3H), 1.56 - 1.52 (m, 2H), 1.46 - 1.42 (m, 2H), 1.31 - 1.27 (m, 2H). LCMS retention time 3.057 min; LCMS MH+ 553. Example 7f: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxy - 3 - methoxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00396] The title compound was prepared with 1 - chloro - 3 - methoxypropan - 2 -ol and heating to 130 °C. White solid, 70 mg, 58.8% yield: 1H NMR (400 Hz, CD3OD) δ 7.57 - 7.53 (t, 1 H), 7.47 - 7.44 (d, 2 H), 7.37 - 7.33 (m, 4 H), 7.26 - 7.24 (d, 1 H), 5.49 (s, 2 H), 4.24 - 4.19 (m, 1H), 4.12 - 4.11 (m, 1H), 4.04 - 3.99 (m, 1H), 3.45 - 3.42 (m, 5H), 3.36 - 3.30 (d, 3H). LCMS retention time 3.044 min; LCMS MH+ 555. Example 7g: 7 - (4 - chlorobenzyl) -1 - (2 - methoxyethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00397] The title compound was prepared with 1 - bromo - 2 - methoxyethane and purified by preparative HPLC. White solid, 40mg, 50.9% yield: 1H NMR (DMSO-d6) δ 7.63 - 7.59 (t, 1H), 7.50 (s, 1H), 7.45 - 7.43 (m, 5H), 7.34 - 7.32 (d, 1H), 5.44 (s, 2H), 4.08 - 4.05 (t, 2H), 3.88 - 3.84 (t, 2H), 3.52 - 3.49 (t, 2H), 3.29 (s, 3H), 3.24 (s, 3H). LCMS retention time 3.322 min; LCMS MH+ 525. Example 7h: 7 - (4 - chlorobenzyl) -1 - (isoxazol - 5 - ylmethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione

[00398] The title compound was prepared with 5 - (chloromethyl)isoxazole and the reaction was catalyzed with TBAI. The crude product was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (isoxazol - 5 - ylmethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (21 mg, 8.9% yield) as a white solid. 1H NMR (DMSO-d6) δ 8.50 - 8.49 (d, 1H), 7.64 - 7.59 (t, 1H), 7.51 (s, 1H), 7.46 - 7.43 (m, 5H), 7.36 - 7.33 (d, 1H), 6.39 - 6.38 (d, 1H), 5.44 ( s, 2H), 5.22 (s, 2H), 3.32 (s, 3H). LCMS retention time 3.269 min; LCMS MH+ 548. Example 7i: N -tert -butyl -1 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6;7 -tetrahydro -1H - purin -1 -yl)methanesulfonamide

[00399] The title compound was prepared with N-tert-butyl-1-chloromethanesulfonamide. White solid, 5180 mg, 68.3% yield: 1H NMR (DMSO-d6) δ 7.64 - 7.59 (t, 1H), 7.49 (s, 1H), 7.45 - 7.39 (m, 6H), 7.35 - 7.33 (d, 1H), 7.14 (s, 1H), 5.45 (s, 2H), 5.21 (s, 2H), 3.31 (s, 3H), 1.28 (s, 9H). LCMS retention time 3.426 min; LCMS MH+ 616. Example 7j: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione

[00400] The title compounds prepared with 2 - bromoethanol. White solid, 11mg, 16.7% yield: 1H NMR (DMSO - d6) δ 7.58 - 7.62 (m, 1H), 7.49 (s, 1H), 7.41 - 7.43 (m, 5H), 7.31 - 7.32 (d, 1H), 5.44 (s, 2H), 4.76 - 4.79 (t, 1H), 3.95 - 3.98 (t, 2H), 3.50 - 3.54 (t, 2H), 3.28 (s, 3H). LCMS retention time 152.690 min; LCMS MH+ 511. Example 7k: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00401] The title compound was prepared with 3 - hydroxybutyl - 4 - methylbenzenesulfonate (Intermediate 33). White solid, 70mg, 61.9% yield: 1H NMR (DMSO-d6) δ 7.59 - 7.55 (t, 1H), 7.46 - 7.39 (d,6H), 7.30 - 7.28 (d, 1H), 5.41 (s, 2H), 4.49 - 4.48 (d, 1H), 4.02 - 3.97 (m, 1H), 3.84 - 3.79 (m, 1H), 3.64 - 3.61 (m, 1H), 3.26 (s, 3H), 1.59 - 1.52 (m, 2H), 1.06 - 1.05 (d, 3H). LCMS retention time 3.159 min; LCMS MH+ 539. Example 8: 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)propanenitrile

[00402] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol, Intermediate 9) in a mixed solution of THF (3 mL) and acetonitrile (5 mL) was added TBAH (0.05 mL, 0.193 mmol) and acrylonitrile (40 mg, 0.642 mmol). The mixture was stirred at 60°C overnight. Then the mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. This crude material was purified by silica gel chromatography eluting with petroleum / ethyl acetate (3:1 to 1:1) to afford 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 - tetrahydro-1H-purin-1-yl)propanenitrile (75 mg, 68.8 %) as a white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.59 (t, 1H), 7.50 (s, 1H), 7.45 - 7.40 (m, 5H), 7.35 - 7.33 (d, 1H), 5.45 (s, 2H), 4.16 - 4.13 (t, 2H), 3.31 (s, 3H) ), 2.89 - 2.86 (t, 2H). LCMS retention time 3.248 min; LCMS MH+ 520. Example 9: 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)acetic acid Step 1: tert -butyl 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl)acetate

[00403] The title compound was prepared using the method of example 6, step 1 to provide 200 mg (100% yield) as yellow oil which was used without purification. LCMS M - 'Bu+H 525. Step 2: 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl)acetic acid

[00404] To a solution of tert-butyl 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)acetate (200 mg, 0.342 mmol) in DCM (5 ml) was added trifluoroacetic acid (2 ml, 26.9 mmol) at 0 °C. The mixture was stirred at 100 °C at room temperature for 3 hours. Then the mixture was concentrated, diluted with DCM and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (180 mg, 99.9% yield) as a white solid. 1H NMR (DMSO-d6) δ 13.06 (s, 1H), 7.64 - 7.59 (t, 1H), 7.55 (s, 1H), 7.48 - 7.43 (m, 155H), 7.36 - 7.34 (d, 1H), 5.43 (s, 2H), 4.53 (s, 2H), 3 .37 (s, 3H). LCMS retention time 2.994 min; LCMS MH+ 525. Example 10: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (4 - methylpiperazin -1 -yl) - 2 - oxoethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00405] To a solution of 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (80 mg, 0.152 mmol, example 9) in NMP (2 mL) was added TEA (0.1 mL, 0.614 mmol), 1-methylpiperazine (0.07 mL, 0.614 mmol) and 0-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87 mg, 0.231 mmol); then the mixture was stirred at 60°C for 16 hours. Then the mixture was diluted with ethyl acetate and water, the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. This crude material was purified by recrystallization from methanol to afford 7-(4-chlorobenzyl) - 3 - methyl -1 - (2 - (4 - methylpiperazin -1 -yl) - 2 - oxoethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione (25 mg, 27.5% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.62 - 7.59 (t, 1H), 7.55 (s, 1H), 7.49 - 7.39 (m, 5H), 7.36 - 7.34 (d, 1H), 5.43 (s, 2H), 4.71 (s, 2H), 3.55 - 3.48 (m, 4H) ), 3.30 (s, 3H), 2.46 - 2.36 (m, 4H), 2.21 (s, 3H). LCMS retention time 2.298 min; LCMS MH+ 607. Example 11: 7-(4-Chlorobenzyl)-1-(3-(dimethylamino)-2-oxopropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride

[00406] The title compound was prepared using the 2 Example Step method 6 to provide 7 - (4 - chlorobenzil) -1 - (3 - (dimethylamine) - 2 - oxopropil) - 3 - 8 - (3 - (trifluorometoxy) phenis) as white solid. 1H NMR (DMSO-d6) δ 10.05 (s, 1H), 7.65 - 7.61 (t, 1H), 7.54 (s, 1H), 7.48 - 7.40 (m, 5H), 7.37 - 7.35 (d, 1H), 5.43 (s, 2H), 4.85 (s, 2H), 4.5 2 (s, 2H), 3.32 (s, 3H), 2.80 (s, 6H). LCMS retention time 2.352 min; LCMS MH+ 566. Example 12: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (4 - methylpiperazin -1 -yl)ethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00407] The title compound was prepared using the method of step 2 of example 6 with 1 -methylpiperazine to provide 7-(4-chlorobenzyl) - 3 - methyl -1 - (2 - (4 - methylpiperazin -1 -yl)ethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (40 mg, 38 .7% yield) as a white solid. 1H - MMR (CD3OD) δ 7.59 - 7.55 (t, 1H), 7.46 - 7.34 (m, 6H), 7.27 - 7.25 (d, 2H), 5.51 (s, 2H), 4.19 - 4.16 (t, 2H), 3.43 (s, 3H), 3.33 - 3.32 ( m, 4H), 3.03 - 3.93 (bs, 4H), 2.82 - 2.73 (t, 2H), 2.69 (s, 3H). LCMS retention time 2.3 min; LCMS MH+ 593. Example 13: 7 - (4 - chlorobenzyl) -1 - (2,3 - dihydroxypropyl) - 3 - methyl - 8 - (3 - 5 (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (oxiran - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00408] The title compound was prepared using the method of example 6, step 1 to provide 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (oxiran - 2 -ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (220 mg, 100% yield) as a yellow solid which was used without purification. LCMS MH+ 523. Step 2: 7 - (4 - chlorobenzyl) -1 - (2,3 - dihydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00409] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (oxiran - 2 -ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (140 mg, 0.268 mmol) in 1,4-dioxane (10 mL) was added TFA (0.11 mL, 1 .48 mmol) and water (2 mL); then the mixture was stirred at 80 °C for 2 h. The mixture was concentrated; in follow from the purified by silica chromatography gel ellicing with DCM/methanol (50: 1 to 20: 1) to provide 7 - (4 - chlorobenzil) -1 - (2.3 - dihydroxypropil) - 3 - methyl - 8 - (3 - (trifluoromethyl) - 1h - Purina - 2.6 (3h, 7h) - diona (70 mg, 48.4 % production) as white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.58 (t, 1H), 7.48 (s, 1H), 7.44 - 7.41 (m, 5H), 7.34 - 7.31 (d, 1H), 5.44 (s, 2H), 4.68 - 4.67 (d, 1H), 4.55 - 4.52 (m, 1H), 4.01 - 3.98 (m, 1H), 3.84 - 3.80 (m, 2H), 3.33 (s, 2H), 3.29 (s, 3H). LCMS retention time 2.811 min; LCMS MH+ 541. Example 14: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxy - 2 - methoxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione Step 1: 1 - (3(tert - butyldimethylsilyloxy) - 2 - hydroxypropyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00410] To a solution of 7 - (4 - chlorobenzyl) -1 - (2,3 - dihydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (100 mg, 0.185 mmol, example product 13) in DCM (10 mL) was added imidazole (11 mg, 0. 16 mmol) and DMAP (10 mg, 0.08 mmol) at 0 °C, then tert-butylchlorodimethylsilane (40 mg, 0.27 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude 1 - (3 - (tert -butyldimethylsilyloxy) - 2 - hydroxypropyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (180 mg, 100% yield) as white solid. LCMS MH+ 655. Step 2: 1 -(3-(tert-butyldimethylsilyloxy)-2-methoxypropyl)-7-(4-chlorobenzyl)-3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00411] To a suspension of sodium hydride (240 mg, 9.6 mmol) in anhydrous THF (10 ml) was added dropwise a solution of 1 - (3 - (tert - butyldimethylsilyloxy) - 2 - hydroxypropyl) - 7 - (4-chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2.6( 3H,7H)-dione (124 mg, 0.19 mmol) in THF (3 mL) at 0 °C under nitrogen. The reaction was stirred at 0°C for 10 minutes. Then iodomethane (1.2 ml, 19.4 mmol) was added dropwise and the resulting mixture was allowed to warm from 0 °C to room temperature over 2 h. The mixture was quenched with ice water (5 mL). The mixture was concentrated, diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product (150 mg, 100% yield) as a yellow oil. LCMS MH+ 669. Step 3: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxy - 2 - methoxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione.

[00412] To a solution of 1-(3-(tert-butyldimethylsilyloxy)-2-methoxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.22 mmol) in ethyl alcohol (5 mL) was added concentrated HCl (0 .1 mL). The reaction was stirred for 10 minutes. It was then concentrated and purified by preparative HPLC to provide 7 - (4 - chlorobenzyl) -1 - (3 - hydroxy - 2 - methoxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione (18 mg, 16.2% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.59 (t, 1H), 7.50 (s, 1H), 7.45 - 7.43 (m, 5H), 7.34 - 7.32 (d, 1H), 5.44 (s, 2H), 4.65 - 4.62 (t, 1H), 4.12 - 4.08 (q, 1H), 3.84 - 3.79 (q, 1H), 3.53 - 3.41 (m, 2H), 3.29 - 3.28 (d, 6H). LCMS retention time 3.089 min; LCMS MH+ 555. Example 15: 7-(4-chlorobenzyl)-1 -(3-(dimethylamino)-2-hydroxypropyl)-3-methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00413] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (oxiran - 2 -ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.192 mmol, example 13, step 1) in THF (10 mL) was added dimethylamine hydrochloride ( 160 mg, 1.98 mmol) and lithium perchlorate (20 mg, 0.189 mmol). The mixture was stirred at 25 °C in a sealed tube for 2 h. The mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. This crude material was purified by preparative HPLC to provide 7-(4-chlorobenzyl) -1 - (3 - (dimethylamino) - 2 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione (50 mg, 46.2% yield) as a white solid. 1H NMR (CD3OD) δ 8.48 (s, 1H), 7.59 - 7.54 (t, 1H), 7.47 - 7.45 (d, 2H), 7.38 - 7.34 (m, 4H), 7.27 - 7.25 (d, 1H), 5.5l (s, 2H), 4.34 - 4.31 (m , 1H), 4.23 - 4.18 (m, 1H), 4.07 - 4.02 (m, 1H), 3.44 (s, 1H), 3.22 - 3.21 (d, 2H), 2.90 (s, 6H). LCMS retention time 2.227 min; LCMS MH+ 568. Example 16: 7 - (4 - chlorobenzyl) -1 - (3 - methoxy - 2 - oxopropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00414] To a solution of 7-(4-chlorobenzyl)-1 -(2-hydroxy-3-methoxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H)-dione (40 mg, 0.072 mmol, example 7f) in methyl sulfoxide (4 mL) was added acetic anhydride (3 7 mg, 0.363 mmol) dropwise. Then the mixture was stirred at 25°C for 16 hours. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. This crude material was further purified by preparative HPLC to afford 7-(4-chlorobenzyl)-1-(3-methoxy - 2 -oxopropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H)-dione (12 mg, 30.2%) as a white solid. 1H NMR (CD3OD) δ 7.56 - 7.52 (t, 1H), 7.42 - 7.39 (d, 2H), 7.36 - 7.31 (m, 4H), 7.24 - 7.22 (d, 1H), 5.45 (s, 2H), 4.92 (s, 2H), 4.24 (s, 2H), 3.46 (s, 3H), 3.39 (s, 3H). LCMS retention time 3.210 min; LCMS MH+ 553. Example 17: N - (2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl)ethyl)propane - 2 -sulfonamide Step 1: 7 - (4 - chlorobenzyl) -1 - (2 - (1,3 - dioxoisoindolin - 2 - yl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00415] The title compound was prepared using the method of example 6, step 1 with 2-(2-bromoethyl)isoindoline-1,3-dione to provide 7 - (4 - chlorobenzyl) -1 - (2 - (1,3 - dioxoisoindolin - 2 - yl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3 H,7H)-dione (150 mg, 72.9% yield) as a white solid. LCMS retention time 2.045 min; LCMS MH+ 640. Step 2: 1 -(2-aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00416] To a solution of 7 - (4 - chlorobenzyl) -1 - (2 - (1,3 - dioxoisoindolin-2-yl)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.157 mmol) in ethanol (10 mL) was added hydrazine hydrate (2 ml) dropwise, then the mixture was stirred at 80 °C for 2 h. The mixture was concentrated to give 1 - (2 - aminoethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 100%) as a yellow oil. LCMS MH+ 510. Step 3: N-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro - 1H -purin-1-yl)ethyl)propane-2-sulfonamide.

[00417] To a solution of 1 - (2 - aminoethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione (100 mg, 0.197 mmol) and TEA (40 mg, 0.393 mmol) in DCM (10 mL) was added propane chloride - 2-sulfonyl (42 mg, 0.295 mmol) dropwise at 0 °C. The resulting mixture was stirred at 40°C for 16 hours. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. This crude material was recrystallized from ethanol to provide N - (2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1-yl)ethyl)propane-2-sulfonamide (20 mg, 16.5% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.59 (t, 1H), 7.48 (s, 1H), 7.45 - 7.41 (m, 5H), 7.35 - 7.33 (d, 1H), 7.26 - 7.18 (m, 1H), 5.45 (s, 2H), 4.01 - 3.97 (t, 1H), 3.29 (s, 6H). LCMS retention time 3.195 min; LCMS MH+ 616. Example 18: (7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide

[00418] A solution of N-tert-butyl-1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide (120 mg, 0.195 mmol, example 7i) in TFA (2 ml, 26, 9 mmol) was stirred at 50°C for 16 hours. The mixture was concentrated and then purified by silica gel chromatography eluting with DCM/methanol (40:1) to afford (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin - 1 -yl)methanesulfonamide (79 mg, 72.4% of production) as a white solid. 1H NMR (DMSO-d6) δ 7.65 - 7.61 (t, 1H), 7.49 (s, 1H), 7.47 - 7.41 (m, 6H), 7.36 - 7.35 (d, 1H), 7.05 (s, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.3l (s, 3H). LCMS retention time 3.004 min; LCMS MH+ 560. Example 19:1 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl) - N - methylmethanesulfonamide

[00419] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 - yl)methanesulfonamide (0.1 g, 0.18 mmol, example 18) in DMF (3 mL) was added iodomethane (16 mg, 0.18 mmol) and potassium carbonate (36 mg, 0.26 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to provide 1 - (7 - (4 - 20-chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8(3 - (trifluoromethoxy) -phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl) - N - methylmethanesulfonamide (23 mg, 22.3% yield) as a white solid. 1H NMR (DMSO - d6) δ 7.63 (t, 1H), 7.50 (d, 1H), 7.41 - 7.46 (m, 4H), 7.34 - 7.37 (m, 1H), 7.19 - 7.23 (m, 1H), 5.45 (s, 2H), 5.20 (s, 2H), 3.31 (s, 3H), 2.60 (d, 3H). LCMS retention time 3.097 min; LCMS MH+574 [1] Example 20: 8-(3,5-bis(trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) -1 - (2 - (2 - ethyl -1,3 - dioxolan - 2 - yl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione

[00420] The title compound was prepared using the method of example 6, step 1 with Intermediate 32 to afford 7-(4-chlorobenzyl) -1 - (2 - (2 - ethyl -1,3 - dioxolan - 2 - yl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H, 7H)-dione (360) mg, 100% yield) as a white solid. LCMS MH+ 595. Step 2: 7-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00421] The title compound was prepared using the method of example 14, step 3 to provide 7-(4-chlorobenzyl)-3-methyl-1-(3-oxopentyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (60 mg, 64.2% yield) as white solid. 1H NMR (DMSO-d6) δ 7.59 - 7.55 (t, 1H), 7.46 - 7.39 (d, 6H), 7.31 - 7.29 (d, 1H), 5.39 (s, 2H), 4.06 - 4.03 (m, 2H), 3.26 (s, 3H), 2.69 - 2.65 (t, 2H), 2.48 - 2.42 (t, 2H), 0.91 - 0.87 (t, 3H). LCMS retention time 3.384 min; LCMS MH+ 551. Example 21: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypentyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00422] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - oxopentyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (150 mg, 0.273 mmol, example 20) in methanol (20 mL) was added sodium borohydride (40 mg, 1.0 5 mmol) at 0 °C under nitrogen. The mixture was stirred at 50 °C for 2 h. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypentyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (50 mg, 33.5% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.58 (t, 1H), 7.49 (s, 1H), 7.44 - 107.42 (m, 5H), 7.34 - 7.31 (d, 1H), 5.44 (s, 2H), 4.48 - 4.46 (d, 1H), 4.08 - 4.0 1 (m, 1H), 3.89 - 3.83 (m, 1H), 3.42 - 3.37 (m, 1H), 3.29 (s, 3H), 1.63 - 1.55 (m, 2H), 1.44 - 1.31 (m, 2H), 0.87 - 0.84 (t, 3H). LCMS retention time 3.372 min; LCMS MH+ 553. Example 22: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 - yloxy) -1H - purine - 2,6(3H,7H) - dione Step 1: 8 - (4 - chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00423] The title compound was prepared from Intermediate 8 using the method of Intermediate 12, step 2 to afford 8-(4-chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (77 mg, 39.5% yield) as white solid. LCMS retention time 1.809 min; LCMS MH+ 485 Step 2: 7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy) - 1H - purine - 2,6(3H,7H) - dione

[00424] The title compound was prepared using the method of example 6, step 1 to provide 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) - 1H - purine - 2,6(3H,7H) - dione (20 mg, 24.4% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.94 - 7.93 (d, 1H), 7.86 - 7.84 (d, 1H), 7.79 - 7.77 (m, 1H), 7.46 (s, 4H), 5.44 (s, 2H), 3.94 - 3.89 (m, 2H), 3.29 (s, 3H) ), 1.14 - 1.10 (t, 3H). LCMS retention time 3,400 min; LCMS MH+ 513 Example 23: 3 - benzyl - 7 - (4 - chlorobenzyl) -1 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 3 - benzyl - 8 - chloro - 7 - (4 - chlorobenzyl) -1 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00425] To a solution of 8 - chloro - 7 - (4 - chlorobenzyl) -1 - methyl - 1H - purine-2,6(3H,7H)-dione (50 mg, 0.154 mmol, Intermediate 10) in DMF (3 mL) was added (bromomethyl)benzene (50 mg, 0.29 mmol) followed by potassium carbonate (40 mg, 0.29 mmol). The mixture was stirred at 40°C overnight. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated.

[00426] The crude product was purified by chromatography on silica gel eluting with petroleum / ethyl acetate (5:1 to 3:1) to give 3 - benzyl - 8 - chloro - 7 - (4 - chlorobenzyl) -1 - methyl -1H - purine - 2,6(3H,7H) - dione (60 mg, 93.6% yield) as white solid. LCMS retention time 1.893 min; LCMS MH+ 415. Step 2: 3 - benzyl - 7 - (4 - chlorobenzyl) -1 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00427] to a solution of 3 - benzil - 8 - chlorine - 7 - (4 - chlorobenzil) -1 - methyl- 1h- Purina -2.6 (3h, 7h) –Diona (60 mg, 0.145 mmol) in DMF (3 ml) was added 3 - (35 mg, 0.215 mmol) (40 mg, 0.29 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product provided was purified by preparative HPLC to provide 3 - benzyl - 7 - (4 - chlorobenzyl) -1 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (31 mg, 41.7% yield) as a white solid. 1H NMR (CDCl3) δ 7.65 (s, 1H), 7.58 - 7.57 (m, 2H), 7.45 - 7.41 (m, 5H), 7.33 - 7.27 (m, 5H), 5.42 (s, 2H), 5.09 (s, 2H), 3.41 (s, 3H). LCMS retention time 3.649 min; LCMS (M+H) 541.

[00428] The following examples 24a to 24m were prepared using the method of step 2 of example 23. Example 24a: 7 - (4 - chlorobenzyl) - 3 - (2 - hydroxyethyl) -1 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00429] White solid, 7 mg, 10.1 % yield: 1H NMR (CDCl3) δ 7.57 - 7.51 (m, 3 H), 7.44 - 7.42 (m, 3 H), 7.34 - 7.32 (m, 2 H), 5.44 (s, 2 H), 4.21 - 4.18 (m, 2 H), 3 .88 - 3.84 (m, 2H), 3.42 (s, 3H). LCMS retention time 3.045 min; LCMS MH+ 495. Example 24b: 7 - (4 - chlorobenzyl) -1 - methyl - 3 - (pyridin - 2 -ylmethyl) - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00430] White solid, 30 mg, 50.4 % yield: 1H NMR (DMSO-d6) δ 8.43 - 8.41 (d, 1 H), 7.71 - 7.63 (m, 5 H), 7.49 - 7.44 (m, 4 H), 7.28 - 7.23 (m, 2 H), 5.46 (s, 2 H), 5.14 (s, 2H), 3.26 (s, 3H). LCMS retention time 103.279 min; LCMS MH+ 542. Example 24c: 3 - benzyl - 7 - (4 - chlorobenzyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00431] White solid, 15 mg, 10.8% yield: 1H NMR (DMSO-d6) δ 7.61 - 7.56 (m, 1H), 7.49 (bs, 1H), 7.41 - 7.39 (m, 5H), 7.31 - 7.24 (m, 6H), 5.41 (s, 2H), 4.9 9 (s, 2H), 3.22 (s, 3H). LCMS retention time 3.705 min; LCMS MH+ 557. Example 24d: 7 - (4 - chlorobenzyl) - 3 - (2 - hydroxyethyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00432] White solid, 58 mg, 18.9 % yield: 1H NMR (DMSO - d6) δ 7.63 - 7.59 (m, 1 H), 7.49 - 7.42 (m, 6 H), 7.34 - 7.31 (m, 1 H), 5.44 (s, 2 H), 4.81 - 4.78 (t, 1 H), 3.94 - 3.90 (m, 2H), 3.60 - 3.37 (m, 2H), 3.24 (s, 3H). LCMS retention time 3.002 min; LCMS MH+ 511. Example 24e: 7 - (4 - chlorobenzyl) -1 - methyl - 3 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00433] White solid, 38 mg, 62.0% yield: 1H NMR (DMSO-d6) δ 8.43 - 8.42 (d, 1H), 7.73 - 7.69 (m, 1H), 7.56 - 7.52 (t, 1H), 7.48 - 7.43 (m, 4H), 7.38 - 7.3 4 (m, 2H), 7.29 - 7.23 (m, 3H), 5.45 (s, 2H), 5.15 (s, 2H), 3.26 (s, 3H). LCMS retention time 3.266 min; LCMS MH+ 558. Example 24f: 8-(3,5-bis(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-ethyl-1 -methyl - 1H - purine - 2,6(3H,7H) -dione

[00434] White solid, 10 mg, 26.2% yield: 1H NMR (DMSO-d6) δ 8.23 (s, 2H), 8.05 (s, 1H), 7.48 - 7.39 (dd, 4H), 5.42 (s, 2H), 3.86 - 3.84 (m, 2H), 3.22 (s, 3 H), 1.14 - 1.11 (t, 3H). LCMS retention time 3.591 min; LCMS MH+ 547. Example 24g: 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00435] White solid, 20 mg, 20.4 % yield: 1H NMR (DMSO-d6) δ 7.61 - 7.59 (t, 1 H), 7.52 (s, 1 H), 7.43 (s, 5 H), 7.33 - 7.32 (d, 1 H), 5.44 (s, 2 H), 3.89 - 3.8 8 (m, 2H), 3.24 (s, 3H), 1.17 - 1.13 (t, 3H). LCMS retention time 3.561 min; LCMS MH+ 495. Example 24h: 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00436] White solid, 20 mg, 24.5% yield: 1H NMR (DMSO-d6) δ 7.79 (s, 1H), 7.73 - 7.67 (m, 3H), 7.47 - 7.42 (m, 4H), 5.45 (s, 2H), 3.90 - 3.85 (q, 2H), 3.3 0 (s, 3H), 1.24 - 1.13 (t, 3H). LCMS retention time 3.511 min; LCMS MH+ 479. Example 24i: 7 - (4 - chlorobenzyl) -1 - methyl - 3 - (pyridin - 4 -ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione

[00437] White solid, 10 mg, 6.21% yield: 1H NMR (DMSO-d6) δ 8.48 - 8.46 (d, 2H), 7.59 - 7.55 (t, 1H), 7.47 - 7.45 (m, 5H), 7.43 - 7.39 (d, 1H), 7.38 - 7.3 7 (d, 1H), 7.31 - 7.24 (m, 2H), 5.45 (s, 2H), 5.05 (s, 2H), 3.25 (s, 3H). LCMS retention time 2.856 min; LCMS MH+ 558. Example 24j: 7 - (4 - chlorobenzyl) -1 - methyl - 3 - (2 - oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione

[00438] White solid, 11 mg, 9.93% yield: 1H NMR (DMSO-d6) δ 7.61 - 7.59 (t, 1H), 7.44 - 7.38 (m, 6H), 7.32 - 7.30 (d, 1H), 5.44 (s, 2H), 4.74 (s, 2H), 3.2 4 (s, 3H), 2.16 (s, 3H). LCMS retention time 3.210 min; LCMS MH+ 523. Example 24k: 7-(4-chlorobenzyl)-3-(2-(2-hydroxyethoxy)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H - purine - 2,6(3H,7H) -dione

[00439] White solid, 31 mg, 45.3 % yield: 1H NMR (DMSO-d) δ 7.59 - 7.56 (t, 1 H), 7.44 - 7.37 (m, 6 H), 7.31 - 7.29 (d, 1 H), 5.42 (s, 2 H), 4.01 - 3.98 (t, 2 H) ), 3.35 (s, 4H), 3.22 (s, 3H). LCMS retention time 2.969 min; LCMS MH+ 555. Example 241: 7 - (4 - chlorobenzyl) -1 - methyl - 3 - propyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00440] White solid, 15 mg, 26.8 % yield: 1H NMR (CDCl3) δ 7.49 - 7.43 (m, 3 H), 7.35 - 7.31 (m, 3 H), 7.24 - 7.15 (m, 2 H), 5.44 (s, 2 H), 3.97 - 3.93 (t, 2 H), 3.43 (s, 3H), 1.76 - 1.70 (m, 2H), 0.94 - 0.90 (t, 3H). LCMS retention time 3.526 min; LCMS MH+ 509. Example 24m: 7 - (4 - chlorobenzyl) - 3 - (isoxazol - 5 - ylmethyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00441] White solid, 16 mg, 16.3 % yield: 1H NMR (DMSO-d6) δ 8.33 - 8.31 (d, 2 H), 7.61 - 7.57 (t, 1 H), 7.45 - 7.41 (m, 6 H), 7.32 - 7.29 (d, 1 H), 5.44 (s, 2 H), 4.34 (bs, 2H), 3.26 (s, 3H). LCMS retention time 3.114 min; LCMS MH+ 548. Example 25: 7 - (4 - chlorobenzyl) - 3 - (2 - (dimethylamino)ethyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione Step 1: 3-(2-bromoethyl)-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00442] To a solution of 7 - (4 - chlorobenzyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol) in DMF (3 mL) was added 1,2 -dibromoethane (0.2 mL, 2.32 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 50°C for 16 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over sodium sulfate, filtered and concentrated to give the crude product (110 mg, 91.6% yield) as a white solid. LCMS retention time 2.099 min; LCMS MH+573. Step 2: 7 - (4 - chlorobenzyl) - 3 - (2 - (dimethylamino)ethyl) -1 - methyl - 8 - (3 (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00443] To a solution of 3 - (2 - bromoethyl) - 7 - (4 - chlorobenzyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (110 mg, 0.192 mmol) in DMF (3 mL) was added dimethylamine hydrochloride (150 mg, 1.84 mmol), followed by potassium carbonate (100 mg, 0.725 mmol). The mixture was stirred at 40 °C for 16 h; then it was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) - 3 - (2 - (dimethylamino)ethyl) -1 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (15 mg, 13.3% yield) as a white solid. 1H NMR (DMSO-d6) ? 2H), 3.39 (m, 2H), 3.26 (s, 3H), 2.79 - 2.78 (d, 6H). LCMS retention time 3.266 min; LCMS MH+ 558. Example 26: 7 - (4 - chlorobenzyl) -1 - methyl - 3 - (2 - oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00444] To a solution of 7 - (4 - chlorobenzyl) -1 - methyl - 3 - (2 - oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione (80 mg, 0.153 mmol, example 24j) in ethanol (3 mL) was added sodium borohydride (12 mg, 0.317 mmol) at 0 °C. The resulting mixture was stirred at 0°C overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the title product (6 mg, 7.47% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.63 - 7.58 (t, 1H), 7.50 (s, 1H), 7.43 - 7.41 (m, 5H), 7.33 - 7.31 (d, 1H), 5.44 (s, 2H), 4.80 - 4.79 (d, 1H), 4.02 - 3.99 (bs, 1H), 3.89 - 3.84 (m, 1H), 3.69 - 3.65 (dd, 1H), 3.24 (s, 3H), 1.01 - 0.99 (d, 3H). LCMS retention time 3.095 min; LCMS MH+ 525. Example 27: 8 - (4 - chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 8 - (4 - chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethoxy)ethyl) -1H - purine - 2,6(3H,7H) - dione

[00445] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.28 mmol, Intermediate 11) in DMF (5 mL) was added 4 - chlorine - 3 - (trifluoromethyl)phenol (81 mg, 0.45 mmol) and potassium carbonate (76 mg, 0.55 mmol). The mixture was stirred at 80°C overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 2.112 min; LCMS MH+- THP 573. Step 2: 8 - (4 - chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

[00446] To a solution of 8 - (4 - chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4-chlorobenzyl)-3-methyl-1 -(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine - 2,6(3H,7H) -dione (100 mg, 0.15 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 8 - (4 - chloro - 3 - (trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (37 mg, 43.1% yield ) as a white solid. 1H NMR (DMSO-d6) δ 7.95 (d, 1H), 7.85 (d, 1H), 7.77 - 7.80 (m, 1H), 7.44 (s, 4H), 5.44 (s, 2H), 4.58 - 4.61 (m, 1H), 4.06 (t, 2H), 3.59 (t, 2H), 3.43 - 3.46 (m, 4H), 103.29 (s, 3). LCMS retention time 3.070 min; LCMS MH+ 573.

[00447] The following examples 28a to 28g were prepared using the method of example 27. Example 28a: 8 - (3,5 - bis(trifluoromethyl)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00448] White solid, 27 mg, 30.1 % yield: 1H NMR (DMSO-d6) δ 8.25 (s, 1 H), 8.09 (s, 1 H), 7.48 (d, 2 H), 7.42 (d, 2 H), 5.46 (s, 2 H), 4.59 (s, 1 H), 4.07 (t, 2H), 3.57 (t, 2H), 3.40 - 3.46 (m, 4H), 3.29 (s, 3H). LCMS retention time 3.150 min; LCMS MH+ 607. Example 28b: 7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H - purine - 2,6(3H,7H) -dione

[00449] White solid, 30 mg, 40.5% yield: 1H NMR (DMSO-d6) δ 7.78 (s, 1H), 7.70 - 7.73 (m, 3H), 7.44 (s, 4H), 5.45 (s, 2H), 4.59 (t, 1H), 4.06 (t, 2H), 3.6 0 (t, 2H), 3.44 (s, 4H), 3.32 (s, 3H). LCMS retention time 2.923 min; LCMS MH+ 539. [2] Example 28c: 7-(4-chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (m -tolyloxy) -1H - purine - 2,6(3H,7H) -dione

[00450] White solid, 21 mg, 29.8 % yield: 1H NMR (DMSO-d6) δ 7.37 - 7.46 (m, 4 H), 7.33 (t, 1 H), 7.09 - 7.12 (m, 3 H), 5.42 (s, 2 H), 4.58 (t, 1 H), 4.06 (t, 2 H), 3.56 (t, 2H), 3.45 (t, 4H), 3.32 (s, 3H), 2.32 (d, 103H). LCMS retention time 2.801 min; LCMS MH+ 485. Example 28d: 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 8 - (3 - methoxyphenoxy) - 3 - methyl -1H - purine - 2,6(3H,7H) -dione.

[00451] White solid, 26 mg, 37.7 % yield: 1H NMR (DMSO - d6) δ 7.38 - 7.47 (m, 4 H), 7.36 (t, 1 H), 6.88 - 6.90 (m, 3 H), 5.42 (s, 2 H), 4.59 (t, 1 H), 4.06 (t, 2 H), 3.76 (s, 3H), 3.56 (t, 2H), 3.45 (s, 4H), 3.29 (s, 3H). LCMS retention time 2.631 min; LCMS MH+ 501. Example 28e 7 - (4 - chlorobenzyl) - 8 - (3 - chlorophenoxy) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl -1H - purine - 2,6(3H,7H) -dione.

[00452] White solid, 33 mg, 36.8 % yield: 1H NMR (DMSO-d6) δ 7.48 - 7.52 (m, 2 H), 7.35 - 7.42 (m, 6 H), 5.43 (s, 2 H), 4.59 (t, 1 H), 4.06 (t, 2 H), 3.58 (t, 2 H), 3.45 (s, 4H), 3.30 (s, 3H). LCMS retention time 2.856 min; LCMS MH+ 505. Example 28f: 7-(4-chlorobenzyl)-8-(3-ethylphenoxy)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

[00453] White solid, 27 mg, 36.8 % yield: 1H NMR (DMSO-d6) δ 7.36 - 7.46 (m, 5 H), 7.11 - 7.15 (m, 3 H), 5.43 (s, 2 H), 4.61 (t, 1 H), 4.06 (t, 2 H), 3.56 (t, 2 H), 3.43 - 3.47 (m, 4H), 3.28 (s, 3H), 2.62 (q, 2H), 1.17 (t, 3H). LCMS retention time 2.909 min; LCMS MH+ 499. Example 28g: 7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(morpholinomethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione

[00454] White solid, 41 mg, 41.1 % yield: 1H NMR (DMSO - d6) δ 7.77 (s, 1 H), 7.51 - 7.58 (m, 2 H), 7.43 - 7.46 (m, 5 H), 5.43 (s, 2 H), 4.32 - 4.37 (m, 2 H), 4.0 3 - 4.06 (m, 2H), 3.85 - 3.90 (m, 4H), 3.54 - 3.57 (t, 2H), 3.44 (m, 4H), 3.27 (s, 3H), 3.00 - 3.09 (m, 4H). LCMS retention time 1.699 min; LCMS MH+ 570. Example 29: 7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-methylbenzyloxy)-1H - purine - 2,6(3H,7H) -dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - methylbenzyloxy) -1 - (2 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethoxy)ethyl) - 1H - purine - 2,6(3H,7H) - dione

[00455] To a solution of m-tolylmethanol (37 mg, 0.3 mmol) in DMF (2 mL) was added sodium hydride (18 mg, 0.45 mmol) at 0°C. After stirring at 0 °C for 30 min, 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethoxy)ethyl) - 1H - purine - 2,6(3H,7H) -dione (80 mg, 0.15 mmol, Intermediate 11) was added. The mixture was stirred at 0 °C for 15 min, then aqueous ammonium chloride solution (2 mL) was added at 0 °C. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.967 min; LCMS MH+-THP 499. Step 2: 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - methylbenzyloxy) - 1H - purine - 2,6(3H,7H) - dione

[00456] The title product was prepared using the method of example 27, step 2. White solid, 12mg, 16.2% yield: 1H NMR (DMSO-d6) δ 7.39 (d, 2H), 7.25 - 7.28 (m, 3H), 7.15 - 7.21 (m, 3H), 5.49 (s, 2H), 5.2 5 (s, 2H), 4.57 (d, 1H), 4.03 (t, 2H), 3.54 (t, 2H), 3.44 (t, 4H), 3.41 (s, 3H). LCMS retention time 2.888 min; LCMS MH+ 499.

[00457] The following examples 30a to 30d were prepared using the method of step 2 of example 29. Example 30a: 7 - (4 - chlorobenzyl) - 8 - (3 - chlorobenzyloxy) -1 - (2 - (2 - hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

[00458] White solid, 15 mg, 19.4% yield: 1H NMR (DMSO-d6) δ 7.37 - 7.44 (m, 6 H), 7.28 (d, 2 H), 5.53 (s, 2 H), 5.28 (s, 2 H), 4.58 (t, 1 H), 4.03 (t, 2 H), 3.5 6 (t, 2H), 3.45 (t, 4H), 3.39 (s, 3H). LCMS retention time 2.894 min; LCMS MH+ 519. Example 30b: 7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethyl)benzyloxy)-1H-purine-2,6(3H,7H)-dione

[00459] White solid, 18 mg, 21.6% yield: 1H NMR (DMSO-d) δ 7.79 (s, 1 H), 7.74 (d, 2 H), 7.63 (t, 1 H), 7.37 (d, 2 H), 7.28 (d, 2 H), 5.62 (s, 2 H), 5.28 (s, 2 H ), 4.58 (t, 1H), 4.04 (t, 2H), 3.55 (t, 2H), 3.44 - 3.45 (m, 4H), 3.42 (s, 3H). LCMS retention time 2.921 min; LCMS MH+ 553. Example 30c: 7 - (4 - chlorobenzyl) -1 - (2 - (2 - hydroxyethoxy)ethyl) - 8 - (3 - methoxybenzyloxy) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00460] White solid, 17 mg, 22.1% yield: 1H NMR (DMSO-d6) δ 7.36 - 7.38 (m, 2H), 7.25 - 7.32 (m, 3H), 6.91 -6.99 (m, 3H), 5.50 (s, 2H), 5.25 (s, 2H), 4.60 (t, 1H), 4.03 (t, 2H), 3.73 (s, 3H), 3.54 (t, 2H), 3.42 - 3.47 (m, 7H). LCMS retention time 2.718 min; LCMS MH+ 515. Example 30d: 7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)benzyloxy)-1H-purine-2,6(3H,7H)-dione

[00461] White solid, 31 mg, 22.1% yield: 1H NMR (DMSO-d) δ 7.53 (t, 1 H), 7.37 - 7.47 (m, 5 H), 7.28 (d, 2 H), 5.58 (s, 2 H), 5.28 (s, 2 H), 4.58 (t, 1 H), 4.04 (t, 2H), 3.54 (t, 2H), 3.44 (t, 4H), 3.42 (s, 3H). LCMS retention time 2.984 min; LCMS MH+ 569. Example 31: 1 -(2-(2-hydroxyethoxy)ethyl)-7-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H - purine - 2,6(3H,7H) - dione

[00462] To a solution of 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.116 mmol, Intermediate 12) in DMF (3 mL) was added 1 - (bromomethyl) - 4 - methoxybenzene (3 5 mg, 0.174 mmol) and potassium carbonate (32 g, 0.232 mmol). The reaction was heated to 50°C for 3 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 1 - (2 - (2 - hydroxyethoxy)ethyl) - 7 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H)-dione (14 mg, 22.2 % production) as a white solid. 1H NMR (DMSO-d6) δ 7.61 (t, 1H), 7.48 (s, 1H), 7.32 - 7.44 (m, 4H), 6.91 (d, 2H), 5.37 (s, 2H), 4.60 (t, 1H), 4.08 (t, 2H), 3.73 (s, 3H), 3.58 (t, 2H), 3.46 (s, 4H), 3.29 (s, 3H). LCMS retention time 2.581 min; LCMS MH+ 551.

[00463] The following products 32a to 32 H were prepared using the method of example 31. Example 32a: 7-(3-chlorobenzyl)-1 -(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00464] White solid, 16 mg, 25.0% yield: 1H NMR (400 MHz, DMSO-d6) δ = 7.61 (t, 1 H), 7.49 (d, 2 H), 7.34 - 7.44 (m, 3 H), 7.33 (d, 2 H), 5.45 (s, 2 H), 4.59 (t, 1 H) ), 4.07 (t, 2H), 3.57 (t, 2H), 3.45 (s, 4H), 3.30 (s, 3H). LCMS retention time 2.876 min; LCMS MH+ 555. Example 32b: 1 -(2-(2-hydroxyethoxy)ethyl)-3-methyl-7-(4-methylbenzyl)-8-(3-(trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00465] White solid, 23 mg, 25.0 % yield: 1H NMR (DMSO-d6) δ 7.61 (t, 1 H), 7.47 (d, 1 H), 7.42 (dd, 1 H), 7.29 - 7.34 (m, 3 H), 7.16 (d, 2 H), 5.77 (s, 2 H), 4.6 0 (t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.44 - 3.47 (m, 4H), 3.30 (s, 3H), 2.27 (s, 3H). LCMS retention time 2.750 min; LCMS MH+ 535. Example 32c: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - (4 - (trifluoromethyl)benzyl) - 1H - purine - 2,6(3H,7H) - dione

[00466] White solid, 19 mg, 27.9% yield: 1H NMR (DMSO-d6) δ 7.74 (d, 2H), 7.61 (t, 3H), 7.44 - 7.48 (m, 2H),7.33 (d, 1H) 5.55 (s, 2H), 4.58 (q, 1H), 4.09 (t, 2H), 3.56 (t, 2H), 3.45 (s, 4H), 3.31 (s, 3H). LCMS retention time 2.831 min; LCMS MH+ 589. Example 32d: 7-(4-ethylbenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

[00467] White solid, 16 mg, 25.4 % yield: 1H NMR (DMSO-d6) δ 7.61 (t, 1 H), 7.46 (s, 1 H), 7.42 (d, 1 H), 7.31 - 7.34 (m, 3 H), 7.19 (d, 2 H), 5.40 (s, 2 H), 4.6 0 (t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.47 (s, 4H), 3.29 (s, 3H), 2.57 (q, 2H), 1.14 (t, 3H). LCMS retention time 2.897 min; LCMS MH+ 549. Example 32e: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 7 - (3 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00468] White solid, 10 mg, 25.0 % yield: 1H NMR (DMSO-d6) δ 7.61 (t, 1 H), 7.48 (s, 1 H), 7.40 - 7.43 (m, 1 H), 7.26 - 7.34 (m, 2 H), 6.87 - 6.98 (m, 3 H), 5.4 1 (s, 2H), 4.60 (t, 1H), 4.07 (t, 2H), 3.71 (s, 3H), 3.57 (t, 2H), 3.46 (s, 4H), 3.30 (s, 3H). LCMS retention time 2.644 min; LCMS MH+ 551. Example 32f: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 7 - (3 - methylbenzyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00469] White solid, 12 mg, 19.6 % yield: 1H NMR (DMSO-d6) δ 7.61 (t, 1 H), 7.46 (s, 1 H), 7.40 (dd, 1 H), 7.33 (d, 1 H), 7.24 (d, 1 H), 7.11 - 7.19 (m, 3 H), 5.4 1 (s, 2H), 4.59 (t, 1H), 4.07 (t, 2H), 3.57 (t, 2H), 3.47 (s, 4H), 3.30 (s, 3H), 2.27 (s, 3H). LCMS retention time 2.726 min; LCMS MH+ 535. Example 32g: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 7 - (3 - (trifluoromethoxy)benzyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00470] White solid, 22 mg, 31.4 % yield: 1H NMR (DMSO-d6) δ 7.61 (t, 1 H), 7.53 (t, 1 H), 7.41 - 7.49 (m, 4 H), 7.33 (d, 2 H), 5.50 (s, 2 H), 4.59 (t, 1 H), 4.0 7 (t, 2H), 3.56 (t, 2H), 3.46 (s, 4H), 3.30 (s, 3H). LCMS retention time 2.865 min; LCMS MH+ 605. Example 32h: 1 - (2 - (2 - hydroxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 7 - (3 - (trifluoromethyl)benzyl) - 1H - purine - 2,6(3H,7H) - dione

[00471] White solid, 10 mg, 31.4 % yield: 1H NMR (DMSO - d6) δ 7.81 (s, 1 H), 7.58 - 7.71 (m, 4 H), 7.41 - 7.46 (m, 2 H), 7.33 (d, 2 H), 5.55 (s, 2 H), 4.59 (t, 1 H), 4.07 (t, 2H), 3.57 (t, 2H), 3.47 (s, 4H), 3.30 (s, 3H). LCMS retention time 2.795 min; LCMS MH+ 589. Example 33: 1 - (2 - (2 - aminoethoxy)ethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 1 - (2 - (2 - bromoethoxy)ethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00472] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (120 mg, 0.26 mmol, Intermediate 9) in DMF (3 mL) was added 1 - bromo - 2 - (2 - bromoethoxy)ethane (77 mg, 0. 33 mmol), potassium carbonate (71 mg, 0.51 mmol). The reaction was heated to 60°C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the crude product (100 mg, 70% purity by HPLC), which was used without purification. LCMS retention time 2.054 min; LCMS MH+ 617. Step 2: 1 - (2 - (2 - aminoethoxy)ethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione.

[00473] 1 - (2 - (2 - bromoethoxy)ethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (100 mg, 0.16 mmol) was dissolved in a preformed solution of ammonia in methanol (15 mL). The reaction was heated at 60°C overnight in a sealed tube. The reaction was cooled to room temperature and the solvent was evaporated. The residue was purified by preparative HPLC to give 1-(2-(2-aminoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-108-(3-(trifluoromethoxy)phenoxy)4H-purine-2,6(3H,7H)-dione (35 mg, 39% yield) as a white solid. 1H NMR (CD3OD) δ 7.94 (s, 3H), 7.62 (t, 1H), 7.41 - 7.49 (m, 6H), 7.34 (d, 1H), 5.45 (s, 2H), 4.10 (t, 2H), 3.65 - 3.67 (m, 4H), 3.30 (s, 3H), 2.94 (q, 2H). LCMS retention time 2.323 min; LCMS MH+ 554. Example 34: 7 - (4 - chlorobenzyl) -1 - (2 - (2 - methoxyethoxy)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00474] The title product was prepared using the method of example 33, step 1 with 2-(2-methoxyethoxy)ethyl methanesulfonate (51 mg, 0.26 mmol, Intermediate 34) as the alkylating agent. White solid, 44mg, 45% yield: 1H NMR (CD3OD) δ 7.61 (t, 1H), 7.50 (s, 1H), 7.40 - 7.45 (m, 5H), 7.33 (d, 1H), 5.44 (s, 2H), 4.05 (t, 2H), 3.51 - 3.57 (m, 4H), 3.36 (s, 2H), 3.29 (s, 3H), 3.20 (s, 3H). LCMS retention time 3.161 min; LCMS MH+ 569. Example 35: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00475] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.257 mmol) in DMF (5 mL) was added 2-bromoethanol (128.9 mg, 1.028 mmol) followed by cesium carbonate (1 67 mg, 0.515 mmol). The resulting mixture was microwave irradiated at 120°C for 30 minutes. The reaction was partitioned between ethyl acetate and saline. The combined organic phase was dried and concentrated to give a residue, which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) -dione (17 mg, 34.7% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.43 (t, 1H), 7.27 - 7.32 (m, 4H), 6.95 - 7.03 (m, 3H), 5.20 (s, 2H), 4.81 (t, 2H), 4.75 (t, 1H), 4.41 (t, 2H), 3.92 - 3.95 ( m, 2H), 3.47 - 3.52 (m, 2H), 3.31 (s, 3H). LCMS retention time 2.731 min; LCMS MH+ 555. Example 36: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 - yloxy)ethyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00476] To a solution of 2-(3-(trifluoromethoxy)phenoxy)ethanol (61 mg, 0.275 mmol, Intermediate 5) in anhydrous THF (10 mL) was added sodium hydride (66 mg, 2.75 mmol) at 0°C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 20 min; Then, a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (70 mg, 0.137 mmol, Intermediate 14) in THF (3 mL) was added dropwise, and the resulting mixture was stirred at 0 °C at room temperature for 16 hours under nitrogen atmosphere. The mixture was quenched with ice water and partitioned between ethyl acetate and saline. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (1:0 to 2:1) to give 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 8 - (2 - 5(3 - (trifluoromethoxy) )phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione (70 mg, 78.2%) as yellow oil. LCMS MH+ - THP 569. Step 2: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00477] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 - yloxy)ethyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione (70 mg, 0.107 mmol) in methanol (3 mL) ) was added concentrated HCl (4 drops). The mixture was stirred for 1 hour at room temperature. The mixture was neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried on sodium sulfate, filtered and concentrated to provide a raw product which has been recrystated ethanol to provide 7 - (4 - chlorobenzil) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (trifluorometoxy) phenomi) Etoxi) - 1h - Purina - 2.6 (3h) 25.6% of production) as white solid. 1H NMR (DMSO-d6) δ 7.45 - 7.41 (t, 1H), 7.32 - 7.27 (m, 4H), 7.03 - 6.95 (m, 3H), 5.19 (s, 2H), 4.81 (s, 2H), 4.49 - 4.46 (t, 1H), 4.41 - 4.40 (d, 2H), 3.91 - 3.88 (t, 2H), 3.44 - 3.40 (m, 5H), 1.69 - 1.65 (t, 2H). LCMS retention time 3.142 min; LCMS MH+ 569. Example 37: 7 - (- 4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 - yloxy)ethyl) - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propoxy) - 1H - purine - 2,6(3H,7H) - dione

[00478] To a solution of 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (95 mg, 0.4 mmol, Intermediate 535) in THF (5 mL) was added sodium hydride (19 mg, 0.40 mmol) at 0 °C. After stirring at 0 °C for 30 minutes, 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 1H - purine - 2,6(3H,7H) - dione (0.1 g, 0.20 mmol, Intermediate 13) was added. The mixture was allowed to warm to room temperature and stirred for 16 hours. Then the reaction was cooled to 0 °C and aqueous ammonium chloride solution (2 mL) was added. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product which was used without purification. LCMS MH+ - THP 569. Step 2: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propoxy)1 H - purine - 2,6(3H,7H) - dione

[00479] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 - yloxy)ethyl) - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propoxy) - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.09 mmol) in ethanol (5 mL) acetyl chloride (0.2 mL) was added at 0 °C. The mixture was stirred at room temperature for 1 hour; Then it was partitioned between ethyl acetate and water. The organic phase was separated and dried over sodium sulfate. This organic layer was then filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propoxy) 1H - purine - 2,6(3H,7H) - dione (20 mg, 39.2% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.40 (t, 1H), 7.28 - 7.33 (m, 4H), 6.92 (dd, 2H), 6.85 (s, 1H), 5.23 (s, 2H), 4.76 (t, 1H), 4.62 (t, 2H), 4.08 (t, 2H), 3.93 (t, 2H), 3.49 (q, 2H), 3.33 (s, 3H), 2.18 - 2.24 (m, 2H). LCMS retention time 3.058 min; LCMS MH+ 569.

[00480] The following examples 38A to 381 were prepared by employing examples of examples 36 and/or 537. Example 38a: 8 - (2 - (3.5 - bis (trifluoromethyl) etoxi) - 7 - (4 - chlorobenzil) -1 - (2 - hydroxyetile) in

[00481] The title product was prepared using Intermediate 65. White solid, 49 mg, 44.6% yield: 1H NMR (DMSO-d6) δ 7.66 (s, 1H), 7.60 (s, 2H), 7.23 - 7.29 (m, 4H), 5.20 (s, 2H), 4.85 (t, 2H), 4.84 (t, 1H), 4.55 - 4.57 (m, 2H), 3.94 (t, 2H), 3.49 (q, 2H), 3.33 (s, 3H). LCMS retention time 3.229 min; LCMS MH+ 607. Example 38b: 7 - (4 - chlorobenzyl) - 8 - (2 - (3 - chlorophenoxy)ethoxy) -1 - (2 - hydroxyethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00482] The title product was prepared using Intermediate 66. White solid, 10 mg, 22.2% yield: 1H NMR (DMSO-d6) δ 7.30 - 7.34 (m, 5 H), 7.01 - 7.04 (m, 2 H), 6.92 - 6.94 (m, 1 H), 5.19 (s, 2 H) ), 4.74 - 4.80 (m, 3H), 4.37 - 4.40 (m, 2H), 3.93 (t, 2H), 3.49 (q, 2H), 3.34 (s, 3H). LCMS retention time 2.837 min; LCMS MH+ 505. Example 38c: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (m - tolyloxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00483] The title product was prepared using Intermediate 67. White solid, 12mg, 27.9% yield: 1H NMR (DMSO-d6) δ 7.27 - 7.32 (m, 4H), 7.15 - 7.19 (m, 1H), 6.74 - 6.79 (m, 3H), 5.19 (s, 2H) ), 4.74 - 4.80 (m, 3H), 4.32 - 4.34 (m, 2H), 3.94 (t, 2H), 3.49 (q, 2H), 3.35 (s, 3H), 2.27 (s, 3H). LCMS retention time 2.676 min; LCMS MH+ 485. Example 38d: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethyl)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00484] The title product was prepared using Intermediate 68. White solid, 10 mg, 20.8% yield: 1H NMR (DMSO-d6) δ 7.54 (t, 1H), 7.24 - 7.33 (m, 7H), 6.74 - 6.79 (m, 3H), 5.19 (s, 2H), 4.81 - 4.83 (m, 2H), 4.75 (t, 1H), 4.45 - 4.46 (m, 2H), 3.94 (t, 2H), 3.49 (q, 2H), 3.35 (s, 3H). LCMS retention time 2.857 min; LCMS MH+ 539. Example 38e: 8 - (2 - (4 - chloro - 3 - (trifluoromethyl)phenoxy)ethoxy) - 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00485] The title product was prepared using Intermediate 71. White solid, 30 mg, 49.2% yield: 1H NMR (DMSO-d6) δ 7.64 - 7.62 (d, 1 H), 7.31 - 7.26 (m, 6 H), 5.20 (s, 2 H), 4.83 - 4.80 (m, 2 H) ), 4.76 - 4.73 (t, 1H), 4.46 - 4.44 (m, 2H), 3.95 - 3.92 (t, 2H), 3.52 - 3.49 (m, 2H), 3.47 (s, 3H). LCMS retention time 2.973 min; LCMS MH+ 573 Example 38f: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (2 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00486] The title product was prepared using Intermediate 70. White solid, 18 mg, 29.7% yield: 1H NMR (DMSO-d6) δ 7.36 - 7.34 (d, 2H), 7.29 - 7.24 (m, 5H), 7.07 - 7.03 (t, 1H), 5.17 (s, 2H) ), 4.85 - 4.83 (m, 2H), 4.77 - 4.74 (t, 1H), 4.46 - 4.44 (m, 2H), 3.95 - 3.92 (t, 2H), 3.51 - 3.48 (m, 2H), 3.47 (s, 3H). LCMS retention time 2.828 min; LCMS MH+ 555. Example 38g: 7 - (4 - chlorobenzyl) -1 - (2 - hydroxyethyl) - 3 - methyl - 8 - (2 - (4 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00487] The title product was prepared using Intermediate 69. White solid, 30 mg, 49.4% yield: 1H NMR (DMSO - d6) δ 7.32 - 7.26 (m, 6 H), 7.06 - 7.03 (m, 2 H), 5.19 (s, 2 H), 4.82 - 4.80 (m, 2 H) ), 4.76 - 4.73 (t, 1H), 4.38 - 4.36 (m, 2H), 3.95 - 3.92 (t, 2H), 3.52 - 3.47 (m, 2H), 3.39 (s, 3H). LCMS retention time 2.908 min; LCMS MH+ 555. Example 38h: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenyl)propoxy) - 1H - purine - 2,6(3H,7H) - dione

[00488] The title product was prepared using the methods of examples 36 and 37, and using Intermediate 37 in the first step. White solid, 12mg, 21.4% yield: 1H NMR (CD3OD) δ 7.35 - 7.49 (m, 5H), 7.07 - 7.17 (m, 3H), 5.28 (s, 2H), 4.54 (t, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 3.45 (s , 2H), 2.75 (t, 2H), 2.11 - 2.18 (m, 2H), 1.83 - 1.91 (m, 2H). LCMS retention time 3.125 min; LCMS MH+ 567. Example 38i: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyloxy) - 1H - purine - 2,6(3H,7H) - dione

[00489] The title product was prepared using the methods of examples 36 and 37, and using 3-trifluoromethoxy-benzyl alcohol in the first step. White solid, 12mg, 16.0% yield: 1H NMR (DMSO-d6) δ 7.27 - 7.55 (m, 8H), 5.57 (s, 2H), 5.28 (s, 2H), 4.47 (t, 1H), 3.90 (t, 2H), 3.56-103.45 (m, 5H), 1.6 5 - 1.90 (m, 2H). LCMS retention time 2.870 min; LCMS MH+ 539. Example 38j: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - ((5 - methylthiazol - 2 -yl)methoxy) - 1H - purine - 2,6(3H,7H) - dione

[00490] The title compound was prepared using the methods of examples 36 and 37, and using (5 - methylthiazol - 2 - yl)methanol (Intermediate 4, step 1) in the first step. White solid, 46mg, 54.1% yield: 1H NMR (CDCl3) δ 7.50 (d, 1H), 7.33 - 7.32 (m, 2H), 7.26 - 7.28 (m, 2H), 5.74 (s, 2H), 5.27 (s, 2H), 4.19 (t, 2H), 3.61 (t, 1H), 3.51 - 3.55 (m, 5H), 2.51 (d, 3H), 1.88 - 1.92 (m, 2H). LCMS retention time 2.366 min; LCMS MH+ 476. Example 38k: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - ((5 - methyloxazol - 2 - yl)methoxy) - 1H - purine - 2,6(3H,7H) - dione

[00491] The title compound was prepared using the methods of examples 36 and 37 and with (5 - methyloxazol - 2 - yl)methanol (Intermediate 40). The crude product was purified by preparative HPLC to afford 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - ((5 - methyloxazol - 2 -yl)methoxy) - 1H - purine - 2,6(3H,7H) -dione (17 mg, 40.9%) as a white solid. 1H NMR (DMSO-d6) δ 7.38 - 7.40 (d, 2H), 7.26 - 7.28 (d, 2H), 6.90 (s, 1H), 5.58 (s, 2H), 5.23 (s, 2H), 4.45 - 4.48 (t, 1H), 3.87 - 3.91 (t, 2H) ), 3.39 - 3.44 (t, 2H), 2.28 (s, 3H), 1.65 - 1.68 (m, 2H). LCMS retention time 2.284 min; LCMS MH+ 460. Example 381: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - ((5 - methylthiazol - 2 -yl)methoxy) - 1H - purine - 2,6(3H,7H) - dione

[00492] The title compound was prepared using the methods of examples 36 and 37 and with (5 - methyloxazol - 2 - yl)methanol (Intermediate 40). White solid, 46mg, 54.1% yield: 1H NMR (DMSO - d6) δ 7.37 - 7.39 (d, 2H), 7.26 - 7.28 (d, 2H), 6.90 (s, 1H), 5.58 (s, 2H), 5.23 (s, 2H), 4.73 - 4.76 (t, 1H) ), 3.93 - 3.95 (t, 2H), 3.47 - 3.51 (m, 2H), 3.43 (s, 3H), 2.28 (s, 3H). LCMS retention time 2.194 min; LCMS MH+ 446. Example 39: 7 - (4 - chlorobenzyl) - 8 - (2 - (3 - ((dimethylamino)methyl)phenoxy)ethoxy) -1 - (2 - hydroxyethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione hydrochloride Step 1: 3 - (2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yloxy)ethoxy)benzaldehyde

[00493] The title compound was prepared using the method of example 36, step 1 using Intermediate 36. The product was purified by silica gel chromatography eluting with petroleum / ethyl acetate (3:1 to 1:1) to afford 3 - (2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo -1 - (2 - (tetrahydro - 2H - pyran - 2-yloxy)ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yloxy)ethoxy)benzaldehyde (64 mg, 36.4% yield) as yellow syrup. LCMS MH+ - THP 499. Step 2: 7-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-3-methyl -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 1H - purine - 2,6(3H,7H) -dione

[00494] To a solution of 3-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo -1 - (2 - (tetrahydro - 2H - pyran - 2 -yloxy)ethyl) - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yloxy)ethoxy)benzaldehyde (100 mg, 0.171 mmol) in meta nol (3 mL) and THF (3 mL) was added acetic acid (0.2 mL, 3.49 mmol) and dimethylamine hydrochloride (90 mg, 1.10 mmol). The mixture was stirred at room temperature for 1 hour. Then the mixture was cooled to 0 °C, sodium cyanoborohydride (16.1 mg, 0.256 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred and allowed to warm to room temperature overnight. The mixture was concentrated and purified by silica gel chromatography eluting with DCM/methanol (60:1) to afford 7-(4-chlorobenzyl) - 8 - (2 - (3 - ((dimethylamino)methyl)phenoxy)ethoxy) - 3 - methyl -1 - (2 - (tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)- dione (26.1 mg, 24.9%) as a white solid. LCMS MH+ 613. Step 3: 7-(4-chlorobenzyl)-8-(2-(3-((dimethylamino)methyl)phenoxy)ethoxy)-1-(2-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione hydrochloride.

[00495] The title compound was prepared using the method of example 37, step 2 to provide 7 - (4 - chlorobenzyl) - 8 - (2 - (3 - ((dimethylamino)methyl)phenoxy)ethoxy) -1 - (2 - hydroxyethyl) - 3 - methyl - 1H - purine - 2,6(3H, 7H) - dione hydrochloride (13.6 mg, 65.2% yield ) as a white solid. 1H NMR (DMSO-d6) δ 10.11 (bs, 1H), 7.42 - 7.38 (t, 1H), 7.33 - 7.28 (m, 4H), 7.18 (s, 1H), 7.11 - 7.09 (d, 1H), 7.06 - 7.04 (m, 1H), 5.20 (s, 2 H), 4.85 - 4.83 (m, 2H), 4.76 - 4.73 (t, 1H), 4.39 - 4.37 (m, 2H), 4.22 (s, 2H), 3.96 - 3.92 (t, 2H), 3.52 - 3.46 (m, 2H), 3.29 (s, 3H), 2.69 (s , 6H). LCMS retention time 1.678 min; LCMS MH+ 553. Example 40: 7-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) -dione Step 1: 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (2 - (dimethylamino)ethyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00496] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H-purine-2,6(3H,7H)-dione (0.2 g, 0.54 mmol, Intermediate 8) in DMF (5 mL) was added 2 - chloro - N,N - dimethylethanamine (0.87 mg, 0.83 mmol), potassium carbonate (0.15 g, 1.08 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated to 80 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product (0.2 g, 84%) as a yellow oil, which was used without purification. LCMS MH+ 442. Step 2: 7 - (4 - chlorobenzyl) -1 - (2 - (dimethylamino)ethyl) - 3 - methyl - 8 - (2 - (3 - 5 (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00497] The title compound was prepared using the method of example 36, step 1 and purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (2 - (dimethylamino)ethyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione (20 mg, 16.4% of production) as a white solid. 1H NMR (DMSO-d6) δ 8.18 (s, 1H), 7.43 (t, 1H), 7.26 - 7.32 (m, 4H), 6.93 - 7.02 (m, 3H), 5.20 (s, 2H), 4.80 - 4.82 (m, 2H), 4.39 - 4.41 (m, 2H) ), 3.99 (t, 2H), 3.67 (s, 3H), 2.58 (t, 2H), 2.30 (s, 6H). LCMS retention time 2.352 min; LCMS MH+ 582 Example 41: 7-(4-chlorobenzyl)-3-methyl-1-propyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) -dione

[00498] The title compound was prepared using the method of step 2 of Example 40 and purified by preparative HPLC to provide 7 - (4 - chlorobenzyl) - 3 - methyl -1 - propyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) -1H - purine - 2,6(3H,7H) -dione (80 mg, 29.7% yield) as a white solid. 1H NMR (DMSO - d6) δ 7.45 - 7.41 (t, 1H), 7.32 - 7.26 (m, 4H), 7.02 - 6.94 (m, 3H), 5.19 (s, 2H), 4.82 - 4.79 (m, 2H), 4.41 - 4.39 (m, 2H), 3.81 - 3.78 (t, 2H), 1.58 - 1.49 (m, 2H), 0.86 - 0.83 (t, 3H). LCMS retention time 3.571 min; LCMS MH+ 553 Example 42: 7-((5-chloropyridin-2-yl)methyl)-1 -(3-hydroxypropyl)-3-methyl-8-(2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7-((5-chloropyridin-2-yl)methyl)-3-methyl-1 -(3-(tetrahydro-2H-pyran-2-yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00499] To a solution of 3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione (60 mg, 0.14 mmol, Intermediate 17) in DMF (5 mL) was added 5 - chlorine - 2-(chloromethyl)pyridine (33 mg, 0.20 mmol), potassium carbonate (37 mg, 0.27 mmol) and TBAI (2 mg, 0.02 mmol). The reaction was heated to 50°C for 8 hours. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product, which was used without purification. LCMS MH+ - THP 570. Step 2: 7-((5-chloropyridin-2-yl)methyl)-1 -(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione.

[00500] To a solution of 7 - ((5 - chloropyridin - 2 - yl)methyl) - 3 - methyl - 1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione (80 mg, 0.1 4 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0 °C and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by preparative HPLC to give 7 - ((5 - chloropyridin - 2 -yl)methyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione (15 mg, 19.0 % yield) as a white solid. 1H NMR (CD3OD) δ 8.33 (d, 1H), 7.70 (dd, 1H), 7.35 (t, 1H), 7.26 (d, 1H), 6.87 (dd, 1H), 6.76 (s, 1H), 5.43 (s, 2H), 4.86 - 4.87 (m, 2H), 4.33 - 4.35 (m, 2H), 4.04 (t, 2H), 3.56 (t, 2H), 3.54 (s, 3H), 1.80 - 1.85 (m, 2H). LCMS retention time 2.606 min; LCMS MH+ 570.

[00501] The following examples 43a to 43e were prepared using the method of example 42. Example 43a: 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((6 - methylpyridin - 3 - yl)methyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - Diona

[00502] White solid, 20 mg, 26.3% yield: 1H NMR (CD3OD) δ 8.55 (s, 1 H), 7.95 (d, 1 H), 7.39 (dd, 2 H), 6.96 (dd, 1 H), 6.90 (d, 1 H), 6.81 (s, 1 H), 5.37 (s, 2 H), 4.93 - 4.95 (m, 2H), 4.43 - 4.45 (m, 2H), 4.07 (t, 2H), 3.61 (t, 2H), 3.50 (s, 3H), 2.55 (s, 3H), 1.84 - 1.88 (m, 2H). LCMS retention time 2.022 min; LCMS MH+ 550. Example 43b: 7 - benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00503] White solid, 17 mg, 23.0% yield: 1H NMR (DMSO - d6) δ 7.43 (t, 1 H), 7.23 - 7.32 (m, 5 H), 6.95 - 7.04 (m, 3 H), 5.20 (s, 2 H), 4.80 - 4.82 (m, 2 H), 4.7 0 (t, 1H), 4.40 - 4.43 (m, 2H), 3.90 (t, 2H), 3.33 - 3.44 (m, 5H), 1.65 - 1.70 (m, 2H). LCMS retention time 2.897 min; LCMS MH+ 535. Example 43c: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00504] White solid, 20 mg, 43.2% yield: 1H NMR (CD3OD) δ 7.39 - 7.35 (t, 1H), 7.28 (s, 1H), 6.93 - 6.80 (m, 2H), 6.79 (s, 1H), 5.56 (s, 2H), 4.89 (s, 2H), 4.39 - 4.36 (dd, 2H), 4.10 - 4.06 (t, 2H) 3.61 - 3.58 (t, 2H), 3.53 (s, 3H), 2.35 (s, 3H), 1.90 - 1.85 (m, 2H). LCMS retention time 2.536 min; LCMS MH+ 556. Example 43d: 7 - ethyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione.

[00505] White solid, 33 mg, 37.1% yield: 1H NMR (CD3OD) δ 7.39 (t, 1 H), 7.01 (dd, 1 H), 6.88 - 6.90 (m, 2 H), 4.87 - 4.88 (m, 2 H), 4.44 - 4.46 (m, 2 H), 4.08 - 4.16 (m, 4H), 3.61 (t, 2H), 3.51 (s, 3H), 1.80 - 1.90 (m, 2H), 1.32 (t, 3H). LCMS retention time 1.526 min; LCMS MH+ 473. Example 43e: 1 - (2 - hydroxyethyl) - 3,7 - dimethyl - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00506] White solid, 16 mg, 50.1% yield: 1H NMR (DMSO-d6) δ 7.41 - 7.45 (t, 1 H), 7.04 - 7.06 (dd, 1 H), 6.97 - 7.00 (m, 2 H), 4.75 - 4.79 (m, 4 H), 4.42 - 4.4 4 (t, 2H), 3.92 - 3.95 (t, 2H), 3.57 (s, 3H), 3.50 - 3.52 (t, 2H), 3.47 (s, 3H). LCMS retention time 2.411 min; LCMS MH+ 445. Example 44: 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((4 - methylthiazol - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00507] To a solution of 1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.25 mmol, Intermediate 13) in DMF (5 mL) was added 2-(chloromethyl)-4-methylthiazole (47.9 mg, 0.32 mmol, Inter average 54) followed by potassium carbonate (51.6 mg, 0.37 mmol) and a catalytic amount of TBAI. The mixture was stirred at 60°C for 4 hours. The mixture was diluted with ethyl acetate and extracted with brine and saturated aqueous ammonium chloride solution. Then the organic phase was dried and concentrated to give a crude product which was purified by preparative HPLC to give 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((4 - methylthiazol - 2 - yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (29 mg, 22.7% yield) as white solid. 1H NMR (DMSO-d6) δ 7.62 (t, 1H), 7.41 - 7.46 (m, 2H), 7.33 (dd, 1H), 7.26 (d, 1H), 5.73 (s, 2H), 4.49 (t, 1H), 3.91 (t, 2H), 3.35 (t, 2H), 3.3l (s, 3H), 2.29 (d, 3H), 1.67 - 1.71 (m, 2H). LCMS retention time 2.681 min; LCMS MH+ 512.

[00508] The following examples 45a to 45m were prepared using the method of example 44. Example 45a: 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - (thiazol - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00509] White solid, 42 mg, 38.1% yield: 1H NMR (DMSO-d6) δ 7.74 - 7.77 (m, 2 H) 7.62 (t, 1 H), 7.41 - 7.49 (m, 2 H), 7.33 (d, 1 H), 5.80 (s, 2 H), 4.47 (t, 1 H), 3.91 (t, 2H), 3.43 (t, 2H), 3.31 (s, 3H), 2.29 (d, 3H), 1.65 - 1.70 (m, 2H). LCMS retention time 2.378 min; LCMS MH+ 498. Example 45b: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00510] White solid, 22 mg, 28.9% yield: 1H NMR (DMSO-d6) δ 1.10 (s, 1 H), 7.63 (t, 1 H), 7.56 (s, 1 H), 7.47 - 7.50 (m, 1 H), 7.34 - 7.37 (m, 1 H), 5.60 (s, 2 H), 4.50 (t, 1 H), 3.95 (t, 2 H), 3.46 (t, 2 H), 3.30 (s, 3 H), 2.59 (s, 3 H), 1.67 - 1.74 (m, 2 H). LCMS retention time 2.419 min; LCMS MH+ 512. Example 45c: 7 - (4 -fluorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00511] White solid, 23 mg, 30.2% yield: 1H NMR (CD3OD) δ 7.46 - 7.55 (m, 3 H), 7.30 (d, 2 H), 7.22 (d, 1 H), 7.07 (t, 2 H), 5.48 (s, 2 H), 4.10 (t, 1 H), 3.6 0 (t, 2H), 3.40 (s, 3H), 1.84 - 1.90 (m, 2H). LCMS retention time 2.944 min; LCMS MH+ 509. Example 45d: 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - (4 - methylbenzyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00512] White solid, 28 mg, 37.3% yield: 1H NMR (CD3OD) δ 7.51 (t, 1 H), 7.19 - 7.31 (m, 4 H), 7.14 (d, 2 H), 5.44 (s, 2 H), 4.10 (t, 1 H), 3.60 (t, 2 H), 3.4 0 (s, 3H), 2.28 (s, 3H), 1.83 - 1.90 (m, 2H). LCMS retention time 3.075 min; LCMS MH+ 505. Example 45e: 4 - ((1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3 - dihydro - 1H - purin - 7(6H) -yl)methyl)benzonitrile

[00513] White solid, 16 mg, 20.7% yield: 1H NMR (CD3OD) δ 7.72 (d, 2H), 7.51 - 7.59 (m, 3H), 7.32 (d, 2H), 7.22 (d, 1H), 5.58 (s, 2H), 4.08 (t, 1H), 3.5 9 (t, 2H), 3.41 (s, 3H), 1.82 - 1.87 (m, 2H). LCMS retention time 2.750 min; LCMS MH+ 516. Example 45f: 1 - (3 - hydroxypropyl) - 7 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00514] White solid, 22 mg, 28.2% yield: 1H NMR (CD3OD) δ 7.52 (t, 2 H), 7.38 (d, 2 H), 7.20 - 7.30 10 (m, 3 H), 6.87 (d, 2 H), 5.41 (s, 2 H), 4.10 (t, 1 H), 3, 75 (s, 3H), 3.60 (t, 2H), 3.40 (s, 3H), 1.83 - 1.89 (111, 2H). LCMS retention time 2.899 min; LCMS MH+ 521. Example 45g: 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((6 - methylpyridin - 3 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00515] White solid, 45 mg, 29.7% yield: 1H NMR (DMSO-d6) δ 8.53 - 8.52 (d, 1 H), 7.71 - 7.69 (dd, 1 H), 7.63 - 7.59 (t, 1 H), 7.52 (s, 1 H), 7.46 - 7.44 (dd, 1 H), 7.34 - 7.32 (d, 1H), 7.25 - 7.23 (d, 1H), 5.43 (s, 2H), 4.53 (bs, 1H), 3.95 - 3.91 (t, 2H), 3.46 - 3.43 (t, 2H), 3.28 (s, 3H), 2.43 (s, 3H), 1.71 - 1.68 (m, 2H). LCMS retention time 1.923 min; LCMS MH+ 506. Example 45h: 7 - ((5 - chloropyridin - 2 - yl)methyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00516] White solid, 49 mg, 37.3% yield: 1H NMR (DMSO-d6) δ 8.54 (s, 1 H), 7.94 - 7.97 (dd, 1 H), 7.57 - 7.61 (t, 1 H), 7.49 - 7.51 (d, 1 H), 7.38 - 7.43 (m, 2 H), 7.30 - 7.32 (d, 1H), 5.58 (s, 2H), 4.44 - 4.47 (t, 1H), 3.85 - 3.89 (t, 2H), 3.40 - 3.42 (t, 2H), 3.30 (s, 3H), 1.63 - 1.66 (m, 2H). LCMS retention time 2.710 min; LCMS MH+ 526. Example 45i 7-((6-chloropyridin-3-yl)methyl)-1 -(3-hydroxypropyl)-3-methyl-8-(3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00517] White solid, 20 mg, 22.4% yield: 1H NMR (DMSO - d6) δ 8.50 - 8.49 (d, 1 H), 7.90 - 7.87 (dd, 1 H), 7.63 - 7.58 (t, 1 H), 7.54 - 7.45 (m, 3 H), 7.33 - 7.3 1 (d, 1H), 5.48 (s, 2H), 3.94 - 3.90 (t, 2H), 3.62 - 3.59 (t, 2H), 3.28 (s, 3H), 1.71 - 1.67 (t, 2H). LCMS retention time 2.625 min; LCMS MH+ 526. Example 45j: 7 - ethyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00518] White solid, 40 mg, 54.9% yield: 1H NMR (DMSO-d6) δ 7.64 - 7.60 (t, 1 H), 7.55 (s, 1 H), 7.47 - 7.45 (dd, 1 H), 7.34 - 7.32 (d, 1 H), 4.25 - 4.20 (m, 2 H), 3.95 - 3.91 (t, 2H), 3.46 - 3.42 (m, 2H), 3.28 (s, 3H), 1.72 - 1.68 (m, 2H), 1.39 - 1.35 (t, 3H). LCMS retention time 2.525 min; LCMS MH+ 429. Example 45k: 1 - (3 - hydroxypropyl) - 3,7 - dimethyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00519] White solid, 40 mg, 55.1% yield: 1H NMR (DMSO - d6) δ 7.64 - 7.60 (t, 1 H), 7.54 (s, 1 H), 7.47 - 7.45 (dd, 1 H), 7.32 - 7.31 (dd, 1 H), 4.49 - 4.46 (t, 1 H), 3.94 - 3.90 (t, 2H), 3.78 (s, 3H), 3.46 - 3.42 (m, 2H), 3.28 (s, 3H), 11.73 - 1.66 (m, 2H). LCMS retention time 2.363 min; LCMS MH+ 415. Example 451: 1 -(3-hydroxypropyl)-3-methyl-7-((2-methylpyrimidin-5-yl)methyl)-8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione

[00520] Light yellow solid, 18 mg, 20.9% yield: 1H NMR (DMSO-d6) δ 8.76 (s, 2 H), 7.64 - 7.58 (m, 2 H), 7.50 - 7.48 (m, 1 H), 7.35 - 7.32 (dd, 1 H), 5.45 (s, 2 H), 3, 94 - 3.91 (t, 2H), 3.46 - 3.42 (m, 2H), 3.29 (s, 3H), 2.96 (s, 3H), 1.71 - 1.68 (m, 2H). LCMS retention time 2.226 min; LCMS MH+ 507. Example 45m: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methyloxazol-2-yl)methyl)-8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00521] Light yellow solid, 15 mg, 20.2% yield: 1H NMR (DMSO-d6) δ 7.64 - 7.60 (t, 1 H), 7.45 - 7.40 (m, 2 H), 7.34 - 7.32 (d, 1 H), 6.78 (s, 1 H), 5.59 (s, 2 H), 4, 50 (bs, 1H), 3.91 - 3.88 (t, 2H), 3.48 (s, 2H), 3.31 (s, 3H), 2.25 (s, 3H), 1.71 - 1.64 (m, 2H). LCMS retention time 2.358 min; LCMS MH+ 496. Example 46: 7 - (4 - ((dimethylamino)methyl)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - (bromomethyl)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00522] The title compound was prepared using the method of example 44 to provide 7 - (4 - (bromomethyl)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione (126 mg, 43.3% yield) as a white solid. LCMS retention time 1.758 min; LCMS MH+ 583. Step 2: 7-(4-((dimethylamino)methyl)benzyl)-1 -(3-hydroxypropyl)-3-methyl-8-(3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00523] The title compound was prepared using example method 25 step 2 and purified by preparative HPLC to afford 7 - (4 - ((dimethylamino)methyl)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 35.3% yield) as solid white. 1H NMR (DMSO-d6) δ 10.94 (s, 1H), 7.62 - 7.57 (m, 3H), 7.50 (s, 1H), 7.46 - 7.44 (m, 2H), 7.42 - 7.39 (dd, 1H), 7.33 - 7.31 (d, 1H), 5.48 (s, 2 H), 4.25 - 4.24 (d, 2H), 3.95 - 3.91 (t, 2H), 3.45 - 3.42 (t, 2H), 3.30 (s, 3H), 2.65 - 2.64 (d, 6H), 1.71 - 1.67 (m, 2H). LCMS retention time 3.183 min; LCMS MH+ 548. Example 47: 7 - benzyl - 3 - ethyl -1 - (isoxazol - 5 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00524] To a solution of 7 - benzyl - 3 - ethyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (40 mg, 0.090 mmol, Intermediate 47) in DMF (3 mL) was added 5-(chloromethyl)isoxazole (30 mg, 0.256 mmol), followed by potassium carbonate (50 mg, 0.362 mmol) and TBAI (5 mg, 0.014 mmol). The reaction was stirred at 60 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give 7 - benzyl - 3 - ethyl -1 - (isoxazol - 5 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine-2,6(3H,7H)-dione (5.9 mg, 12.6% yield) as a white solid. 1H NMR (CD3OD) δ 8.33 - 8.32 (d, 1H), 7.57 - 7.53 (t, 1H), 7.47 - 7.45 (d, 2H), 7.38 - 7.31 (m, 5H), 7.25 - 7.23 (d, 1H), 6.34 - 6.33 (dd, 1H), 5.52 (s, 2H), 5.36 (s, 2H), 4.06 - 4.01 (q, 2H), 1.27 - 1.24 (t, 3H). LCMS retention time 3.269 min; LCMS MH+ 528. Example 48: 7 - (4 - chloro - 3 - methoxybenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 8 - (3 - hydroxyprop -1 - inyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00525] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (300 mg, 0.588 mmol, Intermediate 14) in anhydrous DMF (12 mL) was added prop - 2 - in -1 -ol (0.15 mL, 2.545 mmol), bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.043 mmol), copper iodide (10 mg, 0.053 mmol) (45 mg, 0.402 mmol) and TEA (3 mL, 21.6 mmol). Then the mixture was degassed and recharged with nitrogen 3 times. The reaction was stirred at 85 °C overnight under nitrogen. The mixture was cooled, filtered and the filter cake washed with ethyl acetate. The filtrate was concentrated to give a crude product, which was purified by chromatography on silica gel eluting with DCM / ethyl acetate (3:1 to 1:1) to give 7-(4-chlorobenzyl)-8-(3-hydroxyprop-1 -ynyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2.6(3H,7 H) - dione (170 mg, 59.5% yield) as a pale yellow solid. LCMS retention time 1.523 min; LCMS MH+ 487.

[00526] Step 2: 7 - (4 - chlorobenzyl) - 8 - (3 - hydroxypropyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00527] A solution of 7-(4-chlorobenzyl)-8-(3-hydroxyprop-1 -ynyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H)-dione (120 mg, 0.247 mmol) in methanol (15 mL) was degassed and recharged give with nitrogen 3 times; Then 10% Pd/C (30 mg) was added. The mixture was degassed and recharged with hydrogen 3 times and shaken under 3.16377 kg/cm 2 (45 psi) of hydrogen at room temperature for 20 minutes. The mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated to give 7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 82.6% yield) as a gray solid. LCMS retention time 1.447 min; LCMS MH+ 491. Step 3: 7 - (4 - chlorobenzyl) - 8 - (3 - ethoxypropyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00528] To a solution of 7 - (4 - chlorobenzyl) - 8 - (3 - hydroxypropyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (100 mg, 0.204 mmol) in DMF (3 mL) was added sodium hydride (24.5 mg, 0.612 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred at room temperature for 30 minutes. Iodoethane (63.6 mg, 0.408 mmol) was added to the reaction and it was stirred at room temperature for 16 hours. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give a crude product, which was purified by chromatography on silica gel eluting with petroleum ether/ethyl acetate (2:1 to 1:1) to give 7 - (4 - chlorobenzyl) - 8 - (3 - ethoxypropyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2.6 (3H,7H)-dione (96 mg, 90.6% yield) as a yellow solid. LCMS retention time 1.870 min; LCMS MH+ 519. Step 4: 7 - (4 - chloro - 3 - methoxybenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00529] The title compound was prepared as example 14, step 3 to provide 7 - (4 - chloro - 3 - methoxybenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (51 mg, 56.5% yield) as a white solid. 1H NMR (CD3OD) δ 7.38 - 7.35 (d, 2H), 7.24 - 7.22 (d, 2H), 5.62 (s, 2H), 4.12 - 4.18 (t, 2H), 3.62 - 3.59 (t, 2H), 3.57 (s, 3H), 3.46 - 3.43 (m , 4H), 2.86 - 2.82 (t, 2H), 1.98 - 1.84 (m, 4H), 1.18 - 1.14 (t, 3H). LCMS retention time 2.384 min; LCMS MH+ 435. Example 49: 7 - (4 - chlorobenzyl) -1,8 - bis(3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00530] To a solution of 7 - (4 - chlorobenzyl) - 8 - (3 - hydroxypropyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione (30 mg, 0.061 mmol, example 48, step 3) in ethyl alcohol (20 mL) was added chloride of acetyl (0.2 mL, 2.80 mmol). The reaction was stirred at 0 °C for 10 minutes. The mixture was concentrated to give a crude product, which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1,8 - bis(3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (15 mg, 60.6% yield) as a white solid. 1H NMR (CD3OD) δ 7.37 - 7.35 (d, 2H), 7.21 - 7.22 (d, 2H), 5.62 (s, 2H), 4.11 - 4.08 (t, 2H), 3.62 - 3.59 (t, 4H), 3.56 (s, 3H), 2.87 - 2.83 (t , 2H), 1.95 - 1.83 (m, 4H). LCMS retention time 1.801 min; LCMS MH+ 407. Example 50: 8 - (cyclopentyloxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((4 - methylthiazol - 2 - yl)methyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 7-(4-Chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H - purine - 2,6(3H,7H) -dione (GG-000317-120).

[00531] To a solution of cyclopentanol (67 mg, 0.78 mmol) in THF (5 mL) was added sodium hydride (39 mg, 0.98 mmol) at 0 °C. After stirring at 0 °C for 30 minutes, 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (0.2 g, 0.39 mmol, Intermediate 14) was added. The mixture was stirred at room temperature for 16 hours; Then aqueous ammonium chloride solution (2 mL) was added at 0 °C. The reaction mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to provide a crude solid product. This material was suspended in ice-cold ethanol, collected by filtration, and dried under vacuum to afford 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H -pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (180 mg, 89.5% yield) as a white solid. LCMS retention time 2.085 min; LCMS MH+ - THP 433. Step 2: 8 - (cyclopentyloxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00532] To a solution of 7 - (4 - chlorobenzyl) - 8 - (cyclopentyloxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (180 mg, 0.35 mmol) in methanol (10 mL) was added ammonium formate (220 mg , 3.5 mmol) and 5% Pd/C (20 mg). The reaction was refluxed under a nitrogen atmosphere overnight. The mixture was cooled and filtered. The filtrate was concentrated to give 8-(cyclopentyloxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (120 mg, 87.6% yield) as a white solid. LCMS retention time 1.345 min; LCMS MH+ - THP 309. Step 3: 8 - (cyclopentyloxy) - 3 - methyl - 7 - ((4 - methylthiazol - 2 -yl)methyl) -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00533] To a solution of 8 - (cyclopentyloxy) - 3 - methyl -1 - (3 - (tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.12 g, 0.31 mmol) in DMF (5 mL) was added 2-(chloromethyl)-4-methylthiazole (91 mg, 0. 62 mmol, Intermediate 54), potassium carbonate (85 mg, 0.62 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated to 50 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.704 min; LCMS MH+ - THP 470. Step 4: 8 - (cyclopentyloxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((4 - methylthiazol - 2 -yl)methyl) -1H - purine - 2,6(3H,7H) - dione

[00534] The title compound was prepared using Example Method 48, step 2 to provide 8 - (cyclopentyloxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((4 - methylthiazol - 2 - yl)methyl) - 1H - purine - 2,6(3H,7H) - dione (60 mg, 60.4% yield) as a white solid. 1H NMR (CDCl3) δ 6.84 (d, 1H), 5.55 (s, 2H), 5.46 - 5.50 (m, 1H), 4.19 (t, 2H), 3.69 (s, 1H), 3.56 (s, 3H), 3.52 (s, 2H), 2.42 (d, 3H), 51.87 - 1.97 (m, 6H), 1.62 - 1.79 (m, 4H). LCMS retention time 2.163 min; LCMS MH+ 420.

[00535] The following examples 51a to 51j were prepared following the method of example 50. Example 51a: 7 - ethyl -1 - (3 - hydroxypropyl) - 8 - isbpropoxy - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00536] White solid, 50 mg, 58.8% yield: 1H NMR (DMSO-d6) δ 5.15 - 5.20 (m, 1 H), 4.46 (t, 1 H), 4.02 (q, 2 H), 3.90 (t, 2 H), 3.42 (q, 2 H), 3.34 (s, 3 H), 1.6 6 - 1.70 (m, 2H), 1.38 (d, 6H), 1.25 (t, 3H). LCMS retention time 1.946 min; LCMS MH+ 311. Example 51 b: 1 - (3 - hydroxypropyl) - 8 - isopropoxy - 3 - methyl - 7 - propyl -1H - purine - 2,6(3H,7H) - dione

[00537] White solid, 39 mg, 44.3% yield: 1H NMR (DMSO - d6) δ 5.15 - 5.21 (m, 1 H), 4.46 (t, 1 H), 3.95 (t, 202 H), 3.90 (t, 2 H), 3.41 (q, 2 H), 3.37 (s, 3 H), 1, 64 - 1.71 (m, 4H), 1.37 (d, 6H), 0.81 (t, 3H). LCMS retention time 2.149 min; LCMS MH+ 325. Example 51 c 7 - benzyl -1 - (3 - hydroxypropyl) - 8 - isopropoxy - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00538] White solid, 26 mg, 31.7% yield: 1H NMR (CDC13) δ 7.40 - 7.42 (dd, 2H), 7.28 - 7.36 (m, 3H), 5.27 (s, 2H), 4.17 - 4.20 (t, 2H), 3.77 (m, 1H), 3.51 (m, 5H), 1.88 - 1.92 (m, 2H), 1.43 - 4.44 (d, 6H). LCMS retention time 2.336 min; LCMS MH+ 373. Example 51d: 1 - (3 - hydroxypropyl) - 8 - isopropoxy - 3 - methyl - 7 - ((6 - methylpyridin - 3 -yl)methyl) -1H - purine - 2,6(3H,7H) - dione

[00539] White solid, 50 mg, 30.4% yield: 1H NMR (DMSO-d6) δ 8.47 (s, 1 H), 7.78 - 7.76 (dd, 1 H), 7.31 - 7.29 (d, 1 H), 5.32 (s, 3 H), 4.11 - 4.08 (t, 2 H), 3.6 2 - 3.59 (t, 2H), 3.50 (s, 3H), 2.52 (s, 3H), 1.88 - 1.85 (m, 2H), 1.45 - 1.44 (d, 6H). LCMS retention time 1.581min; LCMS MH+ 388. Example 51e: 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((6 - methylpyridin - 3 -yl)methyl) - 1H - purine - 2,6(3H,7H) -dione.

[00540] White solid, 17 mg, 28.7% yield: 1H NMR (DMSO-d6) δ 8.47 (s, 1 H), 7.75 - 7.78 (dd, 1 H), 7.28 - 7.30 (d, 1 H), 5.32 (s, 3 H), 4.58 - 4.63 (q, 2 H), 4.0 7 - 4.10 (t, 2H), 3.58 - 3.61 (t, 2H), 3.49 (s, 3H), 2.52 (s, 3H), 1.84 - 1.88 (q, 2H), 1.45 - 1.48 (t, 3H). LCMS retention time 1.371 min; LCMS MH+374. Example 51f: 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methyloxazol - 2 - yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00541] White solid, 19 mg, 30.6% yield: 1H NMR (DMSO-d6) δ 6.73 (s, 1 H), 5.42 (s, 2 H), 4.57 - 4.62 (q, 2 H), 4.04 - 4.07 (t, 2 H), 3.56 - 3.59 (t, 2 H), 3.5 3 (s, 3H), 2.31 (s, 3H), 1.82 - 1.86 (q, 2H), 1.40 - 1.44 (t, 3H). LCMS retention time 1.516 min; LCMS MH+ 364. Example 51g: 7 - ((5 - chloropyridin - 2 -yl)methyl) - 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00542] White solid, 13 mg, 31.2% yield: 1H NMR (CDCl3) δ 8.49 (s, 1 H), 7.64 - 7.66 (dd, 1 H), 7.20 - 7.22 (d, 1 H), 5.40 (s, 2 H), 4.55 - 4.60 (q, 2 H), 4.14 - 4.16 (t, 2H), 3.59 - 3.61 (t, 1H), 3.56 (s, 3H), 3.46 - 3.49 (t, 3H), 1.86 - 1.88 (m, 2H), 1.40 - 1.42 (t, 2H). LCMS retention time 1.896 min; LCMS MH+ 394. Example 51h: 8-(cyclopentylmethoxy)-7-ethyl-1-(3-hydroxypropyl)-3-methyl-1H-purine - 2,6(3H,7H)-dione

[00543] Light yellow solid, 11 mg, 20.7% yield: 1H NMR DMSO-d6) δ 4.45 - 4.35 (t, 1 H), 4.35 - 4.33 (d, 2 H), 4.07 - 4.02 (m, 2 H), 3.92 - 3.88 (t, 2 H), 3.45 - 3.4 0 (q, 2H), 3.30 (s, 3H), 2.39 - 2.32 (m, 1H), 1.80 - 1.52 (m, 8H), 1.37 - 1.24 (m, 5H). LCMS retention time 2.485 min; LCMS MH+ 351. Example 51i: 8-(cyclopentylmethoxy)-1-(3-hydroxypropyl)-3-methyl-7-propyl-1H - purine - 2,6(3H,7H) - dione

[00544] White solid, 16 mg, 31.5% yield: 1H NMR (DMSO-d6) δ 4.45 - 4.34 (t, 1 H), 4.35 - 4.33 (d, 2 H), 3.99 - 3.96 (1, 2 H), 3.91 - 3.88 (t, 2 H), 3.44 - 3.4 0 (m, 2H), 3.37 (s, 3H), 2.37 - 2.34 (m, 1H), 1.78 - 1.52 (m, 8H), 1.35 - 1.31 (m, 2H), 0.84 - 0.80 (t, 3H). LCMS retention time 2.670min; LCMS MH+365. Example 51j: 8 - (cyclopentylmethoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((6 - methylpyridin - 3 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00545] White solid, 25 mg, 49.9% yield: 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.61 - 7.58 (dd, 1 H), 7.24 - 7.22 (d, 1 H), 5.22 (s, 2 H), 4.47 - 4.44 (t, 1 H), 4.3 5 - 4.34 (d, 2H), 3.93 - 3.89 (t, 2H), 3.45 - 3.38 (m, 2H), 3.35 (s, 3H), 2.33 (s, 3H), 2.13 - 2.11 (m, 1H), 1.70 - 1.51 (m, 8H), 1.28 - 1.25 (m , 2H). LCMS retention time 1.761 min; LCMS MH+ 428. Example 52: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) - 1H - purine - 2,6(3H,7H) -dione hydrochloride Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 - yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00546] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione (100 mg, 0.195 mmol, Intermediate 14) in DMF (5 mL) was added 6 - methylpyridin - 3-ol (24 mg, 0.22 mmol) followed by potassium carbonate (76 mg, 0.55 mmol) and the mixture was stirred at 85°C for 3 hours. The mixture was cooled and partitioned between ethyl acetate and saline. The layers were separated and the organic layer was washed with saturated aqueous ammonium chloride, dried and concentrated to give 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) -1 - (3 - (tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (79 mg, 75% yield ) as a yellow solid. LCMS retention time 2.297 min; LCMS MH+ - THP 456. Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 - yloxy) - 1H - purine - 2,6(3H,7H) - dione

[00547] A solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 - yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (79 mg, 0.146 mmol) in 1N ethanolic HCl (3 mL) ) was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) - 1H - purine-2,6(3H,7H)-dione (35 mg, 52.6% yield) as a white solid. 1H NMR (DMSO-d6) δ 8.69 (s, 1H), 8.03 - 8.01 (d, 1H), 7.59 - 7.57 (d, 1H), 7.45 (s, 4H), 5.45 (s, 2H), 4.06 - 3.98 (m, 2H), 3.45 - 3.42 (t, 2H) ), 3.28 (s, 3H), 2.59 (s, 3H), 1.71 - 1.67 (t, 2H). LCMS retention time 2.207 min; LCMS MH+ 456.

[00548] The following examples 53a and 53b were prepared using the method of example 52. Example 53a: 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-methylpyridin-4-yloxy)-1H-purine-2,6(3H,7H)-dione hydrochloride.

[00549] White solid, isolated as the HCl salt, 30 mg, 36.6% yield: 1H NMR (DMSO-d6) δ 8.48 - 8.46 (d, 1 H), 8.17 (s, 1 H), 7.43 - 7.33 (m, 4 H), 7.26 - 7.22 (m, 2 H), 5.42 (s, 2H), 4.52 (s, 1H), 3.95 - 3.92 (t, 2H), 3.44 - 3.42 (m, 2H), 3.37 (s, 3H), 2.47 (s, 3H), 1.72 - 1.69 (t, 2H). LCMS retention time 1.716 min; LCMS MH+ 456. Example 53b: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (5 - methylpyridin - 3 - yloxy) -1H - purine - 2,6(3H,7H) - dione

[00550] White solid, 40 mg, 48.8% yield: 1H NMR (DMSO-d6) δ 8.45 - 8.44 (d, 1 H), 8.36 (s, 1 H), 7.65 (s, 1 H), 7.46 - 7.41 (m, 4 H), 5.44 (s, 2 H), 4.50 - 4.4 7 (t, 1H), 3.94 - 3.91 (t, 2H), 3.46 - 3.40 (m, 2H), 3.28 (s, 3H), 2.34 (s, 3H), 1.73 - 1.66 (m, 2H). LCMS retention time 2.259 min; LCMS MH+ 456. Example 54: 7 - butyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (5 - methylpyridin - 3 -yloxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 3 - methyl - 8 - (5 - methylpyridin - 3 - yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00551] The title compound was prepared using the method of example 52, step 1 of Intermediate 16, step 1 to afford 3 - methyl - 8 - (5 - methylpyridin - 3 -yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2.6 (3H,7H)-dione (300 mg, 97.6% yield) as yellow oil. LCMS retention time 1.838 min; LCMS MH+ - THP+H 462. Step 2: 7-(4-chlorobenzyl)-1 -(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy) - 1H - purine - 2,6(3H,7H) - dione

[00552] To a solution of 3 - methyl - 8 - (5 - methylpyridin - 3 - yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (300 mg, 0.554 mmol) in alcohol Ethyl alcohol (10 ml) was added concentrated HCl (3 ml) and the mixture was stirred for 6 hours at reflux. The mixture was cooled, concentrated and filtered to afford 7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione (159 mg, 1086.6% yield) as yellow solid. LCMS retention time 0.356 min; LCMS MH+ 332. Step 3: 7-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine - 2,6(3H,7H) -dione

[00553] The title compound was prepared using the method of example 44, step 3 to provide 7 - butyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (5-methylpyridin-3-yloxy)-1H-purine-2,6(3H,7H)-dione (30 mg, 42.8% yield) as white solid. 1H NMR (DMSO-d6) = 8.48 - 8.47 (d, 1H), 8.37 - 8.36 (d, 1H), 7.7.1 (s, 1H), 4.51 - 4.48 (t, 1H), 4.22 - 4.19 (t, 2H), 3.94 - 3.91 (1, 2H), 3.46 - 3.43 (t, 2H), 3.28 (s, 3H), 2.36 (s, 3H), 1.81 - 1.66 (m, 4H), 1.35 - 1.30 (m, 2H), 0.93 - 0.89 (t, 3H). LCMS retention time 1.854 min; LCMS MH+ 388. Example 55: 8 - (3 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00554] To a solution of 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl - 7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.12 mmol, Intermediate 16) in DMF (3 mL) was added 3-fluorophenol (23 mg, 0.17 mmol) and sodium carbonate potassium (75 g, 0.24 mmol). The mixture was stirred at 80°C for 12 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 8 - (3 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione (11 mg, 20.75% yield) as a solid white. 1H NMR (CD3OD) δ 7.42 - 7.48 (m, 2H), 7.18 - 7.22 (m, 2H), 7.06 - 7.10 (m, 1H), 5.76 (s, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.45 (s, 3H), 2.47 (d , 3H), 1.85 - 1.90 (m, 2H). LCMS retention time 1.273 min; LCMS MH+ 446.

[00555] The following examples 56a to 56i were prepared using the method of example 55. Example 56a: 8 - (3 - chlorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00556] White solid, 17 mg, 30.9 % yield: 1H NMR (CD3OD) δ 7.42 - 7.47 (m, 3 H), 7.30 - 7.35 (m, 2 H), 5.76 (s, 2 H), 4.10 (t, 2 H), 3.61 (t, 2 H), 3.44 (s, 3 H) ), 2.48 (d, 3H), 1.85 - 1.90 (m, 2H). LCMS retention time 2.246 min; LCMS MH+ 462. Example 56b: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(m - tolyloxy) -1H - purine - 2,6(3H,7H) -dione

[00557] White solid, 25 mg, 47.1% yield: 1H NMR (CD3OD) δ 7.42 (d, 1 H), 7.29 - 7.34 (m, 1 H), 7.09 - 7.13 (m, 3 H), 5.75 (s, 2 H), 4.10 (t, 2 H), 3 - 61 (t, 2H), 3.43 (s, 3H), 2.48 (d, 3H), 2.38 (s, 3H), 1.84 - 1.91 (m, 2H). LCMS retention time 2.199 min; LCMS MH+ 442. Example 56c: 1 - (3 - hydroxypropyl) - 8 - (3 - memoxyphenoxy) - 3 - methyl - 7 - ((5 - methylthiazol - 2 - yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00558] White solid, 18 mg, 47.1% yield: 1H NMR (CD3OD) δ 7.41 (d, 1 H), 7.33 (t, 1 H), 6.85 - 6.91 (m, 3 H), 5.74 (s, 2 H), 4.09 (t, 2 H), 3.81 (s, 3 H), 3.61 ( t, 2H), 3.43 (s, 3H), 2.47 (d, 3H), 1.84 - 1.90 (m, 2H). LCMS retention time 2.092 min; LCMS MH+ 458. Example 56d: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(3 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00559] White solid, 45 mg, 47.1% yield: 1H NMR (CD3OD) δ 7.64 - 7.71 (m, 4 H), 7.41 (d, 1 H), 5.78 (s, 2 H), 4.10 (t, 2 H), 3.61 (t, 2 H), 3.45 (s, 3 H), 2.47 (d,3H), 1.85 - 1.91 (m, 2H). LCMS retention time 2.349 min; LCMS MH+ 496. Example 56e: 8 - (4 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00560] White solid, 23 mg, 43.4% yield: 1H NMR (CD3OD) δ 7.42 (d, 1 H), 7.35 - 7.39 (m, 2 H), 7.17 - 7.22 (m, 2 H), 5.76 (s, 2 H), 4.10 (t, 2 H), 3.61 (t, 2 H), 3.45 (s, 3H), 2.48 (d, 3H), 1.85 - 1.90 (m, 2H). LCMS retention time 2.108 min; LCMS MH+ 446. Example 56f: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(4 - (trifluoromethyl)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00561] White solid, 20 mg, 40.4% yield: 1H NMR (CD3OD) δ 7.78 (d, 2 H), 7.57 (d, 2 H), 7.41 (d, 1 H), 5.78 (s, 2 H), 4.10 (t, 2 H), 3.61 (t, 2 H), 3.45 (s, 3 H), 2.48 (d, 3H), 1.85 - 1.90 (m, 2H). LCMS retention time 2.386 min; LCMS MH+ 496. Example 56g: 1 -(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-8-(4 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00562] White solid, 19 mg, 31.1% yield: 1H NMR (CD3OD) δ 7.46 - 7.49 (m, 2 H), 7.38 - 7.42 (m, 3 H), 5.77 (s, 2 H), 4.10 (t, 2 H), 3.61 (t, 2 H), 3.44 (s, 3 H), 2.47 (s, 3H), 1.85 - 1.90 (m, 2H). LCMS retention time 2.432 min; LCMS MH+ 512. Example 56h: 8 - (4 - chlorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00563] White solid, 15 mg, 31.1% yield: 1H NMR (CD3OD) δ 7.42 - 7.48 (m, 3 H), 7.35 - 7.38 (m, 2 H), 5.76 (s, 2 H), 4.10 (t, 2 H), 3.61 (t, 2 H), 3.43 (s, 3 H), 2.48 (d, 3H), 1.85 - 1.91 (m, 2H). LCMS retention time 2.273 min; LCMS MH+ 462. Example 56i: 1 - (3 - hydroxypropyl) - 8 - (4 - methoxyphenoxy) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00564] White solid, 13 mg, 31.1% yield: 1H NMR (CD3OD) δ 7.42 (d, 1 H), 7.23 (dd, 2 H), 6.98 (dd, 2 H), 5.74 (s, 2 H), 4.09 (t, 2 H), 3.82 (s, 3 H), 3.60 (t, 2 H), 3.42 (s, 3H), 2.48 (d, 3H), 1.85 - 1.90 (m, 2H). LCMS retention time 2.104 min; LCMS MH+ 458. Example 57: 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol - 2 -yl)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00565] To a solution of 8 - bromo -1 - (3 - hydroxypropyl) - 3 - methyl - 7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.12 mmol, Intermediate 16) in ethanol (2 mL) was added sodium (10 mg, 0.4 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was purified by preparative HPLC to give 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((5 - methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (27 mg, 59.3%) as a white solid. 1H NMR (CD3OD) δ 7.38 (d, 1H), 5.55 (s, 2H), 4.60 (q, 2H), 4.09 (t, 2H), 3.59 (t, 2H), 3.52 (s, 3H), 2.45 (d, 3H), 1.83 - 1.88 (m, 2H), 1.43 ( d, 3H). LCMS retention time 1.680 min; LCMS MH+ 380. Example 58: 7 - ethyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - ((5 - methylthiazol - 2 -yl)methoxy) - 1H - purine - 2,6(3H,7H) - dione

[00566] The title compound was prepared using method of step 2 of example 36 of Intermediate 6. The product was purified by preparative HPLC to afford 7-ethyl-1-(3-hydroxypropyl)-3-methyl-8-((5-methylthiazol-2-yl)methoxy)-1H-purine-2,6(3H,7H)-dione (5 mg, 6.9% yield) as white solid. 1H NMR (DMSO - d6) δ 7.53 (s, 1H), 5.76 (s, 2H), 4.18 (q, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.54 (s, 3H), 2.52 (s, 3H), 1.80 - 1.90 (m, 2H), 1.36 (t, 3H). LCMS retention time 1.760 min; LCMS MH+ 380. Example 59: 7 - benzyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) – dione Step 1: 7-Benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00567] To a solution of 7 - benzyl - 8 - chloro -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) -dione (4.7 g, 8.58 mmol, Intermediate 18) in DMF (15 mL) was 3-(trifluoromethoxy)phenol (1.83 g, 10.28 mmol) and potassium carbonate (2.4 g, 17.39 mmol) are added. The mixture was stirred at 80°C overnight. The mixture was diluted with ethyl acetate and water, and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7 - benzyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H)-dione (5.3 g , 89.3% of production) as yellow oil. LCMS retention time 3.974 min; LCMS M+Na 713. Step 2: 7 - benzyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00568] To a solution of 7 - benzyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 3 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H)dione (5.3 g, 7.68 mmol) in ethyl alcohol HCl (20 mL) was added concentrated HCl (5 mL). The reaction was stirred at 80 °C overnight. The reaction was concentrated and the residue was neutralized with saturated sodium bicarbonate. This aqueous phase was extracted with ethyl acetate and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7 - benzyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (4.5 g, 100% yield) as a white solid. 1H NMR (DMSO-d6) δ 11.93 (s, 1H), 7.62 - 7.57 (1, 1H), 7.44 - 7.32 (m, 8H), 5.42 (s, 2H), 4.49 - 4.46 (t, 1H), 3.89 - 3.86 (t, 2H), 3.46 - 3.4 1 (m, 2H), 1.72 - 1.65 (m, 2H). LCMS retention time 2.560 min; LCMS MH+ 477. Example 60: 7 - benzyl - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00569] To a solution of 7 - benzyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (1.2 g, 2.52 mmol, example 59) in DMF (5 mL) was added iodoethane (0.7 g, 4.49 mmol), followed by potassium carbonate (0.7 g, 5.07mmol). The reaction was stirred at 80°C for 2 hours; It was then cooled and partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to provide 7 - benzyl - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.62 g, 49.2% yield) as yellow solid. 1H NMR (DMSO-d6) δ 7.62 - 7.57 (t, 1H), 7.50 (s, 1H), 7.42 - 7.31 (m, 7H), 5.44 (s, 2H), 4.51 - 4.48 (t, 1H), 3.95 - 3.85 (m, 4H), 3.47 - 3.42 (q, 2H), 1.73 - 1.67 (m, 2H), 1.16 - 1.13 (t, 3H). LCMS retention time 2.974 min; LCMS MH+ 505. Example 61: 3-Ethyl-1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H - purine - 2,6(3H,7H) -dione Step 1: 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione.

[00570] 7 - benzyl - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.62 g, 1.23 mmol, example 60) was dissolved in ethanol (20 mL); Then the mixture was degassed and recharged with nitrogen three times. Ammonium formate (0.5 g, 7.94 mmol) and 10% Pd/C (30 mg) were added. The mixture was again degassed and recharged with nitrogen three times; Then it was stirred at 80 °C overnight. The reaction was cooled and filtered. The filter cake was washed with methanol. The filtrate was concentrated to give 3-ethyl-1-(3-hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.6 g, 100% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.61 - 7.57 (t, 1H), 7.50 (s, 1H), 7.40 - 7.38 (dd, 1H), 7.31 - 7.29 (d, 1H), 4.50 (s, 1H), 3.95 - 3.85 (m, 4H), 3.44 - 3.43 (m, 2H), 1.73 - 1.66 (t, 2H), 1.17 - 1.13 (t, 3H). LCMS retention time 1.350 min; LCMS MH+ 415. Step 2: 3 - ethyl -1 - (3 - hydroxypropyl) - 7 - ((6 - methylpyridin - 3 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00571] To a solution of 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (110 mg, 0.22 mmol) in DMF (3 mL) was added 5-(chloromethyl)-2-methylpyridine (50 mg, 0.4 mmol), potassium carbonate (91 mg, 0.66 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated to 50°C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 3-ethyl-1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (30 mg, 44.8% yield) as a white solid . 1H NMR (DMSO-d6) δ 8.53 (d, 1H), 7.71 (dd, 1H), 7.55 - 7.63 (m, 2H), 7.50 (dd, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 5.43 (s, 2H), 4.48 (t, 1H), 3.85 - 3.96 (m, 4H), 3.44 (q, 2H), 2.44 (s, 3H), 1.68 - 1.73 (m, 2H), 1.14 (t, 3H). LCMS retention time 2.097min; LCMS MH+ 520.

[00572] The following examples 62a to 62d were prepared using the method of example 61. Example 62a: 7 - ((5 - chloropyridin - 2 - yl)methyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00573] White solid, 30 mg, 28.1% yield: 1H NMR (DMSO-d6) δ 8.47 (s, 1 H), 7.84 - 7.87 (dd, 1 H), 7.53 - 7.57 (t, 1 H), 7.46 - 7.48 (d, 1 H), 7.34 - 7.39 (m, 2 H), 7.22 - 7.24 (d, 1H), 5.63 (s, 2H), 4.03 - 4.08 (m, 4H), 3.56 - 3.59 (t, 2H), 1.82 - 1.85 (q, 2H), 1.26 - 1.29 (t, 3H). LCMS retention time 2.701 min; LCMS MH+ 540. Example 62b: 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00574] White solid, 15 mg, 20.1% yield: 1H NMR (DMSO-d6) δ 7.60 - 7.56 (t, 1 H), 7.49 (s, 1 H), 7.43 - 7.39 (m, 5 H), 7.30 - 7.28 (d, 1 H), 5.40 (s, 2 H), 4.4 9 (bs, 1H), 3.92 - 3.82 (m, 4H), 3.43 - 3.36 (m, 2H), 1.71 - 1.64 (m, 2H), 1.14 - 1.10 (t, 3H). LCMS retention time 1.906 min; LCMS MH+ 539. Example 62c: 3,7 - diethyl -1 - (3 - hydroxypropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00575] White solid, 15 mg, 20.1% yield: 1H NMR (DMSO-d6) δ 7.64 - 7.57 (m, 2H), 7.47 - 7.45 (dd, 1H), 7.34 - 7.32 (d, 1H), 4.49 - 4.47 (t, 1H), 4.25 - 4.2 0 (q, 2H), 3.96 - 3.85 (m, 4H), 3.47 - 3.38 (m, 2H), 1.74 - 1.67 (m, 2H), 1.39 - 1.36 (t, 3H), 1.16 - 1.13 (t, 3H). LCMS retention time 2.667 min; LCMS MH+ Example 62d: 3 - ethyl -1 - (3 - hydroxypropyl) - 7 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00576] White solid, 15 mg, 14.2% yield: 1H NMR (DMSO-d6) δ 7.64 - 7.59 (t, 1 H), 7.56 (s, 1 H), 7.47 - 7.44 (dd, 1 H), 7.33 - 7.31 (d, 1 H), 4.50 - 4.48 (t, 1 H), 3.95 - 3.84 (m, 4H), 3.46 - 3.42 (m, 2H), 1.73 - 1.66 (m, 2H), 1.15 - 1.12 (t, 3H). LCMS retention time 2.504 min; LCMS MH+ 429. Example 63: 1 -(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-3-propyl-8-(3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 1 - (3 - hydroxypropyl) - 3 - propyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00577] The title compound was prepared using the methods of examples 60 and 61, step 1 of the product of example 59. White solid, 180 mg, 70.1% yield, LCMS retention time 1.452 min; LCMS MH+ 429. Step 2: 1 - (3 - hydroxypropyl) - 7 - ((6 - methylpyridin - 3 -yl)methyl) - 3 - propyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00578] The title compound was prepared using the method of example 61, step 2. The product was purified by preparative HPLC to give 1 - (3 - hydroxypropyl) - 7 - ((6 - methylpyridin - 3 - yl)methyl) - 3 - propyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (7.1 mg, 15.1% yield) as a white solid. 1H NMR (DMSO-d6) δ 8.53 - 8.52 (d, 1H), 7.72 - 7.68 (dd, 1H), 7.63 - 7.56 (m, 2H), 7.45 - 7.42 (dd, 1H), 7.33 - 7.31 (dd, 1H), 7.26 - 7.24 (d, 1H) ), 5.42 (s, 2H), 4.50 - 4.47 (t, 1H), 3.95 - 3.91 (t, 2H), 3.82 - 3.78 (t, 2H), 3.46 - 3.42 (q, 2H), 2.44 (s, 3H), 1.73 - 1.58 (m, 4H), 0.82 - 0 .78 (t, 3H). LCMS retention time 2.276 min; LCMS MH+ 534. Example 64: 7-(4-chlorobenzyl)-8-(3-((dimethylamino)methyl)phenoxy)-1 -(3-hydroxypropyl) - 3 - propyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 8 - chloro - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - propyl -1H - purine - 2,6(3H,7H) - dione

[00579] The title compound was prepared using the method of example 60. White solid, 160 mg, 72.3% yield, LCMS retention time 1.574 min; LCMS MH+ 411. Step 3: 3-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yloxy)benzaldehyde

[00580] The title compound was prepared using the method of example 59, step 1. Yellow oil, 190 mg, 70.9% yield, LCMS retention time 1.663 min; LCMS MH+ 497. Step 4: 7 - (4 - chlorobenzyl) - 8 - (3 - ((dimethylamino)methyl)phenoxy) -1 - (3 - hydroxypropyl) - 3 - propyl -1H - purine - 2,6(3H,7H) - dione hydrochloride

[00581] The title product was prepared using the method of example 39, step 2 and the crude product was purified by preparative HPLC. White solid, 15mg, 14.3%: 1H NMR (DMSO-d6) δ 11.04 (bs, 1H), 7.60 (bs, 1H), 7.57 - 7.49 (m, 2H), 7.46 - 7.41 (m, 5H), 5.43 (s, 2H), 4.29 - 4.28 (d, 2H), 3.95 - 3.91 (t, 2H), 3.81 - 3.77 (t, 2H), 3.45 - 3.42 (t, 2H), 2.68 - 2.67 (d, 6H), 1.72 - 1.66 (m, 2H), 1.63 - 1.54 (m, 2H), 0.81 - 0.77 (t, 3H). LCMS retention time 1.755 min; LCMS MH+ 526. Example 65: 7 - (4 - chlorobenzyl) - 8 - (3 - ((dimethylamino)methyl)phenoxy) - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) -dione hydrochloride

[00582] The title compound was prepared using the method of example 64. White solid, 13mg, 14.5% yield: 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 7.63 (s, 1H), 7.58 - 7.50 (m, 2H), 7.47 - 7.42 (m, 5H), 5.43 (s , 2H), 4.31 - 4.29 (d, 2H), 3.95 - 3.91 (t, 2H), 3.89 - 3.83 (m, 2H), 3.46 - 3.42 (1, 2H), 2.69 - 2.67 (d, 6H), 1.73 - 1.66 (m, 2H), 1.15 - 1.1 1 (t, 3H). LCMS retention time 1.668 min; LCMS MH+ 512. Example 66: 7 - (4 - chlorobenzyl) - 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) -1H - purine - 2,6(3H,7H) - dione

[00583] To a solution of 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine-2,6(3H,7H)-dione (70 mg, 0.248 mmol, Intermediate 26) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (80 mg, 0.390 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 60°C for 4 hours, then diluted with ethyl acetate and water and the layers were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) - 8 - ethoxy - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (15 mg, 14.9% yield) as white solid. 1H NMR (DMSO-d6) δ 7.43 - 7.41 (d, 2H), 7.34 - 7.32 (d, 2H), 5.21 (s, 2H), 4.53 - 4.44 (m, 3H), 3.99 - 3.88 (m, 4H), 3.45 - 3.39 (m, 2H), 1.71 - 1.64 (m, 2H), 1.37 - 1.33 (t, 3H), 1.23 - 1.19 (t, 3H). LCMS retention time 2.654 min; LCMS MH+ 407. Example 67: 7-(4-chlorobenzyl)-8-ethoxy-1-(3-hydroxypropyl)-3-propyl-1H-purine - 2,6(3H,7H) -dione

[00584] The title compound was prepared using the methods of Intermediate 26 and Example 66. White solid, 5mg, 17.0% yield: 1H NMR (DMSO-d6) δ 7.43 - 7.42 (d, 2H), 7.33 - 7.31 (d, 2H), 5.21 (s, 152H), 4.52 - 4.47 ( m, 3H), 3.92 - 3.87 (m, 4H), 3.44 - 3.41 (m, 2H), 1.72 - 1.63 (m, 4H), 1.36 - 1.33 (t, 3H), 0.88 - 0.84 (t, 3H). LCMS retention time 2.837 min; LCMS MH+ 421. Example 68: 7 - (4 - chlorobenzyl) - 8 - (2 - ethoxyethoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00585] The title compound was prepared using the two-step method of Example 36. White solid, 33 mg, 26.2% yield: 1H NMR (DMSO-d6) δ 7.34 - 7.41 (m, 4H), 5.21 (s, 2H), 4.58 (t, 2H), 4.47 (t, 1H), 3.90 (t, 2H) ), 3.69 - 3.72 (m, 2H), 3.41 - 3.47 (m, 7H), 1.65 - 1.70 (m, 2H), 1.08 (t, 3H). LCMS retention time 2.423 min; LCMS MH+ 437. Example 69: 7 - (4 - chlorobenzyl) - 8 - (isopropylsulfonyl) -1 - (isoxazol - 5 - ylmethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 8 - (isopropylthio) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00586] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H-purine-2,6(3H,7H)-dione (0.2 g, 0.54 mmol, Intermediate 8) in DMF (5 mL) was added propane-2-thiol (0.2 g, 2.7 mmol) and potassium carbonate (0.38 g, 2.7 mmol). The reaction was heated to 80 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product (0.2 g) which was used without purification. LCMS retention time 1.015 min; LCMS MH+ 365. Step 2: 7 - (4 - chlorobenzyl) - 8 - (isopropylsulfonyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00587] To a solution of 7-(4-chlorobenzyl)-8-(isopropylthio)-3-methyl - 1H - purine - 2,6(3H,7H) - dione (0.2 g, 0.55 mmol) in chloroform (10 mL) was added MCPBA (0.19 g, 1.37 mmol) portionwise at 0°C. The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude solid product which was triturated in ethanol and collected to give 7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.19 g, 84.5% yield) as a white solid. LCMS retention time 1.322 min; LCMS MH+ 397. Step 3: 7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-1-(isoxazol-5-ylmethyl)-3-methyl-1H - purine - 2,6(3H,7H) - dione To a solution of 7-(4-chlorobenzyl)-8-(isopropylsulfonyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (80 mg, 0.20 mmol) in DMF (5 mL) was added 5-(chloromethyl)isoxazole (55 mg, 0.5 mmol, Intermediate 41), potassium carbonate (58 mg, 0.42 mmol), and TBAI (2 mg , 0.02 mmol). The reaction was heated to 50 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) - 8 - (isopropylsulfonyl) -1 - (isoxazol - 5 - ylmethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (39 mg, 40.6% yield) as a white solid. 1H NMR (CD3OD) δ 8.49 (d, 1H), 7.41 (dd, 2H), 7.28 (d, 2H), 6.43 (d, 1H), 5.87 (s, 2H), 5.21 (s, 2H), 3.60 - 3.73 (m, 1H), 3.47 (s, 3H), 1.25 (d , 6H). LCMS retention time 2.772 min; LCMS MH+ 478 Example 70: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (methylsulfonyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (methylthio) -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione

[00588] 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.35 mmol, Intermediate 14) was dissolved in sodium thiomethoxide (5 mL). The reaction was heated to 80 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.875 min; LCMS MH+ - THP 395. Step 2: 7-(4-chlorobenzyl)-1 -(3-hydroxypropyl)-3-methyl-8-(methylsulfonyl)-1H - purine - 2,6(3H,7H) - dione

[00589] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (methylthio) - 1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (0.14 g, 0.35 mmol) in chloroform (10 mL) was added MCPBA (0.15 g, 0.87 mmol) portion by portion at 0°C. The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil. This oil was dissolved in ethanol (5 mL); Then acetyl chloride (0.2 ml) was added dropwise at 0 °C. The reaction was stirred at this temperature for 1 hour. The mixture was concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(methylsulfonyl)-1H-purine-2,6(3H,7H)-dione (15 mg, 10.0% yield) as a white solid. 1H NMR (CD3OD) δ 7.34 - 7.42 (m, 4H), 5.97 (s, 2H), 4.11 (t, 2H), 3.61 (t, 2H), 3.57 (s, 3H), 3.38 (s, 3H), 1.84 - 1.89 (m, 2H). LCMS retention time 2.052 min; LCMS MH+ Example 71: 7 - (4 - chlorobenzyl) - 8 - (ethylsulfonyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 7-(4-chlorobenzyl)-8-(ethylthio)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H - purine - 2,6(3H,7H) -dione

[00590] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (0.15 g, 0.29 mmol, Intermediate 14) in DMF (10 mL) was added ethanethiol (27 mg , 0.44 mmol) and potassium carbonate (81 mg, 0.58 mmol). The reaction was heated to 80 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.912 min; LCMS MH+ - THP 409. Step 2: 7-(4-chlorobenzyl)-8-(ethylsulfonyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine - 2,6(3H,7H) - dione

[00591] The title compound was prepared using Example Method 70, step 2 and purified by preparative HPLC to provide 7 - (4 - chlorobenzyl) - 8 - (ethylsulfonyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (26 mg, 20.5% yield) as a white solid. 1H NMR (CD3OD) δ = 7.34 - 7.41 (m, 4H), 5.98 (s, 2H), 4.11 (t, 1H), 3.62 (t, 2H), 3.57 (s, 3H), 3.47 - 3.53 (m, 2H), 1.85 - 1.90 (m, 2H), 1.31 ( t, 3H). LCMS retention time 2.192 min; LCMS MH+ 441. Example 72: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - (isopropylsulfonyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00592] The title compound was prepared using the method of example 71 and purified by preparative HPLC to provide 7-(4-chlorobenzyl) - 8 - (ethylsulfonyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (26 mg, 20.5% yield) as white solid. 1H NMR (CDCl3) δ 7.43 - 7.45 (d, 2H), 7.31 - 7.34 (d, 2H), 5.97 (s, 2H), 4.19 - 4.22 (t, 2H), 3.73 - 3.76 (m, 1H), 3.59 (s, 3H), 3.54 - 3.59 ( m, 2H), 3.04 - 3.06 (t, 1H), 1.90 - 1.93 (m, 2H), 1.38 - 1.40 (d, 6H). LCMS retention time 2.311 min; LCMS MH+ 455. Example 73: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenylthio) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenylthio) -1H - purine - 2,6(3H,7H) - dione

[00593] The title compound was prepared using the method of example 71, step 1 using 3-(trifluoromethoxy)benzenethiol. Yellow oil, 100 mg, 81.9% yield. LCMS retention time 2.098 min; LCMS MH+ - THP 541 Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenylthio) -1H - purine - 2,6(3H,7H) - dione

[00594] The title compound was prepared using Example method 37, step 2. Light yellow solid, 20mg, 23.1% yield: 1H NMR (DMSO-d6) δ 7.47 - 7.42 (t, 1H), 7.33 - 7.30 (m, 5H), 7.24 - 7.22 (d, 2H), 5.63 (s, 2H), 4.49 - 4.46 (t, 1H), 3.95 - 3.92 (t, 2H), 3.47 - 3.42 (m, 2H), 3.39 (s, 3H), 1.72 - 1.69 (m, 2H). LCMS retention time 2.950 min; LCMS MH+ 541 Example 74: 8 - (butylsulfonyl) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00595] The title compound was prepared using the method of example 71. Light yellow oil, 30 mg, 39.3% yield: 1H NMR (CD3OD) δ 7.40 - 7.35 (m, 4H), 5.99 (s, 2H), 4.14 - 4.10 (t, 2H), 3.64 - 3.61 (t, 2H), 3.5 7 (s, 3H), 3.44 - 3.40 (m, 2H), 1.90 - 1.86 (m, 2H), 1.69 - 1.65 (m, 2H), 1.44 - 1.38 (m, 2H), 0.92 - 0.89 (t, 3H). LCMS retention time 1.671 min; LCMS MH+ 469 Example 75: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) - dione

[00596] The title compound was prepared using the method of Example 71. Light brown solid, 30 mg, 39.5% yield: 1H NMR (CD3OD) δ 7.40 - 7.34 (m, 4H), 5.99 (s, 2H), 4.13 - 4.09 (t, 2H), 3.63 - 3.60 (t, 2H), 3, 57 (s, 3H), 3.43 - 3.39 (t, 2H), 1.89 - 1.85 (m, 2H), 1.80 - 1.75 (m, 2H), 1.04 - 0.99 (t, 3H). LCMS retention time 2.353 min; LCMS MH+ 455 Example 76: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)benzylthio) - 1H - purine - 2,6(3H,7H) - dione

[00597] To a solution of 7 - (4 - chlorobenzyl) - 8 - mercapto - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (100 mg, 0.216 mmol) in DMF (5 mL) was added 1 - (bromomethyl) - 3 - (trifluoro methoxy)benzene (66 mg, 0.259 mmol), followed by potassium carbonate (89 mg, 0.645 mmol). The reaction was stirred at 80°C for 2 hours. The mixture was cooled, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)benzylthio) - 1H - purine - 2,6(3H,7H) -dione (120 mg, 87.3%) as a light yellow oil . LCMS retention time 2.106 min; LCMS MH+ - THP 555. Step 2: 7-(4-chlorobenzyl)-1 -(3-hydroxypropyl)-3-methyl-8-(propylsulfonyl)-1H - purine - 2,6(3H,7H) - dione

[00598] The title compound was prepared using Example method 70, step 2. White solid, 14.3% yield: 1H NMR (CD3OD) δ 7.47 - 7.43 (t, 1H), 7.32 - 7.30 (d, 2H), 7.27 - 7.23 (d, 2H), 7.18 - 7.16 (d, 3H) ), 5.64 (s, 2H), 4.91 (s, 2H), 4.10 - 4.07 (t, 2H), 3.62 - 3.59 (s, 5H), 1.88 - 1.81 (m, 2H). LCMS retention time 2.922 min; LCMS MH+ 587. Example 77: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzylsulfinyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)benzylsulfinyl) - 1H - purine - 2,6(3H,7H) - dione

[00599] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (3 - (trifluoromethoxy)benzylthio) - 1H - purine - 2,6(3H,7H) - dione (60 mg, 0.108 mmol, example 129, Step 2) in THF ( 4 mL) and water (2 mL) was added Oxone (73 mg, 0.119 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with aqueous sodium thiosulfate, partitioned between DCM and water, and the phases separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. This crude material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (1:0 to 1:1) to afford 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)benzylsulfinyl) -1H - purine - 2,6(3H,7H) - di one (60 mg, 97.6%) as a yellow oil. LCMS retention time 1.499 min; LCMS MH+ - THP 571. Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzylsulfinyl) -1H - purine - 2,6(3H,7H) - dione

[00600] The title compound was prepared using the method of example 37, step 2. White solid, 30 mg, 557.4% yield: 1H NMR (CD3OD) δ 7.43 - 7.39 (t, 1 H), 7.27 - 7.23 (m, 4 H), 7.17 - 7.12 (m, 3 H), 5.59 (s, 2 H ), 4.89 - 4.74 (m, 2H), 4.12 - 4.08 (t, 2H), 3.62 - 3.59 (m, 5H), 1.88 - 1.84 (m, 2H). LCMS retention time 2552 min; LCMS MH+ 571. Example 78: 7-(4-chlorobenzyl)-1 -(3-hydroxypropyl)-N-isopropyl-3-methyl-2,6 - dioxo - 2,3,6,7 -tetrahydro -1H - purine - 8 - sulfonamide Step 1: 7 - (4 - chlorobenzyl) - N - isopropyl - 3 - methyl - 2,6 - dioxo - 2,3,6,7 - tetrahydro - 1H - purine - 8 - sulfonamide

[00601] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 - tetrahydro - 1H - purine - 8 - sulfonyl chloride (115 mg, 0.295 mmol, Intermediate 64) in DCM (5 mL) was added isopropylamine (17.4 mg, 0.59 mmol) followed by TEA (60 mg, 0.59 mmol) at 0 °C and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM and washed with brine. The organic phase was dried and concentrated to give a crude product, which was purified by chromatography on silica gel eluting with DCM / methanol (50: 1) to give 7 - (4 - chlorobenzyl) - N - isopropyl - 3 - methyl - 2,6 - dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (59 mg, 48.6% yield) as yellow syrup. LCMS retention time 1.436 min; LCMS MH+ 412. Step 2: 7 - (4 - chlorobenzyl) - N - isopropyl - 3 - methyl - 2,6 - dioxo -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 2,3,6,7 -tetrahydro -1H - purine - 8 - sulfonamide

[00602] To a solution of 7 - (4 - chlorobenzyl) - N - isopropyl - 3 - methyl - 2,6 - dioxo - 2,3,6,7 - tetrahydro - 1H - 10purine - 8 - sulfonamide (59 mg, 0.143 mmol) in DMF (3 mL) was added 2 - (3 - bromopropoxy)tetrahydro - 2H - pyran (32 mg, 0.143 mmol) followed by potassium carbonate (30 mg, 0.214 mmol) and the mixture was stirred at 60°C for 4 hours. The reaction was diluted with ethyl acetate and washed with saline and saturated aqueous ammonium chloride. The organic phase was dried and concentrated to give 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 2,3,6,7 -tetrahydro - 1H - purine - 8 -sulfonamide (61 mg, 77% yield) as a yellow solid. LCMS retention time 1.805 min; LCMS MH+ - THP 470. Step 3: 7 - (4 - chlorobenzyl) - N - isopropyl - 3 - methyl - 2,6 - dioxo -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 2,3,6,7 -tetrahydro -1H - purine - 8 - sulfonamide

[00603] A solution of 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6 - dioxo -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 2,3,6,7 -tetrahydro -1H - purine - 8 - sulfonamide (61 mg, 0.11 mmol) in 1 mM ethanolic HCl (1 mL, mmol /L) was stirred at room temperature for 30 minutes. The mixture was concentrated and purified by preparative HPLC to provide 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - N - isopropyl - 3 - methyl - 2,6 - dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (17.9 mg, 34.6% yield) as a white solid. 1H NMR (CD3OD) δ 7.31 - 7.38 (m, 4H), 5.89 (s, 2H), 4.06 - 4.10 (t, 2H), 3.58 - 3.63 (m, 3H), 3.56 (s, 3H), 1.83 - 1.87 (m, 2H), 1.19 - 1.21 (d , 6H). LCMS retention time 2.315 min; LCMS MH+ 470. Example 79: 7-(4-chlorobenzyl)-N-cyclopropyl-N,1 -bis(3-hydroxypropyl)-3-methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro -1H - purine - 8 - sulfonamide

[00604] The title compound was prepared using the method of example 78 except in step 2, 2 equivalents of 2 - (3 - bromopropoxy)tetrahydro - 2H - pyran was added. The final product was purified by preparative HPLC to provide 7-(4-chlorobenzyl) - N - cyclopropyl - N,1 - bis(3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purine - 8 - sulfonamide (21 mg, 38.9% yield) as a white solid. 1H NMR (CD3OD) δ 7.32 - 7.39 (m, 4H), 5.92 (s, 2H), 4.07 - 4.11 (t, 2H), 3.57 - 3.62 (m, 6H), 3.53 (s, 3H), 2.71 - 2.75 (m, 1H), 1.84 - 1.95 (m , 4H), 0.91 - 0.94 (m, 2H), 0.75 - .078 (m, 2H). LCMS retention time 2.238 min; LCMS MH+ 526. Example 80: N - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro-1H-purin-8-yl)propane-2-sulfonamide Step 1: N - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl)propane - 2 - sulfonamide

[00605] To a solution of 8 - amino - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (95 mg, 0.21 mmol, Intermediate 53) in THF (5 mL) was added sodium hydride (10 mg, 0. 23 mmol) at 0 °C. The reaction was stirred at room temperature for 1 hour; Then, isopropylsulfonyl chloride (29 mg, 0.21 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with aqueous ammonium chloride (2 mL) at 0 °C and then partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the product as a yellow syrup (60 mg) which was used without purification. LCMS retention time 1.519 min; LCMS MH+ - THP 470. Step 2: N - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 - tetrahydro -1H - purin - 8 - yl)propane - 2 - sulfonamide

[00606] The title compound was prepared using the method of example 37, step 2 and purified by preparative HPLC. White solid, 19mg, 37.2% yield: 1H NMR (CD3OD) δ 7.44 (d, 2H), 7.31 - 7.33 (m, 2H), 5.37 (s, 2H), 4.19 (t, 2H), 3.56 (s, 2H), 3.52 (s, 3H), 3.39 (brs, 1), 3.10 (brs, 1H), 1.88 - 1.94 (m, 2H), 1.40 (d, 6H). LCMS retention time 1.942 min; LCMS MH+ 470 Example 81: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenylamino) -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 8 - (3 - (trifluoromethoxy)phenylamino) - 1H - purine - 2,6(3H,7H) - dione (WYS - 000356-026)

[00607] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) - dione (100 mg, 0.196 mmol, Intermediate 14) in toluene (30 mL) was added 3 - (trifluoromethod xi)aniline (45 mg, 0.254 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol), X-phos (10 mg, 0.021 mmol) and potassium tert-butanolate (45 mg, 0.402 mmol). The mixture was degassed and recharged with nitrogen 3 times. The reaction was stirred at 100 °C overnight under nitrogen. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (3:1 to 3:2). The product was collected, concentrated and dried in vacuo to give 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8-(3-(trifluoromethoxy)phenylamino)-1H-purine-2,6(3H,7H)-dione (70 mg, 57.6%) as a yellow solid. LCMS MH+ - THP 524. Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenylamino) -1H - purine - 2,6(3H,7H) - dione

[00608] The title compound was prepared as example 36, step 2, but with aqueous ethanolic HCl. White solid, 13mg, 12.4% yield: 1H NMR (DMSO-d6) δ 9.63 (s, 1H), 7.91 (s, 1H), 7.63 - 7.61 (d, 1H), 7.45 - 7.38 (m, 3H), 7.24 - 7.22 (d, 2H), 6.97 - 6.94 (d, 1H), 5.57 (s, 2H), 4.44 - 4.42 (t, 1H), 3.89 - 3.86 (t, 2H), 3.42 - 3.38 (m, 4H), 3.31 (s, 3H), 1.69 - 1.61 (m, 2H). LCMS retention time 2.853 min; LCMS MH+ 524. Example 82: 7-(4-chlorobenzyl)-1 -((1 -(hydroxymethyl)cyclopropyl)methyl)-3-methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione

[00609] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (80 mg, 0.17 mmol, Intermediate 9) in DMF (5 mL) was added (1 - (hydroxymethyl)cyclopropyl)methyl methanesulfonate (0.1 g, 0.5 mmol, Intermediate 42), potassium carbonate (47 mg, 0.34 mmol) and TBAI (2 mg, 0.02 mmol). The reaction was stirred at 50°C for 8 hours. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - ((1 - (hydroxymethyl)cyclopropyl)methyl) - 3 - methyl - 8 - (3(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (36 mg, 39.9% yield) as a white solid. 1H NMR (CD3OD) δ 7.39 (t, 1H), 7.01 (dd, 1H), 6.88 - 6.90 (m, 2H), 4.87 - 4.88 (m, 2H), 4.44 - 4.46 (m, 2H), 4.08 - 4.16 (m, 4H), 3.61 (t, 2H), 3.51 (s, 3H), 1.80 - 1.90 (m, 2H), 1.32 (t, 3H). LCMS retention time 3.099 min; LCMS MH+533.

[00610] The following examples 83a and 83d were prepared using the method of example 82. Example 83a: 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopentyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00611] The title compound was prepared from Intermediates 9 and 43. White solid, 18mg, 17.9% yield: 1H NMR (CD3OD) δ 7.54 (t, 1H), 7.44 (dd, 2H), 7.32 - 7.36 (m, 4H), 7.22 - 7.25 (m, 1H), 5.48 ( s, 2H), 4.14 - 4.18 (m, 2H), 3.51 (s, 3H), 1.88 - 1.92 (m, 2H), 1.62 - 1.82 (m, 8H). LCMS retention time 3.304 min; LCMS MH+ 561 Example 83b: 7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclobutyl)ethyl)-3-methyl-8-(3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00612] The title compound was prepared from Intermediates 9 and 44. White solid, 20 mg, 17.9% yield: 1H NMR (CD3OD) δ 7.55 (t, 1 H), 7.54 (d, 2 H), 7.32 - 7.38 (m, 4 H), 7.23 - 7.26 (m, 1 H), 5.51 (s, 2H); LCMS retention time 3.111 min; LCMS MH+ 547 Example 83c: 7-(4-chlorobenzyl)-1-(3-hydroxy-3-methylbutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

[00613] The title compound was prepared from Intermediates 9 and 45. White solid, 23mg, 39.6% yield: 1H NMR (CD3OD) δ 7.55 (t, 1H), 7.44 (d, 2H), 7.32 - 7.38 (m, 4H), 7.24 (d, 1H), 5.50 (s, 2H), 4 .11 - 4.15 (m, 2H), 3.42 (s, 3H), 1.78 - 1.82 (m, 2H), 1.29 (s, 6H). LCMS retention time 3.235 min; LCMS MH+ 535 Example 83d: 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00614] The title compound was prepared from Intermediates 9 and 46. White solid, 39mg, 33.9% yield: 1H NMR (CD3OD) δ 7.55 (t, 1H), 7.44 (d, 2H), 7.34 - 7.36 (m, 4H), 7.25 (d, 1H), 5.49 (s, 2H), 4 .26 (t, 2H), 3.42 (s, 3H), 1.84 (t, 2H), 0.62 (t, 2H), 0.38 (t, 2H). LCMS retention time 3.301 min; LCMS MH+ 551 Example 84: 7 - (4 - chlorobenzyl) - 8 - (2 - (cyclohexyloxy)ethoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) - 8 - (2 - (cyclohexyloxy)ethoxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00615] To a solution of 2-(cyclohexyloxy)ethanol (63.4 mg, 0.439 mmol, Intermediate 38) in THF (5 mL) was added sodium hydride (23.4 mg, 0.586 mmol, 60% dispersion in mineral oil) at 0 °C, and the mixture was stirred at room temperature for 30 minutes. Then an 8 - bromic solution - 7 - (4 - chlorobenzil) - 3 - methyl -1 - (3 - (tetrahydro - 2h - piran - 2 - ilóxi) propyl) - 1h - purine - 2.6 (3h, 7h) - diona (150 mg, 0.293 mmol, intermediate 14) in THF (1 ml) was added to the resulting mixture to reflux for 1 hours. The reaction was cooled and quenched with ice water. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give 7 - (4 - chlorobenzyl) - 8 - (2 - (cyclohexyloxy)ethoxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (123 mg, 73% yield) as a yellow solid. LCMS retention time 2.064 min; LCMS MH+ - THP 491. Step 2: 7 - (4 - chlorobenzyl) - 8 - (2 - (cyclohexyloxy)ethoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00616] A solution of 7 - (4 - chlorobenzyl) - 8 - (2 - (cyclohexyloxy)ethoxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (123 mg, 0.214 mmol) in 1 mM ethanolic HCl (2 mL) ) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl) - 8 - (2 - (cyclohexyloxy)ethoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (64 mg, 60.9% yield) as a white solid. 1H NMR (CDCl3) δ 7.41 - 7.44 (d, 2H), 7.28 - 7.31 (d, 2H), 5.26 (s, 2H), 4.63 - 4.65 (m, 2H), 4.17 - 4.20 (t, 2H), 3.81 - 3.84 (m, 2H), 3.68 - 3.70 (br, 1H), 3.21 (m, 5H), 3.30 - 3.34 (m, 1H), 1.87 - 1.93 (m, 4H), 1.75 - 1.77 (t, 2H), 1.55 - 1.58 (m, 1H), 1.23 - 1.36 (m, 5H). LCMS retention time 2.893 min; LCMS MH+ 491. Example 85: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - propoxyethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00617] The title compound was prepared using the method of example 84 and purified by preparative HPLC to provide 7-(4-chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - propoxyethoxy) - 1H - purine - 2,6(3H,7H) -dione (39 mg, 38.7% yield) as a white solid. 1H NMR (CD3OD) δ 7.39 - 7.42 (d, 2H), 7.31 - 7.33 (d, 2H), 5.29 (s, 2H), 4.63 - 4.65 (m, 2H), 4.06 - 4.10 (t, 2H), 3.80 - 3.83 (m, 2H), 3.58 - 3.61 (t, 2H), 3.49 (s, 3H), 3.44 - 3.47 (t, 2H), 1.84 - 1.87 (t, 2H), 1.55 - 1.60 (m, 2H), 0.90 - 0.94 (t, 3H). LCMS retention time 2.561 min; LCMS MH+ 451. Example 86: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) - 1H - purine - 2,6(3H,7H) -dione hydrochloride

[00618] The title compound was prepared from Intermediate 63 using the method of Example 55 except with 6 - methylpyridin - 3 -ol to give 35 mg (44.1% yield) as a white solid. 1H NMR (DMSO-d6) δ 8.69 (s, 1H), 8.03 - 8.01 (d, 1H), 7.59 - 7.57 (d, 1H), 7.45 (s, 4H), 5.45 (s, 2H), 4.06 - 3.98 (m, 2H), 3.45 - 3.42 (t, 2H) ), 3.28 (s, 3H), 2.59 (s, 3H), 1.71 - 1.67 (t, 2H). LCMS retention time 2.207 min; LCMS MH+ 456. Example 87: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - methylpyridin - 4 -yloxy) - 1H - purine - 2,6(3H,7H) -dione hydrochloride

[00619] The title compound was prepared using the method of Example 55. White solid, 30mg, 36.6% yield: 1H NMR (DMSO-d6) δ 8.48 - 8.46 (d, 1H), 8.17 (s, 1H), 7.43 - 7.33 (m, 4H), 7.26 - 7.22 (m, 2H), 5 .42 (s, 2H), 4.52 (s, 1H), 3.95 - 3.92 (t, 2H), 3.44 - 3.42 (m, 2H), 3.37 (s, 3H), 2.47 (s, 3H), 1.72 - 1.69 (t, 2H). LCMS retention time 1.716 min; LCMS MH+ 456. Example 88: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (5 - methylpyridin - 3 - yloxy) - 1H - purine - 2,6(3H,7H) - dione

[00620] The title compound was prepared using the method of example 55. White solid, 40mg, 48.8% yield: 1H NMR (DMSO-d6) δ 8.45 - 8.44 (d, 1H), 8.36 (s, 1H), 7.65 (s, 1H), 7.46 - 7.41 (m, 4H), 5.44 (s, 2H), 4.50 - 4.47 (t, 1H), 3.94 - 3.91 (t, 2H), 3.46 - 3.40 (m, 2H), 3.28 (s, 3H), 2.34 (s, 3H), 1.73 - 1.66 (m, 2H). LCMS retention time 2.259 min; LCMS MH+ 456 Example 89: 7 - butyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (5 - methylpyridin - 3 -yloxy) - 1H - purine - 2,6(3H,7H) - dione. Step 1: 3 - methyl - 8 - (5 - methylpyridin - 3 - yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione

[00621] The title compound was prepared using the method of example 52, step 1. Yellow oil, 300 mg, 97.6% yield, LCMS retention time 1.838 min; LCMS MH+ - THP 462 Step 2: 7-(4-chlorobenzyl)-1 -(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy) - 1H - purine - 2,6(3H,7H) - dione

[00622] To a solution of 3 - methyl - 8 - (5 - methylpyridin - 3 - yloxy) -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 7 - ((2 - (trimethylsilyl)ethoxy)methyl) - 1H - purine - 2,6(3H,7H) - dione (300 mg, 0.554 mmol) in alcohol Ethyl alcohol (10 ml) was added concentrated HCl (3 ml). The reaction was stirred for 6 hours at 90 °C. The reaction was cooled and concentrated to give 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) - 1H - purine - 2,6(3H,7H) - dione (180 mg, 98.9%) as a yellow oil. LCMS retention time 0.356 min; LCMS MH+ 332. Step 3: 7-butyl-1-(3-hydroxypropyl)-3-methyl-8-(5-methylpyridin-3-yloxy)-1H-purine - 2,6(3H,7H) -dione

[00623] The title compound was prepared using the method of example 61, step 2. White solid, 30 mg, 42.8% yield: 1H NMR (DMSO-d6) δ 8.48 - 8.47 (d, 1 H), 8.37 - 8.36 (d, 1 H), 7.71 (s, 1 H), 4.51 - 4.48 (t, 1 H) H), 4.22 - 4.19 (t, 2H), 3.94 - 3.91 (t, 2H), 3.46 - 3.43 (t, 2H), 3.28 (s, 3H), 2.36 (s, 3H), 1.81 - 1.66 (m, 4H), 1.35 - 1.30 (m, 2H), 0.93 - 0.89 (t, 3H). LCMS retention time 1.854 min; LCMS MH+388. Example 90: 7 - (4 - chlorobenzyl) - 8 - (2 - isopropoxyethoxy) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7-(4-chlorobenzyl)-8-(2-isopropoxyethoxy)-3-methyl-1-(3-(tetrahydro-2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00624] The title compound was prepared using the method of example 50, step 1. Yellow oil, 100 mg, 95.2%. LCMS retention time 1.864 min; LCMS MH+ - THP 451 Step 2: 7-(4-chlorobenzyl)-8-(2-isopropoxyethoxy)-3-methyl-1 -(3-(tetrahydro-2H - pyran - 2 -yloxy)propyl) -1H - purine - 2,6(3H,7H) -dione

[00625] The title compound was prepared using the method of Example 37, step 2. White solid, 30mg, 35.1% yield: 1H NMR (CD3OD) δ 7.43 - 7.41 (d, 2H), 7.34 - 7.32 (d, 2H), 5.30 (s, 2H), 4.66 - 4.64 (m, 2H), 4.11 - 4.07 (t, 2H), 3.83 - 3.81 (m, 2H), 3.68 - 3.58 (m, 3H), 3.50 (s, 3H), 1.88 - 1.85 (m, 2H), 1.17 - 1.56 (d, 6H). LCMS retention time 2.464 min; LCMS MH+ 451 Example 91: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzoyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzoyl) -1H - purine - 2,6(3H,7H) - dione

[00626] The title compound was prepared using the method of Intermediate 16, step 3. White solid, 15 mg, 21.5% yield. LCMS retention time 2.159 min; LCMS MH+ 599. Step 2: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzoyl) -1H - purine - 2,6(3H,7H) - dione

[00627] To a solution of 7 - (4 - chlorobenzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzoyl) -1H - purine - 2,6(3H,7H) - dione (15 mg, 0.025 mmol) in DCM (1 ml) was added TFA (1 ml) dropwise followed by trifluoromethanesulfonic acid (0.25 ml) ), both at 0 °C. The reaction was stirred at 0 °C for 10 minutes, then stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The organic phase was washed with water dried over sodium sulfate, filtered and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (10 mg, 83.7%) as yellow oil. LCMS retention time 1.821 min; LCMS MH+ 479. Step 3: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (trifluoromethoxy)benzoyl) - 1H - purine - 2,6(3H,7H) - dione

[00628] The title compound was prepared using the method of Intermediate 14. Yellow oil, 10 mg, 76.8% yield, LCMS retention time 2.176 min; LCMS MH+ - THP 537. Step 4: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzoyl) -1H - purine - 2,6(3H,7H) - dione

[00629] The title compound was prepared using Example method 37, step 2. Light yellow solid, 8mg, 92.6% yield: 1H NMR (DMSO-d6) δ 8.20 - 8.16 (m, 2H), 7.74 - 7.72 (m, 2H), 7.40 - 7.37 (d, 2H), 7.30 - 7.2 8 (d, 2H), 5.93 (s, 2H), 4.51 (s, 1H), 3.97 - 3.93 (t, 2H), 3.47 - 3.39 (m, 5H), 1.73 - 1.69 (m, 2H). LCMS retention time 2.996 min; LCMS MH+ 537 Example 92: 7 - (4 - chlorobenzyl) - 8 - (hydroxy) - 3 - (trifluoromethoxy)phenyl)methyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00630] To a solution of 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.081 mmol, example 91) in methanol (3 mL) was added sodium borohydride (10 mg, 0.263 mmol) at 0 ° C under nitrogen. The reaction was stirred at 0°C for 2 hours. The reaction was quenched and partitioned with ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) - 8 - (hydroxy) - 3 - (trifluoromethoxy)phenyl)methyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H)-dione (10 mg, 22.9%) as a solid white. 1H MMR (CDCl3) δ 7.36 - 7.31 (t, 1H), 7.23 - 7.14 (m, 5H), 6.94 - 6.92 (d, 2H), 5.87 - 5.85 (d, 1H), 5.60 - 5.56 (d, 1H), 5.39 - 5.35 (d, 1H), 4.20 - 4.17 (t, 2H), 3.65 - 3.63 (s, 4H), 3.54 - 3.51 (m, 2H), 3.31 (s, 1H), 1.91 - 1.88 (t, 2H). LCMS retention time 2.605 min; LCMS MH+ 539. Example 93: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 - chlorobenzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00631] To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (130 mg, 0.261 mmol, Intermediate 60) in DMF (3 mL) was added 1 - (bromomethyl)-4-chlorobenzene (70 mg, 0 .345 mmol), followed by potassium carbonate (107 mg, 0.775 mmol) and TBAI (5 mg, 0.014 mmol). The mixture was stirred at 60°C overnight. The reaction was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to provide the crude product 7 - (4 - chlorobenzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine-2,6(3H,7H)-dione (150 mg, 92.5% yield) as a yellow oil. LCMS retention time 2.075 min; LCMS MH+ 629. Step 2: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00632] To a solution of 7 - (4 - chlorobenzyl) -1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (105 mg, 0.167 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise followed by trifluoromethane acid sulfonic acid (0.25 mL) at 0 °C. The reaction was stirred at 0 °C for 10 minutes, then at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with DCM. The organic phase was washed with water, dried over sodium sulfate and concentrated to give 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) -1H - purine - 2,6(3H,7H) - dione (66 mg, 77.6% yield) as a yellow oil. LCMS retention time 2.868 min; LCMS MH+ 509. Step 3: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00633] The title compound was prepared using the method of Intermediate 14 and purified by silica gel chromatography eluting with petroleum / ethyl acetate (10:1 to 2:1) to afford 7-(4-chlorobenzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 8 - (3 - (3 - (trifluoromethoxy)phenoxy) propyl)-1H-purine-2,6(3H,7H)-dione (39 mg, 38.5% yield) as yellow oil. LCMS retention time 2.048 min; LCMS MH+ - THP 567. Step 4: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine - 2,6(3H,7H) - dione

[00634] The title compound was prepared as example 37, step 2 and purified by HPLC to give 7 - (4 - chlorobenzyl) - 1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (3 - (trifluoromethoxy)phenoxy)propyl) - 1H - purine-2,6(3H,7H)-dione (17 mg, 38.3% yield) as white solid. 1H NMR (DMSO-d6) δ 7.41 - 7.36 (m, 3H), 7.23 - 7.21 (d, 2H), 6.93 - 6.90 (dd, 2H), 6.84 (s, 1H), 5.56 (s, 2H), 4.48 - 4.46 (t, 1H), 4.05 - 4.02 (t, 2H), 3.93 - 3.89 (t, 2H), 3.45 - 3.33 (m, 5H), 2.89 - 2.85 (t, 2H), 2.09 - 2.06 (t, 2H), 1.70 - 1.66 (t, 2H). LCMS retention time 2.925 min; LCMS MH+ 567. Example 94: 7 - (4 - chlorobenzyl) - 8 - ethyl -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00635] The title compound was prepared using the method of Intermediate 48 and example 91 and using propionic acid. White solid, 15mg, 22.8% yield: 1H NMR (CD3OD) δ 7.35 - 7.33 (d, 2H), 7.20 - 7.18 (d, 2H), 5.58 (s, 2H), 4.09 - 4.06 (t, 2H), 3.59 - 3.55 (m, 5H), 2.78 - 2.73(q, 2H), 1.88 - 1.81 (m, 2H), 1.23 - 1.19 (t, 3H). LCMS retention time 2.207 min; LCMS MH+ 377. Example 95: 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-propyl-1H-purine - 2,6(3H,7H) -dione

[00636] The title compound was prepared using the methods of Intermediate 48 and example 91 and using butyric acid. White solid, 10mg, 30.4% yield: 1H NMR (CD3OD) δ 7.33 - 7.31 (d, 2H), 7.20 - 7.17 (d, 2H), 5.58 (s, 2H), 4.07 - 4.04 (t, 2H), 3.59 - 3.56 (t, 2H), 3.53 (s , 3H), 2.72 - 2.69(1, 2H), 1.87 - 1.80 (m, 2H), 1.70 - 1.61 (m, 2H), 0.93 - 0.90 (t, 3H). LCMS retention time 2.379 min; LCMS MH+ 391. Example 96: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - (5 - methylthiazol - 2 -yl)ethyl) - 3,4,5,7 -tetrahydro - 1H - purine - 2,6 - dione

[00637] The title compound was prepared using the methods of Intermediate 48 and Example 91 and using Intermediate 49. White solid, 15 mg, 45.4% yield: 1H NMR (CD3OD) δ = 7.32 (d, 2 H), 7.28 (d, 1 H), 7.18 (d, 1 H), 5.58 (s, 2 H), 4.10 (t , 2H), 3.60 (t, 2H), 3.57 (s, 3H), 3.41 (t, 2H), 3.20 (t, 2H), 2.40 (d, 3H), 1.85 - 1.89 (m, 2H). LCMS retention time 2.334 min; LCMS MH+ 474. Example 97: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (6 - methylpyridin - 3 -yloxy) -1H - purine - 2,6(3H,7H) - dione Step 1: 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00638] The title compound was prepared using method example 7k from intermediates 8 and 33. White solid, 275mg, 57.5% yield. LCMS retention time 1.465 min; LCMS MH+ 441 Step 2: 7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-8-(6-methylpyridin-3-yloxy) - 1H - purine - 2,6(3H,7H) - dione

[00639] The title compound was prepared using the method of example 86. White solid, 35mg, 43.9% yield: 1H NMR (DMSO-d6) δ 8.46 - 8.45 (d, 1H), 7.78 - 7.75 (dd, 1H), 7.47 - 7.45 (d, 2H), 7.42 - 107.37 (m , 3H); LCMS retention time 2.390 min; LCMS MH+ 470 Example 98: 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione

[00640] To a solution of 3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.067 mmol, Intermediate 51) in DMF (3 mL) was added 3-hydroxybutyl-4-methylbenzenes sulfonate (24.68 mg, 0.10 mmol), followed by potassium carbonate (27.93 mg, 0.20 mmol). The reaction was stirred at 70°C for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give 1 -(3-hydroxybutyl) - 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromemoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (9 mg, 25, 8%) as a white solid. 1H NMR (CD3OD) δ 8.216 (s, 1H), 7.491 - 7.467 (d, 1H), 7.312 - 7.272 (m, 1H), 7.154 - 6.995 (m, 4H), 5.688 (s, 2H), 4.305 (s, 2H), 4.143 - 4.0 11 (m, 2H), 3.772 - 3.440 (m, 1H), 3.585 (s, 3H), 2.283 (s, 3H), 1.761 - 1.703 (m, 2H), 1.194 - 1.179 (d, 3H). LCMS retention time 2.569 min; LCMS MH+ 518. Example 99: 1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) -dione

[00641] The title compound was prepared using the method of example 98 and using 1 - (2 - bromoethyl)cyclopropanol, Intermediate 46). White solid, 8.7mg, 24.4%: 1H NMR (CD3OD) δ 8.220 (s, 1H), 7.487 - 7.463 (d, 1H), 7.319 - 7.279 (m, 1H), 7.169 - 6.984 (m, 4H), 5.690 (s, 2H), 4.315 ( s, 2H), 4.256-4.221 (m, 2H), 3.589 (s, 3H), 2.282 (s, 3H), 1.834-1.799 (m, 2H), 0.585-0.569 (m, 2H), 0.386-0.356 (m, 2H). LCMS retention time 2.717 min; LCMS MH+ 530. Example 100: 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00642] To a solution of 1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.121 mmol, Intermediate 57) in DMF (3 mL) was added 2-(chloromethyl)-5-methylpyridine hydrochloride (30 mg, 0 .182 mmol, Intermediate 50), followed by potassium carbonate (50 mg, 0.363 mmol) and TBAI (10mg, 0.027mmol). The reaction was stirred at 65 °C overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (20 mg, 31.9% production) as a white solid. 1H NMR (CD3OD) δ 8.319 (s, 1H), 7.663 - 7.640 (d, 1H),7.553 - 7.510 (t, 1H), 7.348 - 7.316 (m, 3H), 7.233 - 7.208 (m, 1H), 5.609 (s, 2H), 4.1 12 - 4.004 (m, 2H), 3.763 - 3.731 (m, 1H), 3.457 (s, 3H), 2.339 (s, 3H), 1.758 - 51.698 (m, 2H), 1.197 - 1.182 (d, 2H). LCMS retention time 2.714 min; LCMS MH+ 520. Example 101: 1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00643] To a solution of 1 -(2-(1 -hydroxycyclopropyl)ethyl)-3-methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.117 mmol, Intermediate 58) in DMF (3 mL) was added 2 - (chloromethyl) - 5 - methylpyridine hydrochloride (24.9 mg, 0.176 mmol, Intermediate 50), followed by potassium carbonate (48.6 mg, 0.351 mmol) and TBAI (10 mg, 0.027 mmol). The reaction was stirred at 65 °C overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give 1 -(2-(1-hydroxycyclopropyl)ethyl)-3-methyl - 7 - ((5 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine-2,6(3H,7H)-dione (21 mg , 33.7% yield) as a white solid. 1H NMR (CD3OD) δ 8.320 - 8.315 (d, 1H), 7.662 - 7.636 (d, 1H), 7.561 - 7.517 (t, 1H), 7.363 - 7.315 (m, 3H), 7.240 - 7.215 (m, 1H), 5.608 (s, 2H), 4.247-4.212 (t, 2H), 3.462 (s, 3H), 2.338 (s, 3H), 1.829-1.793 (t, 2H), 0.582-0.554 (m, 2H), 0.370-0.340 (m, 2H). LCMS retention time 2.869 min; LCMS MH+ 532. Example 102: 1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00644] The title compound was prepared using the method of example 101. White solid, 20mg, 32.9% yield: 1H NMR (CD3OD) δ 8.488 - 8.475 (d, 1H), 7.831 - 7.627 (t, 1H), 7.562 - 7.521 (t, 1H), 7.446 - 7 .427 (d, 1H), 7.375 - 7.341 (m, 3H), 7.240 - 7.220 (d, 1H), 5.656 (s, 2H), 4.242 - 4.207 (t, 2H), 3.465 (s, 3H), 1.823 - 1.788 (t, 2H), 0.562 - 0.546 (m, 2H), 0.364 - 0.335 (m, 2H). LCMS retention time 2.759 min; LCMS MH+ 518. Example 103: 7 - ((5 - chloropyridin - 2 -yl)methyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00645] The title compound was prepared using the method of example 101. White solid, 30mg, 49.4% yield: 1H NMR (CD3OD) δ 8.469 - 8.464 (d, 1H), 7.868 - 7.841 (d, 1H), 7.557 - 7.535 (t, 1H), 7.484 - 7 .463 (d, 1H), 7.385 - 7.370 (m, 2H), 7.252 - 7.231 (d, 1H), 5.638 (s, 2H), 4.237 - 4.201 (t, 2H), 3.460 (s, 3H), 1.820 - 1.784 (t, 2H), 0.563 - 0.548 (m, 2H), 0.366 - 0.337 (m, 2H). LCMS retention time 153.058 min; LCMS MH+ 552. Example 104: 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - ((6 - methylpyridin - 3 -yl)oxy) - 1H - purine - 2,6(3H,7H) - dione

[00646] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (128 mg, 0.282 mmol, Intermediate 56) in DMF (5 mL) was added 6-methylpyridin-3-ol (37 mg, 0. 338 mmol), followed by potassium carbonate (58 mg, 0.423 mmol). The reaction was stirred at 80°C for 2 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - ((6 - methylpyridin - 3 -yl)oxy) - 1H - purine - 2,6(3H, 7H) - dione (110 mg, 80.9% yield) as a white solid. 1H NMR (CD3OD) δ 8.457 - 8.451 (d, 1H), 7.776 - 7.748 (d, 1H), 7.470 - 7.374 (m, 5H), 5.519 (s, 2H), 4.291 - 4.256 (t, 2H), 3.411 (s, 3H), 2, 584 (s, 3H), 1.867 - 1.832 (t, 2H), 0.618 - 0.610 (m, 2H), 0.403 - 0.387 (m, 2H). LCMS retention time 2.619 min; LCMS MH+ 482*. Example 105: 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (4,4,4 -trifluorobutyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00647] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (80 mg, 0.171 mmol, Intermediate 9) in DMF (2 mL) was added 4,4,4-trifluorobutyl methanesulfonate (50 mg, 0.23 9 mmol, Intermediate 52), followed by potassium carbonate (71 mg, 0.518 mmol). The reaction was stirred at 50 °C overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione as a white solid. 1H NMR (CD3OD) δ 7.571 - 7.529 (t, 1H), 7.458 - 7.431 (m, 2H), 7.377 - 7.255 (m, 4H), 7.237 - 7.231 (m, 1H), 5.496 (s, 2H), 4.098 - 4.063 (t, 2H), 3.423 (s, 3H), 2.288 - 2.219 (m, 2H), 1.958 - 1.901 (m, 2H). LCMS retention time 3.653 min; LCMS MH+ 577. Example 106: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) - dione

[00648] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (100 mg, 0.23 mmol, example 97, step 1) in DMF (5 mL) was added propane-1-thiol (20.7 mg, 0.27 mmol) followed by carbonate of potassium (93.9 mg, 0.68 mmol). The reaction was stirred at 60°C for 3 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product (80 mg, 80.9% yield) as a yellow oil. LCMS MH+ 437. Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (propylsulfonyl) -1H - purine - 2,6(3H,7H) - dione

[00649] To a solution of 7 - (4 - chlorobenzyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (propylthio) - 1H - purine - 2,6(3H,7H) - dione (80 mg, 0.18 mmol) in CHCl3 (10 mL) was added MCPBA (126 mg, 0.73 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with aqueous Na2S2O3 and NaHCO3 and extracted with DCM. The phases were separated. The organic phase was washed with aqueous NaHCO3 and brine. It was then dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1 -(3-hydroxybutyl) - 3 - methyl - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) -dione (30 mg, 34.9%) as a white solid. 1H NMR (DMSO-d6) δ 7.429 - 7.408 (d, 2H), 7.278 - 7.257 (d, 2H), 5.870 (s, 2H), 4.511 - 4.500 (d, 1H), 4.044 - 3.973 (m, 1H), 3.874 - 3.805 ( m, 1H); LCMS retention time 2.599 min; LCMS MH+ 469. Example 107: 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (propylsulfonyl) -1H - purine - 2,6(3H,7H) -dione Step 1: 7-(4-chlorobenzyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione

[00650] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (100 mg, 0.27 mmol, Intermediate 8) in DMF (5 mL) was added propane-1-thiol (24.7 mg, 0.32 mmol) followed by potassium carbonate (112.2 mg, 0.8 1mmol). The reaction was stirred at 60°C for 4h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give an off-white solid product (124 mg, 99.9% yield). LCMS MH+ 365. Step 2: 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (propylthio) -1H - purine - 2,6(3H,7H) - dione

[00651] To a solution of 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (propylthio) - 1H - purine - 2,6(3H,7H) - dione (124 mg, 0.34 mmol) in DMF (7 mL) was added 1 - (2 - bromoethyl)cyclopropanol (67.3 mg, 0.41 mmol, Intermediate 46), followed by potassium carbonate (141 mg, 1.02 mmol). The reaction was stirred at 70°C for 5 hours. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude yellow oil product (100 mg, 66.9% yield). LCMS MH+ 449. Step 3: 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) - dione

[00652] To a solution of 7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.22 mmol) in CHCl3 (7 mL) was added MCPBA (153 mg, 0.89 mmol) in portions. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with aqueous Na2S2O3 and extracted with DCM. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7 - (4 - chlorobenzyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) -dione (20 mg, 18.7%) as a white solid. 1H NMR (CD3OD) δ 7.392 - 7.336 (m, 4H), 5.982 (s, 2H), 4.285 - 4.248 (t, 2H), 3.567 (s, 3H), 3.445 - 3.406 (m, 2H), 1.855 - 1.756 (m, 4H), 1, 042 - 1.005 (m, 3H), 0.633 - 0.604 (m, 2H), 0.433 - 0.403 (m, 2H). LCMS retention time 2.734 min; LCMS MH+ 481. Example 108: 8 - (3 - chloro - 5 - (trifluoromethoxy)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00653] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.116 mmol, Intermediate 63) in DMF (2 mL) was added 3 - chloro - 5 - (trifluoromethoxy)phenol (29.82 mg, 0. 140 mmol) followed by potassium carbonate (24.24 mg, 50.175 mmol). The reaction was stirred at 85°C for 2 hours. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give 8 - (3 - chloro - 5 - (trifluoromethoxy)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine-2,6(3H,7H)-dione (35 mg, 53.5% yield) as a solid white. 1H NMR (CD3OD) δ 7.458 - 7.435 (m, 3H), 7.381 - 7.365 (m, 3H), 7.361 (s, 1H), 5.507 (s, 2H), 4.138 - 4.102 (t, 2H), 3.640 - 3.608 (t, 2H), 3, 448 (s, 3H), 1.905 - 1.871 (m, 2H). LCMS retention time 3.325 min; LCMS MH+559. Example 109: 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)phenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00654] The title compound was prepared using the method of example 108. White solid, 30mg, 47.27% yield: 1H NMR (CD3OD) δ 7.588 - 7.566 (m, 1H), 7.491 - 7.425 (m, 3H), 7.392 - 7.37l (d, 2H), 7.347 - 7.310 (m, 1H), 5.520 (s, 2H), 4.127 - 4.091 (t, 2H), 3.633 - 3.602 (t, 2H), 3.390 (s, 3H), 1.914 - 1.847 (m, 2H). LCMS retention time 3.099 min; LCMS MH+ 543. Example 110: 1 - (2 - hydroxyethyl) - 3 - methyl - 7 - ((6 - methylpyridin - 3 -yl)methyl) - 8 - (2 - (3 - (trifluoromethoxy)phenoxy)ethoxy) - 1H - purine - 2,6(3H,7H) - dione

[00655] The title compound was prepared using the method of example 42 and purified by preparative HPLC to provide 1-(2-hydroxyethyl)-3,7-dimethyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (13.1 mg, 29.9% yield) as white solid. 1H NMR (DMSO - d6) δ 8.45 (s, 52H), 7.57 - 7.59 (d, 1H), 7.41 - 7.45 (t, 1H), 7.09 - 7.1 L (d, 1H), 6.97 - 7.04 (m, 3H), 5.20 (s, 2H), 4.79 - 4.8 1 (m, 4H), 4.73 - 4.75 (t, 1H), 4.41 - 4.43 (t, 2H), 3.92 - 3.96 (t, 2H), 3.49 - 3.51 (m, 2H), 3.47 (s, 3H), 2.39 (s, 3H). LCMS retention time 2.003 min; LCMS MH+ 536. Example 111: 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenyl)-1H - purine - 2,6(3H,7H) -dione

[00656] To a solution of 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.195 mmol, Intermediate 14) in toluene and ethanol (6 mL/ 2 mL) was added 3 - (tri fluoromethoxy)phenylboronic acid (60.2 mg, 0.293 mmol) followed by 1 mM aqueous sodium carbonate (1 mL). The mixture was degassed and recharged with a nitrogen atmosphere 3 times. Tetracys(triphenylphosphine)palladium (12 mg, 0.01 mmol) was added and the reaction was stirred at 100°C for 16 hours. The reaction was cooled and partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give a crude product (110 mg). The crude product was dissolved in 1 mM ethanolic HCl (2 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated and purified by preparative HPLC to provide 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenyl) - 1H - purine - 2,6(3H,7H) - dione (49 mg, 49.4% yield) as a white solid. 1H NMR (CD3OD) δ 7.62 - 7.64 (t, 1H), 7.55 (s, 1H), 7.51 - 7.53 (m, 1H), 7.29 - 7.31 (d, 2H), 7.22 - 7.24 (d, 2H), 5.71 (s, 2H), 4.11 - 4.14 (t , 2H), 3.63 (s, 3H), 3.61 - 3.63 (t, 2H), 1.87 - 1.90 (m, 2H). LCMS retention time 2.746 min; LCMS MH+ 509. Example 112: 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione Step 1: 7 - (4 -chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 - yloxy)propyl) - 1H - purine - 2,6(3H,7H) - dione (JF-000357-069)

[00657] The title compound was prepared from Intermediate 39 using the method of Intermediate 14 to afford 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) - 3 - methyl -1 - (3 - (tetrahydro - 2H - pyran - 2 -yloxy)propyl) - 1H - purine - 2,6(3H,7H) -dione (43.1 mg, 85.1% yield) as a yellow solid. LCMS retention time 2.046, LCMS MH+ - THP 541. Step 2: 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00658] The title compound was prepared using the hydrolysis method of Example 111 to provide 7 - (4 - chlorobenzyl) - 8 - (2 -fluoro - 5 - (trifluoromethoxy)benzyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (17 mg, 38.8% yield) as a white solid. 1H NMR (CD3OD) δ 7.22 - 7.25 (m, 2H), 7.08 - 7.17 (m, 4H), 7.01 - 7.02 (d, 1H), 5.67 (s, 2H), 4.22 (s, 2H), 4.08 - 4.1L (t, 2H), 3.59 - 3.62 (t , 2H), 3.54 (s, 3H), 1.85 - 1.89 (s, 2H). LCMS retention time 2.862 min; LCMS MH+

[00659] The following examples 113a to 113c were prepared using the methods of Intermediate 39 and example 112. Example 113a: 8 - (4 - chloro - 3 - (trifluoromethoxy)benzyl) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00660] White solid, 10.7 mg, 35.2% yield: 1H NMR (CD3OD) δ 7.35 - 7.37 (d, 1 H), 7.19 - 7.23 (m, 3 H), 7.02 - 7.04 (m, 3 H), 5.65 (s, 2 H), 4.24 (s, 2 H), 4.0 9 - 4.12 (t, 2H), 3.58 - 3.62 (t, 2H), 3.59 (s, 3H), 1.86 - 1.89 (m, 2H). LCMS retention time 3.033 min; LCMS MH+ 557. Example 113b: 8 - (3 - chloro - 5 - (trifluoromethoxy)benzyl) - 7 - (4 - chlorobenzyl) - 1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00661] White solid, 24.7 mg, 35.5% yield: 1H NMR (CD3OD) δ 1.19 - 7.21 (m, 2 H), 7.12 (s, 1 H), 6.97 - 7.04 (m, 4 H), 5.67 (s, 2 H), 4.24 (s, 2 H), 4.09 - 4.1 3 (t, 2H), 3.60 - 3.63 (t, 2H), 3.59 (s, 3H), 1.86 - 1.90 (m, 2H). LCMS retention time 3.044 min; LCMS MH+ 557. Example 113c: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - (2 - methoxy - 5 - (trifluoromethoxy)benzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00662] White solid, 36.5 mg, 60.1% yield: 1H NMR (CD3OD) δ 7.22 - 7.24 (m, 2 H), 7.10 - 7.13 (d, 1 H), 7.04 - 7.06 (d, 2 H), 6.90 - 6.98 (m, 2 H), 5.64 (s, 2 H), 4.15 (s, 2H), 4.07 - 4.11 (t, 2H), 3.78 (s, 3H), 3.58 - 3.61 (t, 2H), 3.55 (s, 3H), 1.85 - 1.88 (m, 2H). LCMS retention time 2.914 min; LCMS MH+553. Example 114: 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) - dione Step 1: 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) - dione

[00663] The title compound was prepared using the method of Intermediate 39 and purified by trituration with ethanol to afford 1 - (4 - methoxybenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione (136 mg, 81.6% yield) as white solid. LCMS retention time 1.638 min; LCMS MH+461. Step 2: 1 - (4 - methoxybenzyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) -1 H - purine - 2,6(3H,7H) - dione

[00664] To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (136 mg, 0.295 mmol) in DMF (2 mL) was added 2-(bromomethyl)pyridine hydrobromide (112 mg, 442 mmol) followed by potassium carbonate (102 mg, 0.738 mmol). The reaction was stirred at 65°C for 2 hours. The mixture partitioned between ethyl acetate and saline. The organic layer was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM / methanol (45:1) to give 1 -(4-methoxybenzyl)-3-methyl-7-(pyridin-2-ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione (96 mg, 59% yield) as a white solid. LCMS retention time 1.791 min; LCMS MH+ 552. Step 3: 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) - dione

[00665] The title compound was prepared using the method of Intermediate 39, step 3 to furnish 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione (61 mg, 81.2% yield) as a pale yellow solid. LCMS retention time 1.276 min; LCMS MH+ 432. Step 4: 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) -1H - purine - 2,6(3H,7H) - dione

[00666] To a solution of 3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.07 mmol) in DMF (1 mL) was added 3-hydroxybutyl 4-methylbenzenesulfonate (25.6 mg, 0.105 mmol, Inter average 33) followed by potassium carbonate (14.5 mg, 0.105 mmol) and a catalytic amount of TBAI. The reaction was stirred at 60°C for 2 hours. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give the crude product, which was purified by preparative HPLC to give 1 -(3-hydroxybutyl) - 3 - methyl - 7 - (pyridin - 2 -ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine-2,6(3H,7H)-dione (11.2 mg, 32% yield) as a white solid. 1H NMR (CD3OD) δ 8.38 - 8.39 (d, 1H), 7.65 - 7.69 (t, 1H), 7.23 - 7.31 (m, 2H), 7.07 - 7.17 (m, 2H), 5.72 (s, 2H), 4:32 (s, 2H), 4.01 - 4.11 (m , 2H), 3.75 - 3.77 (m, 1H), 3.58 (s, 3H), 1.71 - 1.75 (m, 2H), 1.17 - 1.19 (d, 3H). LCMS retention time 2.480 min; LCMS MH+ 504. Example 115: 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione

[00667] The title compound was prepared using method, example 114, step 4 and purified by preparative HPLC to give 1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (14.1 mg, 33 .8%) as a white solid. 1H NMR (CD3OD) δ 8.39 - 8.40 (d, 1H), 7.65 - 7.69 (t, 1H), 7.28 - 7.32 (t, 1H), 7.23 - 7.25 (m, 1H), 7.16 - 7.19 (d, 1H), 7.08 - 7.12 (m, 3H), 5.72 (s, 2H), 4.33 (s, 2H), 4.21 - 4.24 (t, 2H), 3.59 (s, 3H), 1.79 - 1.82 (t, 2H), 0.55 - 0.58 (t, 2H), 0.34 - 0.37 (t, 2H). LCMS retention time 2.609 min; LCMS MH+ 516. Example 116: 7 - (4 - chlorobenzyl) -1 - ((2 - hydroxycyclopentyl)methyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00668] The title compound was prepared from intermediates 9 and 72 using the method of example 82 and purified by preparative HPLC to afford 7-(4-chlorobenzyl)-1-((2-hydroxycyclopentyl)methyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (20 mg, 33.1% yield) as solid white. 1H NMR (DMSO-d6) δ 7.62 - 7.58 (t, 1H), 7.48 (s, 1H), 7.44 - 7.42 (m, 5H), 7.33 - 7.31 (dd, 1H), 5.44 (s, 2H), 4.43 - 4.42 (d, 1H), 3.92 - 3.87 (m, 1H), 3.81 - 3.71 (m, 2H), 3.29 (s, 3H), 2.21 - 2.16 (m, 1H), 1.85 - 1.19 (m, 6H). LCMS retention time 3.307 min; LCMS MH+ 565. Example 117: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxycyclobutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione Step 1: 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00669] The title compound was prepared using the method of example 52, step 1 and purified by chromatography on silica gel eluting with DCM/ methanol (60:1) to give 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (110 mg, 50.1% yield) as a white solid. LCMS retention time 2.378 min; LCMS MH+ 627. Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxycyclobutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00670] To a solution of 1 - (3 - (benzyloxy)cyclobutyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (110 mg, 0.175 mmol) in methanol was added 5% Pd/C (15 mg). The mixture was hydrogenated at 3.16 kg/cm 2 (45 psi) for 30 minutes. The reaction was filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (11 mg, 17.7% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.53 - 7.57 (t, 1H), 7.43 - 7.45 (d, 2H), 7.36 - 7.38 (d, 2H), 7.31 - 7.33 (m, 1H), 7.23 - 7.25 (d, 1H), 5.79 - 5.84 (m, 0, 65 H), 5.50 (s, 2 H), 4.83 - 4.85 (m, 0.35 H), 4.64 - 4.66 (m, 0.65 H), 4.00 - 4.02 (m, 0.35 H), 3.40 (s, 3 H), 3.16 - 3.19 (m, 1.3 H), 2.88 - 2.91 ( m, 0.7H), 2.66 - 2.70 (m, 0.7H), 2.25 - 2.30 (m, 1.3H). LCMS retention time 3.131 min; LCMS MH+ 537. Example 118: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxycyclobutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00671] The title compound was prepared from the product of example 117 using the method of example 117, step 2, but with a longer hydrogenation time. The product was purified by preparative HPLC to give 7 - benzyl -1 - (3 - hydroxycyclobutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (46 mg, 52.3% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.54 - 7.58 (t, 1H), 7.42 - 7.44 (d, 2H), 7.23 - 7.37 (m, 5H), 7.22 - 7.24 (d, 1H), 5.80 - 5.84 (m, 0.6H), 5.50 (s, 2H), 4, 77 - 4.82 (m, 0.4H), 4.62 - 4.66 (m, 0.6H), 4.00 - 4.04 (m, 0.4H), 3.39 (s, 3H), 3.16 - 3.23 (m, 1.2H), 2.83 - 2.91 (m, 0.8H), 2.68 - 2.73 (m , 0.8H), 2.25 - 2.31 (m, 1.2H). LCMS retention time 2.961 min; LCMS MH+ 503. Example 119: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxycyclobutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione

[00672] The title compound was prepared using the method of example 82 with intermediates 9 and 74 and purified by preparative HPLC to afford 7 - (4 - chlorobenzyl) -1 - (3 - hydroxycyclopentyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (29 mg, 24.6% yield ) as a white solid. 1H NMR (DMSO-d6) δ 7.53 - 7.57 (t, 1H), 7.43 - 7.45 (d, 2H), 7.32 - 7.38 (m, 6H), 7.24 - 7.26 (dd, 1H), 5.52 - 5.56 (m, 1H), 5.50 (s, 2H), 4.21 - 4.24 (m, 0.4H), 3.42 (s, 3H), 2.33 - 2.38 (m, 1H), 2.22 - 2.27 (m, 1H), 2.13 - 2.16 (m, 1H), 1.89 - 1.99 (m, 2H), 1.77 - 1.80 (m, 1H). LCMS retention time 3.168, LCMS MH+ 551. Example 120 7-(4-chlorobenzyl)-1 -(3-(hydroxymethyl)cyclobutyl)-3-methyl-8-(3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione Step 1: Benzyl 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1 H - purin -1 - yl)cyclobutanecarboxylate

[00673] The title compound was prepared using the method of example 82 with intermediates 9 and 75 to afford 3-(7-(4-chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 - tetrahydro - 1H - purin -1 -yl)cyclobutanecarboxylate (59 mg, 26.1% of production) as a yellow solid. LCMS retention time 1.981 min; LCMS MH+ 655. Step 2: 7 - (4 - chlorobenzyl) -1 - (3 - (hydroxymethyl)cyclobutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00674] To a solution of 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 - yl)cyclobutanecarboxylate (59 mg, 0.09 mmol) in THF (3 mL) was added LAH (6.8 mg, 0.18 mmol ) in one portion and the mixture was stirred at room temperature for 2 hours. The reaction was carefully quenched with ethyl acetate and filtered. The filtrate was concentrated to dryness to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-(hydroxymethyl)cyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (17 mg, 34.3% yield) as a white solid. 1H NMR (CDCl3) δ 7.40 - 7.48 (m, 3H), 7.33 - 7.35 (m, 2H), 7.21 - 7.26 (m, 2H), 7.15 - 7.17 (d, 1H), 5.52 - 5.63 (m, 1H), 5.44 (s, 2H), 3.73 - 3.80 (m, 2H), 3.11 - 3.17 (q, 1H), 2.96 - 2.98 (m, 1H), 2.60 - 2.64 (m, 1H), 2.34 - 2.38 (m, 1H), 2.08 - 2.14 (m, 1H). LCMS retention time 3.054; LCMS MH+551. Example 121: 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione

[00675] The title compound was prepared from Intermediate 57 using the method of Example 100 and 5 purified by preparative HPLC to afford 1 - (3 - hydroxybutyl) - 3 - methyl - 7 - (pyridin - 2 - ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (40 mg, 21.9 % production) as a white solid. 1H NMR (CD3OD) δ 8.49 - 8.48 (d, 1H), 7.88 - 7.81 (t, 1H), 7.53 - 7.51 (t, 1H), 7.45 - 7.43 (d, 1H), 7.36 - 7.33 (m, 3H), 7.23 - 7.19 (d, 1H), 5.66 (s, 2H), 4.14 - 3.98 (m, 2H), 3.78 - 3.71 (m, 1H), 3.46 (s, 3H), 1.75 - 1.71 (m, 2H), 1.19 - 1.18 (d, 3H). LCMS retention time 2.575 min; LCMS MH+ 506.0. Example 122: 7-((5-chloropyridin-2-yl)methyl)-1 -(3-hydroxybutyl)-3-methyl-8-(3 - (trifluoromethoxy)phenoxy)-1H - purine - 2,6(3H,7H) -dione

[00676] The title compound was prepared from Intermediate 57 using the method of example 100 and 15 purified by preparative HPLC to afford 7 - ((5 - chloropyridin - 2 -yl)methyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) - dione (40 mg, 21.9% yield) as a white solid. 1H NMR (CD3OD) δ 8.47 - 8.46 (d, 1H), 7.87 - 7.84 (d, 1H), 7.57 - 7.46 (t, 1H), 7.37 - 7.36 (d, 1H), 7.25 - 7.22 (m, 2H), 7.14 - 7.12 (d, 1H), 5.64 (s, 2H), 4.13 - 3.97 (m, 2H), 3.78 - 3.72 (m, 1H), 3.45 (s, 3H), 1.75 - 1.69 (m, 2H), 1.19 - 1.18 (d, 3H). LCMS retention time 2.944 min; LCMS MH+ 540. Example 123: 7-((5-fluoropyridin-2-yl)methyl)-1 -(3-hydroxybutyl)-3-methyl-8-(3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00677] The title compound was prepared from Intermediate 57 using the method of example 100 and purified by preparative HPLC to afford 7 - ((5 -fluoropyridin - 2 -yl)methyl) -1 - (3 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (40 mg, 21 .1% yield) as a white solid. 1H NMR (CD3OD) δ 8.38 - 8.37 (d, 1H), 7.66 - 7.51 (m, 3H), 7.37 - 7.35 (m, 2H), 7.24 - 7.22 (d, 1H), 5.64 (s, 2H), 4.12 - 3.97 (m, 2H), 3.77 - 3.72 (m, 1H), 3.45 (s, 3H), 1.75 - 1.68 (m, 2H), 1.19 - 1.18 (d, 3H). LCMS retention time 2.733 min; LCMS MH+ 524. Example 124: 7 - ((5 -fluoropyridin - 2 -yl)methyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00678] The title compound was prepared from Intermediate 58 using the method of example 100 and purified by preparative HPLC to afford 7 - ((5 - fluoropyridin - 2 - yl)methyl) -1 - (2 - (1 - hydroxycyclopropyl)ethyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (2 5 mg, 33.7% yield) as a white solid. 1H NMR (CD3OD) δ 8.49 (d, 1H), 7.51 - 7.65 (m, 3H), 157.36 - 7.39 (m, 2H), 7.24 (dd, 1H), 5.64 (s, 2H), 4.22 (t, 2H), 3.44 (s, 3H), 1.81 (t, 2H) ), 0.56 (t, 2H), 0.35 (t, 2H). LCMS retention time 2.894 min; LCMS MH+ 536. Example 125: 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - ((5 - methylpyridin - 3 -yl)oxy) -1 H - purine - 2,6(3H,7H) - dione

[00679] To a solution of 8 - chloro - 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (30 mg, 0.08 mmol, Intermediate 78) in DMF (2 mL) was added 5-methylpyridin-3-ol (12.36 mg. 0.12 mmol), followed by carbonate of potassium (15.66 mg, 0.11 mmol). The reaction was stirred at 80°C for 3 hours. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-((5-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione (8 mg, 22.5%) as a white solid. 1H NMR (CD3OD) δ 8.35 - 8.42 (d, 2H)5 7.68 (s, 1H), 7.38 - 7.48(m; 4H), 5.52 (s, 2H), 4.01 - 4.14 (m, 4H), 3.61 - 3.64 (m, 2H), 2.43 (s, 3H), 1.87 - 1.90 (m, 2H), 1.22 - 1.26 (m, 3H). LCMS retention time 2.511 min; LCMS MH+ 470. Example 126: 7 - (4 - chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - (propylsulfonyl) - 1H - purine - 2,6(3H,7H) - dione

[00680] The title compound was prepared using the method of example 106 and purified by preparative HPLC to provide 7-(4-chlorobenzyl) - 3 - ethyl - 1 - (3 - hydroxypropyl) - 8 - (propylsulfonyl) -1H - purine - 2,6(3H,7H)-dione (7 mg, 16.3%) as a white solid. 1H NMR (CD3OD) δ 7.35 - 7.41 (m, 4H), 5.98 (s, 2H), 4.10 - 4.18 (m, 4H), 3.60 - 3.64 (m, 2H), 3.40 - 3.44 (m, 2H), 1.77 - 1.89 (m, 4H), 1.32 - 1.36 (m, 3H), 1.00 - 1.04 (m, 3H). LCMS retention time 2.521 min; LCMS MH+ 469. Example 127: 8 - (4 - chloro - 3 - (trifluoromethoxy)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00681] The title compound was prepared from Intermediate 63 using the method of example 108 and purified by preparative HPLC to afford 8 - (4 - chloro - 3 - (trifluoromethoxy)phenoxy) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (39.4 mg, 30.1% of production) as a white solid. 1H NMR (CD3OD) δ 7.66 - 7.68 (d, 2H), 7.58 (s, 1H), 7.44 - 7.46 (d, 2H), 7.36 - 7.40 (m, 2H), 5.51 (s, 2H), 4.10 - 4.13 (t, 2H), 3.60 - 3.63 (t , 2H), 3.43 (s, 3H), 1.87 - 1.90 (m, 2H). LCMS retention time 3.268 min; LCMS MH+ 559.

[00682] The title compound was prepared from Intermediate 63 using the method of example 108 and purified by preparative HPLC to afford 7 - (4 - chlorobenzyl) - 8 - (4 -fluoro - 3 - (trifluoromethoxy)phenoxy) -1 - (3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (52.9 mg, 55.6% yield) as solid white. 1H NMR (CD3OD) δ = 7.55 - 7.56 (m, 1H), 7.44 - 7.46 (d, 2H), 7.39 - 7.42 (m, 1H), 7.37 - 7.39 (d, 2H), 5.50 (s, 2H), 4.13 - 4.09 (t, 2H), 3.60 - 3.63 (t, 2H), 3.42 (s, 3H), 1.86 - 1.90 (m, 2H). LCMS retention time 3.114 min; LCMS MH* 543.0 Example 129: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - (2 - methoxy - 5 - (trifluoromethoxy)phenoxy) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00683] The title compound was prepared from Intermediate 63 using the method of Example 108 and purified by preparative HPLC to afford 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - (2 - methoxy - 5 - (trifluoromethoxy)phenoxy)-3-methyl-1H-purine-2;6(3H,7H)-dione (56.5 mg, 43.5% yield) as solids white. 1H NMR (CD3OD) δ 7.50 - 7.52 (d, 2H), 7.38 - 7.40 (d, 2H), 7.37 (s, 1H), 7.21 - 7.26 (m, 2H), 5.49 (s, 2H), 4.08 - 4.11 (t, 2H), 3.75 (s, 3H), 3.59 - 3.62 (t, 2H), 3.36 (s, 3H), 1.85 - 1.89 (m, 2H). LCMS retention time 3.066 min; LCMS MH+ 555. Example 130: 7 - benzyl - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 - trifluoropropyl) - 1H - purine - 2,6(3H,7H) - dione

[00684] The title compound was prepared from Intermediate 80 using method example 100 and purified by preparative HPLC to afford 7 - benzyl - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1 -(3,3,3-trifluoropropyl)-1H-purine-2,6(3H,7H)-dione (35.6 mg, 59.1% yield) as solid white. 1H NMR (CD3OD) δ 7.52 - 7.56 (t, 1H), 7.44 - 7.46 (d, 2H), 7.29 - 7.38 (m, 5H), 7.22 - 7.24 (d, 1H), 5.52 (s, 2H), 4.27 - 4.30 (t, 2H), 3.42 (s , 3H), 2.54 - 2.60 (m, 2H). LCMS retention time 3.382 min; LCMS MH+ 529. Example 131 7 - ((5 - chloropyridin - 2 - yl)methyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 -trifluoropropyl) -1 H - purine - 2,6(3H,7H) - dione

[00685] The title compound was prepared using the method of example 100 and purified by preparative HPLC to provide 7 - benzyl - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1 - (3,3,3 -trifluoropropyl) - 1H - purine - 2,6(3H,7H) - dione (18.7 mg, 29.1% yield) as a white solid. 1H NMR (CD3OD) δ 8.52 (s, 1H), 8.46 (s, 1H), 7.84 - 7.87 (dd, 1H), 7.53 - 7.57 (t, 1H), 7.47 - 7.49 (d, 1H), 7.36 - 7.37 (m, 1H), 7.22 - 7.24 (d , 1H), 5.63 (s, 2H), 4.19 - 4.23 (t, 2H), 3.45 (s, 3H), 2.50 - 2.55 (m, 2H). LCMS retention time 3.369 min; LCMS MH+ 564. Example 132: 7-(4-fluorobenzyl)-8-(2-fluorophenoxy)-1 -(3-hydroxypropyl)-3 - methyl -1H - purine - 2,6(3H,7H) -dione

[00686] To a solution of 8 - bromo - 7 - (4 - fluorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.121 mmol, Intermediate 62) in DMF (1 mL) was added 2-fluorophenol (16.4 mg, 0.146 mmol) followed by potassium carbonate ( 25.2 mg, 0.182 mmol). The reaction was stirred at 80°C for 4 hours. The mixture was partitioned between ethyl acetate and saline. The organic phase was washed with saturated aqueous ammonium chloride, dried and concentrated to give the crude product, which was purified by preparative HPLC to give 7-(4-fluorobenzyl)-8-(2-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl - 1H - purine - 2,6(3H,7H) - dione (19.8 mg, 36.9% yield) as a white solid. 1H NMR (CD3OD) δ 7.52 - 7.56 (m, 2H), 7.43 - 7.45 (t, 1H), 7.2 - 7.38 (m, 3H), 7.08 - 7.13 (t, 1H), 5.51 (s, 2H), 4.09 - 4.13 (t, 2H), 3.60 - 3 .63 (t, 2H), 3.375 (s, 3H), 1.86 - 1.90 (m, 2H). LCMS retention time 2.604; LCMS MH+ 443.

[00687] The compounds in Table 1 were prepared using Example Method 132. Example 277: 7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-p-tolyl-1H-purine-2,6(3H,7H)-dione

[00688] To a solution of 8 - bromo - 7 - (4 - fluorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.121 mmol, Intermediate 62) in toluene (2 mL) and ethanol (0.5 mL) was added p-tolylboronic acid (19.7 mg, 0.1 45 mmol) followed by aqueous sodium carbonate solution (0.5 mL), and the mixture was degassed under nitrogen atmosphere three times. Tetracys(triphenylphosphine)platinum (7.5 mg, 0.006 mmol) was added to the reaction under nitrogen and the resulting mixture was stirred at 100°C for 16 hours. The mixture was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give crude product, which was purified by preparative HPLC to give 7-(4-fluorobenzyl)-1 -(3-hydroxypropyl) - 3 - methyl - 8 - p -tolyl -1H - purine - 2,6(3H,7H) -dione (20.9 mg, 40.9% yield) as white solid. 1H NMR (CD3OD) δ 7.51 - 7.53 (d, 2H), 7.34 - 7.36 (d, 2H), 6.97 - 7.07 (m, 4H), 5.66 (s, 2H), 4.09 - 4.12 (t, 2H), 3.59 - 3.62 (t, 2H), 3.59 (s , 3H), 2.44 (s, 3H), 1.85 - 1.89 (m, 2H). LCMS retention time 2.306; LCMS MH+ 423.

[00689] The examples in Table 2 were prepared using example method 277. Example 319: 7 - ((5 -fluoropyridin - 3 -yl)methyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 -

[00690] To a solution of 1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.15 mmol, Intermediate 15) in DMF (5 mL) was added 3-(chloromethyl)-5-fluoropyridine (80 mg, 0.55 mmol), potassium carbonate (0.55 g, 0.6 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated to 60 °C for 2 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give 7 - ((5 - fluoropyridin - 3 -yl)methyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione (35 mg, 46% yield) as a white solid. LCMS retention time 2.577 min; LCMS MH+ 510. Example 320: 1 - (3-hydroxypropyl) - 3 - methyl - 7 - ((6 - methylpyridin - 2 -yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1 H - purine - 2,6(3H,7H) - dione

[00691] The title compound was prepared using the method of example 319 and purified by preparative HPLC to give 1 - (3 - hydroxypropyl) - 3 - methyl - 7 - ((6 - methylpyridin - 2 - yl)methyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (20 mg, 36.2% of production) as a white solid. 1H NMR (CD3OD) δ 7.60 - 7.56 (t, 1H), 7.42 - 7.40 (m, 2H), 7.27 - 7.25 (d, 1H), 4.30 - 4.26 (t, 2H), 4.13 - 4.10 (t, 2H), 3.64 - 3.61 (t, 2H), 3.44 (s, 3H), 1.94 - 1.87 (m, 4H), 1.02 - 0.980 (t, 3H). LCMS retention time 2.803 min; LCMS MH+ 443.

[00692] The examples in Table 3 were prepared using the 319 example methods. Example 335: 7-(4-chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - propoxy -1H - purine - 2,6(3H,7H) - dione

[00693] To a solution of 8 - chloro - 3 - ethyl - 7 - (4 -fluorobenzyl) -1 - (3 - hydroxypropyl) - 1H - purine - 2,6(3H,7H) - dione (50 mg, 0.117 mmol, Intermediate 78) in propanol (5 mL) was added sodium (10 mg, 0.43 mmol). The reaction was stirred at room temperature for 1 h. The reaction was partitioned between ethyl acetate and saline. The organic phase was dried and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl) - 3 - ethyl -1 - (3 - hydroxypropyl) - 8 - propoxy - 1H - purine - 2,6(3H,7H) - dione (11.6mg, 24.4% yield) as a white solid. 1H NMR (CD3OD) δ 7.24 - 7.29 (s, 4H), 5.21 (s, 2H), 4.39 - 4.42 (t, 2H), 3.98 - 4.05 (m, 4H), 3.49 - 3.53 (m, 2H), 1.73 - 1.81 (m, 4H), 1.20 - 1.23 (m, 3H), 0.90 - 0.94 (m, 3H). LCMS retention time 2.881; LCMS MH+ 421.

[00694] The examples in Table 4 were prepared using Example Method 335. Example 348: 7-(4-Chlorobenzyl) - 3 - methyl -1 - (2 -oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione

[00695] 7 - (4 - Chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H-purine-2,6(3H,7H)-dione (0.25 g, 0.54 mmol, Intermediate 9), potassium carbonate (0.11 g, 0.80 mmol), TBAI (0.10 g) and 1 - chloropropan - 2 - One (0.040 mL, 0.59 mmol) was combined in DMF (3 mL) and heated at 50 °C for 1.5 h. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were washed with 1N lithium chloride (2 x 75 mL) dried with magnesium sulfate, filtered and evaporated under reduced pressure to an off-white solid. The solid was purified using a 25 g silica gel flash column, eluted with 1% methanol/DCM to give 7 - (4 - chlorobenzyl) - 3 - methyl -1 - (2 - oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.22 g, 79% yield) as a white solid. LCMS retention time 4.433 minutes and 99% purity, LCMS MH+ 523. 1H NMR (DMSO-d6) δ 7.60 (t, 1H, J = 8 Hz), 7.50 - 7.53 (m, 1 H), 7.38 - 7.47 (m, 5 H), 7.32 (d, 1 H, J = 8 Hz), 5.40 (s, 2H), 4.73 (s, 2H) 3.28 (s, 3H), 2.19 (s, 3H). Example 349: 7-(4-Chlorobenzyl)-3-methyl-1 -((3-methylisoxazol-5-yl)methyl)-8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione

[00696] The title compound was prepared using the method of example 348. White solid. LCMS retention time = 4.601 minutes and 99% purity, LCMS MH+ 562. 1H NMR (DMSO-d6) δ (DMSO-d6) δ 7.60 (t, 1H, J = 8 Hz), 7.47 - 7.51 (m, 1H), 7.40 - 7.45 (m, 5H), 7.32 (d, 1H, J = 8 Hz), 6.20 (s, 1H), 5.43 (s, 2H), 5.13 (s, 2H), 3.30 (s, 3H), 2.17 (s, 3H). Example 350: Ethyl - 2(7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)acetate

[00697] The title compound was prepared using the method of example 348. White solid. LCMS retention time = 4.697 minutes and 99% purity, LCMS MH+ 553. 1H NMR (DMSO-d6) δ 7.58 (t, 1H, J = 8 Hz), 7.51 - 7.54 (m, 1H), 7.38 - 7.47 (m, 5H), 7.32 (d, 1H, J = 12 Hz), 5.41 (s, 2H), 4.60 (s, 2H), 4.12 (dd, 2H, J = 8 Hz and 16 Hz), 3.30 (s, 3H). 1.18 (t, 3H, J = 8 Hz). Example 351: 7 - (4 - Chlorobenzyl) -1 - (2 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00698] 7 - (4 - Chlorobenzyl) - 3 - methyl -1 - (2 - oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.18 g, 0.35 mmol, example 348) was dissolved in methanol (3 mL) and cooled to 0 °C. Then sodium borohydride (0.040 g, 1.05 mmol) was added portionwise over 20 minutes. The reaction was stirred in the cold for 2 hours. The reaction solvent was removed under reduced pressure, then diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL).

[00699] The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to a light gold solid. The solid was purified using a 12 g silica gel flash column eluted with 1% methanol/DCM to afford 7-(4-chlorobenzyl)-1-(2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine - 2,6(3H,7H)-dione (0.15 g, 79% yield) as a white solid. LCMS retention time = 4.280 minutes and 97% purity, LCMS MH+ 525. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J = 8 Hz), 7.46 - 7.48 (m, 1 H), 7.38 - 7.43 (m, 5 H), 7.31 (d, 1 H, J = 8 Hz ), 5.43 (s, 2H), 4.65 (d, 1H, J = 8 Hz), 3.90 - 3.95 (m, 2H), 3.68 - 3.74 (m, 1H), 3.28 (s, 3H), 1.02 (d, 3H, J = 8 Hz). Example 352: (S*) -1 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)propan - 2 -yl acetate and (R*) - 7 - (4 - chlorobenzyl) -1 - (2 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,6(3H,7H) -dione.

[00700] 7 - (4 - Chlorobenzyl) -1 - (2 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.25g, 0.48 mmol, example 351), vinyl acetate (0.15 mL, 1.67 mmol) and Candida antartica acrylic resin ("Novozym") (0.14 g) were combined in ethyl acetate (5 mL) and stirred at room temperature for 24 h. The reaction was filtered and the filtrate was evaporated under reduced pressure to a clear oil. The oil was purified using a 25 g silica gel flash column, eluted with a gradient of 20% to 30% ethyl acetate/hexanes to yield both (S*) -1 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 -trifluoromethoxy)phenoxy) - 2,3,6,7 - tetrahydro - 1H - purin -1 - acetate yl)propan - 2 -yl (0.12 g, 91% yield). LCMS retention time = 4.448 minutes and 94% purity, LCMS MH+ 567. 1H NMR (DMSO-d6) δ 7.60 (t, 1H, J = 8 Hz), 7.48 - 7.54 (m, 1 H), 7.38 - 7.45 (m, 5 H), 7.32 (d, 1 H, J = 8 Hz ), 5.42 (s, 2 H), 5.10 - 5.19 (m, 1 H), 4.13 - 4.22 (m, 1 H), 3.85 (dd, 1 H, J = 4 Hz and 12 Hz), 3.27 (s, 3 H), 1.79 (s, 3 H), 1.17 (d, 3 H, J = 4 Hz) and (R*) - 7 - (4 - chlorobenzyl) -1 - (2 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,6(3H,7H) - dione (0.11 g, 88% yield) as a clear oil. LCMS retention time = 4.019 minutes and 95% purity, LCMS MH+ = 525. 1H NMR (DMSO - d6) δ 7.59 (t, 1H, J = 8 Hz), 7.45 - 7.48 (m, 1H), 7.39 - 7.44 (m, 5H), 7.31 (d, 1H, J = 8 Hz), 5.43 (s, 2H), 4.65 (d, 1H, J = 4 Hz), 3.89 - 4.00 (m, 2H), 3.67 - 3.74 (m, 1H), 3.28 (s, 3H), 1.02 (d, 3H, J = 8 Hz). Example 353: 2- (7- (4-Chlorobenzyl) - 3 - methyl - 3 - methyl - 2,6 - dioxo - 8 - (3 - 20 (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl) - N - methylacetamide

[00701] The title compound was prepared using the method of example 348, but with heating at 50 °C for 15 h. White solid: 0.18 g, 63% yield, LCMS retention time = 4.084 minutes and 99% purity, LCMS MH+ 538. 1H NMR (DMSO - d6) δ 7.92 - 7.98 (m, NH), 7.60 (t, 1H, J = 8 Hz), 7.47 - 7.51 (m, 1H), 7.38 - 7.45 (m, 5H), 7.29 - 7.34 (d, 1H, J = 8 Hz), 5.42 (s, 2H), 4.41 (s, 2H), 3.28 (s, 3H), 2.57 (d, 3H, J = 4 Hz). Example 354: 7-(4-Chlorobenzyl) - 3 - methyl -1 - (thiazol - 5 -ylmethyl) - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione

[00702] The title compound was prepared using the method of example 348, but with heating at 50 °C for 3 hours. White solid, 0.088 g, 29% yield, LCMS retention time = 4.552 minutes and 99% purity, LCMS MH+ 564. 1H NMR (DMSO-d6) δ 8.97 (s, 1H), 7.85 (s, 1H), 7.58 (t, 1H, J = 8 Hz), 7.46 - 7.48 (m, 1H), 7.39 - 7.43 (m, 5H), 7.30 (d, 1H, J = 12 Hz), 5.43 (s, 2H), 5.24 (s, 2H), 3.29 (s, 3H). Example 355 7-(4-Chlorobenzyl)-1-(2-hydroxy-2-methylpentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H, 7H)-dione

[00703] 7 - (4 - Chlorobenzyl) - 3 - methyl -1 - (2 - oxopropyl) - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.48 mmol, example 348) was dissolved in THF (6 mL), cooled to 0 °C and 2.0 M propyl magnesium bromide in THF (0.36 mL, 0.72 mmol) was added dropwise. The reaction was stirred in the cold for 15 minutes, then warmed to room temperature and stirred 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column, eluted with 20% ethyl acetate/hexanes to give 7 - (4 - chlorobenzyl) -1 - (2 - hydroxy - 2 - methylpentyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H, 7H) - dione (0.88 g, 32 % production) as a clear oil. LCMS retention time = 4.792 minutes and 98% purity, LCMS MH+ = 567. 1H NMR (DMSO - d6) δ 7.59 (t, 1H, J = 8 Hz), 7.47 - 7.50 (m, 1H), 7.38 -7.44 (m, 5H), 7.31 (d, 1H, J = 8 Hz ), 5.42 (s, 2H), 4.23 (s, 1H) 3.92 - 4.02 (dd, 2H, J = 4Hz and 16Hz), 3.29 (s, 3H), 1.30 - 1.41 (m, 4H), 0.99 (s, 3H), 0.80 (t, 3H, J = 8Hz). Example 356: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione Step 1: 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - 2,6(3H,7H) -dione (3.73 g, 7.99 mmol, Intermediate 9) and potassium carbonate (1.66 g, 11.99 mmol) were combined in DMF (56 mL) and (3-bromopropoxy)(tert-but yl)dimethylsilane (2.43 g, 9.59 mmol) was added. The reaction was heated to 100°C. After heating for 3 h the reaction was cooled, diluted with water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined extracts were washed with 1N lithium chloride (2 x 100 mL), dried over magnesium sulfate and evaporated under reduced pressure to afford 1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (5, 7 g of crude) as a light gold oil. LCMS retention time = 5.646 and 98% purity, LCMS MH+ 639. Step 2: 1 -(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (5.7 g crude, 7.99 mmol) was dissolved in ethanol (40 mL) and 6N aqueous HCl (4 mL) was added. The clear solution was stirred at room temperature. After 1 hour the reaction was evaporated under reduced pressure, diluted with water (200ml) and extracted with ethyl acetate (3x100ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to a clear oil. The oil was purified using an 80 g silica gel flash column eluted with 1:1 ethyl acetate/hexanes to provide 7-(4-chlorobenzyl)-1 - (3-hydroxypropyl) - 3 - methyl - 8 - (3-trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) -dione (3.8 g, 90.9% yield) as a white crystalline solid . LCMS retention time = 3.955 and 100% purity, LCMS MH+ 525. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J = 2 Hz), 7.47 (s, 1 H), 7.41 (s, 4 H), 7.41 (m, 1 H), 7.31 (d, 1 H, J = 2 Hz ), 5.42 (s, 2H), 4.44 (t, OH, J = 1 Hz), 3.92 (t, 2H, J = 1 Hz), 3.41 (m, 2H), 3.28 (s, 3H), 1.68 (m, 2H). Example 357: 1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride Step 1: 7 - (4 - Chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine-2,6(3H,7H)-dione (1.0 g, 2.14 mmol, Intermediate 9), 2-(3-bromopropyl)isoindoline -1,3 -dione (0.63 g, 2.36 mmol), potassium carbonate (0.4 4g, 3.21mmol) and TBAI (0.040g) were combined in DMF (20ml) and heated at 100°C for 3 hours. The reaction was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with 1N lithium chloride (2 x 100 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil. The oil was purified using an 80 g silica gel flash column eluted with a gradient of 25% to 50% ethyl acetate/hexanes to give 7-(4-chlorobenzyl)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H, 7H)-dione (1.4 g, 100% yield) as a white solid. LCMS retention time = 4.660 minutes and 100% purity, LCMS MH+ 654. 1H NMR (CDCl3) δ 7.78 - 7.83 (m, 2H), 7.65 - 7.70 (m, 2H), 7.41 (t, 1H, J = 8 Hz), 7.32 (dd, 4H, J = 12 Hz and 28 Hz), 7.10 - 7.23 (m, 4H), 5.35 (s, 2H), 4.05 - 4.14 (m, 2H), 3.76 (t, 2H, J = 8 Hz), 3.38 (s, 3H), 2.01 - 2.11 (m, 2H). Step 2: 7-(4-Chlorobenzyl)-1 -(3-(1,3-dioxoisoindolin-2-yl)propyl)-3-methyl-8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H, 7H) -dione (1.4 g, 2.14 mmol) was suspended in ethanol (20 mL) and hydrazine hydrate (0.42 mL, 8 .56 mmol) was added and the reaction was heated to reflux. The reflux reaction changed to a clear solution, then after 30 minutes it settled as a white mass. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (3 x 75 mL). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide an oil. The oil was purified using a 40 g silica gel flash column eluted with 10% methanol/DCM to give a light brown solid. The solid was dissolved in DCM (5 mL) and excess 1N HCl/diethyl ether was added. The solvent was removed under reduced pressure to afford 1-(3-aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride (0.87 g, 49% yield) as a brown solid. LCMS retention time = 2.802 minutes and 97% purity, LCMS MH+ 524. 1H NMR (DMSO-d6) δ 7.91 - 8.11 (brd s, NH2 and HCl), 7.60 (t, 1H, J = 8 Hz), 7.38 - 7.48 (m, 6H), 7.31 (d, 1H, J = 12 Hz), 5.43 (s, 2H), 3.93 (t, 2H, J = 8 Hz), 3.29 (s, 3H), 2.73 - 2.85 (m, 2H), 1.83 - 1.94 (m, 2H). Example 358: 1 - (2 - aminoethyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione hydrochloride

[00704] The title compound was prepared using the method of example 357. White solid, 0.062 g, 33% yield, LCMS retention time = 2.802 minutes and 99% purity, LCMS MH+ 510. 1H NMR (DMSO-d6) δ 7.82 - 7.99 (brds, NH2 and HCI), 7.62 (t, 1H, J = 8 Hz), 7.38 - 7.48 (m, 6 H), 7.31 (d, 1 H, J = 12 Hz), 5.43 (s, 2 H), 4.11 (m, 2 H) 3.29 (s, 3 H), 2.99 - 2.15 (m, 2 H). Example 359: N - (3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl)propyl)acetamide Notebook: C5-0249-047

[00705] 1 - (3-Aminopropyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL) ). Acetyl chloride (0.28 mL, 0.42 mmol) was added and the reaction was stirred at room temperature for 4 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 52,000 micron preparative TLC plate eluted with 5% methanol / DCM. The target band was scraped off the plate and eluted from silica gel with eluent to provide N - (3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin - 1 -yl)propyl)acetamide (0.053 g, 49% yield) as a brown solid of course. LCMS retention time = 3.789 minutes and 99% purity, LCMS MH+ 566. 1H NMR (DMSO-d6) δ 7.78 - 7.82 (m, 1H), 7.59 (t, 1H, J = 8 Hz), 7.44 - 7.48 (m, 1H), 7.38 - 7.42 (m, 5H), 7.31 (d, 1 H, J = 8 Hz), 5.42 (s, 2 H), 3.87 (t, 2 H, J = 8 Hz), 3.28 (s, 3 H), 2.04 (dd, 2 H, J = 4 Hz and 12 Hz), 1.78 (s, 3 H), 1.61 - 1.70 (m, 2 H). Example 360: N - (3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)propyl)methanesulfonamide

[00706] 1 - (3-Aminopropyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Methanesulfonyl chloride (0.30 mL, 0.38 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol / DCM. The target range was scraped the plate and elucid silica gel to supply n - (3 - (4 - chlorobenzil) - 3 - methyl - 2.6 - dioxo - 8 - (3 - (trifluorometoxy) phenom) - 2,3,6,7 - tetrahydro- 1h -pun -1 -il) production) as a brown solid. LCMS retention time = 4.048 minutes and 99% purity, LCMS MH+ 602. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J = 8 Hz), 7.45 - 7.48 (m, 1 H), 7.39 - 7.43 (m, 5 H), 7.31 (d, 1 H, J = 8 Hz ), 6.96 (t, 1 H), 5.43 (s, 2 H), 3.91 (t, 2 H, J = 8 Hz), 3.29 (s, 3 H), 2.96 (dd, 2 H, J = 4 Hz and 12 Hz), 2.87 (s, 3 H), 1.69 - 1.79 (m, 2 H). Example 361: 2-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid. Step 1: 7 - (4 - Chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine-2,6(3H,7H)-dione (1.0 g, 2.14 mmol, Intermediate 9), tert-butyl 2-bromoacetate (0.34 mL, 2.36 mmol), and potassium carbonate (0.45 g, 3.2 1 mmol) were combined in DMF (20 mL) and heated at 50°C for 2 hours. The reaction was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 1 N lithium chloride (2 x 100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give tert - butyl - 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)a acetate (1.24 g, 100% yield) as a clear oil. LCMS retention time = 4.817 minutes and 97% purity, LCMS MH+ 581. Step 2: tert- Butyl - 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (0.2 0 g, 0.34 mmol) was dissolved in DCM (4 mL) and TFA (0.26 mL, 3.4 mmol) was added. The reaction was stirred at room temperature for 15 hours, then evaporated under reduced pressure to afford 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (0.18g, 100% yield). LCMS retention time = 3.915 minutes and 97% purity, LCMS MH+ 525. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J = 8 Hz), 7.50 - 7.54 (m, 1H), 7.45 (d, 1H, J = 8 Hz), 7.41 (s, 4H), 7.31 (d, 1H, J = 8 Hz), 5.41 (s, 2H), 4.52 (s, 2H), 3.30 (s, 3H). Example 362: 2-(7-(4-Chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl) - N - propylacetamide

[00707] 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (0.25 g, 0.48 mmol, Example 361) and CDI (0.93 g, 0.57 mmol) were combined in DMF (4 mL) and stirred at room temperature for 20 min. Propan -1 -amine was added and the reaction was stirred at room temperature for 3 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were washed with 1N lithium chloride (2 x 75 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to a white solid. The solid was purified using a 25 g silica gel flash column, eluted with 1% methanol/DCM to give 2 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl) - N - propylacetamide (0.13 g, 4 7% yield) as a white solid. LCMS retention time = 4.070 min and 99% purity, LCMS MH+ 566. 1H NMR (DMSO-d6) δ 7.99 (t, NH), 7.60 (t, 1H, J = 8 Hz), 7.48 - 7.52 (m, 1H), 7.39 - 7.46 (m, 5H), 7.32 (d . Example 363 7-(4-Chlorobenzyl) - 3 - methyl -1 - (2 -oxobutyl) - 8 - (3 - (trifluoromethoxy)phenoxy) -1H - purine - 2,6(3H,7H) -dione

[00708] The title compound was prepared using the method of Example 348. White solid, 0.49 g, 85% yield; LCMS retention time = 4.408 min and 99% purity, LCMS MH+ 537. 1H NMR (DMSO-d6) δ 7.60 (t, 1H, J = 8 Hz), 7.51 - 7.54 (m, 1H), 7.37 - 7.47 (m, 5H), 7.30 - 7.33 (m, 1H), 5.40 (s, 2H), 4.72 (s, 2H), 3.28 (s, 3H), 2.55 (dd, 2H, J = 8 Hz and 16 Hz), 0.96 (t, 3H, J = 8 Hz). Example 364: 7-(4-Chlorobenzyl)-8-ethoxy-1-(3-hydroxypropyl)-3-methyl-1H-purine - 2,6(3H,7H) -dione Step 1: Sodium (0.35 g, 15.03 mmol) was dissolved in ethanol (30 mL) and 8 - bromo - 7 - (4 - chlorobenzyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (1.63 g, 3.01 mmol, Intermediate 77) was added and the reaction was stirred at room temperature for 24 h. The reaction was evaporated to dryness under reduced pressure, diluted with water (100ml) and extracted with ethyl acetate (3x75ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - ethoxy - 3 - methyl - 1H - purine - 2,6(3H,7H)-dione (1.5g, 100% yield) as a pale gold oil. LCMS retention time = 5.317 min and 95% purity, LCMS MH+ 507. Step 2: 7 - (4 - Chlorobenzyl) - 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (1.5 g, 3.01 mmol) was dissolved in ethanol (20 mL) and aqueous HCl at 6N (4 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (150 mL) and extracted with DCM (3 x 100 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to an off-white solid. The solid was purified using an 80 g silica gel flash column eluted with 2% methanol/DCM, which provided 7 - (4 - chlorobenzyl) - 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (1.0 g, 84% yield) as a white solid. LCMS retention time = 3.173 min and 98% purity, LCMS MH+ 393. 1H NMR (DMSO-d6) δ 7.35 (dd, 4 H, J = 4 Hz and 12 Hz), 5.20 (s, 2 H), 4.47 ( dd, 2 H, J = 8 Hz and 16 Hz), 4.43 (t, 1 H, J = 4 Hz)), 3.88 (t, 2 H, J = 8 Hz), 3.40 (dd, 2 H, J = 4 Hz and 12 Hz), 3.36 (s, 3 H), 1.62 - 1.71 (m, 2 H), 1.33 (t, 3 H, J = 8 Hz). Example 365: 7-(4-Chlorobenzyl)-1-(2-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione

[00709] 7 - (4 - Chlorobenzyl) - 3 - methyl -1 - (2 - oxobutyl) - 8 - (3 - (trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.44 g, 0.82 mmol, example 363) was dissolved in methanol (8 mL) and DCM (1 mL), then cooled to 0 °C. Sodium borohydride (0.93 g, 2.46 mmol) was added portionwise over 20 minutes and the reaction was stirred in the cold for 2 hours. The reaction solvent was removed under reduced pressure, then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil. The oil was purified using a 40 g silica gel flash column eluted with 1% methanol/DCM to give 7 - (4 - chlorobenzyl) -1 - (2 - hydroxybutyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (0.32 g, 73% yield) as a white solid. LCMS retention time = 4.265 min and 97% purity, LCMS MH+ 539. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J = 8 Hz), 7.45 - 7.48 (m, 1H), 7.38 - 7.45 (m, 5H), 7.30 (d, 1H, J = 12 Hz), 5.43 (s, 2H), 4.56 (d, 1H, J = 4 Hz), 3.92 - 4.00 (m, 1H), 3.65 - 3.76 (m, 2H), 3.28 (s, 3H), 1.23 - 1.41 (m, 2H). Example 366: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl - 8 - (propylamino) - 1H - purine - 2,6(3H,7H) - dione hydrochloride Step 1: 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, Intermediate 77) and propan-1-amine (1.44 mL, 9.2 mmol) were combined in ethanol (5 mL) and heated to reflux for 24 hours. The reaction was cooled to room temperature, diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a pale gold oil. The oil was purified using a 25 g silica gel column, eluted with 20% ethyl acetate/hexanes to give 1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (propylamino) - 1H - purine - 2,6(3H,7H) - dione (0.15 g, 63% yield) as a white solid LCMS retention time = 5.013 min and 97% purity, LCMS MH+ 520 Step 2: 1 - (3 - ((tert-Butyldimethylsilyl)oxy)propyl - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (propylamino)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.29 mmol) was dissolved in ethanol (3 mL) and 6N aqueous HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction solvent was removed under reduced pressure to give 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (propylamino) - 1H - purine - 2,6(3H,7H) - dione hydrochloride (0.13 g, 100 % yield) as a white foam LCMS retention time = 3.021 min and 99% purity, LCMS MH+ 406. 1H NMR (DMSO-d6) δ 7.31 (dd, 4H, J = 8 Hz and 42 Hz), 6.15 - 6.48 (brds, NH2 and HCl), 5.30 (s, 2H), 3.8 4 (t, 2 H, J = 8 Hz), 3.38 (t, 2 H, J = 8 Hz), 3.34 (s, 3 H), 3.26 (t, 2 H, J = 8 Hz), 1.59 - 1.68 (m, 2 H), 1.46 - 1.57 (m, 2 H), 0.81 (s, 3 H, J = 8 Hz). Example 367: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-propoxy-1H - purine - 2,6(3H,7H) -dione

[00710] The title compound was prepared using the method of Example 364. White solid, 0.14 g, 78% yield; LCMS retention time = 2.914 min and 98% purity, LCMS MH+ 379. 1H NMR (DMSO-d6) δ 7.35 (dd, 4H, J = 12 Hz and 40 Hz), 5.21 (s, 2H), 4.36 - 4.44 (m, 3H), 3.89 (t, 2H, J = 4 Hz-), 3.41 (dd, 2H, J = 4 Hz and 12 Hz), 3.35 (s, 3 H), 1.62 - 1.78 (m, 4 H), 0.88 (t, 3 H, J = 8 Hz). Example 368: 7-(4-Chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - methoxy - 3 - methyl - 1H - purine - 252,6(3H,7H) -dione.

[00711] The title compound was prepared using the method of example 364. White solid, 0.14 g, 78%, LCMS retention time = 2.914 min and 98% purity, LCMS MH+ 379. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J = 8 Hz and 48 Hz), 5.21 (s, 2 H), 4.42 (t, 1H, J = 4 Hz), 4.08 (s, 3 H), 3.88 (t, 2 H, J = 8 Hz)), 3.38 - 3.43 (m, 2 H), 3.37 (s, 3 H), 1.62 - 1.70 (m, 2 H). Example 369: 8- Butoxy - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00712] The title compound was prepared using the method of example 364. White solid, 0.15 g, 77% yield, LCMS retention time = 3.690 min and 97% purity, LCMS MH+ 421. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J = 4 Hz and 12 Hz), 5.21 (s, 2H); Example 370: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione

[00713] The title compound was prepared using the method of example 364. White solid, 0.056 g, 30% yield, LCMS retention time = 3.355 min and 94% purity, LCMS MH+ 407. 1H NMR (DMSO-d6) δ 7.36 (dd, 4H, J = 8 Hz and 48 Hz), 5.19 ( s, 2H); = 8Hz). Example 371: 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - morpholinoethoxy) -1H - purine - 2,6(3H,7H) -dione hydrochloride Step 1: (0.053 g, 2.31 mmol) was dissolved in 2 - morpholinoethanol (5 mL) and sodium 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, Intermediate 7 7) has been added. The reaction was stirred at room temperature for 24 hours. The reaction was diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 8 - (2 - morpholinoethoxy) - 1H-purine-2,6(3H,7H)-dione (0.27 g, 100% yield) as a clear oil. LCMS retention time = 2.990 min and 96% purity, LCMS MH+ 592. Step 2: 1 -(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H, 7H)-dione (0.27g, 0. 46 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl (1 mL) and stirred at room temperature for 1 h. The reaction was evaporated and azeotroped with methanol (3x10ml). The solid residue was triturated with methanol (5ml) and filtered. The white solid was washed with diethyl ether (2x10 mL) and dried under high vacuum to afford 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H, 7H)-dione hydrochloride as a white solid. LCMS retention time = 1.908 min and 95% purity, LCMS MH+ 478. 1H NMR (DMSO-d6) δ 11.54 (s, HCl), 7.38 (dd, 4H, J = 12 and 28 Hz), 5.33 (2, 2H), 4.82 - 4.89 (m, 2H), 3.75 - 3.95 (m, 2H), 3.58 - 3.64 (m, 2H), 3.33 - 3.44 (m, 5H), 3.06 (m, 2H), 1.62 - 1.72 (m, 2H). Example 372: 7-(4-chlorobenzyl)-8-(2-(dimethylamino)ethoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H, 7H))-dione hydrochloride.

[00714] The title compound was prepared using the method of example 371. White solid, 0.153 g, 95% yield, LCMS retention time = 1.837 min and 94% purity, LCMS MH+ 436. 1H NMR (DMSO - d6) δ 10.70 (s, HCl), 7.37 - 7.42 (m, 4H), 5 .35 (s, 2H), 4.77 - 4.83 (m, 2H), 3.87 - 3.93 (m, 3H), 3.52 - 3.60 (m, 2H), 3.40 - 3.44 (t, 2H, J = 8 Hz), 3.39 (s, 3H), 2.50 (s, 6H), 1.62 - 1.7 2 (m, 2H). Example 373: 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: Cyclopentanol (0.21 mL, 2.31 mmol) was dissolved in THF (5 mL) and sodium hydride (60% in oil, 0.092 g, 2.31 mmol) was added. The reaction was stirred for 1 hour. 8 - Bromo -1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (0.25 g, 0.46 mmol, Intermediate 77) was added and the reaction was stirred at room temperature for 15 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 100% yield) as a gold oil. LCMS retention time = 5.843 min and 71% purity, LCMS MH+ 547. Step 2: 1 - (3 - ((tert - Butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - (cyclopentyloxy) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.25 g, 0.4 6 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl (1 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 2000 micron preparative TLC plate with ethyl acetate. Target strip was scraped off the plate, eluted from silica gel with ethyl acetate and evaporated under reduced pressure to afford 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.028g, 14% yield) as a white solid. LCMS retention time = 3.656 min and 98% purity, LCMS MH+ 433. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J = 12 and 48 Hz), 5.34 - 5.40 (m, 1H), 5.18 (s, 2H), 4.42 (t, 1H, J = 4 Hz), 3.89 (t, 2H, J = 8 Hz), 3.38 - 3.45 (m, 2H), 3.36 (s, 3H), 1.55 - 1.93 (m, 8H). Example 374: 7-(4-Chlorobenzyl)-8-(cyclohexyloxy)-1-(3-hydroxypropyl)-3-methyl - 1H - purine - 2,6(3H,7H) - dione

[00715] The title compound was prepared using the method of example 373. White solid, 0.86 g, 42% yield, LCMS retention time = 3.929 min and 97% purity, LCMS MH+ 447. 1H NMR (DMSO-d6) δ 7.35 (dd, 4H, J = 12 Hz and 36 Hz), 5.20 (s , 2H); 6H), 1.20 - 1.45 (m, 4H). Example 375: 7-(4-Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (pentyloxy) - 1H - purine - 2,6(3H,7H) - dione

[00716] The title compound was prepared using the method of example 373. White solid, 0.13 g, 63% yield, LCMS retention time = 3.886 min and 98% purity, LCMS MH+ 435. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J = 8 Hz and 44 Hz), 5.21 (s, 2H); Hz). Example 376: 7-(4-Chlorobenzyl) - 8 - (cyclopentylmethoxy) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00717] Using Example Method 373. White solid, 0.13 g, 63% yield, LCMS retention time = 3.970 min and 95% purity, LCMS MH+ 447 and 1H NMR (DMSO-d6) δ 7.34 (dd, 4 H, J = 8 Hz and 44 Hz), 5.21 (s, 2 H), 4.42 (brd s, 1 H), 4.31 (d, 2 H, J = 4 Hz), 3.89 (t, 3 H, J = 8 Hz), 3.41 (t, 2 H, J = 8 Hz), 3.35 (s, 3 H), 2.23 - 2.35 (m, 2 H), 1.62 - 1.72 (m, 4 H), 1.4 4 - 1.59 (m, 4H), 1.16 - 1.28 (m, 2H). Example 377: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-((6-methylpyridin-3-yl)methoxy)-1H-purine-2,6(3H,7H)-dione

[00718] The title compound was prepared using the method of example 373. White solid, 0.0.87 g, 44% yield, LCMS retention time = 2.255 min and 97% purity, LCMS MH+ 470. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J = 8 Hz and 44 Hz), 5.21 ( s, 2H); 8Hz). Example 378: Ethyl 2-(7-(4-chlorobenzyl)-1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yl)acetate. Step 1: Diethyl malonate (0.35 mL, 2.31 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% in oil, 0.74 g, 1.85 mmol) was added portionwise. The mixture was stirred for 15 minutes and 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 -chlorobenzyl) - 3 - methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.92 mmol, Intermediate 77) was added. The reaction was heated at 100°C for 15 hours. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were washed with 1N lithium chloride (2 x 100 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column, eluted with 20% ethyl acetate / hexanes to give diethyl - 2 - (1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7-tetrahydro-1H-purin-8-yl)malonate ( 0.23 g, 40% yield) as a clear oil. LCMS retention time = 5.015 min and 95% purity, LCMS MH+ 621. 1H NMR (DMSO-d6) δ 7.27 (dd, 4H, J = 8 Hz and 72 Hz), 5.62 (d, 2H, J = 12 Hz), 5.54 (s, 2H), 5.61 (s, 1H), 3.9 0 - 4.03 (m, 6H), 3.62 (t, 2H, J = 8 Hz), 3.37 (s, 3H), 1.70 - 1.78 (m, 2H), 1.08 (t, 6H, J = 8 Hz), 0.80 (s, 9H). Step 2: Diethyl - 2 - (1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 - trifluoromethyl)phenyl)malonate (0.23 g, 0.36 mmol) was suspended in 18% aqueous HCl (3 mL) and heated at reflux for 3 hours, yielding a clear solution. The solvent was removed under reduced pressure and the residue was dried under high vacuum for 15 hours to afford 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetic acid (0.14 g, 100% yield) as a brown solid. LCMS retention time = 2.318 min and 70% purity, LCMS MH+ 407. Step 3: Crude 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-25-tetrahydro-1H-purin-8-yl)acetic acid (0.14 g, 0.36 mmol) was dissolved in ethanol (5 mL) and concentrated sulfuric acid (1 drop. The reaction was heated to reflux for 1 hour. The reaction was cooled, evaporated under reduced pressure to remove the ethanol, then diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a pale gold oil. The oil was purified using a 12 g silica gel flash column elu Acid with 20% ethyl acetate / hexanes to give ethyl 2 - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H-purin-8-yl) acetate (0.062, 40% yield) as a light brown solid. LCMS retention time = 2.804 min and 99% purity, LCMS MH+ 435. 1H NMR (CDCl3) δ 7.21 (dd, 4H, J = 8Hz and 84Hz), 5.57 (s, 2H), 4.11 - 4.23 (m, 4H), 3.77 (s, 2H), 3.59 (s, 3H), 3.50 - 3.56 ( m, 2H), 3.32 - 3.39 (m, 1H), 1.86 - 1.94 (m, 2H), 1.25 (t, 3H, J = 8 Hz). Example 379: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H, 7H)-dione Step 1: Sodium hydride (60% in oil, 0.15 g, 3.69 mmol) was added portionwise to ethyl - 2 - (3 - 10(trifluoromethoxy)phenyl)acetate (1.03 g, 4.15 mmol) in DMF (5 mL) and the dark gold solution was stirred at room temperature for 20 min. 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (0.50 g, 0.92 mmol, Intermediate 77) was added and the reaction was heated at 100°C for 2 hours. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 1N lithium chloride (2 x 100 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 40 g silica gel flash column eluted with 10% ethyl acetate/hexanes to give ethyl-2-(1 -(3-((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 - tetrahydro - 1H - purin - 8 - yl) - 2 - (3-trifluoromethoxy)phenyl)acetate (0.54 g, 82% yield) as a pale gold oil. LCMS retention time = 5.407 min and 99% purity, LCMS MH+ 709. Step 2: Ethyl - 2 - (1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2-(3-trifluoromethoxy)phenyl)acetate was suspended in 6N HCl (6 mL) and heated at reflux for 1 hour. The reaction solution was cooled, diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a pale gold oil. The oil was purified using a 12 g silica gel flash column eluted with a gradient of 20% ethyl acetate / hexanes to 100% ethyl acetate to give 7-(4-chlorobenzyl)-1 -(3-hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)benzyl) - 1H - purine - 2,6(3H,7H) - dione (0. 088 g, 60% yield) as a clear oil. LCMS retention time = 3.623 min and 98% purity, LCMS MH+ 523. 1H NMR (DMSO-d6) δ 7.33 (t, 1H, J = 8 Hz), 7.25 - 7.29 (m, 2H), 7.05 - 7.18 (m, 5H), 5.61 (s, 2H), 4.41 ( t, 1 H, J = 4 Hz), 4.24 (s, 2 H), 3.89 (t, 2 H, J = 12 Hz), 3.40 (s, 3 H), 3.38 - 3.43 (m, 2 H), 51.62 - 1.72 (m, 2 H). Example 380: Ethyl-2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yl) - 2 - (3 - trifluoromethoxy)phenyl)propanoate

[00719] Sodium (0.025 g, 1.07 mmol) was dissolved in ethanol (3 mL) and ethyl - 2 - (1 - (3 - ((tert - butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 -trifluoromethoxy)phenyl)acetate (0.33 g, 0.47 mmol, example 379, step 1) was added. The reaction was stirred for 10 min and methyl iodide (0.29 mL, 4.7 mmol) and the reaction was heated at reflux for 1 hour. The reaction was cooled, evaporated under reduced pressure, diluted with water (50ml) and extracted with ethyl acetate (3x50ml). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column, eluted with 20% ethyl acetate/hexanes to give ethyl - 2 - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yl) - 2 - (3-trifluoromethoxy)phenyl) propanoate (0.17 g, 67% yield) as a white foam. LCMS retention time = 3.263 min and 99% purity, LCMS MH+ 609. 1H NMR CDCl3) δ 7.06 - 7.24 (m, 5H), 6.73 (d, 2H, J = 8 Hz), 3.95 - 4.05 (m, 2H), 3.81 - 3.89 (m, 2H), 3, 35 - 3.42 (m, 2H), 1.95 (s, 3H), 1.59 - 1.67 (m, 2H), 1.09 (t, 3H, J = 8 Hz). Example 381: 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)benzyl) - 1H - purine - 2,6(3H,7H) - dione Step 1: Ethyl - 2 - (1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 -trifluoromethyl)phenyl)acetate was prepared from Intermediate 77 and 3 - trifluoromethylphenyl) ethyl acetate using method example 378, step 51 (0.45 g, 70% yield) as a yellow foam. LCMS retention time = 5.334 min and 87% purity, LCMS MH+693. Step 2: 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)benzyl) - 1H - purine - 2,6(3H,7H) - dione was prepared using method example 379, step 2. Clear oil, 10 0.032 g, 44% yield, LCMS retention time = 3.523 min and 99% pure, LCMS MH+ 507. 1H NMR (DMSO-d6) δ 7.65 - 7.75 (m, 1H), 7.47 - 7.52 (m, 1H), 7.43 (d, 1H, J = 4Hz), 7.38 (s, 1H), 7.17 (dd, 4H, J = 8Hz and 68Hz ), 5.53 (s, 2H), 4.29 (s, 2H), 4.11 - 4.15 (m, 1H), 3.90 (t, 1H, J = 4 Hz), 3.40 (s, 3H), 3.37 - 3.45 (m, 2H), 1.60 - 1.71 (m, 2H). Example 382: Ethyl 2- (7-(4-chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro -1H - purin - 8 -yl) - 2 - (3 - (trifluoromethyl)phenyl)acetate.

[00720] Ethyl - 2 - (1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 - trifluoromethyl)phenyl)acetate (0.050 g, 0.72 mmol, example 381, step 1) was dissolved in ethanol (3 mL) and 6N aqueous HCl (0.3 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction solvent was removed under reduced pressure, DCM (3 mL) added and directly blotted onto a 2000 micron preparative TLC plate, eluted with 50% ethyl acetate/hexanes. Target strip was scraped off the plate, eluted from silica gel with ethyl acetate and the solvent removed under reduced pressure to afford 2 - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro -1H - purin - 8 - yl) - ethyl 2 - (3 - (trifluoromethyl)phenyl)acetate (0.02 5 g, 50% yield) as a white foam. LCMS retention time = 3.731 min and 96% purity, LCMS MH+ 579. 1H NMR (DMSO-d6) δ 7.55 - 7.65 (m, 3H), 7.48 (t, 1H, J = 8 Hz), 7.12 (dd, 4H, J = 8 Hz and 72 Hz), 5.69 (dd, 2 H . Example 383: Ethyl 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-(3-(trifluoromethyl)phenyl)propanoate.

[00721] Ethyl 2 - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 - (trifluoromethyl)phenyl)propanoate was prepared from Example 381, Step 1 using the method of Example 380. Light yellow foam, 0.13 g, 61% yield, LCMS retention time = 3.999 min and 96% purity, LCMS MH+ 593. 1H NMR (DMSO-d6) δ 7.51 (s, 2H), 7.40 (t, 1H, J =8 Hz), 7.32 (d, 1H, J = 8 Hz), 6.90 (dd, 4H . 1.78 (m, 2H), 1.12 (t, 3H, J = 8 Hz). Example 384: 2- (7-(4-Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 - (trifluoromethoxy)phenyl)acetonitrile Step 1: Sodium hydride (60% in oil, 0.15 g, 3.69 mmol) was added portionwise to 2-(3-(trifluoromethoxy)phenyl)acetonitrile (0.84 g, 4.15 mmol) and stirred at room temperature for 15 minutes. 8 - Bromo -1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl)-3-methyl-1H-purine-2,6(3H, 7H)-dione (0.50 g, 0.92 mmol, Intermediate 77) was added and the reaction stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 1N lithium chloride (2 x 75 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column, eluted with 10% ethyl acetate/hexanes to give 2 - (1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yl) - 2 - (3-trifluoromethoxy)phenyl)acetonitrile (0.58 g, 95% yield) as a yellow foam. LCMS retention time = 5.265 min and 90% purity, LCMS MH+ 662. Step 2: 2-(1 -(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - ( 3-trifluoromethoxy)phenyl)acetonitrile (0.20 g, 0.30 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl (1 mL) was added. The clear solution was stirred at room temperature for 1 hour. The reaction was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a golden oil. The oil was purified using a 25 g silica gel flash column, eluted with a gradient of 20% to 50% ethyl acetate/hexanes to afford 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro - 1H -purin - 8 -yl) - 2 - (3 - (trifluoromethoxy)phenyl a) acetonitrile (0.082 g, 50% yield) as a white foam. LCMS retention time = 3.709 min and 97% purity, LCMS MH+ 548. 1N NMR (CDCl3) δ 7.34 (t, 1 H, J = 8 Hz), 7.05 - 7.25 (m, 5 H), 6.88 (d, 2 H, J = 8 Hz), 5.54 (dd, 2 H, J = 12 Hz and 80 Hz), 254.18 (t, 2H, J = 8 Hz). 3.64 (s, 3H), 3.50 - 3.58 (m, 2H), 3.13 (t, 1H, J = 8 Hz), 1.85 - 1.93 (m, 2H). Example 385: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(1-(3-trifluoromethoxy)phenyl)ethyl-1H-purine-2,6(3H,7H)-dione

[00722] Ethyl - 2 - (7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 - yl) - 2 - (3 - trifluoromethoxy)phenyl)propanoate (0.14 g, 0.23 mmol, example 380) was suspended in 6N H Cl (6 mL) and heated at reflux for 15 h. The clear solution was cooled, diluted with water (75 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a clear oil. The oil was purified using a 2000 micron preparative TLC plate with 50% ethyl acetate/hexanes. Target strip was collected and extracted with ethyl acetate. The extracts were evaporated under reduced pressure to afford 7-(4-chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (1 - (3 -trifluoromethoxy)phenyl)ethyl - 1H-purine-2,6(3H,37)-dione (0.026 g, 22% yield) as a white foam. LCMS retention time = 4.029 min and 96% purity, LCMS MH+ 537. 1H NMR (CDCl3) δ 7.20 - 7.30 (m, 3H), 7.09 (d, 1H, J = 8 Hz), 7.00 - 7.05 (m, 2H), 6.91 (d, 2H, J = 12 Hz), 5.38 (dd, 2 H, J = 16 Hz and 100 Hz), 4.18 (t, 2 H, J = 8 Hz), 4.00 - 4.09 (m, 1 H), 3.67 (s, 3 H), 3.48 - 3.53 (m, 2 H), 3.39 (t, 1 H, J = 4 Hz), 1.85 - 1.9 3 (m, 2H), 1.66 (d, 3H, J = 8Hz). Example 386: 7-(4-Chlorobenzyl) - 8 - (2 - hydroxy -1 - (3 - (trifluoromethoxy)phenyl)ethyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00723] Ethyl 2 - (1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl - 7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yl) - 2 - (3 - trifluoromethoxy)phenyl)acetate (0.25 g, 0.352 mmol , example 379, step 1) was dissolved in THF (4 mL) and sodium borohydride (0.080 g, 2.11 mmol) was added. The reaction was refluxed for 15 min Then methanol (2 mL) was added dropwise via condenser. After refluxing for another 15 minutes, the reaction was cooled and acidified with 6N HCl until pH 1 was reached. The mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (100 mL) and extracted with DCM (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield an oil. The oil was purified using a 25 g silica gel column, eluted with a gradient of 5% to 10% methanol/DCM to give 7-(4-chlorobenzyl) - 8 - (2 - hydroxy -1 - (3 - (trifluoromethoxy)phenyl)ethyl) -1 - (3 - hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.030 g, 13% yield) as a white foam. LCMS retention time = 2.665 min and 98% purity, LCMS MH+ 553. 1H NMR (CDCl3) δ 7.25 - 7.30 (m, 2H), 7.03 (dd, 4H, J = 8 Hz and 91 Hz), 7.1 L (d, 1H, J = 8 Hz), 6.99 - 7.02 (m , 1H); .27 (m, 1H), 1.85 - 1.93 (m, 2H). Example 387: 7-(4-Chlorobenzyl) - 8 - (1 - hydroxyethyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25g, 0.46mmol, Intermediate 77) was dissolved in THF (5ml) and cooled to -78°C. To the clear solution was added 2.5M n-butyl lithium in hexanes (0.20 mL, 0.51 mmol) dropwise. The reaction was stirred in the cold for 5 minutes and acetaldehyde (0.13 mL, 2.31 mmol) was added. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a golden oil. The oil was purified using two 1000 micron preparative TLC plates, eluted with 50% ethyl acetate/hexanes. Target strip was extracted with ethyl acetate and solvent removed under reduced pressure to afford 1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - (1 - hydroxyethyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.052 g, 30% yield) as a clear oil. LCMS retention time = 4.490 min and 97% purity, LCMS MH+ 507. Step 2: 1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - (1 - hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.052 g, 0.10 mmoL) was dissolved in ethanol (2 mL) and 6N aqueous HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (25 mL) and extracted with DCM (3 x 25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 2000 micron preparative TLC plate with 50% ethyl acetate/hexanes. Target strip was extracted with ethyl acetate and the solvent was removed under reduced pressure to give 7 - (4 - chlorobenzyl) - 8 - (1 - hydroxyethyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.012 g, 29% yield) as a clear oil. LCMS retention time = 2.429 min and 96% purity, LCMS MH+ 393. 1H NMR (CDC13) δ 7.25 (dd, 4H, J = 8 Hz and 64 Hz), 5.65 (dd, J = 12 Hz and 40 Hz), 4.91 - 4.97 (m, 1H), 4.19 (t, 2H, J = 4Hz), 3.61 (s, 3H), 3.51 - 3.55 (m, 2H), 2.52 (d, 1H, J = 4Hz), 1.87 - 1.93 (m, 2H), 1.57 (d, 3H, J = 4Hz). Example 388: 7-(4-Chlorobenzyl) - 8 - (1 - hydroxy - 2 - methylpropyl) -1 - (3 - hydroxypropyl) - 3 - methyl -17/-purine - 2,6(3H,7H) -dione Step 1: 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (0.50 g , 0.923 mmol, Intermediate 77) was dissolved in THF (5 mL) and cooled to -78 °C. To the clear solution was slowly added dropwise n 2.5 M - butyl - lithium in THF (0.35 mL, 0.877 mmol) followed by the immediate addition of isobutyraldehyde (0.42 mL, 4.61 mmol). The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to to yield an oil. The oil was purified using a 25 g silica column, eluting with a gradient of 10% to 30% ethyl acetate/hexanes yielding 1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - (1 - hydroxy - 2 - methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)- dione (0.20 g, 40% yield) as a light gold oil. LCMS retention time = 4.923 min and 98% purity, LCMS MH 535. Step 2: 1 - (3 - ((tert - Butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - (1 - hydroxy - 2 - methylpropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.19 g, 0.355 mmol) was dissolved in ethanol (5 mL) and 6N HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (75 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a white solid. The solid was suspended in diethyl ether (4 mL) and collected to give 7 - (4 - chlorobenzyl) - 8 - (1 - hydroxy - 2 - methylpropyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.085g, 56% yield) as a white solid. LCMS retention time = 3.263 min and 94% purity, LCMS MH+ 421. 1H NMR (CDCl3) δ 7.23 (dd, 4H, J = 8 Hz and 68 Hz), 5.59 (dd, 2H, J = 16 Hz and 40 Hz), 4.43 (t, 1H, J = 8 Hz). 4.17 (t, 2H, J = 8 Hz), 3.59 (s, 3 H), 3.48 - 3.54 (m, 2 H), 3.35 - 3.40 (m, 1 H), 2.48 (d, 1 H, J = 8 Hz), 2.08 - 2.16 (m, 1 H), 1.85 - 1.92 (m, 2 H), 1.03 (d, 3H, J = 8 Hz), 0.82 (d, 3H, J = 8 Hz). Example 389: 7-(4-Chlorobenzyl) - 8 - (3 - chlorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H, 7H) - dione Step 1: 8 - Bromo -1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.50 g, 0.92 mmol, Intermediate 77), potassium carbonate (0.255 g, 1.85 mmol) and 3 - chlorophenol (0.1 04ml, 0.97mmol) was combined in DMF (5ml) and heated at 90°C for 3 hours. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were washed with 1N lithium chloride (2 x 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure to yield a pale gold oil (0.65 g). The oil was purified using a 24 g silica gel column eluted with a gradient of 10% to 20% ethyl acetate / hexanes to afford 1-(3-(((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(3-chlorophenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione as an off-white solid (0. 413 g, 76% yield) LCMS retention time = 5.598 min and 98% purity, LCMS MH+ 589.5 Step 2: 1 - (3 - (((tert-Butyldimethylsilyl)oxy)propyl) - 7 - (4 - chlorobenzyl) - 8 - (3 - chlorophenoxy) - 3 - methyl - 1H - purine - 2.6(3H, 7 H)-dione (0.413 g, 0.70 mmol) was dissolved in ethanol (8 mL) and 6N HCl (1 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (75 mL) and extracted with DCM (3 x 75 mL). The combined organic extracts were dried with magnesium sulfate, and concentrated under reduced pressure to leave an off-white solid. The solid was suspended in diethyl ether (3 mL) and filtered to yield 7 - (4 - chlorobenzyl) - 8 - (3 - chlorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H-purine-2,6(3H, 7H)-dione (0.30 g, 90% yield) as an off-white solid. LCMS retention time - 3.810 min and 99% purity, LCMS MH+ 475. 1H NMR (DMSO-d6) δ 7.15 - 7.41 (m, 8H), 5.41 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.49 - 3.51 (m, 2H), 3.45 ( s, 3H), 1.87 - 1.93 (m, 2H).

[00724] The following examples 390a to 390r were prepared using the two-step method of example 389. Example 390a: 7 - (4 - Chlorobenzyl) - 8 - (3,4 - dichlorophenoxy)1 - (3 - hydroxypropyl)-3-methyl-1H-purine-2,6(3H, 7H)-dione

[00725] White solid, 0.34 g, 92% yield, LCMS retention time = 4.080 min and 99% purity, LCMS MH+= 509. 1H NMR (CDCl3) δ 7.50 (d, 1 H, J = 12 Hz), 7.31 - 7.44 (m, 5 H), 7.15 (dd, 2 H , J = 4 Hz and 8 Hz), 5.41 (s, 2H), 3.48 - 3.51 (m, 2H), 3.45 (s, 3H), 1.87 - 1.95 (m, 2H). Example 390b: 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (m - tolyloxy) -1H - purine - 2,6(3H;7H) - dione

[00726] White solid, 0.29 g, 76% yield, LCMS retention time = 3.724 min and 96% purity, LCMS MH+= 455. 1H NMR (CDCl3) δ (CDCl3) δ 7.27 - 7.45 (m, 5 H), 7.01 - 7.13 (m, 3 H), 5.41 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.49 - 3.57 (m, 2H), 3.44 (s, 3H), 2.39 (s, 3H), 1.86 - 1.94 (m, 2H). Example 390c: 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - (3 - methoxyphenoxy) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00727] White solid, 0.14 g, 41% yield, LCMS retention time = 3.550 min and 97% purity, LCMS MH+= 471. 1H NMR (CDCl3) δ (CDCl3) δ 7.29 - 7.44 (m, 5 H), 6.79 - 6.86 (m, 3 H), 5.41 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.82 (s, 3H), 3.50 - 3.55 (m, 2H), 3.44 (s, 3H), 1.87 - 1.94 (m, 2H). Example 390d: 7 - (4 - Chlorobenzyl) - 8 - (3 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 3-methyl-1H-purine-2,6(3H, 7H)-dione

[00728] White solid, 0.23 g, 74% yield, LCMS retention time = 3.584 min and 99% purity, LCMS MH+= 459. 1H NMR (CDCl3) δ (CDCl3) δ 7.30 - 7.43 (m, 5 H), 6.98 - 7.10 (m, 3 H), 5.42 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.49 - 3.55 (m, 2H), 3.45 (s, 3H), 1.88 - 1.93 (m, 2H). Example 390e: 7-(4-Chlorobenzyl)-8-(4-chlorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

[00729] White solid, 0.28 g, 76% yield, LCMS retention time = 3.814 min and 99% purity, LCMS MH+= 475. 1H NMR (CDCl3) δ 7.37 - 7.43 (m, 5 H), 7.30 - 7.35 (m, 2 H), 7.19 - 7.23 (m , 2H), 5.41 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.47 - 3.56 (m, 2H), 3.43 (s, 3H), 1.86 - 1.94 (m, 2H). Example 390f: 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (p - tolyloxy) - 1H - purine - 2,6(3H,7H) - dione

[00730] White solid, 0.14 g, 41% yield, LCMS retention time = 3.732 min and 99% purity, LCMS MLT = 455. 1H NMR (CDCl3) δ (CDCl3) δ 7.46 (dd, 4H, J = 8 Hz and J = 44 Hz), 7.24 (dd, 4H, J = 8 Hz and J = 36 Hz), 5.41 (s, 2 H), 4.19 (t, 2 H, J = 8 Hz), 3.50 - 3.59 (m, 2 H), 3.42 (s, 3 H), 2.38 (s, 3 H), 1.88 - 1.92 (m, 2 H). Example 390g 7 - Benzyl - 8 - (3 - chlorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00731] The title compound was prepared from Intermediate 83 using the method of example 389. White solid, 0.11 g, 61% yield, LCMS retention time = 3.503 min and 98% purity, LCMS MH+ = 441. 1H NMR (CDCl3) δ 7.42 - 7.47 (m, 1H), 7.31 - 7, 38 (m, 5H), 7.24 - 7.30 (m, 2H), 7.14 - 7.18 (m, 1H), 5.45 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.50 - 3.56 (m, 2H), 3.45 (s, 3H), 1.85 - 1.95 (m, 2H) ). Example 390h:7 - Benzyl - 8 - (3 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00732] The title compound was prepared from Intermediate 83 using the method of example 389. White solid, 0.17 g, 88% yield, LCMS retention time = 3.282 min and 98% purity, LCMS MH+ = 425. 1H NMR (CDCl3) δ 7.43 - 7.47 (m, 2H), 7.30 - 7, 41 (m, 4H), 7.04 - 7.08 (m, 2H), 6.96 - 7.02 (m, 1H), 5.45 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.50 - 3.55 (m, 2H), 3.45 (s, 3H), 1.87 - 1.94 (m, 2H) ). Example 390i: 7 - Benzyl - 8 - (4 - chloro - 3 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H, 7H) - dione

[00733] The title compound was prepared from Intermediate 83 using the method of example 389. White solid, 0.25 g, 56% yield, LCMS retention time = 3.860 min and 99% purity, LCMS MH+ = 459. 1H NMR (CDCl3) δ 7.15 - 7.48 (m, 8H), 5.46 (s, 2H), 4.20 (t, 2H, J = 8HZ), 3.50 - 3.61 (m, 3H), 3.43 (s, 3H), 1.87 - 1.94 (m, 2H). Example 390j 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 -phenoxy -1H - purine - 2,6(3H,7H) - dione

[00734] The title compound was prepared from Intermediate 83 using the method of example 389, White solid, 0.18 g, 46% yield, LCMS retention time = 3.435 min and 99% purity, LCMS MH+ = 407. 1H NMR (CDCl3) δ 7.15 - 7.48 (m, 10H), 5.46 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.50 - 3.61 (m, 3H), 53.43 (s, 3H), 1.87 - 1.94 (m, 2H). Example 390k: 7 - Benzyl - 8 - (3 - difluoromethoxy)phenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00735] The title compound was prepared from Intermediate 83 using the method of example 389. White solid, 0.18 g, 39% yield, LCMS retention time = 3.581 min and 97% purity, LCMS MH+ = 473. 1H NMR (CDCl3) δ 7.31 - 7.47 (m, 6H), 7.10 - 7, 14 (m, 2H), 7.02 - 7.06 (m, 2H), 6.34 - 6.72 (t, 1H, J = 18Hz), 5.46 (s, 2H), 4.20 (t, 2H, J = 2Hz). 3.51 - 3.55 (m, 2H), 3.45 (s, 3H), 1.87 - 1.94 (m, 2H). Example 3901: 7 - (4 - Chlorobenzyl) - 8 - (3 - difluoromethoxy)phenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H, 7H) - dione

[00736] Sólido branco, 0,14 g, 27% de produção, tempo de retenção de LCMS = 3,820 min e 99% de pureza, LCMS MH+ 507. 1H NMR (CDCl3) δ 7,44 (s, 1 H), 7,36 (dd, 4 H, J = 12 Hz e 32 Hz), 7,11 - 7,14 (m, 2 H), 7,04 - 7,07 (m, 1 H), 6,54 (t, 1 H, J = 72 Hz), 5,42 (s, 2 H), 4,20 (t, 2 H, J = 2 Hz), 3,48 - 3,56 (m, 2 H), 3,45 (s, 3 H), 1,87 - 1,94 (m, 2 H). Example 390m: 7-(4-Chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-phenoxy-1H - purine - 2,6(3H,7H) -dione

[00737] White solid, 0.24 g, 59% yield, LCMS retention time = 3.471 min and 99% purity, LCMS MH+= 441. 1H NMR (CDCl3) δ 7.41 - 7.45 (m, 4 H), 7.24 - 7.33 (m, 4 H), 5.42 (s, 3 H), 4.20 (t, 2H, J = 8 Hz), 3.51 - 3.54 (m, 2H), 3.43 (s, 3H), 1.87 - 1.94 (m, 2H). Example 390n 3 - ((7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 -tetrahydro - 1H - purin - 8 -yl)oxy)benzonitrile

[00738] The title compound was prepared from Intermediate 83, using the method of example 389. White solid, 0.32 g, 74% yield, LCMS retention time = 3.292 min and 99% purity, LCMS MH+ = 466. 1H NMR (CDCl3) δ 7.52 - 7.65 (m, 4H), 7.36 (dd, 4H, J = 8 Hz and 24 Hz), 5.43 (s, 2 H), 4.20 (t, 2 H, J = 8 Hz), 3.51 - 3.56 (m, 2 H), 3.45 (s, 3 H), 1.88 - 1.93 (m, 2 H). Example 390o: 3 - ((7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 2,6 - dioxo - 2,3,6,7 - tetrahydro -1H - purin - 8 -yl)oxy)benzonitrile

[00739] The title compound was prepared from Intermediate 83 using the method of example 389. White solid, 0.24 g, 74%, LCMS retention time = 3.581 min and 99% purity, LCMS MH+ = 432. 1H NMR (CDCl3) δ 7.54 (s, 3H), 7.46 (d, 3H, J = 8 Hz), 7.30 - 7.40 (m, 3H), 5.48 (s, 2H), 4.21 (t, 52H, J = 8 Hz), 3.50 - 3.56 (m, 2H), 3.45 (s, 3H), 1.88 - 1.96 (m, 2H). Example 390p: 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 8 - (4 - isopropylphenoxy) - 3 - methyl - lif - purine - 2,6(3H,7H) - dione

[00740] White solid, 0.33 g, 88% production, LCMS retention time = 4.160 min and 99% purity, LCMS MH+= 483. 1H NMR (CDCl3) δ 7.38 (dd, 4 H, J = 8 Hz and 44 Hz), 7.22 (dd, 4 H, J = 8 Hz and 40 Hz ), 5.41 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.50 - 3.59 (m, 2H), 3.45 (s, 3H), 2.91 - 2.98 (m, 2H), 1.85 - 1.95 (m, 2H), 1.28 (d, 2H, J = 2 Hz). Example 390q: 7 - Benzyl -1 - (3 - hydroxypropyl) - 8 - (4 - isopropylphenoxy) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00741] The title compound was prepared from Intermediate 83 using the method of example 389. White solid, 0.33 g, 91% yield, LCMS retention time = 3.894 min and 99% purity, LCMS MH+ = 449. 1H NMR (CDCl3) δ 7.48 (d, 2H, J = 8 Hz), 7.31 - 7 .37 (m, 3 H), 7.21 (dd, 4 H, J = 8 Hz and 32 Hz), 5.45 (s, 2 H), 4.20 (t, 2 H, J = 8 Hz), 3.62 (brd s, 1 H), 3.50 - 3.56 (m, 2 H), 3.44 (s, 3 H), 2.90 - 2.93 ( m, 1H), 1.91 (m, 2H), 1.27 (d, 6H, J = 2 Hz). Example 390r: 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy) - 1H - 5 purine - 2,6(3H,7H) - dione

[00742] The title compound was prepared from Intermediate 83, using the method of example 389. White solid, 0.20 g, 79% yield, LCMS retention time = 3.600 min and 99% purity, LCMS MH+ = 475. 1H NMR (CDCl3) δ 7.34 - 7.59 (m, 8H), 5.48 (s, 2H), 4.21 (t, 2H, J = 8 Hz), 3.49 - 3.55 (m, 2H), 3.45 (s, 3H), 1.88 - 1.95 (m, 2H) Example 391: 7 - Benzyl) - 8 - (4 -fluoro - 3 - (trifluoromethyl)phenoxy) -1 - (3 - hydroxypropyl) - 3 - methyl -1 H - purine - 2,6(3H,7H) - dione Step 1: 7 - Benzyl - 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (0.50 g , 0.985 mmol, Intermediate 83), potassium carbonate (0.272 g, 1.97 mmol) and 4 -fluoro - 3 - (trifluoromethyl )phenol (0.19 g, 1.03 mmol) were combined in DMF (5 mL). The reaction was heated to 90°C. After 6 hours, the reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a white solid. This solid was purified using a 25 g silica column, eluted with 20% ethyl acetate / hexanes to give 7 - benzyl -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 8 - (4 -fluoro - 3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.54 g, 90% production) as a white solid. LCMS retention time = 5.342 min and 97% purity, LCMS MH+ = 607. Step 2: 7 - Benzyl -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 8 - (4 -fluoro - 3 - (trifluoromethyl)phenoxy) - 3 - methyl -1H - purine - 2,6(3H,7H) -dione (0.44 g , 0.686 mmol) was dissolved in ethanol (15mL) and DCM (1 mL) then 6N aqueous HCl (2.0 mL) were added. The clear solution was stirred at room temperature. After 1 hour, the reaction was diluted with water (100 mL) and extracted with DCM (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a white solid. The solid was suspended in diethyl ether (6 mL) and filtered to give 7-benzyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.35 g, 1079% yield) as a white solid. LCMS retention time = 3.641 min and 99% purity, LCMS MH+ = 493. 1H NMR (CDCl3) δ 7.23 - 7.52 (m, 8 H), 5.47 (s, 2 H), 4.20 (t, 2 H, J = 8 Hz), 3.47 - 3.54 (m, 2 H), 3.43 (s , 3H), 1.88 - 1.92 (m, 2H). Example 392: 7-(4-Chlorobenzyl) - 8 - (4 -fluoro - 3 - (trifluoromethyl)phenoxy) - 1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H, 7H) -dione

[00743] The title compound was prepared using the two-step method of Example 391. White solid, 0.33 g, 95% yield, LCMS retention time = 3.870 min and 99% purity, LCMS MH+ = 527. 1H NMR (CDCl3) δ 7.25 - 7.56 (m, 7H), 5.43 (s, 2H), 4.20 (t, 2H, J = 8 Hz), 3.55 - 3.51 (m, 2H), 3.45 (t, 2H, J = 8 Hz), 3.43 (s, 3H), 1.89 - 1.92 (m, 2H). Example 393: 8- (4-Chloro - 3 -fluorophenoxy) - 7 - (4 - chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00744] The title compound was prepared using the two-step method of Example 391 except that the crude product was purified by suspension in ether and filtration. White solid, 0.33 g, 95% yield, LCMS retention time = 3.840 min and 99% purity, LCMS MH+ = 493. 1H NMR (CDC13) δ 7.45 (t, 1 H, J = 2 Hz), 7.36 (dd, 4 H, J = 8 Hz and 24 Hz), 7.20 (dd, 1 H , J = 4 Hz and 12 Hz), 7.04 (d, 1 H, J = 8 Hz), 5.41 (s, 2 H), 4.20 (t, 2 H, J = 8 Hz), 3.51 - 3.55 (m, 2 H), 3.43 - 3.47 (m, 5 H), 1.89 - 1.92 (m, 2 H) Example 394 : 3- (7-(4-chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro -1H - purin -1 -yl)propanol

[00745] 7 - (4 - Chlorobenzyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenoxy) - 1H - purine - 2,6(3H,7H) - dione (2.0 g, 3.81 mmol, example 356) and pyridinium chlorochromate (1.64 g, 7.62 mmol) were dissolved in DCM ( 40 mL). The orange solution was stirred at room temperature for 15 h. The solvent was decanted from salts, absorbed onto silica gel and purified using a 40 g silica gel flash column eluted with 40% ethyl acetate / hexanes to give 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl )propanol (1.25 g, 63% yield) as a white solid. 1H NMR (CDCl3) δ 9.84 (s, 1H), 7.12 - 7.47 (m, 8H), 5.40 (s, 2H), 4.38 (t, 2H, J=8 Hz), 3.45 (s, 3H), 2.75 - 2.83 (m, 2H). Example 395 7- Benzyl - 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione Step 1: Sodium metal (0.11 g, 4.93 mmol) was dissolved in ethanol (10 mL) and 7 - benzyl - 8 - bromo -1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (0.50 g, 0.985 mmol, Intermediate 83) was added. The clear solution was stirred at room temperature for 15 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 7 - benzyl -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 3 - ethoxy - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.47 g, 100% yield) as a white solid. LCMS retention time = 5.074 min and 97% purity, LCMS MH+ = 473. Step 2: 7 - Benzyl -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 3 - ethoxy - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.47 g, 0.985 mmol) was dissolved in ethanol (8 mL) and 6N HCl (2.0 mL) was added. The clear solution was stirred at room temperature. After 1 hour the reaction was diluted with water (75 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a white solid. The solid was suspended in hexanes (5 mL) and filtered to give 7 - benzyl - 8 - ethoxy -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione (0.26 g, 73% yield) as a white solid. LCMS retention time = 2.848 min and 97% purity, LCMS MH+ = 359. 1H NMR (CDCl3) δ 7.26 - 7.40 (m, 5 H), 5.26 (s, 2 H), 4.53 - 4.59 (m, 2 H), 4.17 (t, 2 H, J = 8 Hz), 3.49 - 3.51 (m, 5H), 1.85 - 1.91 (m, 2H), 1.45 (t, 3H, J = 8 Hz). Example 396 7- Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - propoxy -1H - purine - 2,6(3H,7H) - dione

[00746] The title product was prepared using the two-step method of Example 395. White solid, 0.32 g, 87% yield, LCMS retention time = 3.119 min and 99% purity, LCMS MH+ = 373. Example 397: tert- Butyl 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - ( 3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl)propanoate

[00747] 7 - (4 - Chlorobenzyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy) -1H - purine-2,6(3H, 7H)-dione (0.50 g, 1.07 mmol, Intermediate 9), tert-butyl 3-bromopropanoate (0.22 mL, 1.29 mmol) and potassium carbonate (0.22 g, 1, 61 mmol) was combined in DMF (5 mL) and heated at 100°C for 24 hours. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were washed with 1N lithium chloride (2 x 50 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a white solid. This solid was purified using a silica gel flash column. of 25 g, eluted with 10% ethyl acetate/hexanes to give tert-butyl 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 - tetrahydro - 1H - purin -1 -yl)propanoate (0.26 g, 41% yield) as a white solid LCMS retention time = 4.841 min and 99% purity, LCMS MH+ = 595. 1H NMR (CDCl3) δ 7.12 - 7.46 (m, 8 H), 5.41 (s, 2 H), 4.29 (t, 2 H, J = 8 Hz), 3.53 (s, 3 H), 2.61 (t, 2 H, J = 8 Hz), 1.43 (s, 9H). Example 398: 3-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoic acid.

[00748] tert -Butyl 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1 -yl)propanoate (0.23 g, 0.383 mmol, Example 397) was dissolved in DCM (4 mL) and TFA (0. 57 mL, 7.66 mmol) was added. The reaction was stirred at room temperature for 1 h; Then the solvent was removed under reduced pressure to leave a golden oil (0.21 g). The oil was purified using a 12 g silica gel column, eluted with 5% methanol/DCM to give 3 - (7 - (4 - chlorobenzyl) - 3 - methyl - 2,6 - dioxo - 8 - (3 - (trifluoromethoxy)phenoxy) - 2,3,6,7 -tetrahydro - 1H - purin -1 -yl)propanoic acid (0.13 g, 63% yield) as a white solid. LCMS retention time = 3.903 minutes and 99% purity, LCMS MH+ = 539. 1H NMR (CDCl3) δ 7.14 - 7.47 (m, 8H), 5.41 (s, 2H), 4.35 (t, 2H, J = 8HZ), 3.44 (s, 3H), 2.77 (t, 2H, J = 8Hz). Example 399: 8-(3-Chlorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H - purine - 2,6(3H,7H) -dione Step 1: 8 - Bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) -dione (0.50 g, 1.03 mmol, Intermediate 82), 3 - chlorophenol (0.14 g, 1.08 mmol), potassium carbonate (0.29 g, 2, 06 mmol) was combined in DMF (5 mL) and heated at 90 °C for 15 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were washed with 1N LiCl (2 x 75 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford 1 - (3-((tert-butyldimethylsilyl)oxy)propyl - 8 - (3 - chlorophenoxy) - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.55 g, 100% production) as a yellow oil. LCMS retention time = 6.238 min and 85% purity, LCMS MH+ = 535. Step 2: 1 - (- 3 - ((tert-butyldimethylsilyl)oxy)propyl) - 8 - (3 - chlorophenoxy) - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.55 g , 1.03 mmol) was dissolved in ethanol (10 mL) and 6N HCl (2 mL) was added and the reaction was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3 x 75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a gold oil. The oil was purified using a 24 g silica gel flash column, eluted with 50% acetate of ethyl/hexanes to afford 8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl--1H-purine-2,6(3H,7H)-dione (0.21 g, 49% yield) as a white solid. LCMS retention time = 3.859 min and 98% purity, LCMS MH+ = 421. 1H NMR (CDCl3) δ 7.35 - 7.38 (m, 2H), 7.24 - 7.28 (m, 1H), 7.18 - 7.25 (m, 1H), 4.27 (t, 2H, J = 8 Hz), 4.20 (t, 2H, J = 8 Hz), 3.52 - 3.58 (m, 3 H), 3.47 (s, 3 H), 1.86 - 1.94 (m, 2 H), 1.70 - 1.78 (m, 2 H), 1.59 - 1.69 (m, 1 H), 0.98 (d, 6H, J = 8 Hz). Example 400: 1-(3-Hydroxypropyl)-7-isopentyl-8-isopropoxy-3-methyl-1H-purine - 2,6(3H,7H) -dione

[00749] Sodium (0.12 g, 5.15 mmol) was dissolved in isopropanol (8 mL) and 8 - bromo -1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl - 7 - isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, Intermediate 82) was added. was stirred at room temperature for 15 hours. The reaction was treated with 6N HCl to reach pH = 1, and stirred at room temperature for 1 hour. The reaction was diluted with water (100 mL) and extracted with DCM (3 x 75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a gold oil. The oil was purified using two 2000 micron preparative TLC plates, eluted with 50% ethyl acetate / hexanes to give 1-(3-hydroxypropyl)-7-isopentyl-8-isopropoxy-3-methyl - 1H - purine - 2,6(3H,7H) - dione (0.27 g, 75% yield) as a white solid. LCMS retention time = 3.325 min and 97% purity, LCMS MH+ = 353.1H NMR ( CDCl3) δ 5.20 - 5.30 (m, 1 H), 4.17 (t, 2 H, J = 8 Hz), 4.07 (t, 2 H, J = 8 Hz), 3.73 (t, 1 H, J = 8 Hz), 3.45 - 3.54 (m, 5 H), 1.85 - 1.93 (m, 2 H), 1.58 - 1.66 (m, 2H), 1.48 - 1.57 (m, 1H), 1.42 (d, 6H, J = 8 Hz), 0.94 (d, 6H, J = 8 Hz). Example 401: 8 - Ethoxy -1 - (3 - hydroxypropyl) - 7 - isopentyl - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00750] The title compound was prepared using the method of example 400 as a white solid. LCMS retention time = 3.050 min and 96% purity, LCMS MH+ 339. 1H NMR (CDCl3) δ 4.53 (dd, 2 H, J = 8 Hz and 16 Hz), 4.17 (t, 2 H, J = 8 Hz), 4.08 (t, 2 H, J = 8 Hz), 3.71 (t, 1 H, J = 4 Hz), 3.47 - 3.53 (m, 5 H), 1.84 - 1.92 (m, 2 H), 1.60 - 1.67 (m, 2 H), 1.49 - 1.58 (m, 1 H), 1.45 (t, 2 H, J = 4 Hz), 0.94 (d, 6H, J = 4 Hz). Example 402: 1 - (3-Hydroxypropyl) - 7 - isopentyl - 3 - methyl - 8 - propoxy - 1f/- purine - 2,6(3H,7H) - dione

[00751] The title compound was prepared using the method of example 400 as a white solid. LCMS retention time = 3.383 min and 95% purity, LCMS MH+ = 352. 1H NMR (CDCl3) δ 4.42 (t, 2H, J = 8 Hz), 4.17 (t, 2H, J = 8 Hz), 4.09 (t, 2H, J = 8 Hz), 3.70 (t, 1H, J = 4 Hz), 3.45 - 3.56 (m, 5H), 1.78 - 1.94 (m, 4H), 1.51 - 1.72 (m, 3H), 1.04 (t, 3H, J = 8 Hz), 0.94 (d, 6H, J = 8 Hz). Example 403: 1 - (3-hydroxypropyl) - 7 - isopentyl - 3 - methyl - 1H - purine - 8 - butoxy 2,6(3H, 7H) - dione.

[00752] The title compound was prepared using the method of example 400 as a white solid. LCMS retention time = 3.681 min and 99% purity, LCMS MH+ = 367. 1H NMR (CDCl3) δ 4.47 (t, 2H, J = 8 Hz), 4.16 (t, 2H, J = 8 Hz), 4.08 (t, 2H, J = 8 Hz), 3.70 (t, 1H, J = 8 Hz), 3.45 - 3.59 (m, 5H), 1.73 - 1.93 (m, 4H), 0.99 (t, 3H, J = 8 Hz), 0.94 (d, 6H, J = 8 Hz). Example 404: 7- Benzyl - 8 - (3,4 - dichlorophenyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione Step 1: 7 - Benzyl - 8 - bromo -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 3 - methyl - 1H-purine-2,6(3H,7H)-dione (0.50 g, 0.985 mmol, Intermediate 83), potassium carbonate (0.326 g, 2.36 mmol), palladium(0) tetracis(triphenylphosphine) ( 0.032 g, 0.028 mmol) and 3,4-dichlorophenylboronic acid (0.206 g, 1.08 mmol) were combined in ethanol (12.0 mL), toluene (2.0 mL) and water (2.0 mL) in a sealed vial. The reaction was heated to 85°C for 18 hours. The reaction was cooled and filtered through Celita. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a gold solid. The solid was purified using a 25 g Combi Flash silica gel column, eluted with 20% ethyl acetate/hexanes to give 7 - benzyl -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 8 - (3,4 - dichlorophenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H)-dione (0.49 g, 86% of production) as a golden oil. LCMS retention time = 5.489 min and 97% purity, LCMS MH+ = 573. Step 2: 7 - Benzyl -1 - (3 - ((tert -butyldimethylsilyl)oxy)propyl) - 8 - (3,4 - dichlorophenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.49 g, 0.8 54 mmol) was dissolved in ethanol (15 mL) and 6N HCl (2.0 mL) was added. The clear solution was stirred at room temperature for 1 hour. The reaction was diluted with water (100 mL) and extracted with DCM (3 x 75 mL). The combined extracts were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide a white solid. The solid was suspended in diethyl ether (5 mL) and filtered to give 7 - benzyl - 8 - (3,4 - dichlorophenyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H-purine-2,6(3H,7H)-dione (0.28 g, 71% yield) as a white solid. LCMS retention time = 3.567 min and 96% purity, LCMS MH+ = 459. 1H NMR (CDCl3) δ 7.71 (s, 1 H), 7.53 (d, 1 H, J = 8 Hz), 7.38 - 7.41 (d, 1 H, J = 4 Hz), 7.26 - 7.29 (m, 3 H), 7.04 (d, 2H), 5.64 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.65 (s, 3H), 3.47 - 3.54 (m, 2H), 3.30 (t, 2H, J=8 Hz). Example 405: 8- (3-Chlorophenyl) -1 - (3 - hydroxypropyl) - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00753] The title compound was prepared from Intermediate 82 using the method of Example 404. Gold yellow solid, 0.31 g, 74% yield, LCMS retention time = 3.516 min and 85% purity, LCMS MH+ = 405. 1H NMR (CDCl3) δ 7.65 - 7.70 (m, 1H), 7.45 - 7.5 4 (m, 3H), 4.33 - 4.39 (m, 2H), 4.23 (t, 2H, J = 4 Hz), 3.63 (s, 3H), 3.52 - 3.58 (m, 2H), 3.43 - 3.48 (m, 2H), 1.89 - 1.96 (m, 152H), 1.69 - 1.7 6 (m, 2H), 1.53 - 1.64 (m, 2H), 0.89 (d, 6H, J = 4Hz). Example 406: 1 - (3-Hydroxypropyl) - 7 - isopentyl - 3 - methyl - 8 - (3 - (trifluoromethyl)phenyl) - 1H - purine - 2,6(3H,7H) - dione

[00754] The title compound was prepared from intermediate 82, using the method of example 404. White solid, 0.089 g, 40% yield, LCMS retention time = 3.598 min and 97% purity, LCMS MH+ = 438. Example 407: 1 - (3-hydroxypropyl) - 7 - isopentyl - 8 - (2 - isopropylphenyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00755] The title compound was prepared from Intermediate 82, using the method of example 404. White solid, 0.089 g, 40% yield, LCMS retention time = 3.749 min and 99% purity, LCMS MH+ = 413. Example 408: 8- (3-Fluorophenoxy) -1 - (3 - hydroxypropyl) - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00756] 8 - Bromo -1 - (3 - ((tert-butyldimethylsilyl)oxy)propyl - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione (0.50 g, 1.03 mmol, Intermediate 82), 3-fluorophenol (0.098 mL, 1.08 mmol) and potassium carbonate (0.29 g , 2.06 mmol) was combined in DMF (8 mL) and heated at 90 °C for 15 h. The reaction was cooled to room temperature and acidified with 6N HCl to pH = 1. The reaction was stirred for 1 h, then diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined extracts were washed with 1N LiCl (2 x 100 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to yield a gold oil. The oil was purified using a 24 g silica gel flash column, eluted with a gradient of 20% ethyl acetate / hexanes to 100% ethyl acetate to provide 8 - (3 -fluorophenoxy) -1 - (3 - hydroxypropyl) - 7 - isopentyl - 3 - methyl - 1H - purine - 2,6(3H) ,7H)-dione (0.20 g, 48% yield) as a white solid. LCMS retention time = 3.524 min and 96% purity, LCMS MH+ = 405. Example 409: 1 - (3-Hydroxypropyl) - 7 - isopentyl - 3 - methyl - 8 - (3 - (trifluoromethyl)phenoxy)-1H-purine-2,6(3H, 7H)-dione

[00757] The title compound was prepared using the method of example 408. White solid, 0.26 g, 55% yield, LCMS retention time = 3.838 min and 99% purity, LCMS MH+ = 455. The following examples 410a to 410w were prepared using the method of example 404. Example 410a 7 - Benzyl - 8 - (4 - chloro - 3 - (trifluoromethyl)phenyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H) - dione

[00758] White solid, LCMS retention time = 3.625 min and 97% purity, LCMS MH+ = 493. 1HNMR (CDCl3) δ 7.91 (s, 1 H), 7.63 (d, 2 H, J = 8 Hz), 7.59 (d, 2 H, J = 8 Hz), 7.30 - 7.35 (m , 2H); Example 410b: 7 - Benzyl - 8 - (3 -fluorophenyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00759] White solid, 0.051 g, 80% yield, LCMS retention time = 3.004 min and 99% purity, LCMS 20 MH+ = 409. Example 410c 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (m -tolyl) - 1H - purine - 2,6(3H,7H) - Diona

[00760] White solid, 0.054 g, 85% yield, LCMS retention time = 3.133 min and 99% purity, LCMS MH+ = 405. Example 410d: 7 - benzyl -1 - (3 - hydroxypropyl) - 8 - (3 - methoxyphenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - Diona

[00761] White solid, 0.051 g, 84% yield, LCMS retention time = 2.950 min and 99% purity, LCMS MH = 421. Example 410e: 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (3 - (trifluoromethoxy)phenyl) -1H - purine - 2,6(3H,7 H) - dione

[00762] White solid, 0.052g, 80% yield, LCMS retention time = 3.312 min and 99% purity, LCMS MH+= 459. Example 410f: 7 - Benzyl - 8 - (4 - chlorophenyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 202.6(3H,7H) - Diona

[00763] White solid, 0.050 g, 91% yield, LCMS retention time = 3.227 min and 98% purity, LCMS MH+ = 425. Example 410g: 7 - Benzyl - 8 - (4 -fluorophenyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H,7tf) - Diona

[00764] White solid, 0.052 g, 60% production, LCMS retention time = 2.977 min and 99% purity, LCMS MH+ = 409. Example 410h: 7 - benzil -1 - (3 - hydroxypry) - 3 - methyl - 8 - (p -tolil) -1h - Purina - 2.6 (3h)

[00765] Clear oil, 0.028 g, 55% production, LCMS retention time = 3.122 min and 98% purity, LCMS MH+405. Example 410i: 7 - Benzyl -1 - (3 - hydroxypropyl) - 8 - (4 - methoxyphenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00766] White solid, 0.049 g, 91% yield, LCMS retention time = 2.944 minutes and 96% purity, LCMS MH+ = 421. Example 410j: 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (4 - (trifluoromethyl)phenyl) - 1H - purine - 2,6(3H,7 H) - dione

[00767] Sólido branco, 0,052 g, 76% de produção, tempo de retenção de LCMS = 3,348 minutos e 99% de pureza, LCMS MH+ = 459. Exemplo 410k: 7 - Benzil - 8 - (2 - clorofenila) -1 - (3 - hidroxipropil) - 3 - metil -1H - purina - 2,6(3H,7H) - diona

[00768] Óleo claro, 0,057 g, 93% de produção, tempo de retenção de LCMS = 2,979 minutos e 99% de pureza, LCMS MH+ = 425. Exemplo 410I: 7 - Benzil - 8 - (2 -fluorofenila) -1 - (3 - hidroxipropil) - 3 - metil - 1H - purina - 2,6(3H,7H) - diona

[00769] Gold oil, 0.030 g, 91% yield, LCMS retention time = 2.858 minutes and 99% purity, LCMS MH+ = 409. Example 410m: 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (o -tolyl) -1H - purine - 2,6(3H,7H) - dione

[00770] White solid, 0.027 g, 77% yield, LCMS retention time = 2.995 min and 98% purity, LCMS MH+= 405. Example 410n: 7 - Benzyl -1 - (3 - hydroxypropyl) - 8 - (2 - methoxyphenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - Diona

[00771] White solid, 0.061 g, 86% yield, LCMS retention time = 2.831 min and 98% purity, LCMS MH+ = 421. Example 410o 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - (trifluoromethyl)phenyl) - 1H - purine - 2,6(3H,7H ) - dione

[00772] White solid, 0.017 g, 57% yield, LCMS retention time = 3.055 min and 97% purity, LCMS MH+ = 459. Example 410p: 7 - Benzyl -1 - (3 - hydroxypropyl) - 8 - (4 - (isopropylsulfonyl)phenyl) - 3 - methyl -1H - purine - 2,6(3H, 7H) - dione

[00773] Colorless oil, 0.057 g, 88% yield, LCMS retention time = 2.886 minutes and 98% purity, LCMS MH+ = 498. Example 410q: 7 - Benzyl -1 - (3 - hydroxypropyl) - 8 - (2 - isopropylphenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - Diona

[00774] Colorless oil, 0.038 g, 79% yield, LCMS retention time = 3.520 min, LCMS MH+ = 433 and 99% pure. Example 410r: 7 - Benzyl -1 - (3 - hydroxypropyl) - 8 - (3 - isopropylphenyl) - 3 - methyl - 1H - purine - 2,6(3H,7H) - dione

[00775] Colorless oil, 0.026 g, 81% yield, LCMS retention time = 3.609 min and 98% purity, LCMS MH+ = 433. Example 410s: 8 - ([1, 1 ' - Biphenyl] - 3 - yl) - 7 - benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2 ,6(3H,7H) - dione

[00776] Colorless oil, 0.045 g, 80% production, LCMS retention time = 3.609 min, LCMS MH+ = 467 and 99% pure. Example 410t: 7 - Benzyl -1 - (3 - hydroxypropyl) - 3 - methyl - 8 - (2 - (trifluoromethoxy)phenyl) - 1H - purine - 2,6(3H,7H) - dione

[00777] Colorless oil, 0.048 g, 83% yield, LCMS retention time = 3.231 min and 99% purity, LCMS MH+ = 475. Example 410u: 7 - Benzyl - 8 - (3 - (difluoromethoxy)phenyl) -1 - (3 - hydroxypropyl) - 3 - methyl - 1H - purine - 2,6(3H) ,7H) - dione

[00778] Colorless oil, 0.048 g, 83%, LCMS retention time = 3.150 min and 99% purity, LCMS MH+ = 457. Example 410v: 7 - Benzyl - 8 - (4 - (difluoromethoxy)phenyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H ) - dione

[00779] Colorless oil, 0.050 g, 78% yield, LCMS retention time = 3.161 min and 99% purity, LCMS MH+ = 457. Example 410w: 7 - Benzyl - 8 - (4 - (difluoromethyl)phenyl) -1 - (3 - hydroxypropyl) - 3 - methyl -1H - purine - 2,6(3H,7H ) - dione

[00780] Colorless oil, 0.048 g, 75% yield, LCMS retention time = 3.098 min and 99% purity, LCMS MH+ = 441. Example 433: 1 - (5- Hydroxyhexyl) - 3,7 - dimethyl -1H - purine - 2,6(3H,7H) - dione

[00781] Pentoxifylline (1.0 g, 3.59 mmol) was dissolved in methanol (20 mL) and DCM (3 mL), then cooled to 0 °C. To the reaction was added sodium borohydride (0.41 g, 10.8 mmol) portionwise over 30 minutes. The reaction was stirred in the cold for 2 hours; then it was evaporated to dryness under reduced pressure, diluted with water (100ml) and extracted with ethyl acetate (3x75ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to afford 1 - (5 - hydroxyhexyl) - 3,7 - dimethyl -1H - purine - 2,6(3H,7H) - dione (0.72 g, 71% yield) as a white solid. LCMS retention time = 1.849 min and 98% purity, LCMS MH+ 281. 1H NMR (DMSO-d6) δ 8.00 (s, 1 H), 4.31 (d, 1 H, J = 4 Hz), 3.88 (s, 3 H), 3.84 (t, 2 H, J = 8 Hz), 3.51 - 3.59 (m, 1H), 1.45 - 1.56 (m, 2H), 1.25 - 1.37 (m, 4H), 1.02 (d, 3H, J = 4Hz). Example 434. Antidepressant Effect of Compounds of the Invention in the Forced Swim Test Model of Depression

[00782] The forced swimming test (FST) is one of the most widely used in vivo models of antidepressant activity. The immobility observed in this test represents depressed stress-evoked behavior that can be reversed by all major classes of antidepressants. (Porsolt et al., Arch Int Pharmacodvn Ther. 229(2):327-36, 1977; Porsolt et al., Nature 266: 730-732, 1977) (Lucki, et al., Psychopharmacology (Berl). 155(3):315-22, 2001). Briefly, groups of male CD-1 mice (7 weeks old, Charles River Labs) were orally dosed with 0.5% methylcellulose (MC) or compounds of the invention at various doses. The positive control, imipramine, was administered via intraperitoneal (IP) injection at 20mg/kg. Immediately following dosing, mice were returned to their home cages. 60 minutes after administration of methylcellulose or administration of compounds of the invention, and 45 minutes after administration of imipramine, mice were placed individually in polycarbonate cylinders (22.2 cm diameter, 25.3 cm height; Fisher Scientific, Pittsburgh, PA) filled with 15 cm of water, maintained at a temperature of 24 ± 1 °C. In the examples below, immobility or swimming behavior was recorded for 6 minutes after exposure to compounds of the invention. After the 6-minute swimming session, the mice were dried with a towel and returned to the home cage.

[00783] The digital video production of swimming sessions was analyzed by a computer with Noldus software (Ethovision XT Version 8 Video Tracking, Noldus Information Technology, Wageningen, Netherlands). Individual mouse immobility time was acquired and the last 4 minutes of the 6-minute swim section analyzed. The software tracked each animal's movement in a defined arena; images of these displacements were acquired five times per second. In multiple examples, compounds of the invention were able to decrease the time that mice remained immobile. Since immobility correlates with depressed stress-evoked behavior, the ability of the compounds to reverse immobility demonstrates an antidepressant treatment effect. Compound 31

[00784] Mice were administered 10 mL/kg of 0.5% methylcellulose (MC) orally, or 0.1, 0.3, or 1 mg/kg of compound 31 orally, 60 minutes before placement in the chamber. Imipramine, was administered by intraperitoneal injection at 20 mg/kg 45 minutes before the test. Compound 260

[00785] Mice were administered 10 mL/kg of 0.5% methylcellulose (MC) orally, or 0.3, 1, or 3 mg/kg of compound 260, 60 minutes before placement in the chamber. The positive control, imipramine, was administered by intraperitoneal injection at 20 mg/kg 45 minutes before testing. Compound 587

[00786] Mice received 10 mL/kg of orally administered 0.5% methyl cellulose (MC), or Compound 587 in doses of 3, 10, 30, or 100 mg/kg, one hour before testing; or they received 20 mg/kg of imipramine, by intraperitoneal injection 45 minutes before the test. Compound 458

[00787] Mice received 10 mL/kg of orally administered 0.5% methyl cellulose (MC) or Compound 458 at 3, 10, or 30 mg/kg one hour before testing; or they received 20 mg/kg imipramine, by intraperitoneal injection 45 minutes before the test. Compound 458 decreased the time the mice spent immobile, demonstrating an anxiolytic effect. Compound 556

[00788] Mice received 10 mL/kg of orally administered 0.5% methyl cellulose (MC) or 10 Compound 556 at 0.3, 1, or 3 mg/kg one hour before testing; or they received 20 mg/kg imipramine, by intraperitoneal injection 45 minutes before the test. Example 435. Antidepressant Effect of Compound 260 in the Tail Suspension Model of Depression

[00789] The Tail Suspension Test as described by Steru et al. (L. Steru, R. Chermat, B. Thierry, and P. Simon, Psychopharmacology 85(3): 367 - 370, 1985) has become one of the most widely used animal models of depression along with the forced swim test. ( Cryan JF, Mombereau C, Vassout A., Neurosci. Biobehav. Rev. 29(4-5): 571-625, 2005 ).

[00790] In summary, NMRI mice were treated with 0.5% methylcellulose (MC) (4000 CPS) orally or compound 260 at oral doses of 0.3, 1, 3 and 10 mg/kg one hour before the test, or desipramine by intraperitoneal injection of 30 mg/kg, 30 minutes before the test. After this, the mice were suspended by their tails, upside down, for a total of six minutes. A one-minute period was allowed to elapse, allowing the mice to acclimatize, and then the amount of time the mice attempted to stand up within five minutes was recorded. The historically untreated mice became immobile, a reaction to the unavoidable and inescapable stress of their situation. This is believed to model a despair-like behavior seen in depressed patients. Clinically effective antidepressants have historically reversed such immobility. (Steru) Compound 260 at all dose levels was also able to reverse immobility as shown in FIG. 1. Example 436. Anxiolytic Effect of Compounds using the Pit Bury Test Model

[00791] Rodents have been shown to use bedding material to bury harmful materials, however they also bury harmless objects such as mouse pellets and glass beads. This behavior is prevented by the administration of serotonin reuptake inhibitors. It has been proposed that marble grave is a compulsive behavior as it can be reduced by serotonin uptake inhibitors which have been found to be effective in obsessive compulsive disorder (Njung'e, K., et al. Pharmacol. Biochem. Behav. 38(1): 63-7. 1991).

[00792] In the examples below, groups of female C57BL/6 mice (7 weeks old, Charles River Laboratories) were dosed orally with 0.5% methylcellulose (MC) or compounds of the invention at various doses. The positive control, 10 mg/kg of zimelidine, was administered by intraperitoneal (IP) injection 45 minutes before testing. Immediately after dosing, the mice were returned to their home cages. Within 60 minutes after vehicle or compound administration, or 45 minutes after zimelidine administration, mice were placed in clean rat cages (45 cm X 24.5 cm X 13 cm) loaded to 5 cm with BetaChip bedding and containing 20 black glass beads evenly spaced on the BetaChip bedding during a 30-minute test session. On completion, the animals were carefully removed and each cage was photographed for further evaluation. Photos were manually graded for the number of marbles >25% visible by a rater blinded to the treatment. The examples below show that the compounds of the invention were able to reduce burying behavior in mice, where treated mice left more pellets unburied than control groups. Compound 31

[00793] The mice were administered 10 mL/kg of 0.5% methylcellulose (MC) orally, or 0.1, 0.3 or 1 mg/kg of compound 31 orally, 60 minutes before the test. The positive control, 10 mg/kg of zimelidine, was given by intraperitoneal injection 45 minutes before the test. At 0.3 & 1 mg/kg, compound 31 was able to reduce the number of pellets buried compared to the oral control. Compound 260

[00794] The mice were administered 10 mL/kg of 0.5% methylcellulose (MC) orally, or 1, 3, or 10 mg/kg of compound 260 orally, 60 minutes before the test. The positive control, 10 mg/kg of zimelidine, was given by intraperitoneal injection 45 minutes before the test. Compound 587

[00795] Mice were administered 10 mL/kg of 0.5% methylcellulose (MC) orally, or 3, 10, or 30 mg/kg of compound 587 orally, 60 minutes before testing. The positive control, 10 mg/kg zimelidine, was given by intraperitoneal injection 45 minutes before the test. Compound 458

[00796] The mice were administered 10 mL/kg of 0.5% methylcellulose (MC) orally, or 3, 10 30 or 60 mg/kg of compound 458 orally, 15 minutes before the test. The positive control, 10 mg/kg of zimelidine, was given by intraperitoneal injection 45 minutes before the test. Example 437. Anxiolytic Effect of Compounds using the Vogel Anxiety Conflict Test

[00797] For over 30 years, the Vogel Conflict Test has been used as an in vivo animal model to assess the ability of drugs to overcome anxiety in rodents. ( Millan MJ, Brocco M, Eur J Pharmacol. 463(1-3): 67-96, 2003 ). In short, water is withheld from animals for a certain period of time such as 48 hours. Then, after the time period has elapsed, the animals are given free access to the water, but they receive mild electrical shocks from the water source at intermittent periods that occur after a set number of licks, such as in shock every 20 licks. Untreated rats develop avoidance behavior manifested by a refusal to drink. This avoidance-like behavior or internal conflict behavior in rats is similar to avoidance conflicts in man. (Cryan JF, Sweeney FF, British Journal of Pharmacology, 2011; 164: 1129-1161).

[00798] However, Riccio et al (Riccio A. et al., Cell 137: 761 - 772, 2009), indicated that these types of conflict avoidance tests may not be appropriate models for all mechanisms of anxiolytic activity. Riccio showed that TrpC5 knockout mice, in a conflict-avoidance test similar to the aforementioned Vogel test, the novelty-suppressed feeding test using food instead of water, did not behave differently from wild-type mice in the conflict-avoidance model, although the knockout mice showed behavioral differences in other models of anxiety behavior.

[00799] Compound 260 was tested for activity in the Vogel Conflict Test Model. In summary, three-month-old male Wistar - Kyoto rats weighing 225 - 250g received 0.5% methylcellulose (4000 CPS), or compound 260 at doses of 0.3, 1.3 and 10 mg/kg orally 1 hour before the test, or Midazolam 1 mg/kg by intraperitoneal injection, 30 minutes before the test. The results are shown in FIG. 2A and FIG. 2B. As expected, compound 260, a TrpC5 antagonist, did not demonstrate positive activity when compared to the control in this conflict avoidance model. Example 438. Anxiolytic Effects of Compounds of the Invention

[00800] The positive elevated maze test is an in vivo model to assess anxiolytic activity. The test is based on the observation by Montgomery (Montgomery, KC, T Comp Physiol Psychol. 48: 15254-260, 1958) that rodents exposed to an open or closed alley spent more time in the closed alley, characterized as an approach-avoidance conflict. Based on this, Handley and Mithani (Handley SL, Mithani S., Naunvn-Schmiedeberg's Arch Pharmacol. 327: 1-5, 1984.) devised an adaptation using an elevated maze in the form of a positive with 2 closed and 2 open branches. In the high positive maze test, a motivational conflict is established, in which the animals' innate tendency to explore a new environment is opposed to their fear of open spaces. Anxiolytic manipulations reduce the direction to avoid the open spaces, thereby increasing entry, and time spent in the open branches. Furthermore, Riccio et al demonstrated through the use of TrpC5 C57/BL6 knockout mice that activation of TrpC5 leads to an increased fear response in the elevated positive maze (Riccio A et al., Cell 137: 761-772, 2009) but not the conflict novelty-avoidance suppressed feeding test.

[00801] In the following examples, compounds of the invention were tested to determine whether these compounds can reproduce the results observed with the knockout mice when tested in wild-type C57/BL6 mice in the high positive anxiety maze. An activation of TrpC5 in wild-type mice with the compounds of the invention would correlate with an anxiolytic treatment benefit. In summary, using the model described in Riccio, wild-type C57/BL6 mice were dosed with vehicle, positive control, or compounds of the invention. Under inverted light, groups of male C57/BL6 mice (10 weeks old, Jackson Labs) were orally dosed with 0.5% methyl cellulose or compounds of the invention. The positive control, 1.5 mg/kg diazepam, was administered via intraperitoneal injection 30 minutes before testing. Immediately after dosing, the mice were returned to their home cages. At 60 minutes after vehicle or compound administration, and 30 minutes after diazepam administration, mice were placed on the elevated positive maze, (0547M, Mouse Elevated Plus Maze, Columbus Instruments, Example 439. Persistence of Effect of Treatment with Compound 31

[00802] Using the methods described above, the duration of effect observed with mice treated with compound 31 was tested. Mice received either an oral dose of 0.5% methylcellulose (MC) 30 minutes before testing; or an oral dose of compound 31, at a dose of 1 mg/kg, 30 minutes, 60 minutes, or 120 minutes before testing. Videos were manually graded for the number of open branch entries by an assessor blinded to the treatment. Mice treated with Compound 31 walked more frequently and spent more time in the open branching areas of the maze than mice treated with MC, indicating that the effect observed with Compound 31 lasts for at least 2 hours. Longer durations have not been tested. Example 440. Anxiolytic Effect of Compounds of the Invention on the Elevated Positive Maze of Wistar Rats - Kyoto of Anxiety.

[00803] Wistar - Kyoto rats were employed in an elevated positive maze assay, using Midazolam 1mg/kg dose and 0.5% methylcellulose as positive and negative controls, respectively, as well as compound 260 at doses of 0.3, 1, 3 and 10 mg/kg. The results showed that the rats did not spend significant time in the open branching parts of the maze (FIGs. 3A and 3B); However, they were more active on the closed-branching parates than mice receiving vehicle or midazolam (FIG. 3C). Rats traversed a greater distance (measured in centimeters) when the dose of compound 260 (FIG. 3D) was increased. Example 441. Stimulating Effects of Compounds of the Invention in NMRI Mice.

[00804] Compound 260 was tested to ensure that mice were not responding to a stimulating effect of compounds of the invention. In this example, phencyclidine (PCP) was tested at 5 mg/kg dose delivered subcutaneously and with 0.5% methylcellulose (MC) (vehicle) (FIG. 4A), or compound 260 at various doses in NMRI mice (FIG. 4B). Mice treated with PCP had a significantly higher level of locomotor activity compared to methylcellulose, demonstrating an enhanced stimulatory effect, whereas compound 260 at multiple doses did not demonstrate any stimulatory effect unlike control. This example demonstrates that the increased exploration of Compound 260-treated rats in the elevated positive maze was not due to a PCP-like effect of Compound 260. Incorporation by Reference

[00805] All publications and patents mentioned herein are hereby incorporated by reference in their entirety, as if each individual patent or publication was specifically and individually indicated to be incorporated by reference. Equivalents

[00806] Those skilled in the art will recognize, or be able to verify using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the following claims.

Claims (7)

1. Composite, characterized in that it is selected from the group consisting of: 2. Compound, characterized by the fact that it presents the 3. Compound, characterized by the fact that it presents the 4. Compound, characterized by the fact that it presents the 5. Compound, characterized by the fact that it presents the 6. Composite, characterized by the fact that it has the structure 7. Salt, characterized by the fact that it is a pharmaceutically acceptable salt of a compound as defined in any one of claims 1 to 6.