N-oxide derivatives as selective cytotoxic agents

Abstract

The present disclosure is directed to N-oxide derivatives of Formula I (I) and their use for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells, and for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS Related Complex (ARC).

Description

N-OXIDE DERIVATIVES AS SELECTIVE CYTOTOXIC AGENTS CROSS-REERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 566,132, filed March 15, 2024, the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, people living with HIV exhibit severe immunodeficiency which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. Multiple clinically approved antiretroviral drugs are available which demonstrate multi-log reductions in viral loads. Treated patients are at risk for acquiring mutations which render the virus in their bodies resistant to available therapies and rapid rebound of viremia is seen when therapy is removed, indicating that current regimens are not curative.

[0003] HIV is a retrovirus whose life cycle involves reverse transcription of a viral RNA genome into DNA via an enzyme known as reverse transcriptase and subsequent integration of the DNA copy into the host chromosomal DNA via the virally encoded integrase. Viral RNA is transcribed and viral proteins are translated using the host cellular machinery in conjunction with viral accessory proteins. Many viral proteins are contained within the GAG and GAG-POL polyproteins, with GAG containing structural proteins and GAG-POL resulting from a frameshift near the carboxy-terminus of GAG and containing protease (PR), reverse transcriptase (RT), and integrase (IN) viral enzymes, in addition to the structural proteins. GAG and GAG-POL are cleaved into individual proteins through the process of maturation which occurs during budding of virions from the infected cell. At this time GAG-POL dimerizes and the now dimeric HIV PR within the GAG-POL dimer forms an active enzyme which can cleave itself out of the polyprotein and catalyze further cleavage to form the remaining viral enzymes and structural proteins.

[0004] Available antiretroviral drugs act by blocking the virus at different stages in the viral life cycle. For example, reverse transcriptase inhibitors target the viral reverse transcriptase and prevent the RNA genome from being copied into DNA, integrase inhibitors block the ability of the copied DNA from being integrated into the host cell, and protease inhibitors prevent viral maturation so that virions produced from cells treated with protease inhibitors are immature and non-infectious. Once integration has occurred, a cell is infected until it dies through either normalcell death pathways, accelerated death due to viral factors, or is targeted by the immune system. While most infected cells are expected to die within ~2 days of being infected, the rapid rebound of viremia when therapy is removed is an indication that infected cells remain even after years on therapy (See, e.g., J. B. Dinoso et al., Proc. Natl. Acad. Sci. U.S.A., 2009, 106(23): 9403-9408). These latently infected and / or persistently virus-expressing cells that remain even during antiretroviral therapy are collectively termed the HIV reservoir and are the reason that people living with HIV require life-long treatment with a high level of adherence to maintain virus at undetectable levels. Thus, new therapies that can selectively kill the HIV infected cells would provide new treatment options for HIV infection. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1+cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4+T cells isolated from people living with HIV-1, thus supporting an immune-independent clearance strategy (See, e.g., C. J. Balibar, et al., Sci. Transl. Med., 2023, 684 (15):eabn2038).

[0005] Treatment with compounds that can accelerate death of HIV infected cells and decrease the overall number of virally infected cells that persist within patients has the potential to decrease residual viremia in HIV suppressed individuals and address co-morbidities associated with chronic viral infection such as chronic inflammation, immune dysfunction, accelerated aging, cardiovascular disease (CVD), central nervous system (CNS) and other tissue and end- organ damage. Furthermore, treatment with compounds that can purge the remaining HIV reservoir may prolong viral remission off therapy and play a role in an HIV cure strategy. SUMMARY OF THE INVENTION

[0006] The present disclosure is directed to N-Oxide derivatives and their use as HIV-Targeted Activator of Cell Kill agents which accelerate the death of HIV GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells. Accordingly, the compounds are useful for selectively killing HIV infected, GAG-POL expressing cells in a subject infected with HIV. Additionally, the compounds disclosed herein are useful for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS Related Complex (ARC). Compositions and methods of use comprising the compounds of this disclosure are also provided.

[0007] In one aspect, the present disclosure provides compounds of Formula (I)their pharmaceutically acceptable salts.

[0008] The present disclosure is directed to N-Oxide derivative compounds and their use for accelerating the death of HIV GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells. In the absence of compounds such as those from the present disclosure, protease (PR) activation takes place during viral maturation and the concentration of mature PR in the cytoplasm is limited. In contrast, the present compounds promote the desired phenotype by catalyzing GAG-POL dimerization inside the infected cell by binding to the immature RT binding site and triggering premature activation of the HIV PR enzyme inside the host infected cell prior to budding. As a result, PR cleaves host substrates within the cell, leading to cytotoxicity and cell death. This effect can be blocked in the presence of an HIV protease inhibitor such as indinavir or darunavir demonstrating the role of HIV protease in the process.

[0009] The compounds presently disclosed herein also have activity as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), due to the homology between the mature and immature RT pocket in HIV that allows the compounds to bind to the mature hydrophobic pocket near the active site of the viral RT enzyme. Binding to mature RT results in inhibition of enzymatic activity and production of the DNA provirus, which prevents infection of naïve CD4+ T-cells.

[0010] While effects of NNRTIs on dimerization of RT and GAG-POL have been documented (Tachedjian et al. Proc. Natl. Acad. Sci. U.S.A.2001, 98(13):7188; Tachedjian et al. FEBS Lett. 2005, 579:379; Figueiredo et al. PLOS Path.2006, 2(11):1051; Sudo et al. J. Virol.2013, 87(6):3348), selective killing of HIV infected cells as a result of enhanced dimerization was first reported by Jochmans et al. (Jochmans et al. Retrovirology 2010, 7:89). The authors generated data showing these effects in chronically infected MT-4 cells, PBMCs, and CD4+ cells. Based on the potencies of tested molecules they concluded that “These data present proof of concept for targeted drug induced elimination of HIV producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic application, the results provide a basis for the development of25909 drugs exploiting this mechanism of action.” More recently, Zerbato et al. (Zerbato et al. Antimicrob. Agents Chemother.2017, 61(3)) measured the activity of NNRTIs in a primary cell model for HIV latency. They saw significant reduction in virus production for certain NNRTIs compared to other classes of antiretrovirals and inferred that this was due to these compounds’ ability to eliminate cells expressing HIV GAG-POL proteins. More recently, in their paper Trinité et al.(Trinité et al., Retrovirology, 2019, 16(17)) stated that NNRTI-induced PR- activation triggers apoptotic cell death of productively HIV-infected resting or activated T-cells.

[0011] The present disclosure is directed to a compound of Formula (I) or a pharmaceuticallyX is N or C(R2);W is N or C(R9);R1 is selected from C1-10alkyl, amino(C0-10alkyl), C1-10fluoroalkyl, (C1-10alkyloxy)(C0-10alkyl), (hydroxy C1-10alkyl)oxy(C0-10alkyl), and hydroxy(C0-10alkyl), whereinR1is substituted by 0, 1, or 2 R10substituents;each R10 independently is halogen, hydroxy, C0-6alkyl, or C1-10alkyloxy;R2 is selected from hydrogen, halogen, C1-10alkyl, cyano, C1-10fluoroalkyl, and C1-10alkyloxy(C0-6alkyl);R3 is selected from hydrogen, halogen, and C1-10alkyl;R4 is selected from hydrogen, halogen, C1-10alkyl, and C1-10fluoroalkyl;R5 is selected from hydrogen, halogen, C1-10alkyl, and C1-10alkyloxy;R6 is selected from hydrogen, cyano, halogen, C1-10alkyl, and C1-10alkyloxy(C0-6alkyl);R7 is selected from hydrogen, halogen, C1-10alkyl, and cyano;R8 is selected from hydrogen, halogen, C1-10alkyl, cyano, C1-10fluoroalkyl, and C1-10alkyloxy(C0-6alkyl); andR9 is hydrogen, halogen, C1-10alkyl, or C1-10alkyloxy(C0-6alkyl).

[0012] In a first embodiment of the invention, X is C(R2), wherein R2is selected fromhydrogen, halogen, C1-6alkyl, cyano, C1-6fluoroalkyl, and C1-6alkyloxy(C0-6alkyl) and theother groups are as provided in the general Formula (I) above. In a variant of this embodiment, Xis C(R2), wherein R2is selected from hydrogen, Br, Cl, F, methyl, ethyl, propyl, isopropyl,butyl, pentyl, tert-butyl, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroethyl, difluoroethyl, methoxy, ethoxy, propoxy, ethoxymethyl, and ethoxyethyl and the other groups are as provide in the general Formula (I) above. In anothera variant of this embodiment, X is C(R2), wherein R2is selected from hydrogen, Br, Cl, F,methyl, cyano, trifluoroethyl, fluoroeth-1yl, difluoroethyl, and methoxy, and the other groups are as provide in the general Formula (I) above. In yet another a variant of this embodiment, X isC(R2), wherein R2is selected from hydrogen, Br, Cl, F, methyl, cyano, 2,2,2-trifluoroethyl,1,1,1-trifluoroethyl, 1,2-difluoroethyl, 2,2,-difluoroethyl, 1,1-difluoroethyl, fluoroeth-1-yl, and methoxy, and the other groups are as provide in the general Formula (I) above.

[0013] In a second embodiment of the invention, X is N, and the other groups are as provided in the general Formula (I) above.

[0014] In a third embodiment of the invention, W is C(R9), wherein R9is selected fromhydrogen, halogen, C1-6alkyl, and C1-6alkyloxy(C0-6alkyl), and the other groups are asprovided in the general Formula (I) above or as in the first through second embodiments.

[0015] In a fourth embodiment of the invention, W is C(R9), wherein R9is selected fromhydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, ethoxymethyl, and ethoxyethyl, and the other groups are as provided in the general Formula (I) above or as in the first through second embodiments.

[0016] In a fifth embodiment of the invention, W is C(R9), wherein R9is selected fromhydrogen, fluoro, chloro, methyl, and methoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through second embodiments.

[0017] In a sixth embodiment of the invention, W is N, and the other groups are as provided in the general Formula (I) above, or as in the first through second embodiments.

[0018] In a seventh embodiment, R1 is selected from C1-10alkyl, amino(C0-6alkyl), C1-6fluoroalkyl, (C1-6alkyloxy)(C0-10alkyl), (hydroxy C1-10alkyl)oxy(C0-6alkyl), andhydroxy(C0-6 alkyl), wherein R1is substituted by 0, 1, or 2 R10substituents, and the othergroups are as provided in the general Formula (I) above, or as in the first through sixth embodiments.

[0019] In an eighth embodiment, R1is selected from amino, methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, hexyl,difluoromethyl, fluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, fluoroethyl, difluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxytert-butyl, hydroxyethoxy, hydroxypropoxy, hydroxybutoxy, methoxy, ethoxy, propoxy, 2-hydroxyethoxymethyl, hydroxyethoxymethyl, 2-hydroxyethoxyethyl,wherein R1is substituted by 0, 1, or 2 R10substituents, and the other groups are as provided inthe general Formula (I) above, or as in the first through sixth embodiments.

[0020] In a ninth embodiment of the invention, R1is selected from amino, 2,2,2-trifluoroethyl, 1,1,1-trifluoroethyl, 1,2-difluoroethyl, 2,2,-difluoroethyl, 1,1-difluoroethyl, fluoroeth-1-yl,hydroxymethyl, hydroxyethoxy, methoxy, ethoxy, and 2-hydroxyethoxymethyl, wherein R1issubstituted by 0, 1, or 2 R10substituents, and the other groups are as provided in the generalFormula (I) above, or as in the first through sixth embodiments.

[0021] In a tenth embodiment of the invention, each R10independently is selected fromhalogen, hydroxy, C0-6alkyl, and C1-6alkyloxy, and the other groups are as provided in thegeneral Formula (I) above, or as in the first through ninth embodiments.

[0022] In an eleventh embodiment of the invention, each R10independently is selected fromfluoro, chloro, bromo, methyl, ethyl, propyl, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through ninth embodiments.

[0023] In a twelfth embodiment of the invention, each R10independently is selected frommethyl and methoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through ninth embodiments.

[0024] In a thirteenth embodiment of the invention, R1substituted by 0, 1, or 2 R10,25909 , or , and the other groups are as sixth embodiments.from hydrogen, fluoro,bromo, chloro, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, and pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through thirteenth embodiments.

[0026] In a fifteenth embodiment of the invention, R3is selected from hydrogen, and fluoro,and the other groups are as provided in the general (I) above, or as in the first throughthirteenth embodiments.

[0027] In a sixteenth embodiment of the invention, R4is selected from hydrogen, halogen, C1-6alkyl, and C1-6fluoroalkyl, and the other groups are as provided in the general Formula (I)above, or as in the first through fifteenth embodiments.

[0028] In a seventeenth embodiment of the invention, R4is selected from hydrogen, fluoro,bromo, chloro, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, difluoroethyl, trifluoroethyl, fluoroethyl, 1,1,3,3-tetrafluoropropyl, 1,1,3,3,3-tetrafluoropropyl, 1,1,2,2- tetrafluoroethyl, 1,1,1,2,2-pentafluoroeth-2yl, and1,1,1,2,2-pentafluoroethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through fifteenth embodiments.

[0029] In an eighteenth embodiment of the invention, R4is selected from hydrogen, fluoro,trifluoroethyl, fluoroeth-1yl, 1,2-difluoroethyl, 2,2,-difluoroethyl, 1,1-difluoroethyl, and 1,1,1,2,2-pentafluoroeth-2yl, and the other groups are as provided in the general Formula (I) above, or as in the first through fifteenth embodiments.

[0030] In a ninteenth embodiment of the invention, R5is selected from hydrogen, halogen, C1-6alkyl, and C1-6alkyloxy, and the other groups are as provided in the general Formula (I)above, or as in the first through eigthteenth embodiments.

[0031] In a twentieth embodiment of the invention, R5is selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, and pentoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through eigthteenth embodiments.

[0032] In a twenty-first embodiment of the invention, R5is selected from hydrogen, fluoro,chloro, methyl, and methoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through eigthteenth embodiments.25909

[0033] In a twenty-second embodiment of the invention, R6is selected from hydrogen, cyano,halogen, C1-6alkyl, and C1-6alkyloxy(C0-6alkyl), and the other groups are as provided in thegeneral Formula (I) above, or as in the first through first embodiments.

[0034] In a twenty-third embodiment of the invention, R6is selected from hydrogen, andcyano, and the other groups are as provided in the general Formula (I) above, or as in the firstthrough twenty-first embodiments.

[0035] In a twenty-fourth embodiment of the invention, R7is selected from hydrogen, halogen,C1-6alkyl, and cyano, and the other groups are as provided in the general Formula (I) above, oras in the first through twenty-third embodiments.

[0036] In a twenty-fifth embodiment of the invention, R7is selected from hydrogen, andcyano, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-third embodiments.

[0037] In a twenty-sixth embodiment of the invention, R8is selected from hydrogen, fluoro,bromo, chloro, methyl, ethyl, propyl, butyl, isopropyl, butyl, pentyl, cyano, trifluoromethyl,difluoromethyl, difluoroethyl, trifluoroethyl, fluoroethyl, 1,1,3,3-tetrafluoropropyl, 1,1,3,3,3- tetrafluoropropyl, 1,1,2,2-tetrafluoroethyl, 1,1,1,2,2-pentafluoroeth-2yl, 1,1,1,2,2- pentafluoroethyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, methoxymethyl, ethoxymethyl, propoxyisopropyl, butoxy, tert-butoxy, and pentoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-fifth embodiments.

[0038] In a twenty-seventh embodiment of the invention, R8is selected from hydrogen, bromo,chloro, methyl, cyano, and difluoromethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-fifth embodiments.

[0039] Non-limiting examples of the Compounds of Formula I include compounds 1 through 45 or a pharmaceutically acceptable salt thereof, as set forth in the Examples: 2-((5-(5-bromo-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-chloro-5-cyanophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2- hydroxyethoxy)-4-methylpyridine 1-oxide; 4-bromo-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-(trifluoromethyl)pyridine 1-oxide;4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-methoxypyridine 1-oxide; 2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-(difluoromethyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-((1-hydroxy-2-methylpropan-2-yl)oxy)-4-methylpyridine 1-oxide; 2-((5-(2-chloro-4-cyano-6-methylphenoxy)-4-(1-fluoroethyl)-6-oxopyrimidin-1(6H)-yl)methyl)- 5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; R-2-((5-(2-chloro-4-cyano-6-methylphenoxy)-4-(1-fluoroethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; S-2-((5-(2-chloro-4-cyano-6-methylphenoxy)-4-(1-fluoroethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-4,5-dimethoxypyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)-yl)methyl)- 5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-chloro-5-cyanophenoxy)-4-(1,1-difluoroethyl)-6-oxopyrimidin-1(6H)-yl)methyl)-4- cyano-5-(2-methoxyethoxy)pyridine 1-oxide; 4-bromo-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-bromo-3-cyano-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methoxyphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-(trifluoromethyl)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-fluoro-5-(2-hydroxyethoxy)pyridine 1-oxide;2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-((1-hydroxypropan-2-yl)oxy)pyridine 1-oxide; S-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-((1-hydroxypropan-2-yl)oxy)pyridine 1-oxide; R-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-((1-hydroxypropan-2-yl)oxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-((2-hydroxyethoxy)methyl)-4-methylpyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-4-(1,1-difluoroethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(hydroxymethyl)pyrazine 1-oxide; 2-((5-(5-bromo-2-chloro-3-cyanophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-((4-cyano-6-methylpyridin-2-yl)oxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-((6-chloro-4-cyanopyridin-2-yl)oxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-3-fluoro-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxy-2-methylpropoxy)-4-methylpyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(hydroxymethyl)pyridine 1-oxide; 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-bromo-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-chloro-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide;25909 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1- oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(methylamino)pyridine 1-oxide; 2-((5-(5-bromo-3-cyano-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-chloro-5-(2-hydroxyethoxy)pyridine 1-oxide; and 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide.

[0040] In one embodiment of the invention, are selective Compounds of Formula I included below or a pharmaceutically acceptable salt thereof, selected from 4-bromo-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-bromo-2-chloro-3-cyanophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide;25909 4-chloro-2-((5-((4-cyano-6-methylpyridin-2-yl)oxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; and 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide.

[0041] In a variant of this embodiment the compound, or a pharmaceutically acceptable salt thereof, is selected from: 4-bromo-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-bromo-2-chloro-3-cyanophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; and 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide.

[0042] In another variant, the compound, or a pharmaceutically acceptable salt thereof, is selected from: 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-((4-cyano-6-methylpyridin-2-yl)oxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide;25909 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; and 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide.

[0043] The invention is directed to the compounds of Formula I herein and all embodiments, examples, classes and sub-classes thereof and includes the compounds of the Examples herein. The invention is further directed to compounds of Formula I which are neutral compounds or salts thereof when such salts are possible, including pharmaceutically acceptable salts.

[0044] The term “e.g.” means “for example.” When the terms “e.g.,” or “for example” are used herein, the example(s) recited are intended to be illustrative and are not intended to be an exhaustive list of all relevant examples. The term “i.e.” means “that is.”

[0045] As used herein, "alkyl" refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range. Forexample, “C1-8alkyl” refers to each of the alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbonatoms, including linear or branched isomers thereof. “C1-8alkyl” includes the “C1-6alkyl”groups and the linear and branched chain alkyls having 7 or 8 carbons in the chain.

[0046] The term “alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, dialkylamino, and trialkylammonium, and the like, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond.

[0047] “Amino” means -NH- or -NH2-, wherein one or more hydrogen atoms may be substituted as further described herein.

[0048] “Celite®” (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0049] “Fluoroalkyl” refers to an alkyl group as described above wherein one or more (in particular, 1 to 10 hydrogen atoms have been replaced by flourine atoms, with up to complete substitution of all hydrogen atoms with halo groups. C1-6 haloalkyl, for example, includes – CH2F, –CHF2,–CF3, –CF2CF3, –CHFCH3, and the like.

[0050] “Halo” or “halogen” refers to chloro, fluoro, bromo and / or iodo. Chloro, fluoro and bromo are a class of halogens of interest, and more particularly fluoro and chloro.

[0051] “Hydroxy” means -OH group.

[0052] “HydroxyC1-10alkyl” or “hydroxyalkyl” refers to alkyl substituted with a hydroxy(OH) group.

[0053] The term “oxy” means an oxygen (O) atom.

[0054] “HIV naïve cell(s)” are cells that are not infected with HIV.25909

[0055] “Compatible anti-HIV agent(s)” are anti-HIV agents excluding HIV protease inhibitors.

[0056] A “latency reversing agent” (LRA) is a pharmaceutical agent capable of re-activating latent HIV (e.g., HIV-1) in an HIV (e.g., HIV-1) infected cell, particularly in a human.

[0057] A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds of the present disclosure are limited to stable compounds embraced by Formula I and its embodiments. For example, certain moieties as defined in Formula I may be unsubstituted or substituted, and the latter is intended to encompass substitution patterns (i.e., number and kind of substituents) that are chemically possible for the moiety and that result in a stable compound.

[0058] This disclosure includes individual diastereomers, particularly epimers, i.e., compounds having the same chemical formula but which differ in the spatial arrangement around a single atom. This disclosure also includes mixtures of diastereomers, particularly mixtures of epimers, in all ratios. This disclosure encompasses compounds of Formula I having either the (R) or (S) stereo-configuration at an asymmetric center and at any additional asymmetric centers that may be present in a compound of Formula I, as well as stereo-isomeric mixtures thereof. Embodiments of this disclosure also include a mixture of enantiomers enriched with 51% or more of one of the enantiomers, including for example 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer. A single epimer is preferred. An individual or single enantiomer refers to an enantiomer obtained by chiral synthesis and / or using generally known separation and purification techniques, and which may be 100% of one enantiomer or may contain small amounts (e.g., 10% or less) of the opposite enantiomer. Thus, individual enantiomers are a subject of this disclosure in pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism this disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios.

[0059] The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or25909 crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis. The present disclosure includes all such isomers, as well as salts, solvates (which includes hydrates), and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0060] As would be understood by one of ordinary skill in the art, certain compounds of the present disclosure may be able to exist as tautomers. All tautomeric forms of such compounds, whether isolated individually or in mixtures, are within the scope of the present disclosure. For example, in instances where an oxo (=O) substituent is permitted on a heterocyclic ring and keto- enol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the –OH as well as the oxo form. Examples of tautomers of compounds herein include but are not limited to the following:

[0061] The atoms in a compound of Formula I may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds of Formula I; for example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds25909 of Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0062] The compounds can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise rious to the recipient thereof). When the compounds of Formula I contain one or more acidic groups or basic groups, the invention includes the corresponding pharmaceutically acceptable salts.

[0063] Thus, the compounds of Formula I that contain acidic groups (e.g., -COOH) can be used according to the invention as, for example but not limited to, alkali metal salts, alkaline earth metal salts or as ammonium salts. Examples of such salts include but are not limited to sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of Formula I, which contain one or more basic groups, i.e., groups which can be protonated, can be used according to the invention in the form of their acid addition salts with inorganic or organic acids as, for example but not limited to, salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present invention also includes all salts of the compounds of Formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0064] The instant disclosure encompasses any composition comprised of a compound of Formula I or a compound that is a salt thereof, including for example but not limited to, a composition comprised of said compound associated together with one or more additional25909 molecular and / or ionic component(s) which may be referred to as a “co-crystal.” The term "co- crystal" as used herein refers to a solid phase (which may or may not be crystalline) wherein two or more different molecular and / or ionic components (generally in a stoichiometric ratio) are held together by non-ionic interactions including but not limited to hydrogen-bonding, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces (van der Waals). There is no proton transfer between the dissimilar components and the solid phase is neither a simple salt nor a solvate. A discussion of co-crystals can be found, e.g., in S. Aitipamula et al., Crystal Growth and Design, 2012, 12 (5), pp.2147–2152.

[0065] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I and salts thereof are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the compounds of this disclosure are likewise encompassed within the scope of the compounds defined by Formula I and the pharmaceutically acceptable salts thereof, along with un-solvated and anhydrous forms of such compounds.

[0066] Accordingly, the invention is directed to compounds of Formula I or salts thereof including pharmaceutically acceptable salts thereof, embodiments thereof and specific compounds described and claimed herein, and encompass all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), co-crystal forms, solvate and hydrate forms, and any combination of the foregoing forms where such forms are possible.

[0067] Another embodiment of the present disclosure is a composition comprising a compound of Formula I wherein the compound or its salt is present in the composition in a substantially pure form. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt. % to 100 wt. %), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a composition or product containing a compound of Formula I or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis such as, high performance liquid chromatography, and / or mass spectrometry or NMR techniques. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level25909 of purity determined, then the method providing the highest purity level governs. A composition comprising a compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis. With respect to a compound of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure composition comprising the compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual stereoisomer.

[0068] The compounds of Formula I herein, and pharmaceutically acceptable salts thereof, are useful for eliciting GAG-POL dimerization in HIV-infected cells and thereby selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells, referred to herein as TACK (Targeted Activator of Cell Kill) activity, or more specifically HIV TACK activity. HIV TACK or TACK have also been previously referred to as Small Molecule Activated Cell Kill (SMACK). Thus, the compounds of Formula I and pharmaceutically acceptable salts thereof are useful for: (i) A method for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis, or delay in the onset or progression of AIDS or ARC in a human subject in need thereof which comprises administering to the human subject an effective amount of the compound according to Formula I, or a pharmaceutically acceptable salt thereof; and / or (ii) A method for eliciting GAG-POL dimerization in HIV-infected cells in a human subject in need thereof which comprises administering to the human subject an effective amount of the compound according to Formula I, or a pharmaceutically acceptable salt thereof; and / or (iii) A method for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a human subject which comprises administering to the human subject an effective amount of the compound according to Formula I, or a pharmaceutically acceptable salt thereof; and / or (iv) A method for augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the human subject an effective amount of the compound according to Formula I, or a pharmaceutically acceptable salt thereof.

[0069] Additionally, the compounds of Formula I and pharmaceutically acceptable salts thereof are useful for any of the methods (i), (ii), (iii) or (iv) above, further comprising administering to the human subject an effective amount of one or more compatible HIV antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-25909 attachment inhibitors and latency reversing agents. In the methods of (i), (ii), (iii) or (iv) immediately above, the human subject can be treated with a compound of Formula I or a pharmaceutically acceptable salt thereof in addition to treatment with one or more compatible HIV antiviral agents.

[0070] The compounds of Formula I and pharmaceutically acceptable salts thereof are also useful for a method for augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the human subject an effective amount of the compound according to Formula I, or a pharmaceutically acceptable salt thereof.

[0071] Other embodiments of the present disclosure include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (b) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of one or more compatible anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators, anti-infective agents and latency reversing agents. (d) The pharmaceutical composition of (c), wherein the compatible anti-HIV agent is selected from one or more of an antiviral selected from the group consisting of nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents. (e) A combination which is (i) a compound of Formula I or a pharmaceutically acceptable salt thereof and (ii) one or more compatible anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators, anti-infective agents and latency reversing agents; wherein the compound and the compatible anti-HIV agent are each employed in an amount that renders the combination effective for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC. (f) The combination of (e), wherein the compatible anti-HIV agent is an antiviral selected from the group consisting of nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse25909 transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents. (g) A method for eliciting GAG-POL dimerization in HIV-infected cells, a method for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells, and / or a method for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis, or delay in the onset or progression of AIDS or ARC, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. (h) The method of (g), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one other compatible HIV antiviral selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents. (i) The method of (g) or (h) comprising administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f). (j) Use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for (1) eliciting GAG-POL dimerization in HIV-infected cells in a subject; (2) selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a subject; (3) treatment or prophylaxis of infection by HIV in a subject; (4) treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a subject; (5) augmenting the suppression of HIV viremia in a subject undergoing treatment with a compatible anti-HIV agent, and / or (6) augmenting the suppression of HIV viremia in a subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents. (k) A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in (1) eliciting GAG-POL dimerization in HIV-infected cells; (2) selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells; (3) treatment or prophylaxis of infection by HIV; (4) the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC; and / or (5) augmenting the suppression of HIV viremia in a subject undergoing treatment with a compatible anti-HIV agent, and / or (6) augmenting the suppression of HIV viremia in a subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents.25909

[0072] Additional embodiments of the present invention include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of Formula I or its salt employed therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "substantially pure" is in reference to a compound of Formula I or its salt per se.

[0073] In another embodiment of the present disclosure are the pharmaceutical compositions, methods, medicaments, uses and combinations set forth herein, wherein the HIV of interest is HIV-1. Thus, for example, in any of the pharmaceutical compositions, methods, medicaments, uses and combinations using the compounds of Formula I or pharmaceutically acceptable salts thereof, the compound or salt thereof is employed in an amount effective against HIV-1; and when used in combination with one or more compatible anti-HIV agent(s), each such additional agent is a compatible HIV-1 antiviral selected from, for example but not limited to, one or more of nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post- attachment inhibitors and latency reversing agents.

[0074] The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula I means providing the compound to the individual in need of treatment or prophylaxis and includes both self-administration and administration to the patient by another person or any other means. When a compound is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating or prophylaxis of HIV infection or AIDS), "administration" and its variants are each understood to include provision of the compound and other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.

[0075] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results from combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means the ingredients must be compatible with each other and not rious to the recipient thereof.

[0076] The term "subject" or “patient” as used herein refers to a human (or “person”) who has been the object of treatment, observation or experiment. Examples of patients to be treated with an HIV TACK agent include but are not limited to, patients who have been infected with HIV,25909 and / or HIV infected patients whose HIV viral load has been suppressed and / or is considered to be undetectable at time of HIV TACK treatment. Patients to be treated with an HIV TACK agent also include, but are not limited to, those using an HIV TACK agent for prophylaxis of HIV infection or for post-exposure prophylaxis after being potentially exposed to HIV to prevent becoming infected.

[0077] “Prophylaxis” includes each of pre-exposure prophylaxis (PrEP), i.e., using a compound of Formula I or a pharmaceutically acceptable salt thereof to prevent HIV infection in a person who does not have HIV, and post-exposure prophylaxis (PEP), i.e., using a compound of Formula I or a pharmaceutically acceptable salt thereof after being potentially exposed to HIV to prevent becoming infected with HIV.

[0078] The term "effective amount" as used herein means an amount of a compound sufficient to elicit GAG-POL dimerization in HIV-infected cells and selectively kill HIV infected GAG- POL expressing cells without concomitant cytotoxicity to HIV naïve cells; and / or exert a therapeutic effect, and / or exert a prophylactic effect after administration. One embodiment of “effective amount” is a "therapeutically effective amount" which is an amount of a compound that is effective for selectively killing HIV infected GAG-POL expressing cells, effective for treating HIV infection, or effective for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a patient infected with HIV. Another embodiment of “effective amount” is a "prophylactically effective amount" which is an amount of the compound that is effective for prophylaxis of HIV infection, or prophylaxis of AIDS or ARC in an HIV-infected patient. It is understood that an effective amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of HIV infection, and a prophylactically effective amount, e.g., for prevention or reduction of risk for developing AIDS or ARC in a subject infected with HIV.

[0079] In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered in the combination are together effective, but wherein a component agent of the combination may or may not be present individually in an effective amount with reference to what is considered effective for that component agent if it were administered alone.

[0080] In the methods of the present invention., (i.e., selectively killing HIV infected GAG- POL expressing cells, the treatment of infection by HIV, prophylaxis of HIV infection or the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC and other methods described herein), the compounds of this invention, or salts thereof, can be administered by means that produce contact of the active agent with the agent's site of action. They can be25909 administered by conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. The compound can be administered itself, but typically is administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally (e.g., via tablet or capsule), parenterally (including subcutaneous injections, intravenous, intramuscular or intrasternal injection, or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The compound could also be administered via an implantable drug delivery device adapted to provide an effective amount of the compound or a pharmaceutical composition of the compound over an extended period of time. FORMULATIONS

[0081] Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art wherein the carrier comprises the active chemical ingredient with polymers and suitable excipients, or utilizing an implantable device for drug delivery. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978085711-062-6 and prior editions.

[0082] Formulations of compounds of Formula I that result in drug supersaturation and / or rapid dissolution may be utilized to facilitate oral drug absorption. Formulation approaches to cause drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticulate25909 systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for preparing them are known in the art. For example, solid dispersions can be prepared using excipients and processes as described in reviews (e.g., A.T.M. Serajuddin, J Pharm Sci, 88:10, pp.1058-1066 (1999)). Nanoparticulate systems based on both attrition and direct synthesis have also been described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp.631-644 (2007)).

[0083] The compounds of Formula I may be administered in a dosage range of, e.g., 1 to 20 mg / kg, or 1 to 10 mg / kg, or about 5 mg / kg of mammal (e.g., human) body weight per day, or at other time intervals as appropriate, in a single dose or in divided doses. The compounds of Formula I may be administered in a dosage range of 0.001 to 2000 mg. per day in a single dose or in divided doses. Examples of dosage ranges are 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, administered orally or via other routes of administration in a single dose or in divided doses.

[0084] For oral (e.g., tablets or capsules) or other routes of administration, the dosage units may contain 100 mg to 1500 mg of the active ingredient, for example but not limited to, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400 or 1500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. Furthermore, the compound may be formulated in oral formulations for immediate or modified release such as extended or controlled release. When the compound of Formula I is administered as a salt, reference to an amount of the compound in milligrams or grams is based on the free form (i.e., the non-salt form) of the compound.

[0085] Daily administration can be via any suitable route of administration but is preferably via oral administration and can be a single dose or more than one dose at staggered times (divided daily doses) within each 24-hour period. Each dose may be administered using one or multiple dosage units as appropriate.

[0086] The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upwards or downwards from the given dose. The amount and frequency of administration will be regulated according to the judgment of the attending clinician considering such factors.

[0087] An "anti-HIV agent" is any agent which is directly or indirectly effective in the inhibition of HIV, the treatment or prophylaxis of HIV infection, and / or the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC. It is understood that an anti- HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and / or diseases or conditions arising therefrom or associated therewith. The present disclosure is additionally directed to use of a compound of Formula I or pharmaceutically acceptable salts thereof, with one or more compatible anti-HIV agents, i.e., anti-HIV agents excluding HIV protease inhibitors (also referred to as “compatible HIV antivirals”). For example, the compounds of Formula I may be administered in combination with effective amounts of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infectives, or vaccines useful for treating HIV infection or AIDS. Suitable compatible HIV antivirals for use in combination with the compounds of the present disclosure include, but are not limited to, those listed in Table A as follows: TABLE A: Antiviral Agents for Treating HIV infection or AIDS Name Type abacavir, ABC, ZIAGEN® NRTIName Type Elvitegravir, VITEKTA® InSTI t i it bi FTC EMTRIVA® NRTI AI inhibitor; NRTI = nucleoside or nucleotide reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTTI = nucleoside reverse transcriptase translocation inhibitor. Some of the drugs listed in Table A are used in a salt form; e.g., abacavir sulfate, delavirdine mesylate.

[0088] The TACK effect elicited by an HIV-TACK agent depends on expression of viral Gag- Pol. Therefore, additional active agents, such as latency reversing agents (“LRA” or “LRAs”), that enhance Gag-Pol production in infected cells and / or activate viral expression in cells that comprise the latent HIV reservoir, when used together with HIV-TACK therapy, are likely to enhance the TACK effect. The present disclosure is additionally directed to use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with one or more LRA(s). For example, the compounds of Formula I may be administered in combination with effective amounts of one or more LRA(s) for treatment of HIV infection or AIDS. Examples of LRAs for use in combination with the compounds of the present disclosure include, but are not limited to epigenetic modifiers such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors, and histone methyltransferase (HMT) inhibitors; Protein Kinase C (PKC)25909 agonists such as prostratins, bryostatins, or ingenols; inducers of P-TEFb release such as BET inhibitors (e.g., JQ1 or a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and / or BRDT), antagonists of C- C chemokine receptor type 5 (CCR5), inducers of non-canonical NF-κB pathway (e.g., second mitochondria-derived activator of caspases (SMAC) mimetics or inhibitor of apoptosis proteins (IAP) antagonists, proteasome inhibitors, toll-like receptor (TLR) agonists, mitogen-activated protein kinase (MAPK) agonists, Ak strain transforming / protein kinase B (AKT / PKB) pathway activators, cytokines and immunomodulatory agents such as immune checkpoint inhibitors and those described elsewhere such as Bullen et al., Nature Medicine, 20:425-429 (2014); Ait- Ammar et al., Frontiers in Microbiology, 10:3060 (2019); and Fujinaga et al., Viruses.12:11 (2020).

[0089] Examples of HDAC inhibitors that can be used as latency reversing agents include, but are not limited to, vorinostat, panabinostat, romidepsin, and valproic acid. Examples of DNMT inhibitors that can be used as latency reversing agents include, but are not limited to, 5-aza-2′- cytidine and 5-aza-2′-deoxycytidine. Examples of HMT inhibitors that can be used as latency reversing agents include, but are not limited to, chaetocin, 3-deazaneplanocin A, tazemetostat (EPZ-6438), N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1-methylethyl)-6- [2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide (GSK-343) and 2- cyclohexyl-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4- quinazolinamine (UNC-0638). Examples of PKC agonists that can be used as latency reversing agents include, but are not limited to, phorbolesters such as prostratin and phorbol myristate acetate (PMA), bryostatin-1, and ingenol. Examples of BET inhibitors that can be used as a latency reversing agents include, but are not limited to, JQ1 ((S)-tert-butyl 2-(4-(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetate), iBET, and N- cyclohexyl-2-(4-(3,5-dimethylisoxazol-4-yl)-2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-amine (UMB-136). Examples of CCR5 antagonist that can be used as latency reversing agent includes, but is not limited to, maraviroc and vicriviroc. Examples of inducers of the non-canonical NF-κB pathway and SMAC mimetics / IAP inhibitors that can be used as latency reversing agents include, but are not limited to, 3,3'-[2,4-hexadiyne-1,6-diylbis[oxy[(1S,2R)-2,3-dihydro-1H- indene-2,1-diyl]]]bis[N-methyl-L-alanyl-(2S)-2-cyclohexylglycyl-L-prolinamide (AZD5582), Ciapavir, Birinapant, LCL161, and DEBIO1143 / AT-406. Examples of proteasome inhibitors that can be used as latency reversing agents include, but are not limited to, bortezomib and ixazomib. Examples of TLR agonists that can be used as latency reversing agents include, but are not25909 limited to, the TLR2 agonist Pam3CSK4, the TLR7 agonist vesatolimod, and the TLR9 agonists Lefitolimod (MGN1703) and CPG 7909.

[0090] An example of an MAPK agonist that can be used as a latency reversing agent includes, but is not limited to, procyanidin trimer C1. An example of an AKT pathway activator that can be used as latency reversing agent includes, but is not limited to, disulfiram. Examples of immunomodulatory cytokines that can be used as latency reversing agents include, but are not limited to, IL-2, IL-7, and IL-15, including the IL-15 superagonist N-803. Examples of immune checkpoint inhibitors include, but are not limited to, inhibitors of Programmed cell death protein 1 (PD1), Programmed death-ligand 1 (PD-L1) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains) (TIGIT) and CD24Fc, a recombinant fusion protein composed of the extracellular domain of the mature human glycoprotein cluster of differentiation 24 (CD24) linked to a human immunoglobulin G1 (IgG1) Fc domain.

[0091] Non-limiting examples of HIV integrase inhibitors that are anti-HIV agents are disclosed in International Patent Application publication WO2018 / 102485, incorporated by reference in its entirety herein, and include: a

[0092] Non-limiting examples of non-nucleoside reverse transcriptase inhibitors that are anti- HIV agents are disclosed in International Patent Application publication WO2014 / 058747, incorporated by reference in its entirety herein, and include: 3-chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (ulonivirine);25909 3-chloro-5-((6-oxo-l-((3-oxo-2,3-dihydropyridazin-4-yl)mcthyl)-4-(trifluoromethyl)-1,6-di- hydropyrimidin-5-yl)oxy)benzonitrile; 3-ch1oro-5-((1-((4-methy1-5-oxo-4,5-dihydropyrazin-2-yl) methyl)-6-oxo-4-(trifluoromethyl)- l,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and 3-chloro-5-((1-((5-(1-hydroxyethy1)-6-oxo-l,6-dihydropyridazin-3-yl)methy1)-6-oxo-4- (trifluo- methyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

[0093] Non-limiting examples of nucleoside reverse transcriptase inhibitors that are anti-HIV agents are disclosed in International Patent Application publication WO2015 / 148746, incorporated by reference in its entirety herein, and include: 3-chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (UNIVIRINE); 3-chloro-5-((6-oxo-l-((3-oxo-2,3-dihydropyridazin-4-yl)mcthyl)-4-(trifluoromethyl)-1,6-di- hydropyrimidin-5-yl)oxy)benzonitrile; 3-ch1oro-5-((1-((4-methy1-5-oxo-4,5-dihyd o pyrazin-2-yl) methyl)-6-oxo-4-(trifluoromethyl)- l,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and 3-chloro-5-((1-((5-(1-hydroxyethy1)-6-oxo-l,6-dihydropyridazin-3-yl)methy1)-6-oxo-4- (trifluo- methyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile or a pharmaceutically acceptable salt, thereof.

[0094] Non-limiting examples of nucleoside reverse transcriptase inhibitors that are anti-HIV agents are disclosed in International Patent Application publication WO2015 / 148746, incorporated by reference in its entirety herein, and include: (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-107-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol; and (2R,3S,5R)-5-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2- (hydroxymethyl)tetrahydrofuran-3-ol; or a pharmaceutically acceptable salt, thereof. or a pharmaceutically acceptable salt, thereof.

[0095] Thus, the compounds of Formula I, or pharmaceutically acceptable salts thereof, used together with a latency reversing agent can be useful for:25909 (i) A method for re-activating latent HIV and eliciting GAG-POL dimerization in HIV- infected cells (e.g., CD4 T cells) in a human subject which comprises administering to the subject an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a latency reversing agent; and / or (ii) A method for re-activating latent HIV and selectively killing HIV-infected GAG-POL expressing cells (e.g., latently HIV- infected CD4 T cells or central memory CD4 T cells), without concomitant cytotoxicity to HIV naïve cells, in a human subject which comprises administering to the subject an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a latency reversing agent.

[0096] Compounds of this invention can be used in combination with any one or more of antiviral agents, e.g., but not limited to those listed in Table A, and / or any one or more of LRAs, e.g., but not limited to, the LRAs described herein.

[0097] It is understood that the scope of combinations of the compounds of this invention with compatible anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes in principle any combination with any pharmaceutical composition useful for the treatment or prophylaxis of HIV AIDS, or ARC, with the exception of HIV protease inhibitors. The compatible HIV antiviral agents and other active agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the current Physicians' Desk Reference, Thomson PDR, 70th edition (2016), Montvale, NJ: PDR Network, or in prior editions thereof. The dosage ranges for a compound of the disclosure in these combinations can be the same as those set forth above.

[0098] The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to the reverse transcriptase region within GAG- POL, e.g., by competitive inhibition. Abbreviations and acronyms employed herein include the following: AcOH = acetic acid mL = milliliters25909 °C = degree Celsius NHS = normal human serum cataCXium® A Pd G2 = chloro[(di(1- nM = nanomolar dmntl)-N-btlh hin)-2-(2-

[0099] Compounds containing a bromine have two masses due to the two bromide isotopes,79Br and81Br in an approximately 1:1 ratio. Intermediate A Section Intermediate A01: 2-fluoro-3-hydroxy-5-methylbenzonitrile (A01)25909 Step 1: 2-(3-bromo- (A01-a)

[0100] 2-bromo-4- g, (443 g, 1740 mmol) were added to a three-necked flask and taken into hexanes (3.0 L). The reaction mixture was degassed with N2.4,4'-di-tert-butyl-2,2'-bipyridine (14 g, 52.3 mmol) and (1,5- cyclooctadiene)(methoxy)iridium(I) dimer (17.3 g, 26.1 mmol) were added, in one portion, to the reaction mixture. The reaction was degassed with N2 and stirred for 12 h at 25 °C. The reaction was concentrated and triturated with MeOH (500 mL), and the resulting solid was filtered off. The solid was dried under vacuum to isolate compound (A01-a). Step 2: 3-bromo-5-chloro-2-fluorophenol (A01-b)

[0101] Intermediate A01-a (210 g, 0.626 mol) and THF (2 L) were added to a three-neck flask and chilled to 0 °C.4 M NaOH (470 mL) was added dropwise over 30 min ensuring internal temperature was kept below 0 °C. The slurry was stirred for 30 min at 0 °C and then brought to 10 °C and stirred for 12 h. The slurry was slowly added into sat aq Na2SO3 keeping the solution below 0 °C. The pH was adjusted to 3-4 with 1 N HCl. The solution was extracted with EtOAc (1 L × 3). The combined organics were washed with sat aq Na2SO3 (1 L × 2) and brine (1 L). The organic was dried over MgSO4, and the organic was concentrated under reduced pressure to isolate title compound A01-b and used directly in the next step.1H NMR: (400 MHz, CDCl3) d 7.08 (dd, J = 2.4, 5.2 Hz, 1H), 6.97 (dd, J = 2.4, 6.8 Hz, 1H), 6.22 (br s, 1H). Step 3: 5-chloro-2-fluoro-3-hydroxybenzonitrile (A01-c)

[0102] Intermediate A01-b (180 g, 0.798 mol) and NMP (1.8 L) were added to a three-necked flask. CuCN (315 g, 3.51 mmol) was added in one portion. The solution was heated to 180 °C and stirred for 2 h. The reaction was cooled and poured into ice water (4 L). The resulting slurry was filtered, and the filter cake was rinsed with MTBE (2 L). The filtrate was extracted with MTBE (3 x 1 L) and the combined organics were washed with water (3 × 1 L), brine (3 x 1 L) and dried over Na2SO4and filtered. The organic was concentrated and the resulting residue was triturated with 1:1 DCM:hexanes (400 mL) to isolate compound A01-c.1H NMR: (400 MHz, DMSO-d6) d 11.31 (br s, 1H), 7.46 (dd, J = 2.4, 4.4 Hz, 1H), 7.30 (dd, J = 2.5, 7.6 Hz, 1H). Step 4: 2-fluoro-3-hydroxy-5-methylbenzonitrile (A01)25909

[0103] Intermediate A01-c (20.0 g, 116 mmol), trimethylborxine (57 g, 454 mmol), Pd(AcO)2(2.62 g, 11 mmol), Sphos (9.57 g, 23 mmol), K3PO4 (49.5 g, 223 mmol) in toluene (400 mL) and water (4 mL) were added to a three-necked flask. The flask was degassed and then purged with N2. The reaction mixture was heated to 100 °C for 1 h. The reaction was brought to ambient temperature and poured into ice water (2 L). The solution was filtered, and the filter cake was rinsed with EtOAc (1 L). The filtrate was extracted with EtOAc (2 x 1 L), and the combined organic was washed with brine (2 x 1 L). The organics were dried over Na2SO4. The slurry was filtered, and the organics were concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, PE:EA = 5:1 to 0:1) to isolate compound A01.1H NMR: (400 MHz, DMSO-d6) d10.59 (br s, 1H), 7.06 - 7.10 (m, 2H), 2.33 (s, 3H). Intermediate A02: 5-bromo-2-fluoro-3-iodophenol (A02)Step 1: (5-bromo-2-fluoro-3-iodophenyl)boronic acid (A02-a)

[0104] A solution of 4-bromo-1-fluoro-2-iodobenzene (3g, 9.97 mmol) and triisopropyl borate (4.6 mL, 19.94 mmol) in THF (33 mL) was chilled to -78 °C.1 M LDA in THF (15 mL, 15 mmol) was added dropwise to the solution and it was stirred for 30 min. The solution was removed from the bath and 1 M H2SO4 (50 mL, 50 mmol) was added. The solution was stirred for an additional 30 min. The reaction mixture was extracted with EtOAc (2 x 50 mL) and the combined organics were washed with brine. The organics were dried over MgSO4 to isolate compound A02-a.1H NMR (500 MHz, CDCl3) d 7.99 (dd, J = 5.9, 2.5 Hz, 1H), 7.93 (dd, J = 5.2, 2.4 Hz, 1H), 5.02 (d, J = 5.9 Hz, 2H). Step 2: 5-bromo-2-fluoro-3-iodophenol (A02)

[0105] Intermediate A02-a (3.437 g, 9.97 mmol) was dissolved in THF (11.100 mL) and chilled to 0 °C. NaOH (2.393 g, 59.8 mmol) was then added to the reaction mixture. Hydrogen peroxide (5.24 mL, 59.8 mmol) was added and stirred for 30 min. The reaction mixture was quenched with sat aq Na2SO3 (20 mL) and extracted with EtOAc (3 x 30 mL). The organics were dried over MgSO4 and then concentrated. The residue was purified by flash chromatography (SiO2, EA:hexanes = 0-30%) to isolate compound A02.1H NMR (500 MHz, CDCl3) δ 7.42 (dd, J = 4.9, 2.3 Hz, 1H), 7.16 (dd, J = 7.2, 2.3 Hz, 1H), 5.45 (s, 1H).25909

[0106] Intermediates A03 through A05, found in Table 1, were synthesized using processes disclosed in international patent application publication WO2020 / 131597. Table 1. Intermediate Intermediate WO2020 / 131597 WO2020 / 131597 Structure Structure Name Example No. PageIntermediate A06: 3-bromo-5-(difluoromethyl)-2-methoxyphenol (A06) Step 1: 3-bromo-

[0107] A solution of BBr3(1.8 mL, 19.04 mmol) in DCM (20 mL) at 0 °C was added to a solution of 3-bromo-4-hydroxy-5-methoxybenzaldehyde (2 g, 8.66 mmol) in DCM (20 mL). The reaction mixture was stirred at 0 °C for 20 min and then at 25 °C for 2 h. The reaction mixture was cooled to 0 °C and quenched by the slow addition of MeOH (20 mL). The solvent was removed under reduced pressure to give the crude product. The crude product was purified by column (SiO2, MeOH:DCM = 0: 1 to 5: 1) to isolate compound A06-a.1H NMR (DMSO-d6) d 10.50 (s, 1H), 10.40 (s, 1H), 9.69 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1 H). Step 2: 3-bromo-5-hydroxy-4-methoxybenzaldehyde (A06-b)25909

[0108] Lithium carbonate (0.752 g, 10.17 mmol) was added to a solution of Intermediate A06- a (1.2 g, 5.09 mmol) in DMF (15 mL). The reaction mixture was stirred at 45 °C for 1 h. MeI (0.382 mL, 6.10 mmol) was added into the solution. The mixture was stirred at 45 °C for 3 h. The reaction mixture was poured into ice water (30 mL), adjusted pH ~ 6 with 1 N HCl and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, PE:EtOAc = 20:1 to 3: 1) to isolate compound A06-b. MS (ESI) m / z 231, 233 [M+1]. Step 3: 3-bromo-5-(difluoromethyl)-2-methoxyphenol (A06)

[0109] DAST (6.86 ml, 51.9 mmol) was added to a solution of Intermediate A06-b (1.2 g, 5.19 mmol) in DCM (10 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into NaHCO3 (50 mL) dropwise and then extracted with DCM (3 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, PE:EtOAc = 30:1 to 3:1) to isolate compound A04.1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.08 (s, 1H), 6.30 – 6.72 (m, 1H), 3.95 (s, 3H). Intermediate A07: 5-bromo-2-chloro-3-hydroxybenzonitrile (A07)Step 1: 2-amino-5-bromo-3-fluorobenzonitrile (A07-a)

[0110] NBS (15.69 g, 88 mmol) was added to a stirred solution of 2-amino-3-fluorobenzonitrile (10 g, 73.5 mmol) in DMF (100 mL) and the mixture was heated at 80 °C for 20 h. The reaction mixture was quenched with water and extracted with EtOAc (200 mL) and washed with brine solution (100 mL). The organic layer was dried with Na2SO3, filtered and the organic was concentrated under vacuum. The residue was purified by flash chromatography (SiO2, 0-4% EA:PE) to isolate compound A07-a. MS (ESI) m / z 215, 217 [M+1]. Step 2: 5-bromo-2-chloro-3-fluorobenzonitrile (A07-b)

[0111] t-Butyl nitrite (19.91 mL, 167 mmol) was added to a mixture of Intermediate A07-a (9 g, 41.9 mmol), copper(I) chloride (12.43 g, 126 mmol) and copper(II) chloride (19.70 g, 146 mmol) in ACN (70 mL) at 25 °C and was stirred for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (3 x3025909 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, EA:PE 10-100%) to isolate compound A07-b.1H NMR (400 MHz, CDCl3) δ 7.67 - 7.63 (m, 1H), 7.59 (dd, J = 2.2, 7.9 Hz, 1H). Step 3: 5-bromo-2-chloro-3-((4-methoxybenzyl)oxy)benzonitrile (A07-c)

[0112] 60% by weight NaH (0.444 g, 11.09 mmol) was added to a stirred solution of (4- methoxyphenyl)methanol (1.179 g, 8.53 mmol) in DMF (40 mL) at 0 °C. After 20 min., intermediate A07-b (2 g, 8.53 mmol) was added and the resulting solution was stirred at 25 °C for 1 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 120 mL). The organic layer was washed with brine (3 x 60 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated with MeOH to isolate compound A07-c. Step 4: 5-bromo-2-chloro-3-hydroxybenzonitrile (A07)

[0113] A solution of intermediate A07-c (30 g, 68.1 mmol) in a mixture of TFA (50 mL) and DCM (300 mL) was stirred at 25 °C for 1 h. TLC (PE:EA=5:1) showed the reaction was finished and a new spot was observed. The residue was concentrated and purified by flash chromatography (PE:EA=10:1) to isolate compound A07.1H NMR (400 MHz, DMSO-d6) δ 11.54 (br s, 1 H) 7.67 (d, J = 2.20 Hz, 1 H) 7.39 (d, J = 2.20 Hz, 1 H). Intermediate A07: 5-bromo-3-hydroxy-2-methylbenzonitrile (A08)Step 1: (5-bromo-3-cyano-2-methylphenyl)boronic acid (A08-a)

[0114] A solution of 5-bromo-2-methylbenzonitrile (1 g, 5.10 mmol) in cyclohexane (10 ml) was purged with N2for 5 min. B2pin2(2.59 g, 10.20 mmol), 3,4,7,8-tetramethyl-1,10- phenanthroline (0.241 g, 1.020 mmol) and bis(cyclooctadiene(methoxy)iridium) (0.676 g, 1.020 mmol) were added and the reaction mixture was stirred for 18 h at 80 °C. The mixture was concentrated to dryness to isolate compound A08-a and used as is in Step 2. Step 2: 5-bromo-3-hydroxy-2-methylbenzonitrile (A08)

[0115] Sodium perborate tetrahydrate (5.77 g, 37.5 mmol) was added to a stirred solution of Intermediate A08-a (3 g, 12.51 mmol) in THF (1 mL) and water (0.4 mL). The resulting mixture was stirred at 15 °C for 1 hr. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (150 mL), dried over Na2SO4, filtered, and25909 concentrated. The residue was purified by prep-HPLC (0.05% TFA) to isolate compound A07. MS (ESI) m / z 212, 214 [M+1]. Intermediate B Section

[0116] Intermediates B01 through B05, found in Table 2, were synthesized using processes disclosed in international patent application publication WO2020 / 131597. Table 2. Intermediate Intermediate Structure WO2020 / 13159 WO2020 / 13159 MS Structure Name 7 Example No. 7 Page and line (ESI) 1] ] ]Intermediate B06: 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (B06)25909

[0117] Intermediate B06 was disclosed in international patentapplication publication B18 page 46. MS (ESI) m / z 325 [M+23]. Intermediate B07: 5-hydroxy-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (B07) Step 1: 5-(tert-4(3H)-one (B07-a)

[0118] Intermediate B06 (3000 mg, 9.93 mmol) was dissolved in anhydrous dioxane (50 mL) followed by the addition of potassium t-butoxide (2228 mg, 19.85 mmol). The resulting mixture was stirred at RT for 2 h. The reaction was concentrated, and the residue was purified by flash chromatography (SiO2, 0-50% EA:hexanes) to isolate compound B07-a. MS (ESI) m / z 357 [M+1]. Step 2: 5-hydroxy-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (B07)

[0119] Intermediate B07-a (3.57 g, 10.02 mmol) was taken into TFA (15.44 ml, 200 mmol) and stirred for 10 min. The reaction is concentrated and taken into EtOAc (100 mL) and washed with sat aq NaHCO3 (30 mL), water (30 mL) and dried over MgSO4. The organic was concentrated, and the residue was purified by flash chromatography (SiO2, 0-100% (3:1 EA:EtOH):hexanes) to isolate compound B07. MS (ESI) m / z 301 [M+1]. Intermediate C Section Intermediate C01: (5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methanol (C01)25909 Step 1: methyl 5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)picolinate (C01-a)

[0120] Methyl 5-hydroxypicolinate (100 mg, 0.653 mmol) was dissolved in DMF (3.3 mL). Cs2CO3(319 mg, 0.980 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (150 mg, 0.718 mmol) were added to the resulting solution. The slurry was stirred at 40 °C for 16 h. The solution was added to EtOAc (50 mL) and the resulting mixture was extracted with water (20 mL), brine (20 mL), and dried over MgSO4. The resulting slurry was filtered, and the organics were concentrated. The residue was purified by flash chromatography (SiO2, 0-100% EA:hexanes) to isolate compound C01-a. MS (ESI) m / z 282 [M+1]. Step 2: (5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methanol (C01)

[0121] Intermediate C01-a (95 mg, 0.338 mmol) was dissolved in THF (1.5 mL) and chilled to 0 ºC where 1 M LAH in THF (77 µl, 0.154 mmol) was added dropwise. Upon completion of addition of LAH, the reaction was stirred at 0 ºC for 30 min. Then, the reaction was quenched with sat aq Rochelle salt solution. The reaction was concentrated and taken into EtOAc (10 mL) and washed with water (2 x 5 mL) and brine (5 mL) and the organic was dried over MgSO4. The resulting organic was concentrated. The residue was purified by flash chromatography (SiO2, 0- 100% EA:hexanes) to isolate compound C01. MS (ESI) m / z 254 [M+1]. Intermediate C02: 2-(chloromethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (C02).

[0122] followed by the addition of DIPEA (2069 µL, 11.84 mmol) and Ms-Cl (738 µl, 9.48 mmol). The resulting mixture was stirred for 16 h. The solution was added to EtOAc (200 mL), and the organic was washed with water (2 x 50 mL), brine (50 mL), dried over MgSO4and concentrated. The residue was purified by flash chromatography (SiO2, 0-100% EA:hexanes) to isolate compound C02. MS (ESI) m / z 272 [M+1]. Intermediate C03: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4- methylpyridine (C03)25909 Step 1: 2-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methylpyridine (C03-a)

[0123] A solution of 6-bromo-4-methylpyridin-3-ol (2.42 g, 12.87 mmol), (2- bromoethoxy)(tert-butyl)dimethylsilane (3.69 g, 15.45 mmol) and K2CO3(3.91 g, 28.3 mmol), stirred in DMF (25.7 mL), was heated to 40 °C for 48 h. The reaction was diluted with sat. NaHCO3 aq. solution (50 mL) and extracted into EtOAc (3 x 50 mL). The combined organic layer was washed with water (5 x 20 mL) then by brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2, 0-40 % EtOAc:hexanes) to isolate compound C03-a. MS (ESI) m / z 346, 348 [M+1]. Step 2: methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methylpicolinate (C03-b)

[0124] Intermediate C03-a (3.318 g, 9.58 mmol) was dissolved in MeOH (31.9 mL). DIPEA (5.02 ml, 28.7added to the solution followed by the addition of PdCl2(dppf)·CH2Cl2adduct (0.782 g, 0.958 mmol). The reaction was heated to 80 °C under 80 psi of CO for 16 h. The reaction was filtered over Celite®and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-40 % EtOAc:hexanes) to isolate compound C03-b. MS (ESI) m / z 326 [M+1]. Step 3: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methylpyridin-2-yl)methanol (C03-c)

[0125] A solution of Intermediate C03-b (2.6831 g, 8.24 mmol) in THF (37.5 ml) was placed under N2 and cooled to 0 °C.2 M LAH in THF (4.12 mL, 8.24 mmol) was added dropwise and warmed to 20 °C over 1 h. The reaction was diluted with Et2O (25 mL) and cooled to 0 °C. Water (0.284 mL) was added followed by 15% aq NaOH (0.284 mL) and then again by water (0.852 mL). The mixture was warmed to ambient temperature, dried over MgSO4, filtered, and concentrated to give compound C03-c. MS (ESI) m / z 298 [M+1], which was used in Step 4 without purification. Step 4: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4-methylpyridine (C03)

[0126] A solution of Intermediate C03-c (1.9458g, 6.54 mmol) in DCE (32.7 mL) was cooled to 0 °C. DIPEA (2.51 mL, 14.39 mmol) was added to the solution, followed by MsCl (0.561 ml, 7.20 mmol). The reaction was warmed to 20 °C for 16 h. The reaction mixture was diluted with sat. aq bicarb (30 mL) and extracted into DCM (3 x 30 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-50 % EtOAc:hexanes) to isolate compound C03. MS (ESI) m / z 316 [M+1]. Intermediate C04: 5-(benzyloxy)-4-chloro-2-(chloromethyl)pyridine (C04)25909 Step 1: 5-

[0127] g, 317 mmol) were added to a solution of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (30 g, 211 mmol) in MeOH (300 mL). The mixture was stirred at 80 °C for 2 h and then concentrated. The residue was poured into water (200 mL) stirred for 1 h. The mixture was filtered to collect the filter cake and washed by PE (2 x 200 mL) to give compound C04-a. MS (ESI) m / z 233 [M+1]. Step 2: 5-(benzyloxy)-2-(hydroxymethyl)pyridin-4-ol (C04-b)

[0128] A solution of Intermediate C04-a (12 g, 51.7 mmol) in conc. NH4OH (75 mL) was stirred at 90 °C for 3 h. The mixture was concentrated to dryness. The crude was purified by trituration in ACN (25 mL) to provide compound C04-b. MS (ESI) m / z 232 [M+1]. Step 3: 5-(benzyloxy)-4-chloro-2-(chloromethyl)pyridine (C04)

[0129] Under N2, POCl3 (2.411 mL, 25.9 mmol) was added to a stirred solution of Intermediate C04-b (1 g, 4.32 mmol) in acetonitrile (15 ml). The resulting mixture was stirred at 85 °C for 12 h. The mixture was concentrated, and the residue was dissolved in DCM. Then the mixture was adjusted to pH = 8 with sat aq NaHCO3. The mixture was extracted with DCM (3 x 50 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to isolate compound C04. MS (ESI) m / z 268 [M+1]. Intermediate C05: 4-bromo-2-(bromomethyl)-5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)pyridine (C05) Step 1: 5-

[0130] DIEA (9.60 mL, 55.0 mmol) and chloro(methoxy)methane (3.02 g, 37.5 mmol) was added at 0 °C to a solution of 6-methylpyridin-3-ol (2 g, 18.33 mmol) in DCM (20 mL). The mixture was stirred at 20 °C for 8 h. The reaction was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 0 –25909 10% EtOAc:PE) to isolate compound C05-a.1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 2.8 Hz, 1H), 7.30 - 7.13 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.09 (s, 2H), 3.41 (s, 3H), 2.43 (s, 3H). Step 2: 4-bromo-5-(methoxymethoxy)-2-methylpyridine (C05-b)

[0131] 1.3 M t-BuLi in pentane (7.53 mL, 9.79 mmol) was added, under N2, to a solution of Intermediate C05-a (600 mg, 3.92 mmol) in THF (2 mL) and cooled to -70 °C. The resulting mixture was stirred for 1 h and 1,2-dibromo-1,1,2,2-tetrachloroethane (1913 mg, 5.88 mmol) was added. The reaction continued to stir at -78 °C for 1 h. The reaction mixture was warmed to 20 °C, diluted with NH4Cl solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by normal phase chromatography (SiO2, 0- 5 % EtOAc:PE) to afford compound C05-b.1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.36 (s, 1H), 5.23 (s, 2H), 3.53 (s, 3H), 2.47 (s, 3H). Step 3: 4-bromo-6-methylpyridin-3-ol (C05-c)

[0132] 4 M HCl in EtOAc (5 mL, 20.00 mmol) was added to a solution of Intermediate C05-b (400 mg, 1.724 mmol) in EtOAc (2 mL). The mixture was stirred at 0 °C for 3 h. The reaction was concentrated to isolate compound C05-c and used directly in Step 4 without further purification. Step 4: 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methylpyridine (C05-d)

[0133] (2-Bromoethoxy)(tert-butyl)dimethylsilane (350 mg, 1.463 mmol) and K2CO3 (3.73 mg, 0.027 mmol) were added to a solution of Intermediate C05-c (250 mg, 1.330 mmol) in DMF (3 mL). The reaction mixture was stirred at 70 °C under N2 for 5 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to isolate compound C05-d, which was used in Step 5 without purther purification. MS (ESI) m / z 346, 348 [M+1]. Step 5: 4-bromo-2-(bromomethyl)-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine (C05)

[0134] NBS (385 mg, 2.166 mmol) -2,2'-(diazene-1,2-diyl)bis(2-methylpropanenitrile)(95 mg, 0.577 mmol) were added to a of C05-d (500 mg, 1.444 mmol) in CCl4 (5 mL). The resulting mixture was stirred at 70 °C for 8 h. The mixture was concentrated, and the resulting residue was purified by prep TLC (SiO2, 25% EtOAc:PE) to isolate compound C05. MS (ESI) m / z 426 [M+1]. Intermediate C06: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4- (trifluoromethyl)pyridine (C06)25909 Step 1:

[0135] BINAP (2.9 g, 4.63 mmol), PdCl2(dppf) (3.4 g, 4.63 mmol) and DIPEA (8.09 mL, 46.3 mmol) were added to a solution of 2,5-dichloro-4-(trifluoromethyl)pyridine (5.0 g, 23.15 mmol) in EtOH (2 L). The reaction was stirred at 60 °C under 2 mbar CO 16 h. The reaction was filtered through Celite®, and the filtrate was concentrated. The crude was purified by flash chromatography (SiO2, 0 - 10 % EtOAc:PE) to isolate product C06-a. MS (ESI) m / z 254 [M+1]. Step 2: ethyl 5-hydroxy-4-(trifluoromethyl)picolinate (C06-b)

[0136] K2CO3 (82 mg, 0.591 mmol) and N-hydroxyacetamide (44.4 mg, 0.591 mmol) were added to a solution of Intermediate C06-a (50 mg, 0.197 mmol) in DMSO (2 mL). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and filtered over Celite®. To the filtrate was added water (2 mL) and the solution was adjusted pH to ~4-5 with 1 M HCl. The mixture was extracted with EtOAc (3 x 5 mL), and the combined organics were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to isolate compound C06-b which was used without purification. MS (ESI) m / z 236 [M+1]. Step 3: ethyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(trifluoromethyl)picolinate (C06-c)

[0137] K2CO3(1763 mg, 12.76 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (3052 mg, 12.76 mmol) were added to a solution of intermediate C06-b (1000 mg, 4.25 mmol) in DMF (1 mL). The reaction was stirred at 80 °C for 6 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was concentrated to isolate compound C06-c, which was used without purification in Step 4. MS (ESI) m / z 394 [M+1]. Step 4: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(trifluoromethyl)pyridin-2-yl)methanol (C06-d)

[0138] This intermediate was prepared in an analogous method to that described for Intermediate C03-c by substituting C03-b for C06-c to provide compound C06-d. MS (ESI) m / z 352 [M+1]. Step 5: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4-(trifluoromethyl)pyridine (C06)

[0139] This intermediate was prepare in an analogous method to that described for Intermediate C03 Step 4 by substituting C03-c for C06-d to provide compound C06. MS (ESI) m / z 370 [M+1].25909 Intermediate C07: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)isonicotinonitrile (C07) Step 1: 2-

[0140] 2.5 n- - was added to a solution of diisopropylamine (8.07 g, 80 mmol) in THF (100 mL). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was then cooled back to -60 °C and 2-bromo-5- methoxypyridine (10 g, 53.2 mmol) in anhydrous THF (50 mL) was added dropwise. The reaction mixture was stirred at -60 °C for 1 h. The mixture was quenched with dry ice, diluted with water (400 mL), and adjusted with 3 M HCl to pH = 4. The solid was precipitated and filtered to isolate compound C07-a.1H NMR (400 MHz, DMSO-d6) δ 13.71 (br s, 1H) 8.34 (s, 1H) 7.69 (s, 1H) 3.92 (s, 3H). Step 2: 2-bromo-5-methoxyisonicotinamide (C07-b)

[0141] Ammonium chloride (2.305 g, 43.1 mmol), HATU (10.65 g, 28.0 mmol) and DIPEA (18.82 mL, 108 mmol) were added to a solution of Intermediate C07-a (5 g, 21.55 mmol) in DMF (30 mL). The reaction was stirred at 25 °C for 2 h. Water (80 mL) was added to the reaction mixture and the residue was extracted with EtOAc (3 x 50 mL). The organic layer was concentrated, and the residue was purified by flash chromatography (SiO2, 0-30 % EtOAc:PE) to isolate compound C07-b.1H NMR (400 MHz, DMSO-d6) δ 8.32 (br d, J = 4.65 Hz, 1H) 7.86 (br d, J = 9.78 Hz, 2H) 7.66 (br d, J = 4.28 Hz, 1H) 3.88 - 4.04 (m, 3H). Step 3: 2-bromo-5-methoxyisonicotinonitrile (C07-c):

[0142] TEA (7.24 mL, 51.9 mmol) and TFAA (4.89 mL, 34.6 mmol) were added to a solution of Intermediate C07-b (4 g, 17.31 mmol) in THF (40 mL). The reaction was stirred at 15 °C for 30 min. Water (50 mL) was added to the reaction and the residue was extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4and concentrated to isolate compound C07-c, which was used directly without purification.1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.08 - 8.19 (m, 1H), 4.00 - 4.08 (m, 3H). Step 4: 2-bromo-5-hydroxyisonicotinonitrile (C07-d):

[0143] BBr3 (15.27 mL, 161 mmol) was added to a solution of Intermediate C07-c (4.3 g, 20.18 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 1 h. The reaction was poured into a solution of DCM (40 mL) and MeOH (10 mL) and then water (50 mL) was added.25909 The residue was extracted with DCM (3 x 50 mL). The organic layer was concentrated, and the residue was purified by flash chromatography (SiO2, 0-25 % EtOAc:PE) to isolate compound C07-d.1H NMR (400 MHz, DMSO-d6) δ 12.04 (br s, 1H), 8.21 (s, 1H), 8.02 (s, 1H). Step 5: 2-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)isonicotinonitrile (C07-e)

[0144] K2CO3 (8.33 g, 60.3 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (9.62 g, 40.2 mmol) were added to a solution of Intermediate C07-d (4 g, 20.10 mmol) in DMF (30 ml). The reaction was stirred at 80 °C for 6 h. Water (40 mL) was added to the reaction and extracted with EtOAc (3 x 30 mL). The combined organic layer was concentrated and purified by flash chromatography (SiO2, 0-50 % EtOAc:PE) to isolate compound C07-e.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.14 (s, 1H), 4.33-4.45 (m, 2H), 3.96 (br d, J = 4.41 Hz, 1H), 0.84 (s, 9H), 0.06 (s, 6H). Step 6: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-vinylisonicotinonitrile (C07-f)

[0145] K2CO3 (4.64 g, 33.6 mmol), C2H3BF3K (1.949 g, 14.55 mmol) and PdCl2(dppf) (0.819 g, 1.119 mmol) were added to a solution of Intermediate C07-e (4 g, 11.19 mmol) in dioxane (20 mL) and water (5 mL). The reaction was stirred at 100 °C under N2 for 1 h. The reaction was concentrated and purified by flash chromatography (SiO2, 0 - 20% EtOAc:PE) to isolate compound C07-f. MS (ESI) m / z 305 [M+1]. Step 7: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-formylisonicotinonitrile (C07-g)

[0146] 4 wt % osmium tetroxide in water (0.093 mL, 0.296 mmol) and 2,6-dimethylpyridine (2.64 g, 24.63 mmol) were added to a solution of Intermediate C07-f (3 g, 9.85 mmol) in dioxane (30 mL) and water (10 mL). The reaction was stirred at 15 °C for 15 min. Then, sodium periodate (7.38 g, 34.5 mmol) was added to the reaction and stirred at 15 °C for 1 h. Water (50 mL) was added to the reaction and the residue was extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated to isolate compound C07-g, which was used directly in Step 8 without purification. MS (ESI) m / z 307 [M+1]. Step 8: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(hydroxymethyl)isonicotinonitrile (C07-h)

[0147] Calcium chloride (0.543 g, 4.90 mmol) and NaBH4(1.111 g, 29.4 mmol) were added to a solution of Intermediate C07-g (3 g, 9.79 mmol) in MeOH (30 mL). The reaction was stirred at 15 °C for 30 min. Water (50 mL) was added to the reaction and the residue was extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by prep HPLC (water:MeCN with 10 mM NH4HCO3) to isolate compound C07-h. MS (ESI) m / z 309 [M+1]. Step 9: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)isonicotinonitrile (C07)25909

[0148] This intermediate was prepared in an analogous method to Intermediate C03 Step 4 substituting C03-c for C07-h to provide compound C07. MS (ESI) m / z 327 [M+1]. Intermediate C08: (4-cyano-5-methoxypyridin-2-yl)methyl methanesulfonate (C08)Step 1: 5-methoxy-2-vinylisonicotinonitrile (C08-a)

[0149] This intermediate was prepared in an analogous method to Intermediate C07-f substituting Intermediate C07-e for Intermediate C07-c to provide compound C08-a. MS (ESI) m / z 161 [M+1]. Step 2: 2-formyl-5-methoxyisonicotinonitrile (C08-b)

[0150] This intermediate was prepared in an analogous method to Intermediate C07-g substituting Intermediate C07-f for Intermediate C08-a to provide compound C08-b.1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.61 (s, 1H), 8.14 (s, 1H), 4.19 (s, 3H). Step 3: 2-(hydroxymethyl)-5-methoxyisonicotinonitrile (C08-c)

[0151] NaBH4(14.0 mg, 0.37 mmol) was added to a solution of Intermediate C08-b (40.0 mg, 0.25 mmol) in MeOH (1 mL). The mixture was stirred at 25 ℃ for 20 min. The resulting mixture was concentrated and was used directly without purification to isolate compound C08-c. MS (ESI) m / z 165 [M+1]. Step 4: (4-cyano-5-methoxypyridin-2-yl)methyl methanesulfonate (C08)

[0152] This intermediate was prepared in an analogous method to Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C08-c to provide compound C08. MS (ESI) m / z 387 [M+1]. Intermediate C09: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)pyridine (C09) Step 1:25909

[0153] This intermediate was prepared in an analogous method to Intermediate C03-a substituting 6-bromo-4-methylpyridin-3-ol for methyl 5-hydroxypicolinate to provide compound C09-a. MS (ESI) m / z 312 [M+1]. Step 2: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (C09-b)

[0154] This intermediate was prepared in an analogous method to Intermediate C03-c by substituting Intermediate C03-b for Intermediate C09-a to provide compound C09-b. MS (ESI) m / z 284 [M+1]. Step 3: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)pyridine (C09)

[0155] This intermediate was prepared in an analogous method to Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C09-b to provide compound C09. MS (ESI) m / z 302 [M+1]. Intermediate C10: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4- (difluoromethyl)pyridine (C10) Step 1: 2-

[0156] 2.5 M n-BuLi in hexanes (45.5 mL, 114 mmol), was slowly added to a solution of diisopropylamine (16.02 mL, 114 mmol) in THF (25 mL) at -70 °C, to not let the temperature of the reaction system exceed -50 °C. After the addition was complete, the reaction was slowly warmed up to -10 °C. The reaction was cooled down to -70 °C and a solution of 2-bromo-5- fluoropyridine (10 g, 56.8 mmol) in THF (100 mL) was added dropwise. DMF (8.31 g, 114 mmol) was added dropwise to the reaction system maintaining the temperature at -50 °C for 2 h. The reaction was quenched with water (200 mL) and adjusted to pH~1 with HCl aq. (6 M, ~50 mL). The reaction was diluted with EtOAc (200 mL) and washed with water (2 x 50 mL). The organic layer was dried over Na2SO4, filtrated and concentrated. The crude product was purified by flash chromatography (SiO2; 0-30 % EtOAc:PE) to isolate compound C10-a.1H NMR (400 MHz, DMSO-d6) δ 10.17 - 10.06 (m, 1H), 8.72 (d, J = 1.5 Hz, 1H), 7.97 (d, J = 5.1 Hz, 1H). Step 2: 2-bromo-4-(difluoromethyl)-5-fluoropyridine (C10-b)

[0157] Under a nitrogen atmosphere, DAST (0.972 mL, 7.35 mmol) at -20 °C was added dropwise to a solution of Intermediate C10-a (1 g, 4.90 mmol) in DCM (10 mL). The mixture was slowly warmed up to 20 °C and stirred for 3 h. The reaction mixture was quenched with25909 saturated NaHCO3(20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layer was dried over Na2SO4, filtrated, and concentrated to provide compound C10-b, which was used without purification.1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.70 (d, J = 4.8 Hz, 1H), 7.02- 6.69 (m, 1H). Step 3: 2-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(difluoromethyl)pyridine (C10-c)

[0158] 2-((tert-butyldimethylsilyl)oxy)ethanol (3.12 g, 17.70 mmol) and KOtBu (1.986 g, 17.70 mmol) were added to a solution of Intermediate C10-b (2 g, 8.85 mmol) in DMA (15 mL). The solution was stirred at 20 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl (80 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0-30 % EtOAc:PE) to provide compound C10-c. MS (ESI) m / z 382, 384 [M+1]. Step 4: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(difluoromethyl)-2-vinylpyridine (C10-d)

[0159] This intermediate was prepared in an analogous method to that of Intermediate C07-f by substituting Intermediate C07-e for Intermediate C10-c to provide compound C10-d. MS (ESI) m / z 330 [M+1]. Step 5: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(difluoromethyl)pyridin-2-yl)methanol (C10-e)

[0160] Osmium tetroxide (19.29 mg, 0.076 mmol) (50 mg / mL, in BuOH) was added to a stirred solution of Intermediate C10-d (86 mg, 2.276 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL). This solution was stirred for 10 min and then sodium periodate (406 mg, 1.897 mmol) was added to the reaction at 0 °C. The resulting mixture was stirred at 20 °C for 4 h. MeOH (1 mL), followed by NaBH4 (86 mg, 2.276 mmol) at 0 °C was added to the reaction mixture and it was stirred for 10 min. The reaction mixture was quenched with sat aq NH4Cl solution (10 mL) at 0 °C. The reaction mixture was extracted with EtOAc (3 x 10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to isolate compound C10-e. Intermediate C10-e was used directly in Step 6 MS (ESI) m / z 334 [M+1]. Step 6: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4-(difluoromethyl)pyridine (C10)

[0161] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 substituting Intermediate C03-c for Intermediate C10-d to provide compound C10. MS (ESI) m / z 352 [M+1]. Intermediate C11: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4- fluoropyridine (C11)25909 Step 1: (6-

[0162] An glovebox with (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.454 g, 0.684 mmol) and 4,4’-di-tert-butyl- 2,2’-bipyridine (0.184 g, 0.684 mmol). THF (50 mL) was added, followed by B2pin2 (8.69 g, 34.2 mmol) and 2-chloro-4-fluoropyridine (9 g, 68.4 mmol). The vial was capped and heated outside of the glovebox at 80° C for 14 h. The reaction was concentrated and purified by flash chromatography (SiO2, 0-30 % EtOAc:PE) to provide compound C11-a. MS (ESI) m / z 176 [M+1]. Step 2: 6-chloro-4-fluoropyridin-3-ol (C11-b)

[0163] NaBO3·4H2O (13.99 g, 171 mmol) was added to a stirred solution of Intermediate C11-a (10 g, 57.0 mmol) in THF (100 mL) and water (40 mL). The reaction was stirred at 15 °C for 1 h. The reaction was poured into water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to provide compound C11-b, which was used without purification. MS (ESI) m / z 148 [M+1]. Step 3: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-4-fluoropyridine (C11-c)

[0164] (2-bromoethoxy)(tert-butyl)dimethylsilane (4.86 g, 20.33 mmol) was added to a solution of Intermediate C11-b (2 g, 13.56 mmol) and K2CO3(3.75 g, 27.1 mmol) in DMF (20 mL). The mixture was stirred at 40 °C for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (100 mL), filtered, and concentrated. The crude mixture was purified by flash chromatography (SiO2, 60 % EtOAc:PE) to provide compound C11-c. MS (ESI) m / z 306 [M+1]. Step 4: methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluoropicolinate (C11-d)

[0165] This intermediate was prepared in an analogous method to that of Intermediate C03-b by substituting Intermediate C03-a for Intermediate C11-c to provide compound C11-d. MS (ESI) m / z 330 [M+1]. Step 5: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluoropyridin-2-yl)methanol (C11-e):

[0166] CaCl2(337 mg, 3.04 mmol) and NaBH4(115 mg, 3.04 mmol) were added to a solution of Intermediate C11-d (500 mg, 1.518 mmol) in MeOH (10 mL). The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated, dissolved in EtOAc, and washed with saturated NH4Cl (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to provide25909 compound C11-e which was used directly in Step 6 without further purification. MS (ESI) m / z 302 [M+1]. Step 6: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-4-fluoropyridine (C11)

[0167] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C11-e to provide compound C11. MS (ESI) m / z 320 [M+1]. Intermediate C12: 5-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-2- (chloromethyl)pyridine (C12) Step 1: 1-(

[0168] TBS-Cl (3.96 g, 26.3 mmol) slowly was added at 0 °C to a solution of propane-1,2-diol (2 g, 26.3 mmol), TEA (4.40 mL, 31.5 mmol) and DMAP (0.128 g, 1.051 mmol) in DCM (20 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (SiO2, 10 % EtOAc:PE) to isolate compound C12-a.1H NMR (400 MHz, CDCl3) δ 3.83 (br s, 1H), 3.58 - 3.63 (m, 1H), 3.32 - 3.39 (m, 1H), 2.46 (d, J = 3.2 Hz, 1H), 1.12 (d, J = 2.4 Hz, 3H), 0.92 (s, 9 H), 0.08 (s, 6H). Step 2: methyl 5-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)picolinate (C12-b)

[0169] di-tert-butyl (1.128 g, 4.90 mmol) at 0 °C was added to a mixture of methyl 5-(0.5 g, 3.27 mmol), Intermediate C12-a (0.622 g, 3.27 mmol) and Ph3P (1.285 g, 4.90 mmol) in THF (20 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 x 25 mL). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 10-15 % EtOAc:PE) to isolate compound C12-b. MS (ESI) m / z 326 [M+1]. Step 3: (5-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyridin-2-yl)methanol (C12-c)

[0170] This intermediate was prepared in an analogous method to that of intermediate C11-e by substituting Intermediate C11-d for Intermediate C12-b to provide compound C12-c. MS (ESI) m / z 298 [M+1]. Step 4: 5-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-2-(chloromethyl)pyridine (C12)25909

[0171] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C12-c to provide compound C12. MS (ESI) m / z 316 [M+1]. Intermediate C13: 2-(chloromethyl)-5-methoxypyridine (C13) Step 1: (5-

[0172] This intermediate was prepared in an analogous method to that of Intermediate C03-c substituting Intermediate C03-b for 5-methoxypicolinic acid to provide compound C13-a.1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.27 - 7.18 (m, 2H), 4.713 (s, 2H), 3.88 (s, 3H). Step 2: 2-(chloromethyl)-5-methoxypyridine (C13):

[0173] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 substituting Intermediate C03-c for Intermediate C13-a to provide compound C13.1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.98-7.92 (m, 2H), 5.31 (s, 2H), 4.06 (s, 3H). Intermediate C14: 1-((6-(hydroxymethyl)-4-methylpyridin-3-yl)oxy)-2-methylpropan-2-ol (C14) Step 1: 1-((6-

[0174] K2CO3 (1733 mg, 12.54 mmol) was added to a stirred solution of 6-chloro-4- methylpyridin-3-ol (600 mg, 4.18 mmol), 1-bromo-2-methylpropan-2-ol (767 mg, 5.01 mmol) in DMF (5 mL). The mixture was stirred at 95 °C for 16 h. The reaction was dissolved in H2O (20 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0-25 % EtOAc:PE) to provide compound C14-a. MS (ESI) m / z 216 [M+1]. Step 2: 2-methyl-1-((4-methyl-6-vinylpyridin-3-yl)oxy)propan-2-ol (C14-b)

[0175] K2CO3(192 mg, 1.391 mmol), XPhos (66.3 mg, 0.139 mmol) and Pd(OAc)2(10.41 mg, 0.046 mmol) were added to a solution of Intermediate C14-a (100 mg, 0.464 mmol) and25909 potassium trifluoro(vinyl)borate (186 mg, 1.391 mmol) in dioxane (1 mL) and water (0.1 mL). The reaction mixture was stirred under N2 at 100 °C for 16 h. The reaction was concentrated and purified by prep TLC (SiO2, 30 % EtOAc:PE) to afford compound C14-b.1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.20 (s, 1H), 6.75 (dd, J = 17.48, 10.88 Hz, 1H), 6.01 (dd, J = 17.55, 1.16 Hz, 1H), 5.37 (dd, J = 10.88, 1.10 Hz, 1H), 3.91 (s, 2H), 2.26-2.31 (m, 3H), 1.38 - 1.40 (m, 6H). Step 3: 1-((6-(hydroxymethyl)-4-methylpyridin-3-yl)oxy)-2-methylpropan-2-ol (C14)

[0176] A solution of Intermediate C14-b (15 mg, 0.072 mmol) in DCM (1 mL) and MeOH(0.1 mL) was stirred under O3at -70 °C for 15 min, then under O2for 20 min. NaBH4(8.21 mg,0.217 mmol) was added at -70 °C and the mixture was stirred at 20 °C for 30 min. The reaction was concentrated and purified by prep TLC (SiO2, 10% MeOH:DCM) to provide compound C14. MS (ESI) m / z 212 [M+1]. Intermediate C15: 5-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)oxy)-2- (chloromethyl)-4-methylpyridine (C15) Step 1: ethyla)

[0177] K2CO3(1444 mg, 10.45 mmol) was added to a stirred solution of 6-chloro-4- methylpyridin-3-ol (500 mg, 3.48 mmol) and ethyl 2-bromo-2-methylpropanoate (1494 mg, 7.66 mmol) in DMF (20 mL). The reaction mixture was stirred at 85 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic was washed with brine (3 x 150 mL), dried over Na2SO4, filtered, and concentrated to provide the crude product C15-a which was used directly without purification. MS (ESI) m / z 258 [M+1]. Step 2: 2-((6-chloro-4-methylpyridin-3-yl)oxy)-2-methylpropan-1-ol (C15-b)

[0178] This intermediate was prepared in an analogous method to that of Intermediate C03-c by substituting Intermediate C03-b for Intermediate C15-a to provide compound C15-b. MS (ESI) m / z 216 [M+1]. Step 3: 5-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)oxy)-2-chloro-4- methylpyridine (C15-c)

[0179] Under N2, tert-butylchlorodimethylsilane (908 mg, 6.03 mmol) and 1H-imidazole (616 mg, 9.04 mmol) were added to a solution of Intermediate C15-b (650 mg, 3.01 mmol) in CH2Cl2 (12 mL). The mixture was stirred for at 20 °C 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 30 mL). The combined organic was washed25909 with brine (90 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 0-30 % EtOAc:PE) to provide compound C15-c. MS (ESI) m / z 330 [M+1]. Step 4: 5-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)oxy)-4-methyl-2-vinylpyridine (C15-d)

[0180] This intermediate was prepared in an analogous method to that of Intermediate C14-b by substituting Intermediate C14-a for Intermediate C15-c to provide compound C15-d. MS (ESI) m / z 322 [M+1]. Step 5: (5-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)oxy)-4-methylpyridin-2- yl)methanol (C15-e)

[0181] This intermediate was prepared in an analogous method to that of Intermediate C14 Step 3 by substituting Intermediate C14-b for Intermediate C15-d to provide compound C15- e. MS (ESI) m / z 326 [M+1]. Step 6: 5-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)oxy)-2-(chloromethyl)-4- methylpyridine (C15)

[0182] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C15-e to provide compound C15. MS (ESI) m / z 344 [M+1]. Intermediate C16: 5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-2-(chloromethyl)pyridine (C16)Step 1:

[0183] 60% NaH (1595 mg, 39.9 mmol) at 0 °C was added portion-wise, to a solution of (6- bromopyridin-3-yl)methanol (5000 mg, 26.6 mmol) in DMF (50 mL). After 20 min stirring at RT, methyl 2-bromoacetate (8136 mg, 53.2 mmol) was added. The reaction was stirred at 20 °C for 6 h. The reaction was quenched with sat aq NH4Cl (20 mL) slowly. The solution was extracted with ethyl acetate. The organic was dried over Na2SO3and the organic was concentrated. The residue was purified by flash chromatography (SiO2, 5-20 % EtOAc:PE) to provide compound C16-a. MS (ESI) m / z 260, 262 [M+1]. Step 2: 2-((6-bromopyridin-3-yl)methoxy)ethanol (C16-b)25909

[0184] This intermediate was prepared in an analogous method to that of Intermediate C11-e by substituting Intermediate C11-d for Intermediate C16-a to provide compound C16-b. MS (ESI) m / z 332, 334 [M+1]. Step 3: 2-bromo-5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)pyridine (C16-c)

[0185] This intermediate was prepared in an analogous method to that of Intermediate C15-c by substituting Intermediate C15-b for Intermediate C16-b to provide compound C16-c. MS (ESI) m / z 346, 348 [M+1]. Step 4: 5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-2-vinylpyridine (C16-d)

[0186] This intermediate was prepared in an analogous method to that of Intermediate C07-f by substituting Intermediate C07-e for Intermediate C16-c to provide compound C16-d. MS (ESI) m / z 294 [M+1]. Step 5: (5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)pyridin-2-yl)methanol (C16-e)

[0187] This intermediate was prepared in an analogous method to that of Intermediate C14 Step 3 by substituting Intermediate C14-b for Intermediate C16-d to provide compound C16- e. MS (ESI) m / z 298 [M+1]. Step 6: 5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-2-(chloromethyl)pyridine (C16)

[0188] This was prepared in an analogous method to that of Intermediate C03 Step 4 byIntermediate C03-c for Intermediate C16-e to provide compound C16. MS (ESI) m / z 316 [M+1]. Intermediate C17: (4,5-dimethoxypyridin-2-yl)methyl 4-methylbenzenesulfonate (C17)

[0189] (4,5-was added to a vial and was dissolved in DCE (24 mL). DIPEA (2.5 mL, 14.19 mmol) was added. The reaction mixture was chilled to 0 °C where 4-methylbenzenesulfonic anhydride (2315 mg, 7.09 mmol) then was added. The reaction was stirred overnight at RT. The organic was washed with water (2 x 10 mL) and the organic was over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, 0-10% MeOH:DCM) to isolate compound C17. MS (ESI) m / z 324 [M+1]. Intermediate C18: 5-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-2-(chloromethyl)pyridine (C18)25909 Step 1:

[0190] (500 mg, 3.27 mmol) and 2-iodoethanol (842 mg, 4.90 mmol) in ACN (5 mL). The reaction mixture was stirred at 60 °C for 2 h. Water (10 mL) was added to the reaction and extracted with EtOAc (2 x 10 mL). The combined organic was dried over Na2SO4, filtered, and the organic was concentrated to isolate compound C18-a. Step 2: methyl 5-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)picolinate (C18-b)

[0191] Imidazole mg, 2.66 mmol) and TBDPSCl (585 mg, 2.13 mmol) were added to a mixture ofC18-a (350 mg, 1.77 mmol) and stirred at RT for 5 min. Water (10 mL) was added to the reaction mixture and extracted with EtOAc (2 x 10 mL). The combined organic was dried over Na2SO4, filtered, and the organic was concentrated to isolate compound C18-b. MS (ESI) m / z 436 [M+1]. Step 3: (5-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (C18-c)

[0192] This was prepared in an analogous method to that of Intermediate C03-c byC03-b for Intermediate C18-b to provide compound C18-c. MS (ESI) m / z 408 [M+1]. Step 4: 5-(2-((tert-butyldiphenylsilyl)oxy)ethoxy)-2-(chloromethyl)pyridine (C18)

[0193] This intermediate was prepared in an analogous method to that of intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C18-d to provide compound C18. MS (ESI) m / z 425 [M+1]. Intermediate C19: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(chloromethyl)pyrazine (C19) Step 1: (5-

[0194] NaBH4 (1.64 g, 43.46 mmol) was added portion wise at 20 °C to a mixture of methyl 5- chloropyrazine-2-carboxylate (5 g, 28.97 mmol) in MeOH (30 mL). The reaction mixture was25909 stirred for 2.5 h. The reaction was concentrated to isolate compound (C19-a) and used directly in Step 2. MS (ESI) m / z 145 [M+1]. Step 2: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-chloropyrazine (C19-b)

[0195] This intermediate was prepared in an analogous method to that of Intermediate C15-c by substituting Intermediate C15-b for Intermediate C19-a and by substituting TBSCl for TBDPSCl to provide compound C19-b. MS (ESI) m / z 383 [M+1]. Step 3: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-vinylpyrazine (C19-c)

[0196] This intermediate was prepared in an analogous method to that of Intermediate C07-f by substituting Intermediate C07-e for Intermediate C19-b to provide compound C19-c. MS (ESI) m / z 375 [M+1]. Step 4: 5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrazine-2-carbaldehyde (C19-d)

[0197] was prepared in an analogous method to Intermediate C07-g byC07-f for Intermediate C19-c to provide compound C19-d. MS (ESI) m / z 377 [M+1]. Step 5: (5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrazin-2-yl)methanol (C19-e)

[0198] NaBH4(0.121 g, 3.19 mmol) was added to a solution of Intermediate C19-d (0.6 g, 1.594 mmol) in methanol (10 mL). The mixture was stirred for 2 h at 25 °C. The reaction was quenched with water and concentrated to give a residue, which was dissolved into ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and filtered, concentrated to isolate compound C19-e that was used directly in Step 6. MS (ESI) m / z 379 [M+1]. Step 6: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(chloromethyl)pyrazine (C19-f)

[0199] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C19-e to provide compound C19-f. MS (ESI) m / z 397 [M+1]. Intermediate C20: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methyl 4- methylbenzenesulfonate (C20)by substituting (4,5-Dimethoxypyridin-2-yl)methanol for C09-b to provide compound C20. MS (ESI) m / z 438 [M+1]25909 Intermediate C21: (4-methyl-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2- yl)methanol (C21) L), triethenyl-, mmol), H2O (3.60 L), and Pd(PPh3)4(55.26 g, 47.824 mmol were placed into a 20-L 4-necked round- bottom flask that was purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 4 hr at 100 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated. The residue was purified by flash chromatography (SiO2, EA / PE, 1:10) to isolate compound C21-a. Step 2: 5-bromo-4-methylpicolinic acid (C21-b)

[0202] Intermediate C21-a (569.00 g, 2872.823 mmol), propan-2-one (5.69 L), water (5.69 L), and tetraoxo(potassio)manganese (724.15 g, 5745.647 mmol) were placed into a 20-L 4- necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 3 days at RT. The solution was filtered and concentrated. The residue was purified by flash chromatography (SiO2, EA / PE, 1:10) to isolate compound C21-b. Step 3: methyl 5-bromo-4-methylpicolinate (C21-c)

[0203] Intermediate C21-b (438.00 g, 2027.4 mmol) and methanol (4.5 L) were placed into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. Chlorotrimethylsilane (4405.26 g, 40549.17 mmol) was then added dropwise with stirring at RT. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3 x 1 L). The organic phase was dried over anhydrous Na2SO4 and concentrated to isolate compound C21-c. Step 4: methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (C21-d)

[0204] Intermediate C21-c (327.00 g, 1421.3 mmol), dioxane (3.5 L), potassium acetate (209.24 g, 2132.043 mmol), tricyclohexylphosphane (31.89 g, 113.709 mmol), Pd2(dba)3(52.06 g, 56.854 mmol), and B2Pin2 (362.98 g, 1429.369 mmol) were placed into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting25909 solution was stirred for 16 h at 90 °C. The reaction mixture was cooled to room temperature and was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3 x 1 L). The organic phase was dried over anhydrous Na2SO4and concentrated to isolate compound C21-d. Step 5: methyl 5-hydroxy-4-methylpicolinate (C21-e)

[0205] Intermediate C21-d (400.00 g, 1847.508 mmol), oxolane (4 L), and H2O2(30%, 188.53 g, 5542.525 mmol) were placed into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4and concentrated to isolate compound C21-e. Step 6: methyl 4-methyl-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)picolinate (C21-f)

[0206] Intermediate C21-e (121.00 g, 723.8 mmol), DMF (1.21 L), 2-(2-bromoethoxy)oxane (181.61 g, 868.6 mmol), and K2CO3(221.69 g, 1592.448 mmol) were placed into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed. The resulting solution was stirred for 2 hr at 80 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3 x 500 mL). The organic phase was concentrated. The residue was purified by flash chromatography (SiO2, EA / PE, 1:5) to isolate compound C21-f. Step 7: (4-methyl-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methanol (C21)

[0207] Intermediate C21-f (150.00 g, 507.8 mmol) and DCM (2250.00 mL) were placed into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. This was followed by the dropwise addition of DIBAL-H (212.95 mL, 1497.340 mmol) with stirring at 0 °C in 1 hr. The resulting solution was stirred for 1 hr at 0 °C in a water / ice bath. The resulting solution was allowed to react, with stirring, for an additional 2 hr at RT. The reaction mixture was cooled to 0 °C with a water / ice bath. The reaction was then quenched by the addition of 247 mL of water. The residue was dissolved in 500 mL of DCM and the organic phase was concentrated. The residue was purified by flash chromatography (SiO2, EA) to isolate compound C21. MS (ESI) m / z 268 [M+1]. Intermediate C22: 2-(hydroxymethyl)-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)isonicotinonitrile (C22)°C and 2.5 M n-flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred for 15 min at -78 °C. To the reaction mixture a solution of 2-chloro-5-fluoropyridine (1.5 kg, 11404.2 mmol) in tetrahydrofuran (500 mL) was added dropwise with stirring at -78 °C °C over 40 min. A solution of I2(3.19 kg, 12544.667 mmol) in tetrahydrofuran (1.5 L) then was added dropwise with stirring at -78 °C over 90 min. The resulting solution was allowed to react for an additional 35 min at - 78 °C. The reaction was then quenched by the addition of 2 L of sat aq NH4Cl sol at -78 °C. The resulting solution was diluted with 20 L of H2O. The resulting solution was extracted with DCM (2 x 3 L) and the organic layers combined. The resulting mixture was washed with sat. aq sodium bisulfate sol (2 x 20 L). The resulting mixture was washed with brine (20 L). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to isolate compound C22-a. Step 2: 2-chloro-5-fluoroisonicotinonitrile (C22-b)

[0209] A solution of Intermediate C22-a (2.2 kg, 8546.013 mmol) in NMP (10 L), and CuCN (0.77 kg, 8546.013 mmol) was placed into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 6 h at 130 °C in an oil bath. The reaction was then quenched by the addition of 5 L of water. The resulting solution was diluted with 5 L of EA. The solids were filtered out. The filtrate was extracted with ethyl acetate (2 x 5 L) and the organic layers combined. The resulting mixture was washed with sat aq sodium chloride (2 x 2 L). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (3:1) to isolate compound C22-b. Step 3: methyl 4-cyano-5-fluoropicolinate (C22-c)

[0210] A solution of Intermediate C22-b (798 g, 5097.7 mmol) in methanol (5 L), TEA (1031.68 g, 10195.477 mmol) and Pd(dppf)Cl2(186.50 g, 254.887 mmol) was placed into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of CO. The resulting solution was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature. The organic phase was washed with water (2 x 1.5 L) and extracted with EA (3 x 3L), the organic phase was concentrated in vacuum. The crude product was purified by silica gel column (PE / EA=3:1) to isolate compound C22-c. Step 4: methyl 4-cyano-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)picolinate (C22-d)

[0211] 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (4869 mg, 33.3 mmol) was dissolved into DMF (22 mL) where 60% NaH by weight (999 mg, 24.98 mmol) was added and the solution sonicated for 10 mins. Intermediate C22-c (3000 mg, 16.65 mmol) was dissolved into DMF (20 mL). The previous solution was added dropwise. The reaction was complete after 1 h. The reaction mixture was quenched with sat aq NH4Cl sol (10 mL) and was then extracted with EtOAc (50 mL) and the organic was dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (SiO2, hexanes: EA) to isolate compound (C22-d). MS (ESI) m / z 307 [M+1]. Step 5: 2-(hydroxymethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)isonicotinonitrile (C22)

[0212] This intermediate was prepared in an analogous method to that of Intermediate C03-c by substituting Intermediate C03-b for Intermediate C22-d to provide compound C22. MS (ESI) m / z 279 [M+1]. Intermediate C23: 2-((6-(chloromethyl)pyridin-3-yl)oxy)ethan-1-ol (C23)

[0213] and 1 M TBAF in THF (7.47 mL, 7.47 mmol) was added and stirred for 1 h. The solution was concentrated and taken into EtOAc (100 mL) and washed with water (2 x 30 mL) and dried over MgSO4. The organic was then filtered and concentrated. The resulting residue was purified flash chromatography (SiO2, hexanes:EA) to isolate compound. MS (ESI) m / z 188 [M+1]. Intermediate C24: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-3- fluoropyridine (C24) Step 1: 5-a)25909

[0214] 6-chloro-5-fluoropyridin-3-ol (1000 mg, 6.78 mmol) was dissolved in DMF (13.6 mL) followed by the addition of K2CO3 (3747 mg, 27.1 mmol) and tert-butyl(2- iodoethoxy)dimethylsilane (1940 mg, 6.78 mmol). The reaction was heated to 45°C for 16 h. The reaction was added to EtOAc and extracted with water, brine, and the organic was dried over MgSO4. The organic was filtered and concentrated, and the resulting residue was taken into DCM and purified by flash chromatography eluting with 0-60% EtOAc:hexanes to isolate compound C24-a. MS (ESI) m / z 306 [M+1]. Step 2: methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoropicolinate (C24-b)

[0215] This intermediate was prepared in an analogous method to that of Intermediate C03-b by substituting Intermediate C03-a for Intermediate C24-a to provide compound C24-b. MS (ESI) m / z 330 [M+1]. Step 3: (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoropyridin-2-yl)methanol (C24-c)

[0216] This intermediate was prepared in an analogous method to that of Intermediate C03-c by substituting Intermediate C03-b for Intermediate C24-b to provide compound C24-c. MS (ESI) m / z 302 [M+1]. Step 4: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(chloromethyl)-3-fluoropyridine (C24) This intermediate was prepare in an analogous method to that of Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C24-c to provide compound C24. MS (ESI) m / z 320 [M+1]. Intermediate 25: 2-(chloromethyl)-5-fluoroisonicotinonitrile (C25) Step 1: 5-fluoro-2-

[0217] This intermediate was prepared in an analogous method to that of Intermediate C03-c by substituting Intermediate C03-b for Intermediate C22-c to provide compound C25-a. MS (ESI) m / z 153 [M+1]. Step 2: 2-(chloromethyl)-5-fluoroisonicotinonitrile (C25)

[0218] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 by substituting Intermediate C03-c for Intermediate C25-a to provide compound C25. MS (ESI) m / z 171 [M+1].25909 Intermediate 26: 4-chloro-2-(chloromethyl)-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)pyridine (C26) Step 1:

[0219] - - in conc. NH4OH (60 mL) was stirred at 90 °C for 3 h. The reaction was concentrated to dryness. The residue was purified by trituration in ACN (5 mL) to isolate compound C26-a.1H NMR (400 MHz, DMSO-d6) δ 11.09 (br s, 1H), 7.24 - 7.48 (m, 6H), 5.01 (br s, 2H), 4.33 (br d, J = 3.30 Hz, 2H). Step 2: 5-(benzyloxy)-4-chloro-2-(chloromethyl)pyridine (C26-b)

[0220] POCl3(45.8 mL, 493 mmol) was added to a stirred solution of Intermediate C26-a (19 g, 82 mmol) in ACN (200 mL) under N2. The mixture was stirred at 85 °C for 12 h. The mixture was concentrated, and the residue was dissolved in DCM. Then the mixture was adjusted to pH ~ 8 with sat aq NaHCO3. The mixture was extracted with EA (3 x 3 L), and the organic layer was dried over Na2SO4, filtered, and concentrated to isolate C26-b and used as-is in Step 3. MS (ESI) m / z 268 [M+1]. Step 3: 4-chloro-6-(hydroxymethyl)pyridin-3-ol (26-c)

[0221] A stirred solution of Intermediate C26-b (8.3 g, 31.0 mmol) in DCM (83 mL) and H2SO4(8.3 mL) was stirred at 15 °C for 1 h. The mixture was basified with aq NaHCO3to pH ~ 7. The mixture was concentrated to isolate compound C26-c and the compound was used directly in Step 4. MS (ESI) m / z 160 [M+1]. Step 4: (4-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methanol (C26-d)

[0222] This intermediate was prepared in an analogous method to that of Intermediate C03-a by substituting 6-bromo-4-methylpyridin-3-ol for Intermediate C26-c and (2- bromoethoxy)(tert-butyl)dimethylsilane for 2-(2-bromoethoxy)tetrahydro-2H-pyran at 80 °C for 2 h to provide compound C26-d. MS (ESI) m / z 288 [M+1]. Step 5: 4-chloro-2-(chloromethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (C26)

[0223] This intermediate was prepared in an analogous method to that of Intermediate C03 Step 4 by substituting C03-c for C26-d to provide compound C26. MS (ESI) m / z 306 [M+1].25909 Intermediate C27: 2-(chloromethyl)-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)isonicotinonitrile (27) C03 StepC27. MS (ESI) m / z 297 [M+1]. Intermediate C28: 2-(chloromethyl)-5-(2-methoxyethoxy)isonicotinonitrile (28) Step 1: (6-

[0225] K2CO3 (2.90 g, 21.02 mmol) was added to a stirred solution of 2-chloro-6- (hydroxymethyl)-4-iodopyridin-3-ol (2 g, 7.01 mmol) and 1-bromo-2-methoxyethane (1.461 g, 10.51 mmol) in DMF (40 mL). The mixture was stirred at 60 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography eluting with 0-25% EA:PE to isolate compound C28-a. MS (ESI) m / z 343 [M+1]. Step 2: 2-chloro-6-(hydroxymethyl)-3-(2-methoxyethoxy)isonicotinonitrile (C28-b)

[0226] Dicyanozinc (1.709 g, 14.55 mmol), zinc (0.057 g, 0.873 mmol) and (tBu3P)2Pd (0.298 g, 0.582 mmol) were added to a solution of Intermediate C28-a (1 g, 2.91 mmol) in DMF (15 mL) under N2. The resulting mixture was stirred at 110 °C for 1 h. The mixture was diluted with water, filtered, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography 0-25% EtOAc:PE to isolate compound C28-b. MS (ESI) m / z 243 [M+1]. Step 3: 2-(hydroxymethyl)-5-(2-methoxyethoxy)isonicotinonitrile (C28-c)

[0227] Pd-C (877 mg, 0.824 mmol) and potassium acetate (121 mg, 1.236 mmol) were added to a stirred solution of Intermediate C28-b (100 mg, 0.412 mmol) in MeOH (3 mL). The reaction was stirred under 15 Psi of H2 for 16 h. The mixture was filtered. The filtrate was concentrated to isolate compound C28-c and used directly in Step 4. MS (ESI) m / z 209 [M+1]. Step 4: 2-(chloromethyl)-5-(2-methoxyethoxy)isonicotinonitrile (C28)25909

[0228] DIPEA (0.201 mL, 1.153 mmol) and MsCl (60 µL, 0.768 mmol) were added to a stirred solution of C28-c (80 mg, 0.384 mmol) in DCM (3 mL). The reaction was stirred for 1 h. The reaction was concentrated to isolate compound C28. MS (ESI) m / z 227 [M+1]. Intermediate C29: 4-bromo-2-(bromomethyl)-5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)pyridine (C29) Step 1: 5-

[0229] DIPEA (9.60 mL, 55.0 mmol) and chloro(methoxy)methane (3.02 g, 37.5 mmol) were added to a solution of 6-methylpyridin-3-ol (2 g, 18.33 mmol) in DCM (20 mL) at 0 °C. The mixture was stirred at 20 °C for 8 h. The reaction was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The organic layer washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0– 10% EtOAc:PE) to isolate compound C29-a.1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 2.8 Hz, 1H), 7.30 - 7.13 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.09 (s, 2H), 3.41 (s, 3H), 2.43 (s, 3H). Step 2: 4-bromo-5-(methoxymethoxy)-2-methylpyridine (C29-b)

[0230] A solution of intermediate C29-a (600 mg, 3.92 mmol) in THF (2 mL) was cooled to -70 °C and t-BuLi (7.53 ml, 9.79 mmol) was added under N2. The resulting mixture was stirred for 1 h and then, 1,2-dibromo-1,1,2,2-tetrachloroethane (1913 mg, 5.88 mmol) was added. The reaction continued to stir at -78 °C for 1 h. The reaction mixture was warmed to 20 °C, diluted with sat aq NH4Cl solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated. The crude was purified by flash chromatography (SiO2, 0-5 % EtOAc:PE) to isolate product C29-b.1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.36 (s, 1H), 5.23 (s, 2H), 3.53 (s, 3H), 2.47 (s, 3H). Step 3: 4-bromo-6-methylpyridin-3-ol (C29-c)

[0231] 4 M HCl in EtOAc (5 mL, 20.00 mmol) was added to a solution of Intermediate C29-b (400 mg, 1.724 mmol) in EtOAc (2 mL). The mixture was stirred at 0 °C for 3 h. The reaction was concentrated to isolate C29-c and used directly in Step 4. Step 4: 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-methylpyridine (C29-d)25909

[0232] This intermediate was prepared in an analogous method to that of Intermediate C03-a substituting 6-bromo-4-methylpyridin-3-ol for Intermediate C29-c at 70 °C to provide compound C29-d. MS (ESI) m / z 346, 348 [M+1]. Step 5: 4-bromo-2-(bromomethyl)-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine (C29)

[0233] NBS (385 mg, 2.166 mmol) and AIBN (95 mg, 0.577 mmol) were added to a solution of Intermediate C29-d (500 mg, 1.444in CCl4(5 mL). The resulting mixture was stirred at 70 °C for 8 h. The mixture was concentrated, and the resulting residue was purified by prep TLC (SiO2, 25% EtOAc:PE) to afford compound C29. MS (ESI) m / z 426 [M+1]. Intermediate AB Section Intermediate AB01: 5-bromo-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5- yl)oxy)benzonitrile (AB01) Step 1:(trifluoromethyl)pyrimidin-4(3H)-one (AB01-a)

[0234] Intermediate B04 (430 mg, 1.423 mmol) was dissolved in DMF (7.1 mL). K2CO3 (433 mg, 3.13 mmol) and Intermediate A02 (541 mg, 1.707 mmol) were added to the solution and the solution was heated to 90 °C for 16 h. EtOAc (100 mL) was added to the reaction mixture and resulting mixture washed with water (2 x 25 mL), brine (25 mL), and dried over MgSO4. The organic was concentrated to isolate title compound AB01-a. The material was used directly in the n. MS (ESI) m / z 599, 601 [M+1]. Step 2: 5-bromo-2-fluoro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile (AB01-b)

[0235] Under N2,copper(I) cyanide (299 mg, 3.34 mmol) was added to a stirred solution of Intermediate AB01-a (200 m26g, 0.334 mmol) in DMA (6 mL). The resulting mixture was stirred at 140 °C for 3.5 h. The mixture was quenched with water (50 mL), extracted with EtOAc (3 x 70 mL), washed with brine (80 mL) and dried over Na2SO4, filtered, and concentrated to isolate material AB01-b. The material was used directly in Step 3. MS (ESI) m / z 498, 500 [M+1].25909 Step 3: 5-bromo-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5- yl)oxy)benzonitrile (AB01)

[0236] A solution of Intermediate AB01-b (120 mg, 0.241 mmol) in TFA (1 mL) and TFAA (0.5 mL) was stirred at 100 °C for 3 h. The mixture was concentrated and diluted with H2O (10 mL) and was adjusted pH = 7-8 with sat aq NaHCO3, extracted with EtOAc (3 x 30 mL), dried over Na2SO4, filtered, and concentrated to isolate compound AB01. MS (ESI) m / z 378, 400 [M+1].

[0237] Intermediates AB02 through AB011, were synthesized using processes disclosed in the appropriate international patent application publication as indicated in Table 3. Table 3. Intermediate Intermediate Patent and Patent Page MS (ESI) Structure Structure Name Example No. and line m / z [M+1].25909 Intermediate Intermediate Patent and Patent Page MS (ESI) Structure Structure Name Example No. and line m / z [M+1]. number25909 Intermediate Intermediate Patent and Patent Page MS (ESI) Structure Structure Name Example No. and line m / z [M+1]. numberIntermediate AB12: 5-(difluoromethyl)-2-methoxy-3-((6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile (AB12) Step 1:(trifluoromethyl)pyrimidin-4(3H)-one (AB12-a)

[0238] K2CO3 (770 mg, 5.57 mmol) was added to a solution of Intermediate A06 (470 mg, 1.857 mmol) and Intermediate B06 (561 mg, 1.857 mmol) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into H2O (30 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (5 mL), filtered, and concentrated. The residue was purified by flash chromatography (SiO2, PE: EtOAc = 3: 1) to isolate compound AB12-a. MS (ESI) m / z 535, 537 [M+1]. Step 2: 5-(difluoromethyl)-2-methoxy-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile (AB12-b)25909

[0239] Under N2, dicyanozinc (592 mg, 5.04 mmol), zinc (132 mg, 2.018 mmol) and Pd(tBu3P)2(103 mg, 0.202 mmol) were added to a stirred solution of Intermediate AB12-a (540 mg, 1.009 mmol) in DMF (2 mL). The mixture was stirred at 100 °C for 9 h. The mixture was filtered, diluted with H2O (10 mL), and then extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, PE:EA=15:1~3:1) to isolate compound AB12-b. MS (ESI) m / z 482 [M+1]. Step 3: 5-(difluoromethyl)-2-methoxy-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5- yl)oxy)benzonitrile (AB12)

[0240] TFAA (1.995 mL, 14.13 mmol) was added to a solution of Intermediate AB12-b (340 mg, 0.706 mmol) in TFA (3 mL). The reaction was sealed and stirred at 110 °C for 4 h. The reaction was concentrated to isolate compound AB12. MS (ESI) m / z 362 [M+1]. Intermediate AB13: 2-fluoro-5-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile (AB13) Step 1: 2-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile (AB13-a)

[0241] To a solution of Intermediate A01 (500 mg, 1.496 mmol) in DMF (5 mL) was added Intermediate B04 (249 mg, 1.646 mmol) and K2CO3 (413 mg, 2.99 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water (50 mL), extracted with EA (2 x 50 mL), the combined organic washed with brine (3 x 60 mL), dried with Na2SO4, filtered, and concentrated to give title compound AB13-a which was used directly in the next reaction. MS (ESI) m / z 466 [M+1]. Step 2: 2-fluoro-5-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5- yl)oxy)benzonitrile (AB13)

[0242] TFAA (2 mL) was added to a solution of Intermediate AB13-a (650 mg, 1.397 mmol) in TFA (2 mL). The reaction was stirred at 110 °C for 5 h. The reaction mixture was diluted with25909 saturated aqueous solution of NaHCO3(10 mL) and then extracted with EtOAc (2 x 10 mL), washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated. Then the residue was purified by flash chromatography (SiO2: PE:EA=10:1 to 1:1) to isolate compound AB13. MS (ESI) m / z 346 [M+1].

[0243] Intermediates AB14 through AB19, as depicted in Table 4, were prepared in an analogous method to that described for making Intermediate AB13 by using the noted starting intermediate in place of either A01 or B04. Table 4 IntermediateIntermediate StructureName25909 Intermediate AB20: 2-chloro-6-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5- yl)oxy)isonicotinonitrile (AB20) N Cl N NH Step 1: 2- 5-yl)oxy)isonicotinonitrile (AB20-a)

[0244] Intermediate B07 (3 g, 9.99 mmol) was added to DMA (20 mL) and 2,6- dichloroisonicotinonitrile (3.5 g, 19.98 mmol) followed by the addition of KF (2.3 g, 40.0 mmol). The reaction solution was heated to 110 °C for 1 h. The solution was added to EtOAc (200 mL) and washed with water (2 x 50 mL). The organic was dried over MgSO4. The solution was concentrated and purified by flash chromatography eluting with 0-80% EtOAc:hexanes to isolate compound AB20-a. MS (ESI) m / z 437 [M+1]. Step 2: 2-chloro-6-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)isonicotinonitrile (AB20)

[0245] This intermediate was prepared in an analogous method to that of Intermediate AB13 Step 2 by substituting Intermediate AB13-a for Intermediate AB20-a to provide compound AB20. MS (ESI) m / z 317 [M+1]. Intermediate AB21: 2-methyl-6-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5- yl)oxy)isonicotinonitrile (AB21) Step 1: 2-((1-(4-5-yl)oxy)-6- methylisonicotinonitrile (AB21-a)

[0246] Water (1.846 mL) was added to a mixture of Intermediate AB20-a (1.451 g, 3.32 mmol), potassium trifluoro(methyl)borate (0.608 g, 4.98 mmol), Cs2CO3(2.381 g, 7.31 mmol)25909 and cataCXium® A Pd G2 (0.444 g, 0.664 mmol (Sigma-Aldrich Inc., St. Louis, MO) in 1,4- dioxane (9.23 mL) at RT under N2. The resulting mixture was heated at 90 °C for 16 h. The reaction was filtered through Celite®and rinsed with EtOAc (2 mL), water (2 mL) and concentrated. The residue was purified by flash chromatography eluting with 0-80% (3:1 EtOAc:EtOH):hexanes to isolate compound AB21-a. MS (ESI) m / z 417 [M+1]. Step 2: 2-methyl-6-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)isonicotinonitrile (AB21)

[0247] This intermediate was prepared in an analogous method to that of Intermediate AB13 Step 2 by substituting Intermediate AB13-a for Intermediate AB21-a to provide compound AB21. MS (ESI) m / z 297 [M+1].

[0248] Intermediates used in the preparation of Examples 1 through 45 that were not commercially available were prepared as described in the Intermediate Sections A through C above and are noted in the INT column in each of Tables 5-8. EXAMPLE 1 2-((5-(5-bromo-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (1)4- (trifluoromethyl)-1,6- 5-yl)oxy)-2-fluorobenzonitrile (1-a)

[0249] K2CO3(88 mg, , LiBr (18.38 mg, 0.212 mmol), and Intermediate C09 (96 mg, 0.317 mmol) were added to a solution of Intermediate AB01 (80 mg, 0.212 mmol) in DMF (2 mL) at 20 °C. The reaction was stirred at 20 °C for 6 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 0-50% EA:hexanes) to isolate compound 1- a. MS (ESI) m / z 643, 645 [M+1]. Step 2: 2-((5-(5-bromo-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (1)25909

[0250] H2O2(0.1 mL, 1.142 mmol) and AcOH (1 mL) were added into Intermediate 1-a (30 mg, 0.047 mmol) and the solution was stirred at 70 °C for 3 h. The reaction was concentrated, and the reaction was purified by reverse phase chromatography eluting with 30-50% ACN:water (0.1% TFA) to isolate compound 1. MS (ESI) m / z 545, 547 [M+1];1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.25 (br s, 1H), 7.71 (br d, J = 8.8 Hz, 1H), 7.46 (dd, J = 1.9, 4.3 Hz, 1H), 7.29 (br d, J = 1.8 Hz, 1H), 7.18 (br d, J = 8.4 Hz, 1H), 5.25 (s, 2H), 4.17 (br s, 2H), 4.01 (br d, J = 4.0 Hz, 2H).

[0251] The compounds in Table 5 were prepared in an analogous method to that described for Example 1, Step 1, with the following variations. The reaction can be performed under ambient temperature to 45 °C with or without LiBr. The final oxidation step utilized either m-CPBA or H2O2to afford the final N-oxide product. Table 5 Ex. Structure IUPAC Name MSM1INT.23 3 5 4 625909 Ex. Structure IUPAC Name MS[M+1]INT.48 4 0 7 5 8 3 3 725909 Ex. Structure IUPAC Name MS[M+1]INT.73 5 3 1 8 7 9 8 3Example 15 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methoxyphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (15)25909- -

[0252] K2CO3(115 mg, 0.833 mmol), Intermediate C04 (74.4 mg, 0.278 mmol) and LiBr (48.2 mg, 0.555 mmol) were added to a solution of Intermediate AB12 (100 mg, 0.278 mmol) in DMF (2 ml). The mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford compound 15-a, which was used directly without purification in Step 3. MS (ESI) m / z 593 [M+1]. Step 2: 3-((1-((4-chloro-5-hydroxypyridin-2-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2- dihydropyridin-3-yl)oxy)-5-(difluoromethyl)-2-methoxybenzonitrile (15-b)

[0253] A solution of Intermediate 15-a (120 mg, 0.203 mmol) in DCM (1 mL) and H2SO4 (0.1 mL) was stirred at 15 °C for 1 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was washed with saturated aqueous solution of NaHCO3(10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to afford compound 15-b, which was used directly without purification in Step 3. MS (ESI) m / z 503 [M+1]. Step 3: 3-((1-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloropyridin-2-yl)methyl)-6-oxo-4- 1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-(15-c)

[0254] K2CO3(38.5 mg, 0.278 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (40.0 mg, 0.167 mmol) were added to a solution of Intermediate 15-b (70 mg, 0.139 mmol) in DMF (1 mL). The reaction was stirred at 60 °C for 6 h. The solution was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by prep TLC (SiO2, 50 % EtOAc:PE) to afford compound 15-c. MS (ESI) m / z 661 [M+1]. Step 4: 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methoxyphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (15)25909

[0255] Hydrogen peroxide (0.2 mL, 1.993 mmol) was added to a solution of Intermediate 15-c (30 mg, 0.045 mmol) in AcOH (0.2 mL). The mixture was stirred at 70 °C for 2 h. The reaction was concentrated and purified by prep HPLC (water:MeCN with 0.1 % TFA) to provide compound 15. MS (ESI) m / z 563 [M+1],1H NMR (400 MHz, acetonitrile-d3) δ = 8.73 (s, 1H), 8.09 (s, 1H), 7.58 (s, 2H), 7.23 (s, 1H), 6.74 - 6.36 (m, 1H), 5.08 (s, 2H), 4.12 (t, J= 4.8 Hz, 2H), 4.07 (s, 3H), 3.82 (t, J= 4.4 Hz, 2H). EXAMPLE 16 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide (16)oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)isonicotinonitrile (16-a)

[0256] Intermediate C07 (40.2 mg, 0.123 mmol), K2CO3 (34.0 mg, 0.246 mmol) and LiBr (7.13 mg, 0.082 mmol) were added to a solution of Intermediate AB03 (30 mg, 0.082 mmol) in DMF (3 mL). The mixture was stirred at 15 °C for 16 h. The reaction was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The organic layer was concentrated, and the resulting residue was purified by prep TLC (SiO2, 50 % EtOAc:PE) to afford compound 16-a. MS (ESI) m / z 656 [M+1]. Step 2: 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)isonicotinonitrile (16-b)

[0257] TFA (1 mL) was added to a solution of intermediate 16-a (40 mg, 0.061 mmol) in DCM (3 mL). The reaction was stirred at 15 °C for 16 h. The reaction was concentrated and used directly without purification to isolate 16-b. MS (ESI) m / z 542 [M+1]. Step 3: 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide (16)

[0258] (19.11 mg, 0.111 mmol) was added to a solution of Intermediate 16-b (20 mg, 0.037 mmol) in DCM (2 mL). The reaction was stirred at 40 °C for 4 h. The reaction was concentrated and purified by prep HPLC (water:MeCN with 10 mM NH4HCO3) to provide25909 compound 16. MS (ESI) m / z 558 [M+1].1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H) 8.09 (s, 1H) 7.86 (s, 1H) 7.35 (dd, J = 4.52, 2.45 Hz, 1H) 7.13 (dd, J = 6.97, 2.45 Hz, 1H) 6.10 - 6.47 (m, 1H) 5.13 (s, 2H) 4.17 - 4.30 (m, 2H) 4.06 (br s, 2H).

[0259] The compounds in Table 6 were prepared in an analogous method to that described for Example 16 with the following variations. Step 1 of the reaction can be performed under ambient temperature to 45 °C with or without LiBr. The oxidation step utilized either m-CPBA or H2O2 to afford the final N-oxide product and may be done at either Step 2 or Step 3. Additionally, the deprotection step be accomplished with either TFA or TBAF and either during Step 2 or Step 3. Table 6 Ex. Structure IUPAC Name MS[M+1]INT.59 5 6 6 125909 Ex. Structure IUPAC Name MS[M+1]INT.42 4 6 9 8 4 9 6 925909 Ex. Structure IUPAC Name MS[M+1]INT.30 1 6 0 6 6 4EXAMPLE 29 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxy-2-methylpropoxy)-4-methylpyridine 1-oxide (29)yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2- methylbenzonitrile (29-a)25909

[0260] Intermediate C14 (9.18 mg, 0.043 mmol), Ph3P (15.20 mg, 0.058 mmol) and (E)-di- tert-butyl diazene-1,2-dicarboxylate (13.34 mg, 0.058 mmol) were added to a solution of Intermediate AB07 (10 mg, 0.029 mmol) in DCM (1 mL). The reaction was stirred at 20 °C for 2 h. The reaction was concentrated and purified by prep TLC (SiO2, 50% EtOAc:PE) to afford compound 29-a. MS (ESI) m / z 539 [M+1]. Step 2: 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxy-2-methylpropoxy)-4- methylpyridine 1-oxide (29)

[0261] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting 16-b for 29-a to provide compound 29. MS (ESI) m / z 555 [M+1];1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1 H) 8.04 (s, 1 H) 7.48 (d, J=10.39 Hz, 2H), 6.79 (s, 1H), 6.29 - 6.64 (m, 1H), 5.22 (s, 2H), 3.83 (s, 2H), 2.60 (s, 3H), 2.26 (s, 3H), 1.38 (s, 6H). EXAMPLE 30 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(hydroxymethyl)pyridine 1-oxide (30)yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (30-a):

[0262] This intermediate was prepared in an analogous method to that of Example 1-a by substituting AB01 for AB04 and C09 for 5-chloro-2-(chloromethyl)pyridine to provide compound 30-a. MS (ESI) m / z 521 [M+1]. Step 2: 5-(difluoromethyl)-3-((1-((5-(((4-methoxybenzyl)oxy)methyl)pyridin-2-yl)methyl)-6- oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (30-b)

[0263] A solution of Intermediate 30-a (400 mg, 0.768 mmol) in water (0.7 mL) and 1,4- dioxane (7 mL) was degassed and placed under N2. RuPhos Pd G1 (56.0 mg, 0.077 mmol), potassium trifluoro(((4-methoxybenzyl)oxy)methyl)borate (297 mg, 1.152 mmol) and Cs2CO3 (751 mg, 2.304 mmol) were added. The reaction was heated to 110 °C for 16 h. The reaction was25909 diluted with EtOAc (50 mL), washed with water (2 x 10 mL), dried over MgSO4, filtered and concentrated. The resulting material was purified by flash chromatography (SiO2, 0-80 % EtOAc:hexanes) to provide compound 30-b. MS (ESI) m / z 637 [M+1]. Step 3: 5-(difluoromethyl)-3-((1-((5-(hydroxymethyl)pyridin-2-yl)methyl)-6-oxo-4- (perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (30-c)

[0264] TMS-I (197 µL, 1.445 mmol) was added to a solution of Intermediate 30-b (460 mg, 0.723 mmol) in CH2Cl2 (3.6 mL) at 0 °C. The reaction was stirred at 0 °C for 10 min. The reaction was diluted with Na2SO3(5 mL) and extracted into DCM (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated to provide compound 30-c, which was used directly in Step 4 without purification. MS (ESI) m / z 517 [M+1]. Step 4: 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(hydroxymethyl)pyridine 1-oxide (30)

[0265] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting 16-b for 30-c to provide compound 30. MS (ESI) m / z 533 [M+1];1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 7.53 – 7.47 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.89 (t, J = 55.2 Hz, 1H), 5.49 (s, 1H), 5.22 (s, 2H), 4.48 (s, 2H), 2.46 (s, 3H). EXAMPLE 31 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (31)dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile (31-a)

[0266] This example was prepared in an analogous method to that of Example 1 by substituting Intermediate AB01 for Intermediate AB06 and Intermediate C09 for Intermediate C04 at 40 °C to provide compound 31-a. MS (ESI) m / z 565 [M+1]. Step 2: 5-chloro-3-((1-((4-chloro-5-hydroxypyridin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile (31-b)25909

[0267] A solution of Intermediate 31-a (160 mg, 0.283 mmol) in DCM (1 mL) and H2SO4(0.1 mL) was stirred at 15 °C for 10 min. The mixture was basified with sat aq NaHCO3 to pH=8, diluted with water (30 mL), and extracted with DCM (3 x 40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to provide compound 31-b which was used in Step 3 without purification. MS (ESI) m / z 475 [M+1]. Step 3: 3-((1-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloropyridin-2-yl)methyl)-6-oxo-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile (31-c)

[0268] K2CO3(105 mg, 0.758 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (72.5 mg, 0.303 mmol) were added to a solution of Intermediate 31-b (120 mg, 0.253 mmol) in DMF (2 mL). The reaction was stirred at 60 °C for 2 h. The mixture was poured in to 100 mL water. A precipitate formed and was filtered to give compound 31-c which was used in Step 4 without purification. MS (ESI) m / z 633 [M+1]. Step 4: 5-chloro-3-((1-((4-chloro-5-(2-hydroxyethoxy)pyridin-2-yl)methyl)-6-oxo-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile (31-d)

[0269] This intermediate was prepared in an analogous method to that of Intermediate C23 by substituting Intermediate C09 for Intermediate 30-c to provide compound 31-d. MS (ESI) m / z 519 [M+1]. Step 5: 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (31)

[0270] intermediate was prepared in an analogous method to that of Example 16 Step 3 by Intermediate 16-b for Intermediate 31-d to provide compound 31. MS (ESI) m / z 535 [M+1];1H NMR (400 MHz, Acetonitrile-d3) δ 8.76 (s, 1H), 8.09 (s, 2H), 7.61 (s, 1H), 7.51 (dd, J = 4.5, 2.5 Hz, 1H), 7.31 (dd, J = 7.1, 2.4 Hz, 1H), 5.09 (s, 2H), 4.11-4.14 (m, 2H), 3.80 - 3.84 (m, 2H).

[0271] The compounds in Table 7 were prepared in an analogous method to that described for Example 31 with the following variations. Step 2 could be done using either H2SO4 or HBr / HOAc. The final oxidation step can utilize either m-CPBA or H2O2to afford the final N- oxide product.25909 Table 7 Ex. Structure IUPAC Name MS[M+1]INT.04 1 4 7 42-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide (35)2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (35- a)

[0272] To a vial containing TPP (825 mg, 3.15 mmol), Intermediate AB06 (700 mg, 2.098 mmol) and Intermediate C21 (561 mg, 2.098 mmol) was taken into CH2Cl2(10 mL) and chilled to 0 °C. DIAD (490 µL, 2.52 mmol) was added slowly and the solution was brought to ambient temperature and stirred for 2 h. DCM (10 mL) was added to the reaction and the organic layer was extracted with water (2 x 5 mL). The organic layer was concentrated, and the residue was25909 purified by flash chromatography (SiO2, EtOAc:hexanes, 0-100%) to isolate compound 35-a. MS (ESI) m / z 583 [M+1]. Step 2: 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-methyl-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine 1-oxide (35-b)

[0273] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting Intermediate 16-b for Intermediate 35-a to provide compound 35-b. MS (ESI) m / z 599 [M+1]. Step 3: 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide (35)

[0274] Intermediate 35-b (177 mg, 0.296 mmol) was dissolved in MeOH (1478 µL) where pTsOH · H2O (281 mg, 1.478 mmol) was added to a vial and stirred 16 h. The solution was concentrated, and the residue was purified by reverse phase chromatography eluting with 5-95% ACN:Water (0.05% NH4OH) to isolate compound 35. MS (ESI) m / z 515 [M+1];1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.13 (s, 1H), 7.94 - 7.83 (m, 2H), 7.34 (s, 1H), 5.16 (s, 2H), 4.91 (t, J = 5.5 Hz, 1H), 4.05 (t, J = 4.7 Hz, 2H), 3.70 (q, J = 5.1 Hz, 2H), 2.13 (s, 3H).

[0275] The compounds in Table 8 were prepared in an analogous method to that described for Example 35 with the following variations. The oxidation step utilized either m-CPBA or H2O2 to afford the final N-oxide product and could be done at either Step 2 or Step 3. The deprotection step could be done with either pTsOH or DuPont™ AmberChrom™ 50WX2 (Dupont, Wilmington, DE) during Step 2 or Step 3. Table 8 Ex Structure IUPAC Name MS INT.72 6 225909 Ex. Structure IUPAC Name MS[M+1]INT.7-c2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide (39)tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-fluoroisonicotinonitrile (39-a)

[0276] This intermediate was prepared in an analogous method to that of Example 1-a by substituting Intermediate C09 for Intermediate C25 and Intermediate AB01 for Intermediate AB05 to provide compound 39-a. MS (ESI) m / z 532 [M+1]. Step 2: 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-4-cyano-5-fluoropyridine 1-oxide (39-b)

[0277] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting Intermediate 16-b for Intermediate 39-a and 70 °C to provide compound 39-b. MS (ESI) m / z 548 [M+1]. Step 3: 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1- oxide (39)

[0278] Intermediate 39-b (60 mg, 0.110 mmol) was dissolved in 1,4-dioxane (2.2 mL). Ethane-1,2-diol (34.0 mg, 0.548 mmol) and Cs2CO3 (357 mg, 1.095 mmol) then was added to the reaction and heated to 75 °C for 16 h. The reaction was filtered, and the organic was25909 concentrated. The residue was purified by reverse phase chromatography eluting with 5-95% ACN:Water (0.05% TFA) to compound 39. MS (ESI) m / z 590 [M+1];1H NMR (500 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.39 (s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.26 (s, 1H), 6.93 – 6.40 (m, 2H), 5.24 (s, 2H), 4.34 – 4.17 (m, 2H), 4.00 – 3.88 (m, 2H). EXAMPLE 40 2-((5-(3-cyano-5-(difluoromethyl)-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (40)-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile (40-a)

[0279] Thiswas prepared in an analogous method to that of Example 34-a by substituting Intermediate C21 for Intermediate C09-b to provide compound 40-a. MS (ESI) m / z 599 [M+1] Step 2: 3-((1-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methyl)-6-oxo-4- 5-yl)oxy)-2-fluoro-5-vinylbenzonitrile (40-b)

[0280] To a(770 mg, 1.285 mmol) in dioxane (5.3 mL) and water (1 mL) was added K3PO4 (546 mg, 2.57 mmol), potassium vinyltrifluoroborate (189 mg, 1.414 mmol), and cataCXium®A Pd G2 (86 mg, 0.129 mmol). The vial was degassed with N2for 5 minutes and heated to 110 °C for 16 h. The reaction was filtered over Celite®and concentrated. The resulting oil was dissolved in EtOAc, washed with water, dried over MgSO4and the organic was concentrated. The residue was purified by flash chromatography eluting with 0-75% EtOAc:hexanes to isolate compound 40-b. MS (ESI) m / z 591 [M+1]. Step 3: 3-((1-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methyl)-6-oxo-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-fluoro-5-formylbenzonitrile (40-c)

[0281] This intermediate was prepared in an analogous method to that of Intermediate C07-g by substituting Intermediate C07-f for Intermediate 40-b to provide compound 40-c. MS (ESI) m / z 593 [M+1].25909 Step 4: 3-((1-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methyl)-6-oxo-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-fluorobenzonitrile (40-d)

[0282] Deoxofluor (231 µL, 1.250 mmol) was added to vial containing Intermediate 40-c (247 mg, 0.417 mmol) and DCE (2.1 mL) at 25 °C. The resulting vial was sealed and stirred at 50 °C for 3 h. The reaction was slowly added to cold sat aq NaHCO3solution. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography eluting with 0-80% EtOAc / hexanes to isolate compound 40-d. MS (ESI) m / z 615 [M+1]. Step 5: 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-((5-(3-cyano-5-(difluoromethyl)-2- fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)-yl)methyl)pyridine 1-oxide (40-e)

[0283] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting Intermediate 16-b for Intermediate 40-d to provide compound 40-e. MS (ESI) m / z 631 [M+1] Step 6: 2-((5-(3-cyano-5-(difluoromethyl)-2-fluorophenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (40)

[0284] This intermediate was in an analogous method to that of Intermediate C23 by substituting Intermediate C09 for40-e to provide compound 40. MS (ESI) m / z 517 [M+1];1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 4.1 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.15 – 6.79 (m, 2H), 5.18 (s, 2H), 4.92 (s, 1H), 4.11 – 3.95 (m, 2H), 3.69 (s, 2H). EXAMPLE 41 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (41)25909 Step 1: 3-((4-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methyl)-5-fluoro- 6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one (41-a)

[0285] This intermediate was prepared in an analogous method to that of Example 1-a by substituting Intermediate C09 forand Intermediate AB01 for Intermediate B02 to provide compound 41-a. MS (ESI) m / z 484 [M+1]. Step 2: 3-((1-((4-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methyl)-6- oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2- methylbenzonitrile (41-b)

[0286] Intermediate 41-a (280 mg, 0.579 mmol), Intermediate A03 (117 mg, 0.637 mmol), K2CO3(176 mg, 1.273 mmol) and ACN (2.9 mL) were added to a vial. The reaction was heated to 80 °C for 16 h. The solution was filtered and concentrated. The resulting residue was purified by reverse phase chromatography eluting with 0-100% EtOAc:hexanes to isolate compound 41- b. MS (ESI) m / z 647 [M+1]. Step 3: 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)pyridine 1-oxide (41-c)

[0287] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting Intermediate 16-b for Intermediate 41-b to provide compound 41-c. MS (ESI) m / z 663 [M+1]. Step 4: 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (41)

[0288] This intermediate was in an analogous method to that of Example 34 Step 3 by substituting Intermediate 34-Intermediate 41-c to provide compound 41. MS (ESI) m / z 579 [M+1];1H NMR (500 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.36 (s, 1H), 7.75 (s, 2H), 7.35 (s, 1H), 6.88 (t, J = 55.2 Hz, 2H), 5.15 (s, 2H), 4.96 (s, 1H), 4.18 - 4.12 (m, 2H), 3.72 (s, 2H), 2.48 (s, 3H). EXAMPLE 42 4-cyano-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (42)

[0289] This intermediate was prepared in an analogous method to Intermediate hat of Example 1-a by substituting Intermediate C09 for Intermediate C27 and Intermediate AB01 for Intermediate B01 to provide compound 42-a. MS (ESI) m / z 443 [M+1]. Step 2: 4-cyano-2-((5-fluoro-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine 1-oxide (42-b) This intermediate was prepared in an analogous method to that of Example 16 step 3 by substituting Intermediate 16-b for Intermediate 42-a to provide compound 42-b. MS (ESI) m / z 459 [M+1]. Step 3: 4-cyano-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine 1-oxide (42-c)

[0290] Intermediate 42-b (100 mg, 0.218 mmol), Intermediate A01 (36.3 mg, 0.240 mmol) and K2CO3 (66.3 mg, 0.480 mmol) were added to a vial. ACN (1091 µL) then was added to the vial. The reaction was heated to 80 °C for 16 h. The reaction was cooled, filtered, concentrated and the residue was purified by flash chromatography to isolate compound 42-c. MS (ESI) m / z 590 [M+1]. Step 4: 4-cyano-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (42)

[0291] This intermediate was prepared in an analogous method to that of Example 34 step 3 by substituting Intermediate 34-b for Intermediate 42-c to provide compound 42. MS (ESI) m / z 506 [M+1];1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.46 (dd, J = 25.7, 6.5 Hz, 2H), 5.16 (s, 2H), 5.00 (t, J = 5.3 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.72 (q, J = 5.0 Hz, 2H), 2.24 (s, 3H). EXAMPLE 43 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(methylamino)pyridine 1-oxide (43)- -

[0292] This intermediate was prepared in an analogous method to that of Example 1-a by substituting Intermediate C09 for Intermediate C25 and Intermediate AB01 for Intermediate AB04 to provide compound 43-a. MS (ESI) m / z 530 [M+1]. Step 2: 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(methylamino)isonicotinonitrile (43-b)

[0293] Intermediate 43-a (50 mg, 0.094 mmol), 2.0 M methylamine in THF (283 µL, 0.283 mmol), and dioxane (472 µL) were added to a vial and stirred at for 16 h. The solution was concentrated to isolate compound 43-b. MS (ESI) m / z 541 [M+1]. Step 3: 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(methylamino)pyridine 1-oxide (43)

[0294] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting 16-b for 43-b to provide compound 43. MS (ESI) m / z 557 [M+1];1H NMR (600 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.81 (s, 1H), 7.71 (s, 2H), 7.40 (s, 1H), 6.98 – 6.63 (m, 2H), 5.05 (s, 2H), 2.70 (d, J = 4.6 Hz, 3H), 2.42 (s, 3H). EXAMPLE 44 2-((5-(5-bromo-3-cyano-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-chloro-5-(2-hydroxyethoxy)pyridine 1-oxide (44)25909 Step 1: 3-((1-((5-(benzyloxy)-4-chloropyridin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)-5-bromo-2-methylbenzonitrile (44-a)

[0295] This intermediate was prepared in an analogous method to that of Example 1-a by substituting Intermediate AB01 for Intermediate AB18 and Intermediate C09 for Intermediate C04 to provide compound 44-a. MS (ESI) m / z 607 [M+1]. Step 2: 5-bromo-3-((1-((4-chloro-5-hydroxypyridin-2-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (44-b)

[0296] H2SO4(0.1 mL) at 0 °C was added to a solution of Intermediate 44-a (200 mg, 0.367 mmol) in DCM (1mL). The mixture was stirred at 20 °C for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layer washed with aq NaHCO3, brine, dried over Na2SO4, filtered, and concentrated to isolate compound 44-b. MS (ESI): 517 M / (Z+1). Step 3: 5-bromo-3-((1-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloropyridin-2- yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2- methylbenzonitrile (44-c)

[0297] This intermediate was prepared in an analogous method to that of Example 30-c substituting Intermediate 30-b for Intermediate 44-b to provide compound 44-c. MS (ESI) m / z 673, 675 [M+1]. Step 3: 2-((5-(5-bromo-3-cyano-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-chloro-5-(2-hydroxyethoxy)pyridine 1-oxide (44)

[0298] This intermediate was prepared in an analogous method to that of Example 1 Step 2 by substituting Intermediate 1-a for Intermediate 44-c to provide compound 44. MS (ESI) m / z 557 [M+1];1H NMR (400 MHz, ACETONITRILE-d3) δ 8.73 (s, 1H), 8.09 (s, 1H), 7.52-7.70 (m, 2H), 7.13 (d, J = 1.47 Hz, 1H), 5.08 (s, 2H), 4.13 (t, J = 4.46 Hz, 2H), 3.75 - 3.89 (m, 2H), 2.43 (s, 3H). EXAMPLE 45 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (45)25909 Step 1: 5-(3-bromo-5-chloro-2-fluorophenoxy)-3-((4-chloro-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)pyridin-2-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one (45- a)

[0299] This intermediate was prepared in an analogous method to that of Example 1-a substituting Intermediate AB01 for Intermediate AB19 and Intermediate C09 for Intermediate C26 to provide compound 45-a. MS (ESI) m / z 690 [M+1]. Step 2: 5-chloro-3-((1-((4-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2- yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2- fluorobenzonitrile (45-b)

[0300] DMF (2.5 mL) was added under N2to a vial containing Intermediate 45-a (356 mg, 0.516 mmol), Pd(Ph3P)4 (119 mg, 0.103 mmol) and Zn(CN)2 (30.9 mg, 0.263 mmol). The resulting mixture was degassed for 5 min and then heated at 110 °C for 16 h. The reaction mixture was poured into a flask containing water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography eluting with 0-80% EtOAc:hexanes to isolate compound 45-b. MS (ESI): 635 M / (Z+1). Step 3: 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)pyridine 1-oxide (45-c)

[0301] This intermediate was prepared in an analogous method to that of Example 16 Step 3 by substituting 16-b for 45-b to provide compound 45-c. MS (ESI) m / z 651 [M+1]. Step 4: 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide (45)

[0302] This intermediate was prepared in an analogous method to that of Example 34 Step 3 by substituting Intermediate 34-b for Intermediate 45-c to provide compound 45. MS (ESI) m / z 567 [M+1];1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.36 (s, 1H), 7.77 (s, 3H), 7.05 - 6.71 (m, 1H), 5.16 (s, 2H), 4.95 (s, 1H), 4.21 - 4.09 (m, 2H), 3.71 (d, J = 4.4 Hz, 2H). Determination of cell kill (HIV-TACK) activity:

[0303] PBMCs derived from healthy donors were grown in complete media (RPMI 1640 with L-glutamine; 10 % heat inactivated Fetal Bovine Serum; 100 U / mL Penicillin-Streptomycin) containing 5 µg / mL Phytohemagglutinin at about 2.5 x 106cells / mL for 3 days at 5 % CO2, 37 °C, and 90 % humidity. On day 4, PHA stimulated cells were washed and resuspended at about 20 x 106cells / mL in complete media with IL-2 (10 U / mL) with VSV-G pseudotyped HIV25909 virus stock (VSV-G / pNLG1-P2A-∆Env - 20 µg / mL p24) and incubated for 4 hours at 37 °C, 5 % CO2 and 90 % humidity. VSV-G / pNLG1-P2A-∆Env is a VSV-G pseudotyped virus derived from pNL43 with egfp inserted 5’ of nef and eGFP expression driven off normal spliced RNA transcripts. Virus contained Vif truncated by 50 amino acids due to deletion of a single nucleotide causing a frameshift and does not express Nef due to a stop codon after gfp. HIV Env is not expressed due to a frameshift resulting in multiple stop codons. Infected cells were then washed with complete media plus 10U / mL IL-23-times with centrifuging at 200 x g for 3 minutes at 22 °C. Cells were resuspended at 5 x 106cells / mL in complete media plus 10 U / mL IL-2 and incubated overnight at 37 °C, 5 % CO2 and 90 % humidity. For compound treatment infected PBMCs were diluted to 4 x 105cells / mL with RPMI 1640 with L-glutamine, 50 % Normal Human Serum (NHS), 100 U / mL Penicillin-Streptomycin plus IL-2 (10 U / mL) and 20,000 cells were transferred to each well in a 384-well poly-D-lysine coated compound plate containing compounds with final DMSO <0.5 %. Compounds were tested with 10-point 3-fold titration. Plates were analyzed on an Acumen ex3 imager using the Blue Laser 488 nm and the number of GFP positive objects were collected with loss of GFP representing death of infected cells. Titration curves and EC50values were calculated using a four-parameter logistic fit. Results are shown in Table 9. Table 9 TACK TACK TACK TACK Ex. No. EC50Ex. No. EC50Ex. No. EC50Ex. No. EC50

Claims

25909 WHAT IS CLAIMED IS:

1. A compound of Formula I: or a pharmaceutically 2X is N or C(R );W is N or C(R9);R1 is selected from C1-10alkyl, amino(C0-10alkyl), C1-10fluoroalkyl, (C1-10alkyloxy)(C0-10alkyl), (hydroxy C1-10alkyl)oxy(C0-10alkyl), and hydroxy(C0-10alkyl), whereinR1is substituted by 0, 1, or 2 R10substituents;each R10independently is halogen, hydroxy, C0-6alkyl, or C1-10alkyloxy;R2 is selected from hydrogen, halogen, C1-10alkyl, cyano, C1-10fluoroalkyl, and C1-10alkyloxy(C0-6alkyl);R3 is selected from hydrogen, halogen, and C1-10alkyl;R4 is selected from hydrogen, halogen, C1-10alkyl, and C1-10fluoroalkyl;R5 is selected from hydrogen, halogen, C1-10alkyl, and C1-10alkyloxy;R6 is selected from hydrogen, cyano, halogen, C1-10alkyl, and C1-10alkyloxy(C0-6alkyl);R7 is selected from hydrogen, halogen, C1-10alkyl, and cyano;R8 is selected from hydrogen, halogen, C1-10alkyl, cyano, C1-10fluoroalkyl, and C1-10alkyloxy(C0-6alkyl); andR9 is selected from hydrogen, halogen, C1-10alkyl, and C1-10alkyloxy(C0-6alkyl).

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.25909 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinX is C(R2).

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, Br, Cl, F, methyl, ethyl, propyl, isopropyl, butyl, pentyl, tert-butyl, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroethyl, methoxy, ethoxy, propoxy, ethoxymethyl, and ethoxyethyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is N.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein W is C(R9), wherein R9is selected from hydrogen, fluoro, chloro, bromo, methyl,ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, ethoxymethyl, and ethoxyethyl.

7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof wherein R1is selected from amino, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,difluoromethyl, fluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, fluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxytert-butyl, hydroxyethoxy, hydroxypropoxy, hydroxybutoxy, methoxy, ethoxy, propoxy,2-hydroxyethoxymethyl, hydroxyethoxymethyl, and 2-hydroxyethoxyethyl, wherein R1issubstituted by 0, 1, or 2 R10substituents.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof whereineach R10independently is selected from fluoro, chloro, bromo, methyl, ethyl, propyl, methoxy,and ethoxy.

9. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof wherein R3is selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, and pentyl.25909 10. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof wherein R4is selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, difluoroethyl, trifluoroethyl, fluoroethyl, 1,1,3,3- tetrafluoropropyl, 1,1,3,3,3-tetrafluoropropyl, 1,1,2,2-tetrafluoroethyl, 1,1,1,2,2-pentafluoroeth- 2yl, and 1,1,1,2,2-pentafluoroethyl.

11. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable saltthereof wherein R5is selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl, propyl,butyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, andpentoxy.

12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable saltthereof wherein R6is selected from hydrogen and cyano.

13. The compound of any one of claims 1 to 12 or a pharmaceutically acceptablesalt thereof wherein R7 is selected from hydrogen, halogen, C1-6alkyl, and cyano.

14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptablesalt thereof wherein R8is selected from hydrogen, fluoro, bromo, chloro, methyl, ethyl,propyl, butyl, isopropyl, tert-butyl, pentyl, cyano, trifluoromethyl, difluoromethyl, difluoroethyl, trifluoroethyl, fluoroethyl, 1,1,3,3-tetrafluoropropyl, 1,1,3,3,3- tetrafluoropropyl, 1,1,2,2-tetrafluoroethyl, 1,1,1,2,2-pentafluoroeth-2yl, 1,1,1,2,2- pentafluoroethyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, methoxymethyl, ethoxymethyl, propoxyisopropyl, butoxy, tert-butoxy, and pentoxy.

15. The compound of claim 1 that is selected from: 2-((5-(5-bromo-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-chloro-5-cyanophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2- hydroxyethoxy)-4-methylpyridine 1-oxide; 4-bromo-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide;25909 2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-(trifluoromethyl)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-methoxypyridine 1-oxide; 2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-(difluoromethyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-((1-hydroxy-2-methylpropan-2-yl)oxy)-4-methylpyridine 1-oxide; 2-((5-(2-chloro-4-cyano-6-methylphenoxy)-4-(1-fluoroethyl)-6-oxopyrimidin-1(6H)-yl)methyl)- 5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; R-2-((5-(2-chloro-4-cyano-6-methylphenoxy)-4-(1-fluoroethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; S-2-((5-(2-chloro-4-cyano-6-methylphenoxy)-4-(1-fluoroethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-4,5-dimethoxypyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)-yl)methyl)- 5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-chloro-5-cyanophenoxy)-4-(1,1-difluoroethyl)-6-oxopyrimidin-1(6H)-yl)methyl)-4- cyano-5-(2-methoxyethoxy)pyridine 1-oxide; 4-bromo-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-bromo-3-cyano-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methoxyphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-(trifluoromethyl)pyridine 1-oxide;25909 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-fluoro-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-((1-hydroxypropan-2-yl)oxy)pyridine 1-oxide; S-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-((1-hydroxypropan-2-yl)oxy)pyridine 1-oxide; R-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-((1-hydroxypropan-2-yl)oxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-((2-hydroxyethoxy)methyl)-4-methylpyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-4-(1,1-difluoroethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(hydroxymethyl)pyrazine 1-oxide; 2-((5-(5-bromo-2-chloro-3-cyanophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-((4-cyano-6-methylpyridin-2-yl)oxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-((6-chloro-4-cyanopyridin-2-yl)oxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-3-fluoro-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxy-2-methylpropoxy)-4-methylpyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1(6H)- yl)methyl)-5-(hydroxymethyl)pyridine 1-oxide; 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-bromo-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-chloro-5-(2-hydroxyethoxy)pyridine 1-oxide;25909 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (trifluoromethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1-oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)-4-methylpyridine 1-oxide; 2-((5-(2-chloro-3-cyano-5-(difluoromethyl)phenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-4-cyano-5-(2-hydroxyethoxy)pyridine 1- oxide; 2-((5-(3-cyano-5-(difluoromethyl)-2-fluorophenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-chloro-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-2-fluoro-5-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; 4-cyano-2-((5-(3-cyano-5-(difluoromethyl)-2-methylphenoxy)-6-oxo-4- (perfluoroethyl)pyrimidin-1(6H)-yl)methyl)-5-(methylamino)pyridine 1-oxide; 2-((5-(5-bromo-3-cyano-2-methylphenoxy)-6-oxo-4-(trifluoromethyl)pyrimidin-1(6H)- yl)methyl)-4-chloro-5-(2-hydroxyethoxy)pyridine 1-oxide; and 4-chloro-2-((5-(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)pyrimidin- 1(6H)-yl)methyl)-5-(2-hydroxyethoxy)pyridine 1-oxide; or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 further comprising an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non-25909 nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents.

18. A method for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a human subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. A method for eliciting GAG-POL dimerization in HIV-infected cells in a human subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. A method for selectively killing HIV infected GAG-POL expressing cells in a human subject which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

21. A method for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a human subject which comprises administering to the human subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. A method for augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 19 to 22 further comprising administering to the human subject an effective amount of one or more additional compatible HIV antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents.25909 24. The compound according to any one of claims 1 to 15 for use in therapy.

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