EA045274B1 - PYRIMIDONE DERIVATIVES AS SELECTIVE CYTOTOXIC AGENTS AGAINST HIV-INFECTED CELLS - Google Patents

Description

Prerequisites for creating the invention

The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, people infected with HIV exhibit severe immunodeficiency, making them highly susceptible to indolent and ultimately fatal opportunistic infections. Several clinically approved antiretroviral drugs are available that demonstrate multi-log reductions in viral load. Patients undergoing treatment are at risk of acquiring mutations in the virus that make the virus in their body resistant to available treatments, and when therapy is stopped, there is a rapid return of viremia, indicating that current treatment regimens do not provide effective treatment.

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

Available antiretroviral drugs work by blocking the virus at different stages of 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 copied DNA to integrate into the host cell, and protease inhibitors prevent virus maturation so that virions produced from cells treated with protease inhibitors are immature and non-infectious. Once integration has occurred, the cell becomes infected until it dies through normal cell death, accelerated death due to viral factors, or until it becomes a target of the immune system. Although most infected cells are expected to die within ∼2 days of infection, the rapid resumption of viremia after cessation of treatment is an indication that infected cells remain even after many years of treatment (see, e.g., J.B. Dinoso et al., Proc. Natl. Acad. Sci. U.S.A., 2009, 106(23): 9403-9408). Thus, new treatments that can selectively kill HIV-infected cells will provide new treatment options for HIV infection. Treatment with compounds that can accelerate the death of HIV-infected cells and reduce the total number of virus-infected cells that persist in patients is important for reducing low-level viremia in immunosuppressed patients and may also play an important role in HIV treatment strategies.

The essence of the invention

The present invention relates to pyrimidone derivatives and their use as an HIV targeting and cell killing activator that accelerates the death of cells expressing HIV GAG-POL without concomitant cytotoxicity to HIV-naïve (uninfected) cells. Accordingly, the compounds described herein are useful for treating or preventing HIV infection, or for treating, preventing, or delaying the onset of progression of AIDS or AIDS-associated complex (ARC). In addition, these compounds are useful for selectively killing HIV-infected cells expressing GAG-POL in a subject infected with HIV. Also provided are compositions comprising the compounds of the invention and methods of use using the compounds of the invention.

Detailed Description of the Invention

The present invention relates to pyrimidone-derived compounds and their use to promote the death of cells expressing HIV GAG-POL without concomitant cytotoxicity to non-HIV-infected cells. In the absence of compounds such as the compounds of the invention, protease (PR) activation occurs during virus maturation and the concentration of mature PR in the cytoplasm is limited. In contrast, the compounds of the invention promote the desired phenotype by catalyzing the dimerization of GAG-POL within the infected cell by binding to the immature RT binding site and triggering premature activation of the HIV PR enzyme within the infected cell prior to virus exit. As a result, PR degrades 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, indicating a role for HIV protease in this process.

The compounds described herein also have activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to homology between the mature and immature RT pocket

HIV, which allows the compounds of the invention to bind to a mature hydrophobic pocket near the active site of the viral RT enzyme. Binding to mature RT leads to inhibition of enzymatic activity and production of proviral DNA, which prevents infection of naive

CD4+ T cells.

The effects of NNRTI on PT and GAG-POL dimerization have been previously described (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). Jochmans et al. first reported selective killing of HIV-infected cells as a result of enhanced dimerization (Jochmans et al. Retrovirology 2010, 7:89). The authors obtained data showing these effects in chronically infected MT-4 cells, PBMCs, and CD4+ cells. Based on the effectiveness of the molecules tested, they concluded that these data provide proof of concept for drug targeting to kill HIV-producing cells. Although NNRTIs alone may not be effective enough for therapeutic use, the results provide a basis for the development of drugs that exploit this mechanism of action. More recently, Zerbato et al. (Zerbato et al. Antimicrob. Agents Chemother. 2017, 61(3)) measured NNRTI activity in a primary cell model of HIV latency. They showed a significant reduction in virus production for some NNRTIs, compared with other classes of antiretroviral drugs, and concluded that this was due to the ability of these compounds to kill cells expressing HIV GAG-POL proteins. More recently, Trinite et al. (Trinite et al., Retrovirology, 2019, 16(17)) documented how NNRTI-induced PR activation triggers the apoptotic death of productive HIV-infected resting or activated T cells.

The present invention relates to a compound which is selected from the group consisting of: 5 -(difluoromethyl)-2-methoxy-3-((1 -((2-methyl-6-oxo-1,6-dihydropyrimide in-5 yl) methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile;

-(difluoromethyl)-5 -((1 -((2-methyl-6-oxo-1,6-d ihydropyrimidin-5 -yl)methyl)6-oxo-4-(1,1,2,2-tetrafluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile;

2,5-dichloro-3 -((4-(1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-1 ,6-dihydropyrimidin-5yl)oxy)benzonitrile;

-chloro-3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin5-yl)methyl)-6-oxo-1,6- dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile;

-(difluoromethyl)-3 -((1 -((2,6-dimethyl-4-oxo-4,5-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(1,1,2-trifluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

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-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile;

-bromo-5 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyr imide in-5 -yl)methyl)-6oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile;

-(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2methoxybenzonitrile;

-(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2,2 -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methoxybenzonitrile;

4-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimide in- 5 -yl)oxy)-3,5-dimethylbenzonitrile;

-chloro-4-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1, 6-dihydropyrimidin5 -yl)methyl)-6-oxo-1, 6 -dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile;

3,5-dichloro-4-((4-(1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-1 ,6-dihydropyrimidin-5yl)oxy)benzonitrile;

-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5- yl)oxy)-2,4,5-trifluorobenzonitrile;

-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2fluorobenzonitrile;

4-((4-( 1,1-difluoroethyl)-1 -((4-hydroxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidin-5-yl)oxy)- 3-methyl-5-(trifluoromethyl)benzonitrile;

-cyclopropyl-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-5methylbenzonitrile;

-(difluoromethyl)-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2,2 -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5methylbenzonitrile;

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2-chloro-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile;

-(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)-6-oxo-1, 6-d ihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)benzonitrile;

-chloro-3 -((4-( 1,1-difluoroethyl)-1 -((4-methyl-6-oxo-2-((pyrimidin-2yloxy)methyl)-1, 6-d ihydropyrimidin-5 -yl )methyl)-6-oxo-1,6-dihydropyrimide in-5 yl)oxy)-2-fluorobenzonitrile;

-((4-( 1,1-difluoroethyl)-1 -((4-methyl-6-oxo-2-((pyrimidin-2-yloxy)methyl)1,6-dihydropyrimidin-5-yl)methyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5(difluoromethyl)-2-methylbenzonitrile;

3-((4-bromo-1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidin-5-yl)oxy )-2,5-dimethylbenzonitrile;

2-amino-5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-( 1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile;

(5)-5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

(7?)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-4-(1-fluoroethyl)-6- oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

(S)-5 -chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-4(1 -fluoroethyl)-6-oxo -1,6-d ihydropyrimidin-5 -yl)oxy)-2-fluorobenzonitrile;

(7?)-5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4(1-fluoroethyl)-6-oxo -1, 6-d ihydropyrimidin-5 -yl)oxy)-2-fluorobenzonitryl;

(5)-5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)-6 -oxo-1,6-d ihydropyrimidin-5 -yl)oxy)-2fluorobenzonitrile,

- 4 045274 (7?)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-4-(1-fluoroethyl) -6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2fluorobenzonitrile;

(5)-5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methoxybenzonitrile;

(7?)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-4-(1-fluoroethyl)-6- oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methoxybenzonitrile;

3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile;

3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5- yl)oxy)-5-chloro-2-fluorobenzonitrile;

3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)- 1,6-dihydropyrimidin-5 -yl)oxy)-5-chloro-2 fluorobenzonitrile;

3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-2-fluoro-5 methylbenzonitrile;

-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5- yl)oxy)-2-fluoro-5-methylbenzonitrile;

3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-5-ethyl-2 fluorobenzonitrile;

5-chloro-2-fluoro-3-((1-((2-(hydroxymethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile;

-(difluoromethyl)-3 -((1 -((2-(3-hydroxypropyl)-6-oxo-1, 6-dihydropyrimidin 5-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

-(difluoromethyl)-2-methyl-3 -((1 -((2-( 1 -methyl-17/-pyrazol-4-yl)-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6 -oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile;

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-(difluoromethyl)-3 -((1 -((2-(hydroxymethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile;

-(difluoromethyl)-3 -((1 -((2-(3-hydroxypropyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile;

4-(( 1 -((2-(3-hydrox-ipropyl)-4-methyl-6-oxo-1, 6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-3,5dimethylbenzonitrile;

-(difluoromethyl)-3 -((1 -((2-(methoxymethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-( 1,1,2 ,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile;

-(difluoromethyl)-2-methyl-3 -((1 -((4-methyl-2-(2-methylprop-1 -en-1 -yl)-6-oxo1,6-dihydropyrimidin-5-yl)methyl )-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile;

-chloro-2-fluoro-3 -((1 -((2-(3-methoxypropyl)-4-methyl-6-oxo-1,6dihydropyrimide in-5 -yl)methyl)-6-oxo-4-( perfluoroethyl)-1,6-dihydropyrimidin-5 yl)oxy)benzonitrile;

methyl-3 -(5 -((5 -(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4(perfluoroethyl)pyrimidin-1 (6H)-yl)methyl)-4-methyl-6 -oxo-1,6-dihydropyr imidin-2 yl)propanoate;

-((1 -((2-amino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6-d ihydropyrimidine -5 -yl)oxy)-5 -(d fluoromethyl)-2methylbenzonitrile;

3-((1 -((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1,1 difluoroethyl)-6-oxo-1,6- dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile;

3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)- 1,6-d ihydropyrimidin-5 -yl)oxy)-5 -(methyl difluoro)-2methylbenzonitrile;

3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(trifluoromethyl)-1,6-dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile;

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-(difluoromethyl)-3 -((1 -((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimide in-5 yl)methyl)-6-oxo-4-( 1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

2-(( 1 -((4-cyclopropyl-6-methoxy-2-methylpyrimidin-5 -yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine -5 -yl)oxy)-5 -(difluoromethyl)-2methylbenzonitrile;

-(difluoromethyl)-3 -((1 -((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimide in-5 yl)methyl)-6-oxo-4-(perfluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

-(difluoromethyl)-3 -((1 -((4-(fluoromethyl)-2-methyl-6-oxo-1,6dihydropyrimide in-5 -yl)methyl)-6-oxo-4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5 yl)oxy)-2-methylbenzonitrile;

-(difluoromethyl)-3 -((1 -((4-(d iforomethyl)-2-methyl-6-oxo-1,6dihydropyrimide in-5 -yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5 yl)oxy)-2-methylbenzonitrile;

-(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2,2 -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile;

-(difluoromethyl)-2-methyl-3 -((1 -((2-methyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitrile;

2-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo 4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile;

3-(difluoromethyl)-5-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-( 1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile;

-(difluoromethyl)-2-methyl-3 -((1 -((2-methyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile;

3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) oxy)-2,4-difluorobenzonitrile;

-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo 4-(perfluoroethyl)-1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile;

3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-2-methylbenzonitrile;

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3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-2-methylbenzonitrile;

4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1 , 6-d ihydropyrimidin-5 -yl)oxy)-3,5-d immethylbenzonitrile;

4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-3-methoxy-5-methylbenzonitrile;

4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(trifluoromethyl)-1,6-d ihydropyrimidine-5 - yl)oxy)-3,5-dimethylbenzonitrile;

4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-3,5-dimethylbenzonitrile;

-(difluoromethyl)-2-methyl-3 -((1 -((4-methyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile;

2,5-dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile;

-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(1,1,2,2-tetrafluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile;

-bromo-2-chloro-3 -((1 -((2,4-d imethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitrile;

-(difluoromethyl)-3 -((1 -((4-methox and-2,6-d imethylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-2-methylbenzonitrile;

3-(difluoromethyl)-5-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy )benzonitrile;

3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-2-fluorobenzonitrile;

-bromo-5 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 -yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5 -yl)oxy)benzonitrile;

-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimide in-5 -yl)oxy)-2-fluorobenzonitryl;

3-((1 -((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile ;

-bromo-2-chloro-3 -((1 -((2,4-d imethyl-6-oxo-1, 6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(trifluoromethyl)-1 ,6-dihydropyrimide in-5-yl)oxy)benzonitrile;

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2,5-dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile;

-((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile;

5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo|4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)-2-fluorobenzonitrile;

-((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy )-2-fluoro-5-methylbenzonitrile;

2-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-5(trifluoromethyl)benzonitrile;

-chloro-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimidin-5- yl)oxy)-5-methylbenzonitrile;

3,5-dichloro-4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile;

3,5-dichloro-4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile;

-chloro-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(1,1,2,2-tetrafluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention relates to a compound that is:

(3,5-dichloro-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-4-(1 fluoroethyl)-6-oxo-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitriles its (6) and (R) stereoisomers;

(3-chloro-4-(( 1 -((2,4-d imethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1 fluoroethyl)-6-oxo-1, 6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitriles its (5) and (R) stereoisomers;

2,5 - dichloro-3 -((1 -((2,4-d imethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-4-(1 fluoroethyl)-6-oxo- 1,6-dihydropyrimidin-5-yl)oxy)benzonitriles its (6) and (R) stereoisomers;

4-((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1-fluoroethyl)-6oxo-1,6-dihydropyrimidin-5-yl )oxy)-3,5-dimethylbenzonitrile and its (S) and (R) stereoisomers;

-chloro-2-fluoro-3 -((1 -((2-(1 -hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimide in5-yl)methyl)-2-oxo-4-( 1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridin-3yl)oxy)benzonitrile and its (5) and (R) stereoisomers; And

-(difluoromethyl)-3 -((1 -((2-( 1 -hydroxyethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile and its (S) and (R) stereoisomers;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound representing F

or a pharmaceutically acceptable salt thereof.

- 9 045274

In another embodiment, the invention relates to a compound that is

In another embodiment, the invention relates to a compound that is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound that is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound that is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound that is

- 10 045274

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound that is

The term for example means a possible example or in particular. When the terms such as or particularly are used herein, the example or examples listed are intended to be illustrative and are not intended to constitute an exhaustive list of all relevant embodiments.

HIV-naive cells are cells that are not infected with HIV.

Compatible anti-HIV agents are anti-HIV agents/medicines other than HIV protease inhibitors.

A stable compound is a compound that can be prepared and isolated and whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject) . The compounds of the invention are limited to stable compounds.

The present invention covers individual diastereomers, in particular epimers, i.e. compounds that have the same chemical formula but differ in their spatial arrangement around a single atom. The invention also covers mixtures of diastereomers, especially mixtures of epimers, in all proportions. The invention covers compounds having either an (R) or (S) stereoconfiguration at the asymmetric center and at any additional asymmetric centers that may be present in the compound, as well as stereoisomeric mixtures thereof. Embodiments of the present invention also include a mixture of enantiomers enriched by 51% or more in one of the enantiomers, including, for example, a content of one enantiomer of 60% or more, 70% or more, 80% or more, or 90% or more. A separate epimer is preferred. A single or single enantiomer refers to an enantiomer obtained by chiral synthesis and/or using well-known separation and purification techniques, and which may constitute 100% of one enantiomer or may contain small amounts (eg, 10% or less) of the opposite enantiomer. Thus, the object of the present invention is the individual enantiomers in pure form, both levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all proportions. In the case of cis/trans isomerism, the invention covers both the cis form and the trans form, as well as mixtures of these forms in all proportions.

If desired, the preparation of individual stereoisomers can be accomplished by separating the mixture by conventional methods, such as chromatography or crystallization, using stereochemically homogeneous starting materials for the synthesis, or stereoselective synthesis. Optional derivatization may be performed before stereoisomer separation. Separation of a mixture of stereoisomers

- 11 045274 can be carried out at an intermediate stage during the synthesis of the compound, or it can be carried out in relation to the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, which are optionally derivatized with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopic analysis. The present invention covers all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

The compounds can be administered in the form of pharmaceutically acceptable salts. The term pharmaceutically acceptable salt refers to a salt that has the potency of the parent compound and that is not biologically or otherwise undesirable (eg, toxic or harmful to the recipient). When the compounds contain one or more acidic groups or basic groups, the invention includes the corresponding pharmaceutically acceptable salts.

Thus, compounds that contain acidic groups (eg -COOH) can be used in accordance with the invention, for example, but not limited to, as alkali metal salts, alkaline earth metal salts or 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 that contain one or more basic groups, that is, groups that can be protonated, can be used according to the invention in the form of their acid addition salts with inorganic or organic acids, for example, but not limited to, in the form of a salt with hydrogen chloride, hydrogen bromide , phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, ptoluenesulfonic acid, naphthalene disulfonic acids, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and the like. If the compounds simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned above, internal salts or betaines (zwitterions). Salts can be prepared from compounds by conventional methods known to one 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 compounds which, due to their low physiological compatibility, are not directly suitable for use in pharmaceutical preparations, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

Accordingly, the compounds or salts thereof, including their pharmaceutically acceptable salts, embodiments and specific compounds described and claimed herein cover all possible stereoisomers.

Another embodiment of the present invention is a compound where the compound or a salt thereof is in substantially pure form. As used herein, the term substantially pure means that the product containing the compound or a salt thereof (e.g., the product isolated from the reaction mixture providing the compound or salt) consists of the compound or a salt thereof, with a content of the compound or salt thereof of at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (for example, from about 90 wt.% to about 99 wt.% .%), even more preferably at least about 95 wt.% (for example, from about 95 wt.% to about 99 wt.% or from about 98 wt.% to 100 wt.%), and most preferably at least at least about 99 wt.% (for example, 100 wt.%). The purity level of compounds and salts can be determined using a standard analytical method such as high performance liquid chromatography (HPLC) and/or mass spectrometry (MS) or NMR techniques. If multiple analytical methods are used and the methods provide experimentally significant differences in a given level of purity, the method providing the highest level of purity shall take precedence. A compound or salt of 100% purity is a compound that contains no detectable impurities according to a standard method of analysis. With respect to a compound of the invention which has one or more asymmetric centers and which may be present as mixtures of stereoisomers, a substantially pure compound may be either a substantially pure mixture of stereoisomers or a substantially pure individual stereoisomer.

The compounds and their pharmaceutically acceptable salts are useful for inducing dimerization of GAGPOL in HIV-infected cells, and thereby selectively killing HIV-12 045274 infected cells expressing GAG-POL, without concomitant cytotoxicity to HIV-uninfected (HIV-naïve) cells. ) cells, referred to herein as TACK (targeted activation of cell death) activity, or more specifically as HIV TACK activity. TACK HIV or

TACK was previously also referred to as small molecule-activated cell death (SMACK). Thus, the compounds and their pharmaceutically acceptable salts are useful in the following ways:

(i) a method of treating or preventing an infection caused by HIV, or treating, preventing or delaying the onset of progression of AIDS or ARC in a person in need thereof, which includes administering to the person an effective amount of a compound or a pharmaceutically acceptable salt thereof;

(ii) a method of inducing GAG-POL dimerization in HIV-infected cells of a human in need thereof, which comprises administering to the human an effective amount of the compound or a pharmaceutically acceptable salt thereof; and/or (iii) a method of selectively killing HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to non-HIV-infected cells in a human, which comprises administering to the human an effective amount of the compound or a pharmaceutically acceptable salt thereof.

In addition, the compounds and their pharmaceutically acceptable salts are useful in any of methods (i), (ii) or (iii) above, wherein the methods further comprise administering to a human an effective amount of one or more compatible antiviral agents active against HIV selected 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 and downstream inhibitors. In methods (I), (II) or (III) above, the subject is a human and may receive treatment with the compound or a pharmaceutically acceptable salt thereof in addition to treatment with one or more compatible antiviral agents active against HIV.

The compounds and their pharmaceutically acceptable salts are also useful for a method of enhancing suppression of HIV viremia in a human, wherein the viremia is suppressed by administering one or more compatible antiviral agents active against HIV, wherein the method includes additionally administering to the human an effective amount of the compound or a pharmaceutically acceptable salt thereof.

Other embodiments of the invention include the following aspects of the present invention.

(a) A pharmaceutical composition containing an effective amount of a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(b) A method of treating or preventing infection caused by HIV, or treating, preventing, or delaying the onset of progression of AIDS or AIDS-associated complex (ARC) in a person in need thereof, which includes administering to the person an effective amount of a compound or a pharmaceutically acceptable salt thereof.

(c) A method for inducing GAG-POL dimerization in HIV-infected cells of a human in need thereof, which comprises administering to the human an effective amount of the compound or a pharmaceutically acceptable salt thereof.

(d) A method for selectively killing HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to non-HIV-infected cells in a human, which comprises administering to the human an effective amount of the compound or a pharmaceutically acceptable salt thereof.

(e) The method of any of (b)-(d), further comprising administering to a human an effective amount of one or more additional compatible antiviral agents active against HIV 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 and downstream inhibitors.

(f) A method of enhancing suppression of HIV viremia in a human, wherein the viremia is suppressed by administration of one or more compatible antiviral agents active against HIV, which further comprises administering to the human an effective amount of the compound or a pharmaceutically acceptable salt thereof.

(g) The use of a compound, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of HIV infection, or for the treatment, prevention or delay of the onset or progression of AIDS or ARC in humans.

(h) Use of a compound, or a pharmaceutically acceptable salt thereof, to selectively kill HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to non-HIV-infected cells in humans.

(i) The use of a compound, or a pharmaceutically acceptable salt thereof, for enhancing the suppression of HIV viremia in a human, wherein the viremia is suppressed by one or more compatible antiviral agents active against HIV.

- 13 045274 (j) Method according to any one of paragraphs. (b)-(d) or (f), wherein HIV is HIV-1.

(j) Use according to any of (g)-(i), wherein HIV is HIV-1.

Additional embodiments of the present invention include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound or salt thereof used is substantially pure. With respect to a pharmaceutical composition containing a compound or a salt thereof and a pharmaceutically acceptable carrier and optionally one or more excipients, the term substantially pure is understood to refer to the compound or salt thereof as such.

In another embodiment, the present invention provides the pharmaceutical compositions, methods and uses set forth above, wherein the HIV of interest is HIV-1.

The term administration and its variations (eg, administering a compound) with respect to a compound means providing the compound to a subject in need of treatment or prophylaxis, and includes both self-administration and administration to the subject by another person or by any other means. When a compound is provided in combination with one or more other active agents (eg, antiviral agents useful for treating or preventing HIV or AIDS infection), the terms administration and variations thereof are understood to include providing the compound and the other agents at the same time or at different time. When the combination agents are administered simultaneously, they may be administered together in a single composition or they may be administered separately.

As used herein, the term composition is intended to define a product containing the specified ingredients, as well as any product that is the result of combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means that the ingredients must be compatible with each other and not harmful to their recipient.

Prevention includes each of pre-exposure prophylaxis (PrEP), i.e. the use of a compound or a pharmaceutically acceptable salt thereof to prevent HIV infection in a person not infected with HIV, and post-exposure prophylaxis (PEP), i.e. use of the compound or a pharmaceutically acceptable salt thereof after possible exposure to HIV to prevent HIV infection.

As used herein, the term effective amount means an amount of compound sufficient to cause dimerization of GAG-POL in HIV-infected cells and to selectively kill HIV-infected cells expressing GAG-POL, without concomitant cytotoxicity to non-HIV-infected cells; and/or have a therapeutic effect and/or have a prophylactic effect after administration. One embodiment of an effective amount is a therapeutically effective amount, which is an amount of a compound that is effective to selectively kill HIV-infected cells expressing GAG-POL, effective to treat HIV infection, or effective to treat, prevent, or delay the onset or progression of AIDS, or ARC in a patient infected with HIV. Another option for an effective amount is a prophylactically effective amount, which is an amount of a compound that is effective for preventing HIV infection or preventing AIDS or ARC in an HIV-infected patient. It is understood that an effective amount can simultaneously be both a therapeutically effective amount, for example, to treat an HIV infection, and a prophylactically effective amount, for example, to prevent or reduce the risk of developing AIDS or ARC in a subject infected with HIV.

An effective amount in a combination therapy of the invention may refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered in the combination are effective together, but where the individual agent that is a component of the combination may or may not be present in an effective amount in an effective amount, relative to the amount that would be considered effective for a given agent if administered alone.

In the methods of the present invention (i.e., selectively killing HIV-infected cells expressing GAG-POL, treating HIV infection, preventing HIV infection or treating, preventing or delaying the onset or progression of AIDS or ARC), the compounds of the invention or salts thereof may administered by means that bring the active agent into contact with the site of action of the agent. They can be administered by conventional routes available for use in combination with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. The compound may be administered as such, but is typically administered in conjunction with a pharmaceutical carrier selected based on the route of administration and standard pharmaceutical practice. The compounds of the invention may, for example, be administered orally (e.g., in the form of a tablet or capsule), parenterally (including subcutaneous injection, intravenous, intramuscular or intrasternal injection or infusion methods), by inhalation spray, or rectally in the form of a unit dose of a pharmaceutical composition, containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients. The compound can also be administered via an implantable delivery device

- 14 045274 medicinal product adapted to provide an effective amount of a compound or pharmaceutical composition of a compound over an extended period of time.

Compositions

Solid preparations suitable for oral administration (for example, powders, pills, capsules and tablets) can be prepared according to techniques known in the art, and solid excipients such as starches, sugars, kaolin, lubricants, binders can be used. , disintegrants, etc. Liquid preparations suitable for oral administration (for example, suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art, and any conventional media can be used, such as water, glycols, oils , alcohols, etc. Compositions for parenteral administration can be prepared according to techniques known in the art and typically use sterile water as the carrier, and optionally other ingredients such as solubility aids. Injectable solutions can be prepared by methods known in the art, and the carrier includes saline solution, glucose solution, or a solution containing a mixture of saline solution and glucose. Implantable compositions can be prepared by methods known in the art, wherein the carrier includes the active chemical ingredient with polymers and suitable excipients, or they are used in the composition of an implantable drug delivery device. Additional descriptions of methods suitable for use in preparing pharmaceutical compositions for use in the present invention, as well as ingredients suitable for use in said compositions, are provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6, as well as in previous editions.

Compositions of compounds that result in drug supersaturation and/or rapid dissolution can be used to facilitate oral absorption of the drug. Compositions that provide drug supersaturation and/or rapid dissolution include, but are not limited to, nanoparticle systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for their preparation are known in the art. For example, solid dispersions can be prepared using excipients and methods as described in a number of reviews (see, for example, A. T. M. Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticle systems based on both milling and direct synthesis have also been described in a number of reviews, for example in the publication by Wu et al (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

The compounds can be administered in a dosage range of, for example, 1 to 20 mg/kg, or 1 to 10 mg/kg, or about 5 mg/kg mammal (eg, human) body weight per day, or at other time intervals , depending on the situation, in a single dose or in divided doses. The compounds can be administered at a dose of 0.001 to 2000 mg per day once or in divided doses. Examples of dosage ranges are from 0.01 to 1500 mg per day, or from 0.1 to 1000 mg per day, orally or through other routes of administration as a single dose or in divided doses.

For oral administration (e.g., tablets or capsules) or other routes of administration, dosage units may contain from 100 mg to 1500 mg of active ingredient, such as, 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 at symptomatic dosage adjustments for the patient being treated. In addition, the compound may be formulated for oral administration in the form of immediate or modified release formulations, such as sustained or controlled release. When a compound is administered as a salt, reference to the amount of compound in milligrams or grams is based on the amount of compound in the free form (ie, non-salt form) of the compound.

Daily administration may be by any suitable route of administration, but preferably by oral administration, and may be a single dose or multiple doses administered at different times (divided daily doses) during each 24-hour period. Each dose may be administered using one or more dosage units, depending on the situation.

The specific dosage level and frequency of dosing for any given patient may vary and will depend on a variety of factors, including the potency of the particular compound being used, its metabolic stability, and the duration of action of that compound, as well as the patient's age, body weight, general health, gender, diet, route and time of administration, rate of elimination, combination of medications taken, severity of the particular condition and condition of the particular subject being treated. In some cases, depending on the activity of the compound or the individual response of the subject, it may be necessary to deviate more or less from the prescribed dose. The amount and frequency of administration will be adjusted according to the judgment of the attending physician, taking into account such factors.

An anti-HIV agent is any agent that is directly or indirectly effective in

- 15 045274 in relation to the inhibition of HIV, treatment or prevention of HIV infection and/or in relation to the treatment, prevention or delay of the onset or progression of AIDS or ARC. It is understood that the anti-HIV agent is effective for treating, preventing or delaying the onset or progression of HIV or AIDS infection and/or diseases or conditions arising therefrom or associated therewith. The present invention further relates to the use of the compound or pharmaceutically acceptable salts thereof with one or more compatible anti-HIV agents, that is, anti-HIV agents other than HIV protease inhibitors. Thus, for example, the compounds may be administered in combination with effective amounts of one or more compatible anti-HIV agents selected from antivirals active against HIV, immunomodulators, anti-infective agents, or vaccines useful for treating HIV infection or AIDS. Suitable compatible antiviral agents against HIV that can be used in combination with the compounds of the present invention include, without limitation, the following drugs listed in table. A.

Table A ____Antiviral agents for treating HIV infection or AIDS

Name Type abacavir, ABC, ZIAGEN® NRTI abacavir+lamivudine, EPZICOM® NRTI abacavir+lamivudine+zidovudine, TRIZIVIR® NRTI AZT, zidovudine, azidothymidine, RETROVIR® NRTI bictegravir InSTI bictegravir+tenofovir alafenamide fumarate+emtricitabine, BIKTARVY® InSTI/NRTI/NRTI capravirine NNRTI ddC, zalcitabine, dideoxycytidine, HIVID® NRTI ddl, didanosine, dideoxyinosine, VIDEX® NRTI ddl (enteric coating), VIDEX EC® NRTI delavirdine, DLV, RESCRIPTOR® NNRTI dolutegravir, TIVICAY® InSTI dolutegravir+abacavir+lamivudine, TRIUMEQ® InSTI/NRTI/NRTI doravirine, PIFELTRO™ NNRTI doravirine/lamivudine/tenofovir disoproxil fumarate, DELSTRIGO™ NNRTI/NRTI/NRTI efavirenz, EFV, SUSTIVA®, STOCRIN® NNRTI efavirenz/emtricitabine/tenofovir disoproxil fumarate, ATRIPLA® NNRTI/NRTI/NRTI EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) NRTI

- 16 045274

elvitegravir, VITEKTA® InSTI emtricitabine, FTC, EMTRIVA® NRTI emtricitabine + tenofovir disoproxil fumarate, TRUVADA® NRTI/NRTI emivirine, COACTINON® NNRTI enfuvirtide, FUZEON® FI enteric-coated didanosine, VIDEX EU® NRTI etravirine, TMS-125 NNRTI IBalizumab-uik (TROGARZO®) Downstream inhibitor or monoclonal antibody lamivudine, ZTS, EPIVIR® NRTI lamivudine+zidovudine, COMBIVIR® NRTI/NRTI maraviroc, SELZENTRY® EI nevirapine, NVP, VIRAMUNE® NNRTI raltegravir, ISENTRESS™ InSTI rilpivirine, EDURANT® NNRTI stavudine, d4T, didehydrodeoxythymidine, ZERIT® NRTI tenofovir disoproxil fumarate (TDF), VIREAD® NRTI tenofovir alafenamide fumarate (TAF) NRTI vikrivirok EI

E1=penetration inhibitor; FI=UHru6uTop merge; InSTI=UHru6umop integrase; 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 the table are used in the form of salts; for example, abacavir sulfate, delavirdine mesylate.

It is understood that combinations of the compounds of the present invention with compatible anti-HIV agents/tools are not limited to the anti-HIV antiviral agents listed in Table 1. A, but generally includes any combination with any pharmaceutical composition useful for the treatment or prevention of HIV infection, AIDS or ARC, excluding HIV protease inhibitors. Compatible HIV antiviral agents and other active agents generally can be used in these combinations at their usual dosage ranges and schedules as described in the art, including, for example, those dosages described in the current Physicians' Desk Reference , Thomson PDR, 70th edition (2016), Montvale, NJ: PDR Network, or in previous editions. The dosage ranges of the compounds of the present invention in these combinations may be as indicated above.

The compounds of the present invention are also useful in assay formulations and screening for antiviral compounds. For example, the compounds of the invention are useful for isolating enzyme mutants, which are excellent tools for screening for more potent antiviral compounds. In addition, the compounds of the invention are useful for establishing or determining the binding site of other antiviral agents to the reverse transcriptase region of GAGPOL, for example, by competitive inhibition.

Throughout this specification, the following acronyms and abbreviations are used and have the meanings indicated:

- 17 045274

ACX=acetonitrile

AcOH = acetic acid, water. = aquatic

B ₂ Р1п ₂₌ bis(pinacolato)diborone

BPO=benzoyl peroxide

CAM=cerium ammonium nitrate precatalyst cataCXium APd O2=chloro[(di(1-adamantyl)-X-butylphosphine)-2-(2aminobiphenyl)]palladium(II);

DAST = (diethylamino) sulfur trifluoride

DCE= 1,2-dichloroethane

OCM=dichloromethane

OOP=2,3-dichloro-5,6-dicyano-1,4-benzoquinone

O1AO=diisopropyl azodicarboxylate

DHP=3,4-dihydro-2H-pyran

O1VAG-H=diisobutyl aluminum hydride

DIPEA - diisopropylethylamine

OME=dimethoxyethane

DMF=N, N-dimethylformamide

Dess-Martin periodinan = 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one

PM8O=dimethyl sulfoxide

- 18045274

DMSO-d ₆ -deuterated dimethyl sulfoxide ed = for example, but not limited to

EDC= 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EOTA=ethylenediaminetetraacetic acid

EAAc=ethyl acetate

EUN=ethanol

EB8=fetal bovine serum

OEP=green fluorescent protein

HIV, H1V=human immunodeficiency virus

HOB1=hydroxybenzotriazole

HPLC, HPLC=high performance liquid chromatography hour=hour, hours

bd=intermediate

Ir[(Oshe)( 1,5 -SOP)] ₂ = d imer (1,5 -cyclooctadiene)(methoxy)iridine (I)

ECAP=liquid chromatography area percentage

EC-M8=liquid chromatography-mass spectroscopy

EOA=lithium diisopropylamide

EAN=lithium aluminum hydride m-CPB A=3-chloroperbenzoic acid

Me=methyl

Me1=methyl iodide

MeOH=methanol

Me-THE=2-methyltetrahydrofuran

MTBE=methyl tert-butyl ether min=minute, minutes

MS, MS=mass spectroscopy

M8C1=methanesulfonyl chloride

Nb8=181-bromosuccinimide n-BiE1=n-butyllithium

HC8=H-chlorosuccinimide

RH8=normal human serum

- 19 045274

XMP=X-methyl-2-pyrrolidinone

NMR=nuclear magnetic resonance

PBMC=peripheral blood mononuclear cells

PB8=phosphate buffered saline

Pd ₂ (dba)3=τpis(dibenzylideneacetone)dipalladium (0)

PdCl ₂ (dppf) = [1,G-bis(diphenylphosphino)ferrocene] dichloro palladium (II)

Pd(OAc) ₂ = palladium (II) acetate | Pd(Pd ₃ P) ₄ = tetrakis(triphenylphosphine) palladium (0)

PE=petroleum ether

PHA=phytogeagglutinin

PMH=4-methyloxybenzyl

PMBC1=4-methoxybenzyl chloride

PPT8=4-toluene sulfonic acid

RT=room temperature

SNAr=nucleophilic aromatic substitution

TBAE=tetrabutylammonium fluoride

Tc=thiophene carboxylate

1-ViOH=tert-butanol

1-ViOK=potassium tert-butoxide precatalyst t-buXPhos Pd G3 = [(2-di-tert-butylphosphino-2', 4',6'-triisopropyl1,1'-biphenyl)-2-(2'-amino- Palladium (II) 1,1'-biphenyl)]methanesulfonate

TEA=triethylamine

TPA=trifluoroacetic acid

TRAA=trifluoroacetic anhydride

THP=tetrahydrofuran

TLC, TLC=thin layer chromatography

TM8-C1=trimethylsilyl chloride

X-Pio8=2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Several methods for preparing the compounds of the invention are described in the following schemes and examples. The starting materials and intermediates can be purchased or prepared using known procedures, or, as shown below, using five intermediates (A, B, C, AB and BC). A commonly used route for preparing compounds is shown in Scheme 1 below.

Scheme 1.

Scheme 1 illustrates the method for preparing the compounds. The AB intermediate was prepared according to the procedures illustrated in the AB Intermediates section. Reak

- 20 045274 Mitsunobu reaction or alkylation was carried out using a suitable benzyl alcohol or pyrimidone halide (intermediate C) to give intermediate ABC. Intermediate C typically has a protected pyrimidone moiety, which is shown in Scheme 1 as Z. The synthesis of intermediate C is illustrated in Intermediate C. The resulting intermediate ABC may optionally undergo further modification, followed by a deprotection step, to produce the compounds.

Scheme 2.

Scheme 2 illustrates another method for preparing compounds. To prepare intermediate ABC, an SNA reaction is used between phenol A (either commercially available or prepared using the procedures shown in the Intermediates A section) and intermediate BC (prepared using the procedures shown in the Intermediates BC section). The pyrimidone ring C is typically protected by a protecting group (PG'), such as methyl or a PMB group. The resulting ABC intermediate may then optionally undergo further modification followed by a deprotection step to produce compounds.

Reactions sensitive to moisture or air were carried out under nitrogen or argon atmosphere using anhydrous solvents and reagents. Microwave-assisted reactions were typically performed using an Emrys Optimizer from Personal Chemistry or an Initiator from Biotage. The solutions were concentrated on a rotary evaporator under reduced pressure.

The progress of the reactions was monitored either by analytical thin layer chromatography (TLC), typically performed on TLC plates pre-coated with E. Merck 60F254 silica gel at a layer thickness of 0.25 mm, or by analytical liquid chromatography-mass spectrometry (LC-MS). An LC-MS analytical system typically used consisted of a Waters ZQ™ electrospray ionization unit operating in positive ion detection mode using an Agilent 1100 Series HPLC with automatic sampling. The column was typically a Waters Xterra MS C18, 3.0 x 50 mm, 5 µm, or a Waters Acquity UPLC® VEN C18 1.0 x 50 mm, 1.7 µm. The flow rate was 1 mL/min and the injection volume was 10 μL. UV detection was carried out in the range of 210–400 nm. The mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of 100% solvent A over 0.7 min followed by a transition to 100% solvent B over 3 min. 75 min, hold for 1.1 min, then move to 100% solvent A for 0.2 min. LC-MS analysis was performed using a Waters Classing Aquity system equipped with TUV and MS detectors and a Waters SQD mass spectrometer, Shimadzu 20 UV at 254 and 220 nm, with a Shimadzu 2010 or 2020 mass spectrometer or an Agilent 1200 HPLC with DAD/ELSD and G6110 MSD, using one of the following conditions: 1) Ascentis Express C18 (3x50 mm) 2.7 µm column, using a mobile phase containing A: 0.05% trifluoroacetic acid in water and B: 0.05% trifluoroacetic acid acid in acetonitrile, with a gradient from 90:10 (A:B) to 5:95 (A:B) over 6 min, at a flow rate of 1.8 ml/min, UV detection at 210 nm; 2) Aquity BEH C18 column, (1.0x50 mm) 1.7 µm, using a mobile phase containing A: 0.05% trifluoroacetic acid in water and B: 0.05% trifluoroacetic acid in acetonitrile, with a gradient of 90 :10 (A:B) to 5:95 (A:B) for 2 min at a flow rate of 0.3 ml/min, UV detection at 215 nm; 3) Agilent YMC J'Sphere H-80 column (3x50 mm) 5 µm, using a mobile phase containing A: 0.1% trifluoroacetic acid in water and B: acetonitrile, with a gradient of 95:5 (A:B) up to 0:100 (A:B) for 3.6 min, and 0:100 (A:B) for 0.4 min at a flow rate of 1.4 ml/min, UV detection at 254 and 220 nm, and Agilent 1100 quadrupole mass spectrometer; 4) Agilent TC-C18 column (2.1x50 mm) 5 µm, using a mobile phase containing A: 0.0375% trifluoroacetic acid in water and B: 0.01875% trifluoroacetic acid in acetonitrile, with a gradient of 90:10 (A:B) for 0.4 min from 90:10 to 0:100 (A:B) for 3 min, and 10:90 (A:B) for 0.6 min, at a flow rate of 0, 8 ml/min, UV detection at 254 and 220 nm, and an Agilent 6110 quadrupole mass spectrometer.

Preparative HPLC purification was typically performed using either a mass spectrometry system or a non-mass controlled system. Typically purification was performed on a Waters Chromatography Workstation, with an LC-MS system consisting of:

- 21 045274 topics MS Waters ZQ™ with electrospray ionization, Waters 2525 gradient pump, Waters 2767 injector/manifold, Waters 996 PDA detector, under conditions: MS 150-750 amu, positive electrospray, MS signal selection, and Waters SUNFIRE® column s-18 5 µm, 30 mm (ID) χ 100 mm. Mobile phases consisted of mixtures of acetonitrile (10–100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL/min, the injection volume was 1800 μL, and the UV detection range was 210–400 nm. As an alternative preparative HPLC, a Gilson workstation was used, consisting of: GilsonGX-281 injector/collector, GilsonUV/VIS155 detector, Gilson 333 and 334 pumps, using one of the following columns: Phenomenexd Synergi C18 (150 mm χ 30 mm χ 4 microns), YMC-Actus Pro C18 (150 mm χ 30 mm χ 5 microns), Xtimate C18 (150 mm χ 25 mm χ 5 microns), Boston Green ODS (150 mm χ 30 mm χ 5 microns), XSELECT C18 (150 mm x 30 mm x 5 microns) and Waters XSELECT C18 (150 x 30 x 5 microns). Conditions included either high pH (eluent 0-100% acetonitrile/water containing 0.1% v/v 10 mM NH ₄ HCO ₃ or 0.05% NH ₄ OH) or low pH (0-95% eluent acetonitrile/water containing 0.1% v/v TFA). The injection volume ranged from 1000 to 8000 μL, and the UV detection range was 210–400 nm. Mobile phase gradients were optimized for individual compounds.

Flash chromatography was typically performed using a Biotage® Flash Chromatography Device (Dyax Corp.), ISCO CombiFlash® Rf or ISCO CombiFlash® Companion XL, on silica gel (32-63 µm, 60 A pore size) in pre-packaged cartridges of the specified size .

Chiral SFC separations were performed on a Sepiate Prep SFC 100, Multigram II (MG II), THAR80 prep SFC, or Waters SFC (80, 200, or 350), using the following conditions: Chiral Method A: AD-H column, 15% ethanol/ CO ₂ ; Chiral method B: AD-H column, 20% 1PA/ _CO2 ; Chiral method C: AS-H column, 20% MeOH/CO ₂ ; Chiral method D: AD-H column, 20% ethanol/CO ₂ ; Chiral method E: Lux Cellulose-4 column, 30% ethanol/CO ₂ ; Chiral method F: column IA, 15% ethanol/CO ₂ ; Chiral method G: column IA, 40% methanol/CO ₂ ; Chiral method H: AD-H column, 10% methanol/CO ₂ ; Chiral method I: AD-H column, 30% ethanol/CO ₂ ; Chiral method J: AD-H column, 40% ethanol/ _CO2 ; and Chiral method K: IG column, 12% methanol/CO ₂ . Chiral analytical chromatography was most often performed on one of the CHIRALPAK® AS, CHIRALPAK®AD, CHIRALCEL® OD, CHIRALCEL® IA, or CHIRALCEL® OJ columns (250 x 4.6 mm) (Daicel Chemical Industries, Ltd.), using mixtures as isocratic systems solvents with the specified percentage of ethanol in hexane (% Et/Hex) or isopropanol in heptane (% IPA/Hep). Chiral preparative chromatography was carried out on one of the columns CHIRALPAK AS, of CHIRALPAK AD, CHIRALCEL® OD, CHIRALCEL®IA, CHIRALCEL® OJ (20x250 mm) (Daicel Chemical Industries, Ltd.), using mixtures of solvents specified for chiral analytical chromatography or under supercritical fluid (SFC) conditions.

Proton or 1H NMR was recorded using a Varian Unity-Inova 400 MHz NMR spectrometer with a Varian 400 ATB PFG 5 mm probe, a Nalorac DBG 400-5 or Nalorac IDG 400-5, a Varian-400MHz MR spectrometer with an Auto X ID PFG Probe 5 mm , a Varian 400 MHz VNMRS spectrometer with a PFG 4Nuc Probe 5 mm probe, or a Bruker AvanceIII 500 MHz spectrometer with a RABBO Probe 5 mm probe, in accordance with standard analytical methods, unless otherwise specified, and spectral analysis data were obtained. 1H NMR spectra were obtained in CDCl ₃ solutions unless otherwise stated. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal standard in _CD3Cl solutions, and the residual CH3OH peak or TMS was used as an internal standard in CD3OD solutions. Coupling constants (J) are presented in Hertz (Hz).

It is understood that the chiral center in compounds can exist in the S or R stereoconfiguration, or both for mixtures. Within a molecule, each bond, drawn as a straight line from the chiral center, covers each of the (R) and (S) stereoisomers, as well as mixtures thereof, unless otherwise noted. Compounds in Examples 17, 18, 28-36, 43, 44, 53 and 54 contain a chiral center. The mixture of isomers obtained in each of Examples 17, 18, 28-36, 43, 44, 53 and 54 was separated to give one or both of isomers A (the faster eluting isomer) and isomer B (the slower eluting isomer), based on their observed elution order as indicated in the examples. The elution time and/or order of elution of the separated isomers may differ if performed under conditions other than those used and indicated in the examples. The absolute stereochemistry (R or S) of the chiral center in each of the separated A and/or B stereoisomers in Examples 17, 18, 28-36, 43, 44, 53 and 54 has not been determined, and A and B refer only to the order of elution at performing cleaning under the specified conditions. An asterisk (*) may be used in the corresponding illustrations of the chemical structure of compounds in the Examples to indicate a chiral center.

- 22 045274

Example Cleaning conditions 17 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, 1PA/CO ₂ =45%, 80 ml/min. 18 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, ethanol/CO ₂ =45%, 80 ml/min. 32 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, 1PA/CO ₂ =30%, 60 ml/min. 33 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, 1PA/CO ₂ =30%, 60 ml/min. 34 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, 1PA/CO ₂ =45%, 73 ml/min. 35 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, 1PA/CO ₂ =20%, 60 ml/min. 36 SFC Chiralpak IC-H, 250 x 30 mm ID, 5 µm, 1PA/CO ₂ =20%, 60 ml/min.

Intermediates A.

Intermediate A01.

HE

3-(Difluoromethyl)-5-hydroxybenzonitrile.

Step 1: 3-chloro-5-((4-methoxybenzyl)oxy)benzonitrile.

To a solution of 3-chloro-5-hydroxybenzonitrile (30 g, 0.20 mol) in ACN (300 ml) was added PMBCl (34 g, 0.21 mol) and K ₂ CO ₃ (55 g, 0.4 mmol), the mixture was then stirred at 70°C for 4 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash silica chromatography (2% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ): δ 7.33 (d, J=8.0 Hz, 2H), 7.23 (s, 1H), 7.19 (s, 1H), 7.11 (s , 1H), 6.94 (d, J=8.0 Hz, 2H), 5.00 (s, 2H), 3.83 (s, 3H).

Step 2: 3-((4-methoxybenzyl)oxy)-5-vinylbenzonitrile.

To a solution of 3-chloro-5-((4-methoxybenzyl)oxy)benzonitrile (50 g, 0.18 mol) in dioxane/H ₂ O (400 ml/80 ml) was added potassium vinyl trifluoroborate (25 g, 0.18 mol ), K ₂ CO ₃ (50 g, 0.36 mol), X-Phos (17 g, 36 mmol) and Pd(OAc) ₂ (4.1 g, 18 mmol) under N ₂ atmosphere, the mixture was stirred at 80 °C for 2 hours. After cooling to RT, the resulting mixture was filtered and extracted with EtOAc (3x400 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (1-2% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ): δ 7.34 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 7.20 (s, 1H), 7.09 (s , 1H), 6.93 (d, J=8.4 Hz, 2H), 6.63 (dd, J=17.6, 12.0 Hz, 1H), 5.78 (d, J=17, 6 Hz, 1H), 5.38 (d, J=12.0 Hz, 1H), 5.01 (s, 2H), 3.82 (s, 3H).

Step 3: 3-formyl-5-((4-methoxybenzyl)oxy)benzonitrile.

To a stirred solution of 3-((4-methoxybenzyl)oxy)-5-vinylbenzonitrile (28 g, 0.1 mol) in dioxane/H ₂ O (180 ml/60 ml) was added 2,6-lutidine (22 g 0. 2 mol), OsO ₄ (1.3 g, 5 mmol) and NaIO ₄ (43 g, 0.2 mol), the mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the mixture was diluted with water, extracted with EtOAc (3x200 ml ). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2-10% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, DMSO- _d6 ): δ 9.95 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7 .37 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.14 (s, 2H), 3.73 (s, 3H).

Step 4: 3-(difluoromethyl)-5-((4-methoxybenzyl)oxy)benzonitrile.

To a stirred solution of 3-formyl-5-((4-methoxybenzyl)oxy)benzonitrile (22 g, 82 mmol) in DCM (250 ml) was added DAST (106 g, 0.6 mol) at 0°C under N ₂ , then the mixture was stirred for 3 hours at RT. Upon completion of the reaction, the mixture was quenched with water and extracted with DCM (3x200 ml). The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

Step 5: 3-(difluoromethyl)-5-hydroxybenzonitrile.

A solution of 3-(difluoromethyl)-5-((4-methoxybenzyl)oxy)benzonitrile (23.7 g, 82 mmol) in TFA/TFAA (100 ml/50 ml) was stirred at 110°C for 3 hours. Once complete reaction, the resulting mixture was quenched with saturated aqueous NaHCO ₃ (100 ml) and extracted with EtOAc (3x150 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.66 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 6. 97 (t, J=56.0 Hz, 1H).

- 23 045274

Intermediate A02.

HE

Step 1: 5-formyl-2-methylbenzonitrile.

A solution of 5-bromo-2-methylbenzonitrile (750 g, 38.26 mol) in tetrahydrofuran (6 L) was placed in a 20-liter four-neck round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, and added dropwise at -78°C BuLi (1.54 L, 38.26 mol), the resulting solution was stirred for 30 min, N,N-dimethylformamide (295 g, 4.04 mol, 1.05 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes in a liquid nitrogen bath, and then the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl (5 L). The resulting solution was extracted with EtOAc (3x5 L). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

Step 2: 3-bromo-5-formyl-2-methylbenzamide.

A solution of 5-formyl-2-methylbenzonitrile (245 g, 1.69 mol) in sulfuric acid (980 ml) was placed in a 3-liter four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 60°C, and 1-bromopyrrolidine-2,5dione (300 g, 1.69 mol) was added in 3 portions. The resulting solution was stirred at 60°C for 30 minutes. The reaction was then quenched by adding 5 L of water/ice and stirred for 1 hour. The solids were collected by filtration and dried in vacuo to give the title compound, which was used directly in the next step.

Step 3: 3-bromo-5-formyl-2-methylbenzonitrile.

A solution of 3-bromo-5-formyl-2-methylbenzamide (500 g, 2.07 mol) in dichloromethane (10 L), pyridine (524.5 g) was placed in a 20-liter four-neck round-bottom flask, purged and maintained under an inert nitrogen atmosphere. , 6.63 mol). The resulting solution was stirred at 0°C, and 2,2,2-trifluoroacetate (1305 g, 6.21 mol) was added dropwise. The resulting solution was stirred for 30 min at room temperature, then quenched with water/ice (5 L) and extracted with DCM (3x5 L). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (20% EtOAc/hexane) to give the title compound.

Step 4: 3-bromo-5-(difluoromethyl)-2-methylbenzonitrile.

To a solution of 3-bromo-5-formyl-2-methylbenzonitrile (360 g, 1.61 mol) in dichloromethane (5.4 L) at room temperature was added dropwise DAST (260 g, 1.61 mol, 1.00 eq. .). The resulting solution was stirred at room temperature for 1 hour and then quenched with water/ice (3 L). The resulting solution was extracted with DCM (3x5 L). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound, which was directly used in the next step.

Step 5: 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile.

To a solution of 3-bromo-5-(difluoromethyl)-2-methylbenzonitrile (320 g, 1.30 mol) in 1,4-dioxane (1.6 L) was added a solution of KOH (146 g, 2.60 mol) in water (1.6 L), Pd ₂ (dba) ₃ (67 g, 64.92 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (55 g, 129.53 mmol). The resulting mixture was purged with nitrogen (3x) and stirred at 90°C for 1 hour and then partitioned between ice water (4 L) and EtOAc (3x2 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (33% EtOAc/hexane) to give the title compound. MS: 182 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.65 (s, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.26 (d, J=1.5 Hz, 1H), 6.99 (s, 1H), 2.34 (d, J=1.3 Hz, 3H).

Intermediate connection A03.

HE

5-Bromo-2-chloro-3-hydroxybenzonitrile.

Step 1: 2-amino-5-bromo-3-fluorobenzonitrile.

To a stirred solution of 2-amino-3-fluorobenzonitrile (10 g, 73.5 mmol) in DMF (10 ml) was added NBS (13.07 g, 73.5 mmol) and the resulting mixture was stirred at 0°C for 12 h. After completion of the reaction, the mixture was diluted with water (50 ml). The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound. MS:

- 24 045274

215 and 217 (M+1).

Step 2: 5-bromo-2-chloro-3-fluorobenzonitrile.

To a mixture of 2-amino-5-bromo-3-fluorobenzonitrile (9 g, 41.9 mmol), copper(1) chloride (12.43 g, 126 mmol) and copper(II) chloride (19.70 g, 146 mmol) tert-butyl nitrite (19.91 mL, 167 mmol) was added to ACN (80 mL) at 0°C. The resulting mixture was stirred at 25°C for 6 hours. The mixture was diluted with water (150 ml) and extracted with EtOAc (3x100 ml). The organic layer was washed with brine (3x50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (10-100% EtOAc/PE) to give the title compound.

Step 3: 5-bromo-2-chloro-3-((4-methoxybenzyl)oxy)benzonitrile.

NaH (0.931 g, 23.29 mmol) was added to a stirred solution of (4-methoxyphenyl)methanol (2.475 g, 17.91 mmol) in DMF (100 mL) at 0°C. After stirring for 20 minutes, 5-bromo-2chloro-3-fluorobenzonitrile (4.2 g, 17.91 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours, then partitioned between water (50 ml) and EtOAc (3x50 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (15-100% EtOAc/PE) to give the title compound.

Step 4: 5-bromo-2-chloro-3-hydroxybenzonitrile.

A solution of 5-bromo-2-chloro-3-((4-methoxybenzyl)oxy)benzonitrile (3.5 g, 9.93 mmol) in TFA (10 ml) and DCM (50 ml) was stirred at 25°C for 3 hours After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by flash silica chromatography (15-100% EtOAc/PE) to give the title compound.

Intermediate A04.

HE

2,5-Dichloro-3-hydroxybenzonitrile.

Step 1: 2-amino-5-bromo-3-fluorobenzonitrile.

To a stirred solution of 2-amino-3-fluorobenzonitrile (5 g, 36.7 mmol) in DMF (50 ml) was added 1-chloropyrrolidine-2,5-dione (5.15 g, 38.6 mmol), and the resulting mixture stirred at 60°C for 6 hours. The mixture was partitioned between water (200 ml) and EtOAc (2x150 ml). The combined organic layers were washed with brine (3x300 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without purification. MS: 171.1 (M+1).

Step 2: 2,5-dichloro-3-fluorobenzonitrile.

To a mixture of 2-amino-5-chloro-3-fluorobenzonitrile (6.217 g, 36.4 mmol), copper(I) chloride (10.82 g, 109 mmol) and copper(II) chloride (17.15 g, 128 mmol) in ACN (60 ml) at 25°C was added tert-butyl nitrite (17.34 ml, 146 mmol) over 1 hour. The reaction mixture was diluted with water (180 ml) and extracted with EtOAc (3x120 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (10-100% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, chloroform-d): δ 7.51 (dd, J=2.26, 1.65 Hz, 1H), 7.44-7.47 (m, 1H).

Step 3: 2,5-dichloro-3-((4-methoxybenzyl)oxy)benzonitrile.

NaH (1.034 g, 25.9 mmol) was added to a stirred solution of (4-methoxyphenyl)methanol (2.75 g, 19.89 mmol) in DMF (40 mL) at 0°C. The mixture was stirred at 0°C for 30 minutes, then 2,5-dichloro-3-fluorobenzonitrile (3.78 g, 19.89 mmol) was added, and then stirred at 25°C for 2 hours. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (3x150 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound. MS: 308.1 (M+1).

Step 4: 2,5-dichloro-3-hydroxybenzonitrile.

To a stirred solution of 2,5-dichloro-3-((4-methoxybenzyl)oxy)benzonitrile (6.13 g, 19.89 mmol) in DCM (60 ml) was added TFA (20 ml) and then stirred at 25° C for 1 hour. At the end of the reaction, the reaction mixture was poured into us. aq. NaHCO ₃ (30 ml), extracted with DCM (3x60 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used directly without further purification. MS: 187.9 (M-1).

- 25 045274

Intermediate A05.

t X ^x f he

3-Bromo-5-chloro-2-fluorophenol.

Step 1: 2-(3-bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

B ₂ Pin ₂ (363.7 g, 1.43 mol) was added to a solution of 2-bromo-4-chloro-1-fluorobenzene (300 g, 1.43 mol) in hexane (4.5 L) after purging with nitrogen three times. , Ir[(Ome)(1,5-COD)] ₂ (14.2 g, 21.42 mmol), 4-tert-butyl2-(4-tert-butylpyridin-2-yl) pyridine (11.5 g , 42.85 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by flash chromatography on silica (0-100% EtOAc/PE) to give the title compound.

Step 2: 3-bromo-5-chloro-2-fluorophenol.

To a solution of 2-(3-bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (385 g, 1.15 mol) in THF (3.85 l) at 0°C, a solution of sodium hydroxide (138 g, 3.45 mol) in water (3 l), 35% aq. was added. hydrogen peroxide. (390 g, 3.44 mol). The resulting solution was stirred at 0°C for 2 hours and quenched with sat. aq. Na ₂ S ₂ O ₃ solution. After adjusting the pH of the solution to 3-4 with HCl (1M), the resulting solution was extracted with EtOAc (3x3 L). The combined organic layers were washed with brine, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica (0-90% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ): δ 11.31 (br s, 1H), 7.47 (dd, J=2.4, 4.4 Hz, 1H), 7.30 (dd, J= 2.4, 7.6 Hz, 1H).

Intermediate A06.

,>N ^C|

I t he

5-Chloro-2-fluoro-3-hydroxybenzonitrile.

To a solution of 3-bromo-5-chloro-2-fluorophenol (86 g, 343 mmol) in NMP (860 mL) was added CuCN (154 g, 1.72 mol, 5.0 eq.) in one portion. The resulting reaction mixture was stirred at 180°C for 2 hours, then partitioned between ice water (1 L) and EtOAc (3x800 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (2-33% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, DMSO-d ₆ ): δ 11.33 (br s, 1H), 7.49 (dd, J=2.5, 4.5 Hz, 1H), 7.30 (dd, J=2.5, 7.6 Hz, 1H).

Intermediate A07.

SK

XX he

5-Chloro-3-hydroxy-2-methylbenzonitrile.

Step 1: 2,3-difluorobenzaldehyde.

To a solution of 1,2-difluorobenzene (1668 g, 14.62 mol) in THF (16.7 L) cooled to -78°C, a solution of n-BuLi in THF (6.44 L) was added dropwise with stirring over 60 min , 16.08 mol). N,N-dimethylformamide (5340 g, 73.06 mol) was then added dropwise to this mixture at -78°C with stirring over 60 minutes. The resulting solution was stirred at -78°C for 1 hour. The reaction was then quenched with saturated aqueous NH ₄ Cl (10 L), then extracted with EtOAc (3x10 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (2% EtOAc/PE) to give the title compound.

Step 2: (E)-N-[(2,3-difluorophenyl)methylidene]hydroxylamine.

A mixture of 2,3-difluorobenzaldehyde (2410 g, 16.96 mol) in 70% NH ₂ OH (672 g, 20.35 mol) in DMFA (10 L) at 20°C was stirred for 3 hours, then distributed between water (6 l) and EtOAc (3x8 l). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2% EtOAc/PE) to give the title compound.

Step 3: 2,3-difluorobenzonitrile.

A solution of (E)-N-[(2,3-difluorophenyl)methylidene]hydroxylamine (2025 g, 12.89 mol) in DMFA (11 L) was treated with POCl ₃ (5688 g, 37.10 mol). The resulting solution was stirred at 25°C for 3 hours,

- 26 045274 was then distributed between water (6 L) and EtOAc (3x6 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (2% EtOAc/PE) to give the title compound.

Step 4: 2-amino-3-fluorobenzonitrile.

In a sealed reactor, a solution of 2,3-difluorobenzonitrile (1273 g, 9.15 mol) in EtOH (13 L) was bubbled with NH3 (gas). The resulting solution was stirred at 140°C for 8 hours, cooled to RT, then concentrated under reduced pressure. The residue was distributed between water (5 L) and MTBE (3x8 L). The combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

Step 5: 2-amino-5-chloro-3-fluorobenzonitrile.

A solution of 2-amino-3-fluorobenzonitrile (934 g, 6.86 mol) in DMFA (14 L) was treated with NCS (1008 g, 7.55 mol). The resulting solution was stirred at 45°C for 2 hours, then distributed between ice water (20 L) and EtOAc (3x12 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (3% EtOAc/PE) to give the title compound.

Step 6: 2-bromo-5-chloro-3-fluorobenzonitrile.

To a mixture of t-BuONO (815 g, 7.88 mol) and CuBr ₂ (1365 g, 6.13 mol) in ACN (8 L), a solution of 2-amino-5-chloro-3-fluorobenzonitrile ( 747 g, 4.38 mol) in ACN (7 L) for 90 min. The resulting mixture was stirred at room temperature for 10 hours and diluted with water (15 L) and then extracted with EtOAc (3x10 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (3% EtOAc/PE) to give the title compound.

Step 7: 5-chloro-3-fluoro-2-methylbenzonitrile.

A mixture of 2-bromo-5-chloro-3-fluorobenzonitrile (768 g, 3.28 mol), 1,4-methylboronic acid (297 g, 4.96 mol), potassium carbonate (913 g, 6.61 mol) and PdCl ₂ (dppf) (213 g, 0.33 mol) in degassed 1,4dioxane (4500 ml) and water (450 ml) was stirred at 100°C for 60 min and then diluted with water (4 L) and extracted with EtOAc (3x6 l). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (3% EtOAc/PE) to give the title compound.

Step 8: 5-chloro-3-[(4-methoxyphenyl)methoxy]-2-methylbenzonitrile.

To a solution of 4-methoxybenzyl alcohol (410 g, 2.97 mol) in DMF (3200 ml) under nitrogen was added sodium hydride (128 g, 5.33 mol), followed by dropwise addition of a solution of 5-chloro-3fluoro-2- methylbenzonitrile (418 g, 2.46 mol) in DMF (800 ml). The resulting solution was stirred at 25°C for 12 hours, then diluted with ice water (2 L) and extracted with EtOAc (3x3 L). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was washed with petroleum ether and collected on a filter to give the title compound.

Step 9: 5-chloro-3-hydroxy-2-methylbenzonitrile.

A solution of 5-chloro-3-[(4-methoxyphenyl)methoxy]-2-methylbenzonitrile (518 g, 1.80 mol) in DCM (1500 ml) was treated with TFA (500 ml). The resulting solution was stirred at 25°C for 1 hour. The solids were collected on a filter to give the title compound. MS: 166 (M-1). 1H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.3 2-7.33 (d, 1H), 7.07-7.08 (d, 1H), 2. 24 (s, 3H).

Intermediate connection A08.

F

HE

3-Bromo-5-(difluoromethyl)-2-methoxyphenol.

Step 1: 3-bromo-4,5-dihydroxybenzaldehyde.

To a solution of 3-bromo-4-hydroxy-5-methoxybenzaldehyde (10 g, 43.3 mmol) in DCM (100 ml) at 0°C was added a solution of BBr ₃ (9.00 ml, 95 mmol) in DCM (100 ml ), then the reaction mixture was stirred at 0°C for 20 min and 25°C for 2.5 h. Upon completion, the reaction was quenched by slow addition of MeOH (50 ml). The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica (0-20%, MeOH/DCM) to give the title compound. MS: 216.9 (M+1).

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Step 2: 3-bromo-5-hydroxy-4-methoxybenzaldehyde.

Lithium carbonate (4.09 g, 55.3 mmol) was added to a solution of 3-bromo-4,5-dihydroxybenzaldehyde (6 g, 27.6 mmol) in DMF (80 mL). After stirring at 45°C for 1 hour, the reaction mixture was treated with MeI (2.59 ml, 41.5 mmol). The reaction mixture was stirred at 45°C for another 2 hours, then poured into ice water (400 ml), and the pH was adjusted to ~6 with 1N. HCl and extracted with EtOAc (3x150 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (5-33% EtOAc/PE) to give the title compound. MS: 231.0 (M+1).

Step 3: 3-bromo-5-(difluoromethyl)-2-methoxyphenol.

To a solution of 3-bromo-5-hydroxy-4-methoxybenzaldehyde (3.23 g, 13.98 mmol) in DCM (30 mL) was added DAST (18.47 mL, 140 mmol). The reaction mixture was stirred at 20°C for 1 hour and then quenched by the slow addition of sat. aq. NaHCO ₃ (100 ml), extracted with DCM (3x50 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (3-25% EtOAc/PE) to give the title compound. MS: 253.8 (M+1).

Intermediate connection A09.

Vg

F OH

4-Bromo-2-methyl-6-(trifluoromethyl)phenol.

Step 1: 4-bromo-2-iodo-6-(trifluoromethyl)phenol.

A solution of 4-bromo-2-(trifluoromethyl)phenol (4 g, 16.60 mmol), KI (16 g, 96 mmol) and I ₂ (8.5 g, 33.5 mmol) in water (50 ml) was treated NH3/H2O (200 ml) and stirred at 30°C for 16 hours. After completion of the reaction, the reaction mixture was neutralized with HCl (6M) to pH 7, and the precipitate was collected on a filter to give the title compound. MS: 366.7 (M+1).

Step 2: 4-bromo-2-methyl-6-(trifluoromethyl)phenol.

To a solution of 4-bromo-2-iodo-6-(trifluoromethyl)phenol (5 g, 13.63 mmol) in NMP (10 ml) was added Pd ₂ (dba) ₃ (0.374 g, 0.409 mmol) and triphenylphosphine (0.715 g , 2.73 mmol). The mixture was purged with N2 and heated at 50°C for 10 min followed by the addition of copper(I) iodide (0.260 g, 1.363 mmol). After the mixture was heated at 50°C for 10 minutes, tetramethylstannane (3.66 g, 20.44 mmol) was added to the reaction mixture and the mixture was heated at 120°C for 3 hours. After complete conversion, the mixture was diluted with sat. aq. KF (50 ml) and extracted with EtOAc (3x40 ml). The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 255 (M+1).

Intermediate A10.

HE

2-Chloro-3-hydroxy-5-methylbenzonitrile.

Step 1: 2-chloro-3-((4-methoxybenzyl)oxy)-5-methylbenzonitrile.

To a solution of 5-bromo-2-chloro-3-((4-methoxybenzyl)oxy)benzonitrile (see step 3 for intermediate A03) (0.350 g, 0.993 mmol) in 1,4-dioxane (10 ml) was added K2CO3 (0.274 g, 1.985 mmol) and H ₂ O (1 ml), then methyl boronic acid (0.059 g, 0.993 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(P) dichloride dichloromethane complex (0.081 g, 0.099 mmol). The resulting mixture was heated at 80°C for 16 hours and then quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (PE 100%) to give the title compound.

Step 2: 2-chloro-3-hydroxy-5-methylbenzonitrile.

To a solution of 2-chloro-3-((4-methoxybenzyl)oxy)-5-methylbenzonitrile (0.185 g, 0.643 mmol) in DCM (20 mL) at 0°C was added TFA (0.050 mL, 0.643 mmol). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica (EtOAc/PE=0-20%) to give the title compound. MS: 168.0 (M+1).

Intermediates listed in table. 1 were purchased from commercial sources.

Table 1

Prom. conn. Structure IUPAC name CAS No. AP jO He 2-fluoro-Z- hydroxybenzonitrile 1000339-24-1 A12 T.J. He Z-bromo-5- hydroxybenzonitrile 770718-92-8 A13 ΊθΓ He 3-hydroxy-5methylbenzonitrile 95658-81-4 A14 N. χτ OH 2,5-dimethyl-3 hydroxybenzonitrile 90563-55-6

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A15 IS 1 Cl o ^Cl H 3,5-dichloro-4hydroxybenzonitrile 1891-95-8 A16 G 1 J Cl With J 1 )H 3-chloro-4-hydroxy-5 methylbenzonitrile 173900-45-3 A17 G OH 2,4-difluoro-3hydroxybenzonitrile 1214373-88-2 A18 cr OH 2-chloro-3 - hydroxybenzonitrile 51786-11-9 A19 OH 3-hydroxy-2methylbenzonitrile 55289-04-8 A20 r 1 f c 1 )H 4-hydroxy-3,5- dimethylbenzonitrile 4198-90-7 A21 ¹ s N 1 D.H. 4-hydroxy-3-methoxy-5 methylbenzonitrile 173900-47-5

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Intermediates B.

Intermediate B01.

ABOUT

F F

5-Fluoro-6-(1,1,2,2-tetrafluoroethyl)-3,4-dihydropyrimidin-4-one.

Step 1: 2,2,3,3-tetrafluoropropanoic acid.

2,2,3,3-tetrafluoropropane- 1-ol (800 g, 6.06 mol). The resulting solution was stirred at 100°C under reflux for 5 hours and then extracted with MTBE (4x2 L). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound, which was used in the next step without purification.

Step 2: 2,2,3,3-tetrafluoro-N-methoxy-N-methylpropanamide.

To a solution of 2,2,3,3-tetrafluoropropanoic acid (crude product from the previous step, 45% purity, 1007 g, 3.15 mol) in THF (4600 ml) at 0°C was added dropwise sulfuroyl dichloride (787.2 g , 6.62 mol) followed by dropwise addition of DMF (753.4 g, 10.31 mol). After stirring at room temperature for 45 min, the reaction mixture was cooled to 0°C and then treated with methoxy(methyl)amine (1222.5 g, 12.53 mol) and TEA (1913 g, 18.91 mol) was added dropwise. . The resulting mixture was stirred at room temperature for 5 hours and then quenched with ice water (2 L) and extracted with MTBE (3 L). The organic layer washed us. aq. NaHCO ₃ and brine, dried over anhydrous sodium sulfate, filtered and distilled to give the title compound.

Step 3: Ethyl 2,4,4,5,5-pentafluoro-3-oxopentanoate.

To a solution of 2,2,3,3-tetrafluoro-N-methoxy-N-methylpropanamide (470 g, 2.49 mol) in THF (4700 ml) at -78°C was added ethyl 2-fluoroacetate (316.2 g , 2.98 mol), 1 M solution of LiHMDS in THF (3729 ml, 3.73 mol). The resulting mixture was stirred at -78°C for 2 hours and then quenched with sat. aq. NH ₄ Cl (1 l). After adjusting the pH of the solution to 3 with HCl (1M), the reaction mixture was extracted with MTBE (3x2 L). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, which was used directly in the next step.

Step 4: 5-fluoro-6-(1,1,2,2-tetrafluoroethyl)-3,4-dihydropyrimidin-4-one.

To a solution of ethyl 2,4,4,5,5-pentafluoro-3-oxopentanoate (533 g, 2.28 mol) in methanol (5330 ml) was added formamidine acetate (1185.1 g, 11.38 mol) and methoxide sodium (492 g, 9.11 mol). The resulting mixture was stirred at room temperature for 2 hours, then quenched with ice water (1.5 L). After the pH of the solution was adjusted to 3 with HCl (2M), the resulting mixture was extracted with MTBE (3x1 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization from MTBE/PE (1:5) to give the title compound. MS: 212.9 (M-1). 1H NMR: (300 MHz, CD3OD): δ 8.10 (1H, s), 6.67 ~ 6.38 (1H, m).

Intermediates listed in table. 2 was prepared according to Scheme C using the procedures described for the synthesis of intermediate B01 using the appropriate fluorinated alkyl alcohol or its corresponding acid/methyl ester.

table 2

Prom. conn. Structure IUPAC name MS (M+1) B02 P-P U—p P / F I P \___/ -ζ. )=O =ζ I 5-fluoro-6-(pentafluoroethyl)-3,4dihydropyrimidin-4-one 231.0 (M-1)

- 31 045274

WHO ABOUT NH f F 6-(1,1-d iforoethyl) - 5 - fluoropyrimidin-4(3N)-one 177.1 (M-1) B04 T G ll ll LL 1_1_ 5-fluoro-6- (trifluoromethyl)pyrimidine- 4(ZN)-on 183.0 (M+1)

Intermediate B05.

4-Chloro-5-fluoro-6-methoxypyrimidine.

Sodium methoxide (3.05 g, 56.5 mmol) was added to a solution of 4,6-dichloro-5-fluoropyrimidine (8.0 g, 47.9 mmol) in MeOH (80 mL) at 0°C. The resulting reaction mixture was stirred at 20°C for 2 hours, then quenched with water (20 ml) and extracted with EtOAc (3x20 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 163.1 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 4.03 (s, 1H).

Intermediate B06.

4-(1-Ethoxyvinyl)-5-fluoro-6-methoxypyrimidine.

Pd( Ph ₃ P) ₄ (0.5 g, 0.433 mmol). The resulting reaction mixture was stirred at 100°C for 4 hours under N2 atmosphere. Upon completion of the reaction, the reaction mixture was diluted with water (30 ml), extracted with EtOAc (3x100 ml). The combined organic layers were treated with sat. aq. KF (80 ml) and stirred at room temperature for 0.5 h, then passed through a CELITE® filter. The filtrate was washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-90% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ): δ 8.49 (s, 1H), 5.08 (d, J=2.8 Hz, 1H), 4.64 (d, J=3.2 Hz, 1H ), 4.06 (s, 3H), 3.93 (m, 2H), 1.42 (m, 3H).

Intermediate B07.

6-Acetyl-5-fluoropyrimidin-4(3H)-one.

To a solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine (4.5 g, 20.43 mmol) in THF (30 ml) at 0°C, 6 M aq. was added dropwise. HCl (20 ml, 120 mmol). The resulting reaction solution was stirred at 20°C for 18 hours and then concentrated under reduced pressure while maintaining the bath temperature at 40°C to obtain the title compound. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.15 (s, 1H), 2.50 (s, 3H).

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Intermediate B08.

5-Fluoro-6-(1,1,2-trifluoroethyl)pyrimidin-4(3H)-one.

Step 1: 2-fluoro-1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone.

To a suspension of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) (0.456 g, 1.29 mmol) in ACN (2 ml) and water (1 ml) was added dropwise for 4 hours a solution of 4-(1-ethoxyvinyl)-5fluoro-6-methoxypyrimidine, B06 (0.2 g, 0.86 mmol) in ACN (3 ml), maintaining the temperature below 15°C. Then the reaction mixture was quenched with sat. aq. NaHCO ₃ (10 ml) and stirred for 10 minutes. After completion of the reaction, the mixture was extracted with EA (3x10 ml). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 189.1 (M+1).

Step 2: 5-fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrimidine.

To a solution of 2-fluoro-1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone (0.15 g, 0.60 mmol) in DCM (2 ml) was added diethylaminosulfur trifluoride (0.578 g, 3.59 mmol ). The resulting reaction mixture was stirred at 20°C for 4 hours, then diluted with water and extracted with EtOAc (3x50 ml). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 4.99 (t, J=12.0 Hz, 1H), 4.88 (t, J=12.0 Hz, 1H) , 4.12 (s, 3H).

Step 3: 5-Fluoro-6-(1,1,2-triFluoroethyl)pyrimidin-4(3N)-one.

Chlorotrimethylsilane was added to a mixture of 5-fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrimidine (0.05 g, 0.238 mmol) and KI (0.119 g, 0.714 mmol) in ACN (15 ml) at RT (0.078 g, 0.714 mmol). The resulting mixture was stirred at 80°C for 4 hours and then diluted with EtOAc, washed with aq. Na ₂ S ₂ O ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 197.1 (M+1).

Intermediate B09.

ABOUT'

ABOUT

5-Fluoro-6-methoxypyrimidine-4-carboxylate.

A solution of 4-chloro-5-fluoro-6 methoxypyrimidine, B05 (410 g, 2.52 mol) in MeOH ( _8.2 l), triethylamine (1.247 kg, 12. 32 mol), PdCl ₂ dppf (201 g, 246.32 mmol). The solution was carbonylated in a vessel under a CO atmosphere at 2 bar pressure and heating at 50°C for 16 hours. The solids were filtered off. The filtrate was concentrated under reduced pressure to remove MeOH and then diluted with EtOAc (4 L). Solids were filtered off.

The filtrate was concentrated again under reduced pressure. The residue was purified by silica column chromatography (10% EtOAc/hexane) and then recrystallized (propan-2-ol:H2O=2:7) to give the title compound MS: 187 (M+1). 1H NMR (400 MHz, CDCl ₃ ): δ 5.587 (s, 1H), 4.109-4.075 (s, 3H), 4.003-3.935 (s, 3H).

Intermediate B10.

Methyl 5-fluoro-6-hydroxypyrimidine-4-carboxylate.

Trimethylsilyl chloride (25.7 ml, 201 mmol) was slowly added to a stirred suspension of methyl 5-fluoro-6-methoxypyrimidine-4-carboxylate, B09 (25 g, 134 mmol) and potassium iodide (33.4 g, 201 mmol) in ACN (300 ml) at 25°C. The resulting mixture was stirred at 25°C for 2 hours. LCMS analysis showed that the reaction was complete. The reaction was quenched with methanol (100 ml) and concentrated to give the title compound, which was used in the next step without further purification.

- 33 045274 drains. MS: 173.0 (M+1). ^1H NMR (400 MHz, DMSO4) 8.12 (s, 1H), 2.59 (s, 3H).

Intermediate B11.

ABOUT

6-Acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

To a solution of 6-acetyl-5-fluoropyrimidin-4(3H)-one, B07 (1.0 g, 5.44 mmol) in DMF (10 ml) was added K ₂ CO ₃ (2.257 g, 16.33 mmol). The resulting reaction mixture was stirred at 20°C for 10 min before adding 1-(chloromethyl)-4-methoxybenzene (1.023 g, 6.53 mmol). The reaction mixture was stirred at 20°C for a further 6 hours and then diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (50% EtOAc/PE) to give the title compound. MS: 277.1 (M+1). ^1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.29 (m, 2H), 6.89 (d, J=8.8, 2H), 5.09 (s, 2H), 3.81 (s, 2H), 2.58 (d, J=8.8, 3H).

The intermediates shown in table. 3 was prepared under conditions similar to the synthesis of intermediate B11, using the corresponding intermediate B, which was prepared as described in the Intermediates B section.

Table 3

Prom. conn. Structure IUPAC name MS (M+1) AT 12 O/A NPMB Me. A. A ^N FF 6-(1,1-difluoroethyl)-5-fluoro-3-(4methoxybenzyl)pyrimidin-4(3D)one 299.0 B13 0 A. NPMB F^f N F^ 5-fluoro-3-(4-methoxybenzyl)-6- (1,1,2-trifluoroethyl)pyrimidine- 4(ZN)-on 317.1 B14 ABOUT F.A./RMV O methyl 5-fluoro-1-(4-methoxybenzyl)6-oxo-1,6-dihydropyrimidine-4carboxylate 293.0 B15 0 F.A.P.M.B. Xo F N F F 5-fluoro-3-(4-methoxybenzyl)-6- (1,1,2,2-tetrafluoroethyl)pyrimidine- 4(ZN)-on 335.1 B16 0 f A /RMV F J J F-y^N F 1 F F 5-fluoro-3-(4-methoxybenzyl)-6- (perfluoroethyl)pyrimidin-4(3N)-one 353.1

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Intermediates C.

Intermediate C01.

[4-[(4-Methoxyphenyl)methoxy]-2-methylpyrimidin-5-yl]methanol.

Step 1: methyl 4-hydroxy-2-methylpyrimidine-5-carboxylate.

A 30% solution of NaOCH ₃ in MeOH (883 ml), MeOH (5 l), 1,3-diethyl-2(ethoxymethylidene) propanedioate ( 350 g, 1.62 mol) and ethanimidamide hydrochloride (152.3 g, 1.61 mol). The resulting mixture was refluxed for 16 hours. The solids were collected on a filter to give the title compound.

Step 2: Methyl 4-[(4-methoxyphenyl)methoxy]-2-methylpyrimidine-5-carboxylate.

A solution of methyl 4-hydroxy-2-methylpyrimidine-5-carboxylate (340 g, 2.02 mol) in 1,4-dioxane (8 L) was placed in a 20 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. 1-(chloromethyl)-4-methoxybenzene (378 g, 2.42 mol) and Ag ₂ O (655.9 g, 2.83 mol). The resulting mixture was refluxed for 15 hours. The solids were filtered off. The filtrate was concentrated under vacuum. The residue was purified by silica column chromatography (10-50% EtOAc/PE) to give the title compound.

Step 3: [4-[(4-methoxyphenyl)methoxy]-2-methylpyrimidin-5-yl]methanol.

A solution of methyl 4-[(4-methoxyphenyl)methoxy]-2-methylpyrimidine-5-carboxylate (600 2.08 mol) in THF (7500 ml) was placed in a 20-liter four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. at -10°C followed by dropwise addition of LAH (2.5 M) (835 ml) with stirring. The resulting solution was stirred at -10°C for 1 hour and then quenched with EtOAc (2500 ml) and MeOH (2500 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (1-10% MeOH/DCM) to give the title compound. MS: 261 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.332 (1H, s), 7.358-7.406 (2H, m), 6.888-6.936 (2H, m), 5.417 (2H, s), 4.615 (2H, s), 3.822 (2H, s), 2.641 (3H, s).

Intermediate C02.

'Ό

(2-Chloro-4-methoxypyrimidin-5-yl)methanol.

Step 1: 5-bromo-2-chloro-4-methoxypyrimidine.

A 5-bromo-2,4-dichloropyrimidine (160 g, 702.14 mmol) and MeOH (3200 ml) were placed in a 4-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, and then at 0°C at While stirring, MeONa (126.8 g, 1.00 eq.) was added dropwise. The resulting solution was stirred at 0°C for 1 hour and then concentrated under reduced pressure. The resulting solution was diluted with water (1 l). The solids were collected on a filter to give the title compound.

Step 2: (2-chloro-4-methoxypyrimidin-5-yl)methanol.

5-Bromo-2-chloro-4-methoxypyrimidine (136 g, 608.62 mmol) and toluene (2500 ml) were placed in a 4-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, and then stirred at -78°C n-BuLi (256 mL, 1.05 eq.) was added dropwise. After stirring for 30 minutes at -78°C, HCOOCH2CH3 (90 g, 1.22 mol) was added dropwise to the reaction mixture. The resulting solution was stirred at -78°C for another 30 min and then MeOH (218 mL) was added dropwise followed by NaBH ₄ (30 g, 793.02 mmol). The reaction solution was stirred at -78°C for another 10 min, then quenched by slowly adding water (1000 ml) and warmed to 10°C. The resulting mixture was extracted with EtOAc (2x2000 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was washed with PE (1000 ml) and collected on a filter to give the title compound. MS: 175 (M+1). 1H NMR (300 MHz, CDCl ₃ , ppm): δ 8.36 (d, J=0.9 Hz, 1H), 4.67 (d, J=0.9 Hz, 2H), 4, 08 (s, 3H).

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Intermediate C03.

(2-Chloro-4-methoxy-6-methylpyrimidin-5-yl)methanol.

Intermediate C03 was prepared by a procedure similar to the synthesis of intermediate C02 using 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine. MS: 189 (M+1).

Intermediate C04.

Ome

(4-Methoxy-2,6-dimethylpyrimidin-5-yl)methanol.

Step 1: 1,3-diethyl-2-(1-hydroxyethyl)propanedioate.

A solution of 1,3-diethyl 2-acetylpropanedioate (5000 g, 24.73 mol) in AcOH (25 L) was placed in a 50 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. NaBH4 (1220 g, 32.25 mol) was then added in several portions at 0°C over 1 hour. The resulting solution was stirred at 0°C for 3 hours and then quenched with water (2 L) and extracted with DCM (3x5 L). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica column chromatography (50% EtOAc/hexane) to give the title compound.

Step 2: 1,3-diethyl-2-[1-(acetyloxy)ethyl]propanedioate.

A solution of 1,3-diethyl-2-(1-hydroxyethyl)propanedioate (3800 g, 18.61 mol) in DCM (38 L), acetic anhydride ( 2280 g, 22.35 mol), TEA (3762 g, 37.18 mol) and 4-dimethylaminopyridine (454 g, 3.72 mol). The resulting solution was stirred at 60°C for 16 hours, then quenched by adding water (4 L) and extracted with DCM (3x5 L). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica column chromatography (2% EtOAc/PE) to give the title compound.

Step 3: 1,3-diethyl-2-ethylidenepropanedioate.

1,3-Diethyl-2-[1-(acetyloxy)ethyl]propanedioate (3200 g, 12.99 mol) was placed in a 10 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. Acetaldehyde (1716 g, 38.95 mol) was then added dropwise at 80°C with stirring over 40 min. The resulting solution was stirred at 80°C for 16 hours, then cooled to 20°C and quenched by adding water (5 L) and then extracted with EtOAc (3x2 L). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica column chromatography (0.5% EtOAc/PE) to give the title compound.

Step 4: Ethyl 2,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate.

A solution of ethanimidamide hydrochloride (1060 g, 11.21 mol) in ethanol (30 L) and NaOEt (1380 g, 14.68 mol) was placed in a 50 L four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. A solution of 1,3-diethyl 2-ethylidenepropanedioate (1700 g, 9.13 mol) in ethanol (4 L) was then added dropwise with stirring at 60°C over 30 min. The resulting solution was stirred at 60°C for 2 hours and then cooled to 20°C. The solid was filtered off. The filtrate was concentrated under reduced pressure to give the title compound, which was used in the next step without purification.

Step 5: Ethyl 2,4-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

A solution of ethyl 2,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate (2500 g, 12.61 mol ) in 1,4-dioxane (25 L), potassium carbonate (7200 g, 52.09 mol), NBS (2300 g, 12.92 mol), BPO (78 g, 304.39 mmol). The resulting solution was stirred at 80°C for 16 hours. The reaction mixture was cooled to 20°C and then quenched by adding water (10 L). The pH of the solution was adjusted to 7 using HCl. The resulting solution was extracted with DCM (3x5 L). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica column chromatography (5% MeOH/DCM) to give the title compound.

Step 6: Ethyl 4-chloro-2,6-dimethylpyrimidine-5-carboxylate.

Ethyl 2,4-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1100 g, 5.61 mol) and POCl ₃ ( 11 l). The resulting solution was stirred at 80°C for 5 hours and then concentrated at

- 36 045274 under reduced pressure to obtain the title compound, which was used in the next step without purification.

Step 7: Ethyl 4-methoxy-2,6-dimethylpyrimidine-5-carboxylate.

A solution of ethyl 4-chloro-2,6-dimethylpyrimidine-5-carboxylate (2000 g, 9.32 mol) in MeOH was placed in a 50-liter four-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. (20 l). The resulting solution was stirred at RT for 2 hours and concentrated under reduced pressure. The residue was dissolved in water (5 L). The resulting solution was extracted with DCM (3x2 L). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica column chromatography (10% EtOAc/PE) to give the title compound.

Step 8: (4-methoxy-2,6-dimethylpyrimidin-5-yl)methanol.

A solution of ethyl 4-methoxy-2,6-dimethylpyrimidine-5-carboxylate (270 g, 1.28 mol) in THF (2.7 L) was placed in a 10 L 4-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen. ). LAH (54 g, 1.42 mol) was then added in several portions at 0°C over 30 min. The resulting solution was stirred at 0°C for 2 hours and then quenched by adding 15% NaOH (65 ml). After stirring for 1 hour, the solids were filtered off. The filtrate was concentrated under reduced pressure to give the title compound. MS: 169 (M+1). 1H NMR (400 MHz, CDCl3): δ 4.678 (s, 2H), 3.988 (s, 3H), 2.562 (s, 3H), 2.493 (s, 3H).

Intermediate C05.

(4-Chloro-6-methoxy-2-methylpyrimidin-5-yl)methanol.

Step 1: 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde.

DMF (2.90 g, 39.6 mmol) was added to a solution of POCl ₃ (31.4 mL, 337 mmol) at 0°C, then the resulting mixture was stirred at 25°C for 0.5 h. Then 2- methylpyrimidine-4,6-diol (5 g, 39.6 mmol). After stirring at 25°C for 1 hour, the reaction mixture was heated at 120°C for 10 hours and then poured onto ice (100 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step. MS: 190.9 (M+1).

Step 2: (4,6-dichloro-2-methylpyrimidin-5-yl)methanol.

To a solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (7.57 g, 39.6 mmol) in MeOH (75 ml) at -40°C was added NaBH ₄ (1.799 g, 47.6 mmol), the mixture was then stirred at 25°C. After 0.5 h, the reaction mixture was quenched with H ₂ O (100 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (5-33% EtOAc/PE) to give the title compound. MS: 193.1 (M+1). ^1H NMR (400 MHz, CDC^): δ 4.91 (s, 2H), 2.69 (s, 3H).

Step 3: (4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methanol.

To a solution of (4,6-dichloro-2-methylpyrimidin-5-yl)methanol (1 g, 5.18 mmol) in MeOH (10 ml) was added sodium methoxide (0.280 g, 5.18 mmol), then the mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with H ₂ O (10 ml), extracted with EtOAc (3x10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 189.1 (M+1).

Intermediates listed in table. 4 was prepared using the procedure described for the synthesis of intermediate CO5, but replacing the 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde in step 2 with the corresponding substituted chloro-pyrimidine-5-carbaldehyde.

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Table 4

Prom. conn. Structure Name according to IU PAK MS (M+1) C06 O\° ^- O t (2,4-dichloro-6methoxypyrimidin-5yl)methanol 211.4 C07 C.I. HO^V^N 1 jj Ο^Ν 1 (4-chloro-6methoxypyrimidin-5yl)methanol 175.2

Intermediate C08.

(4-Methoxy-6-methylpyrimidin-5-yl)methanol.

To a stirred solution of (4-chloro-6-methoxypyrimidin-5-yl)methanol (5 g, 28.6 mmol) in THF (100 ml) in a sealed vessel was added Cs ₂ CO ₃ (18.66 g, 57.3 mmol ) and trimethylboroxine (7.19 g, 57.3 mmol). After degassing with nitrogen for 5 min, 1,1'bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.339 g, 2.86 mmol) was added. The resulting mixture was heated at 70°C for 7 hours and then filtered through CELITE®, washed with EtOAc and concentrated under reduced pressure. The residue was purified by silica column chromatography (50-80% EtOAc/PE) to give the title compound. MS: 155.2 (M+1). 1H NMR (300 MHz, CDCl ₃ ): δ 8.332 (1H, s), 7.358-7.406 (2H, m), 6.888-6.936 (2H, m), 5.417 (2H, s), 4.615 (2H, s), 3.822 (2H, s), 2.641 (3H, s).

Intermediates listed in table. 5 was prepared using the procedure described for the synthesis of intermediate CO8, but replacing (4-chloro-6-methoxypyrimidin-5yl)methanol with (2-chloro-4-methoxypyrimidin-5-yl)methanol, and using methyl boronic acid or vinylboronic acid.

Table 5

Prom. conn. Structure IUPAC name MS (M+1) C09 1 (4-methoxy-2methylpyrimidin-5yl)methanol 155.0 SJ (4-methoxy-6-methyl-2vinylpyrimidin-5yl)methanol 181.3

Intermediate C11.

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1-(5-(Hydroxymethyl)-4-methoxy-6-methylpyrimidin-2-yl)ethan-1-one.

Step 1: (2-(1-ethoxyvinyl)-4-methoxy-6-methylpyrimidin-5-yl)methanol.

Pd(Ph3P) ₄ (49.0 mg, 0.042 mmol), and the resulting mixture was stirred at 100°C for 2 hours. The mixture was then diluted with water (10 ml), extracted with EtOAc (3x20 ml). The combined organic layers were treated with sat. aq. KF (20 ml) and stirred at 20°C for 30 min before filtering through CELITE®. The filtrate was washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ): δ 4.71 (br s, 2H), 4.58 (d, J=1.47 Hz, 1H), 3.94-4.11 (m, 5H) , 2.59 (s, 3H), 1.49 (t, J=7.03 Hz, 3H).

Step 2: 1-(5-(hydroxymethyl)-4-methoxy-6-methylpyrimidin-2-yl)ethan-1-one.

To a solution of (2-(1-ethoxyvinyl)-4-methoxy-6-methylpyrimidin-5-yl)methanol (130 mg, 0.580 mmol) in EtOAc (10 ml) was added 4N. HCl solution in EtOAc (5 ml). The resulting reaction mixture was stirred at 20°C for 1 hour and then concentrated under reduced pressure to obtain the title compound, which was used in the next step without purification. 1H NMR (400 MHz, _DMSOd6 ): δ 4.52 (s, 2H), 3.99 (s, 3H), 2.62 (s, 3H), 2.55 (s, 3H).

Intermediate C12.

(4-Methoxy-6-methyl-2-((pyrimidin-2-yloxy)methyl)pyrimidin-5-yl)methanol.

Step 1: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-chloro-4-methoxy-6-methylpyrimidine.

To a solution of (2-chloro-4-methoxy-6-methylpyrimidin-5-yl)methanol (0.8 g, 4.24 mmol) in THF (14 ml) was added 1H-imidazole (0.866 g, 12.72 mmol) and tert-butylchlorodiphenylsilane (1.749 g, 6.36 mmol). The resulting mixture was stirred at 20°C for 2 hours and then quenched with water and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (1.25% EtOAc/PE) to give the title compound. MS: 472.2 (M+1). 1H NMR (400 MHz, CDCl ₃ ) δ 1.03 (s, 9H) 2.54 (s, 3H) 3.80 (s, 3H) 4.70 (s, 2H) 7.347.49 (m, 6H) 7.66 (dd, J=7.95, 1.34 Hz, 4H).

Step 2: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methoxy-6-methyl-2-vinylpyrimidine.

To a solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-chloro-4-methoxy-6-methylpyrimidine (1.4 g, 3.28 mmol) in 1,4-dioxane (20 ml) and water (4 ml) added K ₂ CO ₃ (0.906 g, 6.56 mmol), 4,4,5,5tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.010 g, 6.56 mmol) and PdCl ₂ (dppf (0.240 g, 0.328 mmol). The resulting mixture was stirred at 100°C for 2 hours and then diluted with water and extracted with EtOAc (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (2% EtOAc/PE) to give the title compound. MS: 419.3 (M+1). 1H NMR (400 MHz, CDCl ₃ ) δ 1 .04 (s, 9H) 2.56 (s, 3H) 3.83 (s, 3H) 4.74 (s, 2H) 5.67 (dd, J=10.30, 1.97 Hz, 1H) 6.51-6.62 (m, 1H) 6.71-6.82 (m, 1H) 7.34-7.48 (m, 6H) 7.69 (dd, J=7.89, 1, 32 Hz, 4H).

Step 3: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methoxy-6-methylpyrimidine-2-carbaldehyde.

To a solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methoxy-6-methyl-2-vinylpyrimidine (1.2 g, 2.87 mmol) in 1,4-dioxane (30 ml) and water (10 ml) osmium oxide (VIII) (0.018 g, 0.072 mmol) and 2,6-dimethylpyridine (0.860 g, 8.03 mmol) were added. The resulting mixture was stirred at 20°C for 30 min before sodium periodate (2.269 g, 10.61 mmol) was added. The reaction mixture was stirred at 20°C for 10 hours and then quenched with saturated aqueous Na ₂ SO ₃ (10 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with 1 M HCl, brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 421.3 (M+1). 1H NMR (400 MHz, CDCl ₃ ) δ 1.03 (s, 9H) 2.68 (s, 2H) 3.86-3.93 (m, 2H) 4.79 (s, 2H) 7.34- 7.49 (m, 6H) 7.61-7.70 (m, 4H) 9.95 (s, 1H).

Step 4: (5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methoxy-6-methylpyrimidin-2-yl)methanol.

Zn(BH ₄ ) ₂ ( 0.386 ml, 0.386 mmol) at -10-0°C. The resulting solution was stirred at this temperature for 30 minutes, then quenched with 4N. HCl (5 ml), diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated at

- 39 045274 under reduced pressure, obtaining the compound indicated in the title. MS: 423.3 (M+1). 1H NMR (400 MHz,

CDCI3) δ 0.99-1.11 (m, 13H) 2.59 (s, 3H) 3.81 (s, 3H) 4.68 (s, 2H) 4.74 (s, 2H) 7.33 -7.49 (m, 8H) 7.63-7.70 (m, 5H).

Step 5: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methoxy-6-methyl-2-((pyrimidin-2-yloxy)methyl)pyrimidine.

To a solution of (5-(((tert-butyldiphenyl)oxy)methyl)-4-methoxy-6-methylpyrimidin-2-yl)methanol (90 mg, 0.213 mmol) in tert-BuOH (5 ml) at 50°C was added 2-chloropyrimidine (24.39 mg, 0.213 mmol) and tBuOK (59.7 mg, 0.532 mmol). The resulting reaction mixture was stirred at 50°C for 2 hours, then diluted with water (20 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without purification. MS: 501.3 (M+1).

Step 6: (4-methoxy-6-methyl-2-((pyrimidin-2-yloxy)methyl)pyrimidin-5-yl)methanol.

To a solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methoxy-6-methyl-2-((pyrimidin-2-yloxy)methyl)pyrimidine (130 mg, 0.260 mmol) in THF (3 ml) TBAF (82 mg, 0.260 mmol) was added at 20°C. The resulting reaction mixture was stirred at 20°C for 2 hours and then diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (100% EtOAc) to give the title compound. MS: 263.1 (M+1).

Intermediate C13.

(4-(Bis(4-methoxybenzyl)amino)-6-methoxy-2-methylpyrimidin-5-yl)methanol.

Step 1: 4-(bis(4-methoxybenzyl)amino)-6-chloro-2-methylpyrimidine-5-carbaldehyde.

4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (600 mg, 3.14 mmol) was dissolved in DCM (15.7 ml) and cooled to 0°C, after which Hunig's base (1207 µl, 6.91 mmol) followed by the addition of bis(4-methoxybenzyl)amine (889 mg, 3.46 mmol). The solution was stirred at 0°C for 4 hours. The reaction mixture was added to DCM (20 ml). The solution was washed with water (2x10 ml) and concentrated under reduced pressure. The residue was purified by silica column chromatography (050% EtOAc/hexane) to give the title compound. MS: 412.2 (M+1).

Step 2: (4-(bis(4-methoxybenzyl)amino)-6-methoxy-2-methylpyrimidin-5-yl)methanol.

4-(bis(4-methoxybenzyl)amino)-6-chloro-2-methylpyrimidine-5-carbaldehyde (1.2 g, 2.91 mmol) was placed in the flask and dissolved in THF (14.57 ml), and then cooled to -78°C, added sodium methoxide (25 wt.% in MeOH) (1.382 ml, 5.83 mmol) and stirred at 0°C for 50 minutes. NaBH ₄ (0.110 g, 2.91 mmol) was added at 0°C and stirred for an additional 1 hour. Water (1000 μl) was added to the solution at 0°C and stirred for 10 minutes. The solution was then transferred to DCM (20 ml), washed with water (2x10 ml) and the organic layer was concentrated under reduced pressure to give the title compound. MS: 410.3 (M+1).

Intermediate C14.

<d

Yes

5-(chloromethyl)-4-methoxy-2,6-dimethylpyrimidine.

To a stirred solution of (4-methoxy-2,6-dimethylpyrimidin-5-yl)methanol, CO4 (1 g, 5.95 mmol) in DCM (15 ml) at 0°C under N2 was added DIPEA (3.12 ml , 17.84 mmol) and MsCl (1.390 ml, 17.84 mmol). The resulting reaction mixture was stirred at 15°C for 2 hours, then diluted with water (15 ml) and extracted with DCM (3x20 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (1-33% EtOAc/PE) to give the title compound. MS: 187 (M+1). 1H NMR (400 MHz, CDCl ₃ ): δ 4.63 (s, 1H) 4.01 (s, 1H) 2.58 (s, 1H) 2.52 (s, 1H).

Intermediates listed in table. 6 was prepared using the procedure described for the synthesis of intermediate C14, but replacing (4-methoxy-2,6-dimethylpyrimidin-5yl)methanol with the corresponding (pyrimidin-5-yl)methanol, as indicated in table. 6 regarding source material.

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Table 6

Prom. conn. Ref. mat. Structure Name according to IU PAK MS (M+1) C15 C09 1 5-(chloromethyl)-4-methoxy-2- methylpyrimidine 173.0 C16 C08 5-(chloromethyl)-4-methoxy-6- methylpyrimidine 173.2 S20 POPs Al 0 N Cl 2-chloro-5-(chloromethyl)-4- methoxy-6-methylpyrimidine 207.0 S21 JV 0 1 -(5 -(chloromethyl)-4-methoxy-6methylpyrimidin-2-yl)ethanone 215.1 S22 C05 D ₂ 4-chloro-5-(chloromethyl)-6- methoxy-2-methylpyrimidine 207.0 S23 C06 Cl Ah. CI^N^CI 2,4-dichloro-5-(chloromethyl)-6- methoxypyrimidine 226.9 S24 C10 _I (O O 5-(chloromethyl)-4-methoxy-6methyl-2-vinylpyrimidine 199.0 S25 C12 CI'^^tA^N AA A\ ,ν. . l- 5-(chloromethyl)-4-methoxy-6methyl-2-((pyrimidin-2yloxy)methyl)pyrimidine 281.1

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AB intermediates.

Intermediate connection AB01.

2,5-Dichloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 3-bromo-5-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

To a solution of 5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (cat. MK8507) (100 mg, 0.28 mmol)) in NMP (0 .5 ml) 2,5-dichloro-3-hydroxybenzonitrile, A04 (105 mg, 0.56 mmol), and K ₂ CO ₃ (192 mg, 1.39 mmol) were added. The resulting reaction mixture was stirred at 140°C for 2 hours and then filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound as the TFA salt. MS: 477 (M+1).

Step 2: 2,5-dichloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a mixture of 2,5-dichloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile (50 mg, 0.107 mmol) in TFA (2 ml), TFAA (0.227 ml, 1.609 mmol) was added. The resulting solution was heated to 110°C for 2 hours and then concentrated under reduced pressure to give the crude title compound, which was used directly in the next step without further purification. MS: 346.1 (M+1).

Intermediates listed in table. 7 was prepared using the procedure described above for the synthesis of intermediate AB01, which can be briefly summarized as follows: SN _Ar reaction between 5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidine- 4(3H)one and the corresponding phenol from intermediates A, followed by deprotection to remove the PMB group using TFA/TFAA.

Table 7

Prom. conn. Structure IUPAC name MS (M+1) AB02 T T o γ ^NH FF 5-chloro-3-((4-(1,1-d iforoethyl)-6oxo-1,6-dihydropyrimidin-5yl)oxy)-2-methylbenzonitrile 326 AVOS O. Il ^NH F 1 F 3 -((4-(1,1-difluoroethyl)-6-oxo-1,6dihydropyrimide in-5-yl)oxy)-5 (difluoromethyl)-2methylbenzonitrile 342

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Intermediate connection AB04.

F

F

5-(Difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2-trifluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

Step 1: 5 -(difluoromethyl)-3 -((1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2-trifluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)- 2-methylbenzonitrile.

To a mixture of 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2-trifluoroethyl)pyrimidin-4(3H)-one, B13 (0.075 g, 0.237 mmol) and K ₂ CO ₃ (0.066 g , 0.474 mmol) in DMA (2 ml) at 15°C under N ₂ atmosphere was added 5(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (0.043 g, 0.237 mmol) in one portion. The mixture was stirred at 100°C for 16 hours. The mixture was concentrated and diluted with EtOAc (5 ml), washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative plate TLC (100% EtOAc) to give the title compound. MS: 480.2 (M+1).

Step 2: 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2-trifluoroethyl)-1,6-dihydropyrimidin5-yl)oxy)benzonitrile.

To a solution of 5-(difluoromethyl)-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2-trifluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (70 mg, 0.146 mmol) in TFA (1 ml), TFAA (1 ml) was added and the mixture was stirred at 100°C for 4 hours. The mixture was concentrated and diluted with EtOAc (5 ml), washed with H ₂ O, saturated aqueous solution NaHCO ₃ and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude title compound. MS: 360.1 (M+1).

Intermediates listed in table. 8 was prepared using the procedure described above for the synthesis of intermediate AB04, which can be briefly summarized as follows: SN _Ar reactions using the corresponding phenol from intermediates A and the corresponding pyrimidone from intermediates B, followed by deprotection to remove the PMB group using TFA/TFAA.

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Table 8

Prom. conn. Structure IUPAC name MS (M+1) AB05 F N.\ 1 TT ^F o F 5 -(difluoromethyl)-2-methyl-3 -((6-oxo- 4-(trifluoromethyl)-1,6- dihydropyrimidin-5 yl)oxy)benzonitrile 346.1 AB06 jTj ^F О Cl V NH \ 1 FN f tf F 5 -(difluoromethyl)-2-methyl-3 -((6-oxo4-(perfluoroethyl)-1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 396.1 AB07 z \/ Yats° V/ z >=O Г·” ν/ V ΞΕ 5 -(difluoromethyl)-2-methyl-3 -((6-oxo4-(1,1,2,2-tetrafluoroethyl)-1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 378.1

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AB08 FNC. /= Tj ^{F 0} 3-((4-(1,1-difluoroethyl)-6-oxo-1,6d ihydropyrimidin-5-yl)oxy)-5 (difluoromethyl)benzonitrile 328 AB09 z O g Vo )—-π -η l: 3 -(difluoromethyl)-5 -((6-oxo-4(1,1,2,2-tetrafluoroethyl)-1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 364.0 AB10 Ν% ,// .Cl ϊϊ F^Y 0 // F F 5 -chloro-2-fluoro-3 -((6-oxo-4-( 1,1,2,2tetrafluoroethyl)- 1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 366.1 AB11 CN jOk 1 ° o. th V ^H V% F 3,5-d imethyl-4-((6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 341.9 AB12 V_==/CI IJ F'^Y O °>Anh FV N FTt F 5 -chloro-2-fluoro-3 -((6-oxo-4(perfluoroethyl)-1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 384.0 AB13 ^NC =-%= ^Br %; F 3 -bromo-5-((6-oxo-4-( 1,1,2,2tetrafluoroethyl)- 1,6- d ihydropyrimidin-5 yl)oxy)benzonitrile 392.0

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Intermediate connection AB14.

2-Chloro-5-(difluoromethyl)-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)ben zonitrile.

Step 1: 5-bromo-2-chloro-3-((1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5 -yl )oxy)benzonitrile.

To a stirred solution of 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin4(3H)-one, B15 (2 g, 5.98 mmol), 5-bromo- 2-chloro-3-hydroxybenzonitrile, A03 (1.391 g, 5.98 mmol), in sulfolane (75 ml) was added K ₂ CO ₃ (1.654 g, 11.97 mmol) and the solution was stirred at 130°C for 16 h The mixture was diluted with water (4x50 ml) and extracted with EtOAc (3x50 ml). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (25-100% EtOAc/PE) to give the title compound. MS: 548.0 (M+1).

Step 2: 2-chloro-3-((1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin5-yl)oxy)-5- vinylbenzonitrile.

To a stirred solution of 5-bromo-2-chloro-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy )benzonitrile (1.45 g, 2.65 mmol) in 1,4-dioxane (24.07 ml) and water (4.93 ml) under an atmosphere of N ₂ was added potassium vinyl trifluoroborate (0.426 g, 3.18 mmol), K ₂ CO ₃ (0.733 g, 5.30 mmol) and PdCl ₂ (dppf) (0.194 g, 0.265 mmol). The resulting mixture was heated to 100°C for 2 hours and then diluted with water (50 ml) and extracted with EtOAc (3x30 ml). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (25-100% EtOAc/PE) to give the title compound. MS: 494.1 (M+1).

Step 3: 2-chloro-5-formyl-3-((1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)benzonitrile.

To a solution of 2-chloro-3-(( 1 -(4-methoxybenzyl)-6-oxo-4-( 1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5 -vinylbenzonitrile (950 mg, 1.924 mmol) in 1,4-dioxane (15 ml) and water (5 ml) added osmium oxide (OS) (98 mg, 0.385 mmol) and 2,6-dimethylpyridine (206 ml), mg , 1.924 mmol). The resulting mixture was stirred for 15 minutes before sodium periodate (1234 mg, 5.77 mmol) was added. The resulting mixture was stirred at 25°C for 12 hours and then quenched with saturated aqueous Na ₂ SO ₃ , diluted with water (50 ml) and extracted with EtOAc (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 496.1 (M+1).

Step 4: 2-chloro-5-(difluoromethyl)-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidine-5)- yl)oxy)benzonitrile.

To a stirred solution of 2-chloro-5-formyl-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy )benzonitrile (950 mg, 1.916 mmol) in DCM (20 ml), DAST (2532 µl, 19.16 mmol) was added and the solution of this mixture was stirred at 0°C for 12 hours. The mixture was diluted with water (40 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (25-100% EtOAc/PE) to give the title compound. MS: 518.1 (M+1).

Step 5: 2-chloro-5-(difluoromethyl)-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

Solution of 2-chloro-5-(difluoromethyl)-3-(( 1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy )benzonitrile (80 mg, 0.154 mmol) in TFA (1 ml) and TFAA (0.5 ml) was stirred at 110°C for 1 hour. The mixture was concentrated under reduced pressure. The rest was processed for us. aq. NaHCO ₃ (0.5 ml) and water (30 ml) and extracted with EtOAc (3x15 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: 398.0 (M+1).

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Intermediate connection AB15.

3-((4-(1,1-Difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-fluorobenzonitrile.

Intermediate AB15 was prepared in a manner similar to that described for intermediate AB14 using the corresponding intermediate A and intermediate B. MS: 346.1 (M+1).

Intermediate connection AB16.

4-((4-Acetyl-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5 -yl)oxy)-3,5-dimethylbenzonitrile.

4-Hydroxy-3,5- dimethylbenzonitrile (144 mg, 0.977 mmol) and K ₂ CO ₃ (135 mg, 0.977 mmol). The resulting reaction mixture was stirred at 80°C for 40 min and then diluted with water (5 ml), extracted with EtOAc (3x10 ml). The combined organic layers were washed with water, brine, filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.24 (s, 2H), 7.15 (s, 1H), 7.13 (s, 1H), 6.80 (d, J=8.8, 2H), 5.23 (s, 2H), 3.73 (s, 2H), 2.51 (s, 3H), 2.11 (s, 6H).

Intermediate connection AB17.

3-Chloro-4-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile.

Step 1: 4-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)3,5-dimethylbenzonitrile.

To a solution of 4-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3,5dimethylbenzonitrile (160 mg, 0.357 mmol) in DCM (3, 0 ml) at 20°C, DAST (0.472 ml, 3.57 mmol) was added. The resulting reaction mixture was stirred at 50°C for 18 hours and then diluted with water (3.0 ml) and extracted with DCM (3x5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 7.52 (s, 2H), 7.24 (d, J=8.4, 2H), 6.89 (d , J=8.4, 2H), 4.99 (s, 2H), 3.72 (s, 3H), 2.06 (s, 6H), 1.99 (m, 3H).

Step 3: 4-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3,5-dimethylbenzonitrile.

Suspension of 4-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)3,5-dimethylbenzonitrile (100 mg 0.212 mmol) in TFA (0.8 ml, 10.38 mmol) and TFAA (0.4 ml, 2.83 mmol) were stirred at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO ₃ to adjust pH to 9 and then extracted with DCM (3x10 ml).

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The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 306.1 (M+1).

Intermediate connection AB18.

F

5-(Difluoromethyl)-2-methoxy-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

Step 1: 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)-6-(1,1,2,2tetrafluoroethyl)pyrimidin-4(3H)-one.

To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one, B15 (300 mg, 0.898 mmol) in DMF (5 ml) 3-bromo-5-(difluoromethyl)-2-methoxyphenol, A08 (227 mg, 0.898 mmol) and K ₂ CO ₃ (372 mg, 2.69 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours, poured into H ₂ O (30 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (33% EtOAc/PE) to give the title compound. MS: 567.0 (M+1). ^1H NMR (400 MHz, CDCl ₃ ): δ 8.10 (s, 1H), 7.45 (s, 1H), 7.25-7.27 (m, 2H), 6.88-6.92 (m, 2H), 6.79 (s, 1H), 6.14-6.65 (m, 2H), 5.06 (s, 2H), 3.95 (s, 3H), 3.80- 3.83 (m, 3H).

Step 2: 5 -(difluoromethyl)-2-methoxy-3 -((1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl )oxy)benzonitrile.

To a solution of 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)-6-(1,1,2,2tetrafluoroethyl)pyrimidin-4(3H)-one (140 mg , 0.247 mmol) in DMF (2 ml) under N2 atmosphere was added dicyanozinc (145 mg, 1.234 mmol), zinc (32.3 mg, 0.494 mmol) and bis(tri-tert-butylphosphine)palladium(0) (25.2 mg, 0.049 mmol). The resulting mixture was stirred at 110°C for 12 hours and then filtered. The filtrate was diluted with H ₂ O (10 ml), extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 514.0 (M+1).

Step 3: 5-(difluoromethyl)-2-methoxy-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin5-yl)oxy)benzonitrile.

To a solution of 5-(difluoromethyl)-2-methoxy-3-(( 1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5-yl )hydroxy)benzonitrile (80 mg, 0.156 mmol) in TFA (1 ml) was added trifluoroacetic anhydride (0.440 ml, 3.12 mmol). The resulting reaction mixture was stirred at 110°C for 1 hour and then concentrated under reduced pressure. The residue was purified by preparative plate TLC (33% EtOAc/PE) to give the title compound. MS: 394.1 (M+1).

Intermediate AB19.

CN

F F

3,5-Dichloro-4-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 5-(4-bromo-2,6-dichlorophenoxy)-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

Mixture of 5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (Cat. MK8507) (400 mg, 1.114 mmol), 4-bromo-2,6 -dichlorophenol (808 mg, 3.34 mmol) and K ₂ CO ₃ (770 mg, 5.57 mmol) in NMP (10 ml) were stirred at 140°C for 27 hours and then diluted with H ₂ O (50 ml ) and extracted with EtOAc (2x50 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. MS: 521 (M+1).

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Step 2: 3,5-dichloro-4-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

A mixture of 5-(4-bromo-2,6-dichlorophenoxy)-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (200 mg, 0.385 mmol) and cyanocopper ( 172 mg, 1.923 mmol) in NMP (10 ml) was stirred at 180°C for 5 hours. The reaction mixture was diluted with H ₂ O (40 ml) and extracted with EtOAc (2x30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified using a preparative TLC plate (33% EtOAc/PE) to give the title compound. MS: 647 (M+1).

Step 3: 3,5-dichloro-4-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Solution of 3,5-dichloro-4-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5 yl)oxy)benzonitrile (100 mg, 0.214 mmol) in TFA (2 ml, 0.214 mmol) and 2,2,2-trifluoroacetic anhydride (1 ml, 0.214 mmol) was stirred at 100°C for 4 h and then concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO ₃ to obtain a solution with pH=78, and then extracted with EtOAc (2x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 346 (M+1).

Intermediate connection AB20.

3-((4-(1,1-Difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methoxybenzonitrile.

Step 1: 6-acetyl-5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)pyrimidin4(3H)-one.

A solution of 6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B11 (546 mg, 1.976 mmol), K ₂ CO ₃ (819 mg, 5.93 mmol) and 3- Bromo-5-(difluoromethyl)-2-methoxyphenol, A08 (500 mg, 1.976 mmol), in DMF (10 ml) was stirred at 80°C for 2 hours and then poured into water (50 ml) and extracted with EtOAc ( 3x30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (5-20% EtOAc/PE) to give the title compound. MS: 509.0 (M+1).

Step 2: 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

To a solution of 6-acetyl-5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (470 mg, 0.923 mmol) in DCM (10 ml) DAST (1.219 ml, 9.23 mmol) was added. The resulting reaction mixture was stirred at 20°C for 1 hour, then poured dropwise into saturated aqueous NaHCO ₃ (50 ml) and extracted with DCM (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (3.3-25% EtOAc/PE) to give the title compound. MS: 531.0 (M+1).

Step 3: 3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5(difluoromethyl)-2-methoxybenzonitrile .

To a solution of 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (335.6 mg , 0.632 mmol) in DMF (5 ml) under N ₂ atmosphere, dicyanozinc (371 mg, 3.16 mmol), zinc (83 mg, 1.263 mmol) and Pd(tBu ₃ P) ₂ (97 mg, 0.189 mmol) were added. The resulting mixture was stirred at 110°C for 12 hours and then diluted with H ₂ O (25 ml) and extracted with EtOAc (3x15 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 478.4 (M+1).

Step 4: 3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2methoxybenzonitrile.

To a solution of 3 -((4-( 1,1 -difluoroethyl)-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5 -yl)oxy)-5 (difluoromethyl)-2-methoxybenzonitrile ( 141 mg, 0.295 mmol) to TFA (2 ml) was added TFAA (1 ml, 7.08 mmol). The resulting reaction mixture was stirred at 110°C for 0.5 h, then carefully poured into ice water (5 ml) and extracted with EtOAc (3x3 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50%

EtOAc/PE), yielding the title compound. MS: 358.0 (M+1).

Intermediates listed in table. 9 was prepared using the procedure described above for the synthesis of intermediate AB20, using the corresponding phenol from intermediate A.

Table 9

Prom. conn. Structure IUPAC name MS (M+1) N 1 XX 3 -chloro-4-((4-( 1,1 -difluoroethyl)-6-oxo- AB21 ^C| X 1,6-d ihydropyrimidin-5-yl)oxy)- 5 - 325.7 A II ^NH methylbenzonitrile |1 1 F 1 F ON Hell 4-((4-(1,1-difluoroethyl)-6-oxo-1,6- AB22 fA I o ^F A d ihydropyrimidin-5 -yl)oxy)-3 - 360.1 II ^NH methyl 5-(trifluoromethyl)benzonitrile \A^ X N F F NC^/^/F Il Ί II 1^ ^F 3 -((4-(1,1-difluoroethyl)-6-oxo-1,6- AB23 d ihydropyrimidin-5 -yl)oxy)-2,4,5 - 332.1 j ⁿ trifluorobenzonitrile F\ A -A AT N AND

Intermediate connection AB24.

5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 6-acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

3-Bromo-5- chloro-2-fluorophenol, A05 (1.959 g, 8.69 mmol), and K ₂ CO ₃ (2.001 g, 14.48 mmol). The resulting mixture was stirred at 60°C for 4 hours and then poured into H ₂ O (100 ml), extracted with EtOAc (3x50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (2-3.3% MeOH/DCM) to give the title compound.

Step 2: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin4(3H)-one.

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To a solution of 6-acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (300 mg, 0.623 mmol) in THF (2 ml) At -30°C, a 0.1 M solution of Zn(BH ₄ ) ₂ in THF (0.934 ml, 0.093 mmol) was added and the mixture was stirred for 10 minutes. Water (1 drop) was added to the reaction mixture and then concentrated under reduced pressure to give the title compound.

Step 3: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

To a solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin4(3H)-one (680 mg, 1.406 mmol) in DCM (10 ml) DAST (0.427 ml, 3.23 mmol) was added at 0°C. The resulting reaction mixture was stirred at 0°C for 1 hour and then diluted with water (5 ml) and extracted with DCM (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

Step 4: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

To a stirred solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4methoxybenzyl)pyrimidin-4(3H)-one (340 mg, 0.700 mmol)) in NMP (3 ml) under N ₂ atmosphere, copper cyano (217 mg, 2.423 mmol) was added. The resulting mixture was stirred at 170°C for 12 hours and then diluted with H ₂ O (30 ml) and EtOAc (30 ml). The mixture was filtered through CELITE®. The filtrate was extracted with EA (3x30 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MeOH (20 ml) to give the title compound.

Step 5: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile (0.217 g, 0.503 mmol) to TFA (1.5 ml) was added TFAA (0.75 ml). The resulting mixture was stirred at 100°C for 6 hours and then diluted with DCM (10 ml) and concentrated under reduced pressure to give the title compound.

The intermediate compound listed in table. 10 was prepared using the procedure described for the synthesis of intermediate AB24, except that 4-bromo-2,6-dichlorophenol was used in step 1 instead of 3-bromo-5-chloro-2-fluorophenol.

Table 10

Prom. conn. Structure IUPAC name MS (M+1) AB25 That Q—--O / ABOUT 3,5 - dichloro-4-((4-( 1 -fluoroethyl)6-oxo-1,6-dihydropyrimidin5-yl)oxy)benzonitrile 328.0

Intermediate connection AB26.

F

2,5-Dichloro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5dichlorobenzonitrile.

2,5- dichloro-3-hydroxybenzonitrile, A04 (1.531 g, 8.14 mmol), and K ₂ CO ₃ (1.876 g, 13.57 mmol). The resulting mixture was stirred at 60°C for 2 hours and then diluted with water (60 ml) and extracted with EtOAc (3x45 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (50-100% EtOAc/PE) to give the title compound. MS: 444.1 (M+1).

Step 2: 2,5-dichloro-3-((6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-4-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)oxy)benzonitrile .

To a solution of 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5dichlorobenzonitrile (800 mg, 1.801 mmol) in THF (10 ml ), NaBH ₄ (68.1 mg, 1.801 mmol) was added. The resulting mixture was stirred at 25°C for 0.5 h and then quenched with water (30 ml), extracted with EtOAc (3x25 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (33% EtOAc/PE) to give the title compound. MS: 448.1 (M+1).

Step 3: 2,5-dichloro-3-((4-( 1 -hydroxyethyl)-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

To a solution of 2,5-dichloro-3-((6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-4-oxo-1,2,3,4-tetrahydropyrimidin5-yl)oxy)benzonitrile (300 mg , 0.669 mmol) to H ₂ O (1 ml) and ACN (4 ml) was added CAN (734 mg, 1.338 mmol). The resulting mixture was stirred at 25°C for 0.5 h and then quenched with water (16 ml) and extracted with EtOAc (3x12 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 446.1 (M+1).

Step 4: 2,5-dichloro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin5-yl)oxy)benzonitrile.

To a solution of 2,5-dichloro-3-((4-(1-hydroxyethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin5-yl)oxy)benzonitrile (173.3 mg, 0.388 mmol) in DCM (4 ml) was added DAST (0.513 ml, 3.88 mmol). The resulting mixture was stirred at 25°C for 1 hour and then carefully quenched with saturated aqueous NaHCO ₃ (16 ml), extracted with DCM (3x12 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (20% EtOAc/PE) to give the title compound. MS: 448.3 [M] ⁺ .

Step 5: 2,5-dichloro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

To a solution of 2,5-dichloro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile (380 mg 0.848 mmol) in TFA (5 ml) TFAA (5 ml, 35.4 mmol) was added. The resulting mixture was stirred at 100°C for 0.5 h and then carefully quenched with saturated aqueous NaHCO ₃ (20 ml) and extracted with EtOAc (3x15 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 382.2 [M] ⁺ .

Intermediate connection AB27.

F

F

5-(Difluoromethyl)-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5(difluoromethyl)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (0.663 g, 3.62 mmol), and 6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B11 (1.0 g, 3.62 mmol), K ₂ CO ₃ (1.001 g, 7.24 mmol) was added to DMF (10 ml). The resulting mixture was stirred at 60°C for 2 hours and then diluted with water (30 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 440.2 (M+1).

Step 2: 5-(difluoromethyl)-3-((6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-4-oxo-1,2,3,4tetrahydropyrimidin-5-yl)oxy)-2- methylbenzonitrile.

To a solution of 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5(difluoromethyl)-2-methylbenzonitrile (1.5 g, 3 .41 mmol) in MeOH (8 ml), NaBH4 (0.129 g, 3.41 mmol) was added. The resulting mixture was stirred at 25°C for 0.5 h and then quenched with water (30 ml),

- 52 045274 extracted with EtOAc (3x25 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 444.1 (M+1).

Step 3: 5-(difluoromethyl)-3-((4-( 1 -hydroxyethyl)-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin5-yl)oxy)-2-methylbenzonitrile.

To a stirred solution of 5-(difluoromethyl)-3-((6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-4-oxo1,2,3,4-tetrahydropyrimidin-5-yl)oxy)-2- methylbenzonitrile (1 g, 2.255 mmol) in THF (12 ml) was added to DDQ (0.563 g, 2.481 mmol). The resulting mixture was stirred at 25°C for 12 hours and then diluted with water (30 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (50-100% EtOAc/PE) to give the title compound. MS: 442.1 (M+1).

Step 4: 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin5-yl)oxy)-2-methylbenzonitrile.

To a stirred solution of 5-(difluoromethyl)-3-((4-(1-hydroxyethyl)-1-(4-methoxybenzyl)-6-oxo1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (900 mg , 1.631 mmol) to DCM (8 ml) was added DAST (2.155 ml, 16.31 mmol). The resulting mixture was stirred at 0°C for 4 hours and then diluted with water (20 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (50-100% EtOAc/PE) to give the title compound. MS: 444.2 (M+1).

Step 5: 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile.

Solution of 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-2-methylbenzonitrile (300 mg, 0.677 mmol) in TFA (2 ml) and TFAA (1 ml) were stirred at 110°C for 0.5 h and then concentrated under reduced pressure. The mixture was then diluted with EtOAc (2 ml) and quenched with saturated aqueous NaHCO ₃ (5 ml). The aqueous layer was further extracted with EtOAc (20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: 324.1 (M+1).

Intermediate connection AB28.

CN

F

3-Chloro-4-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile.

Step 1: 6-acetyl-5-(4-bromo-2-chloro-6-methylphenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

4-bromo- 2-chloro-6-methylphenol (1.058 g, 4.78 mmol) and potassium carbonate (1.101 g, 7.96 mmol). The resulting mixture was stirred at 60°C for 2 hours and then concentrated under reduced pressure. The residue was diluted with water (10 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/PE) to give the title compound. MS: 478.8 (M+1).

Step 2: 5-(4-bromo-2-chloro-6-methylphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-2,3dihydropyrimidin-4(1H)-one.

To a solution of 6-acetyl-5-(4-bromo-2-chloro-6-methylphenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (1.2 g, 2.51 mmol) in EtOAc (6 ml) and THF (9 ml), a 0.1 M solution of Zn(BH ₄ ) ₂ in THF (0.50 ml, 0.05 mmol) was added at -30°C. The resulting mixture was stirred at -30°C for 5 min and then diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: 483.0 (M+1).

Step 3: 5-(4-bromo-2-chloro-6-methylphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin4(3H)-one.

To a solution of 5-(4-bromo-2-chloro-6-methylphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-2,3dihydropyrimidin-4(1H)-one (1 g, 2. 08 mmol) in THF (10 ml) was added 4,5-dichloro-3,6-53 045274 dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (0.236 g, 1.04 mmol). The resulting reaction mixture was stirred at 25°C for 0.5 h and then diluted with water (50 ml) and extracted with EA (3x50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-50%

EtOAc/PE), yielding the title compound. MS: 481.0 (M+1).

Step 4: 5-(4-bromo-2-chloro-6-methylphenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

To a solution of 5-(4-bromo-2-chloro-6-methylphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin4(3H)-one (550 mg, 1.15 mmol) in DCM (11 ml) at 0°C, DAST (0.757 ml, 5.73 mmol) was added. The resulting reaction mixture was stirred at 0°C for 1 hour and then carefully quenched with water (15 ml) and extracted with DCM (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-20% EtOAc/PE) to give the title compound. MS: 483.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51-1.66 (m, 3H) 2.18 (s, 3H) 3.72 (s, 3H) 4.92-5.04 (m, 2H) 5.89-6.16 (m, 1H) 6.89 (d, J=8.82 Hz, 2H) 7.23 (lat, J=7.28 Hz, 2H) 7.46 (br, J=18.74 Hz , 2H) 8.57 (s, 1H).

Step 5: 3-chloro-4-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)5-methylbenzonitrile.

To a stirred solution of 5-(4-bromo-2-chloro-6-methylphenoxy)-6-(1-fluoroethyl)-3-(4methoxybenzyl)pyrimidin-4(3H)-one (383 mg, 0.80 mmol)) Copper cyano (712 mg, 7.95 mmol) was added to NMP (6 mL) under N2. The resulting mixture was stirred at 180°C for 7 hours and then cooled to 25°C, diluted with H ₂ O (20 ml) and EtOAc (20 ml), then filtered through CELITE®. The filtrate was extracted with EA (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: 428.0 (M+1).

Step 6: 3-chloro-4-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile.

Mixture of 3-chloro-4-((4-(1-fluoroethyl)-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5methylbenzonitrile (600 mg, 1.40 mmol) in TFA (10 ml) and TFAA (5 ml) was heated at 100°C for 16 hours. The resulting mixture was concentrated under reduced pressure to give the title compound, which was used in the following steps without further purification. MS: 308.1 (M+1).

Intermediate connection AB29.

3-Cyclopropyl-5-methyl-4-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)ben zonitrile.

Step 1: 5-(4-bromo-2-chloro-6-methylphenoxy)-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin4(3H)-one.

To a stirred solution of 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin4(3H)-one, B15 (700 mg, 2.094 mmol), in NMP (10 ml) 4-bromo-2-chloro-6-methylphenol (696 mg, 3.14 mmol) and potassium carbonate (868 mg, 6.28 mmol) were added. The resulting mixture was stirred at 120°C for 2 hours and then diluted with H ₂ O (15 ml) and extracted with EtOAc (3x15 ml). The combined organic layers were washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-50% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCl ₃ ): δ 7.94 (s, 1H) 7.32 (d, J=2.08 Hz, 1H) 7.28 (d, J=2.08 Hz, 1H) 7 .22 (d, J=8.56 Hz, 2H) 6.90 (d, J=8.68 Hz, 2H) 6.21-6.55 (m, 1H) 4.99 (d, J=2 .45 Hz, 2H) 3.81 (s, 3H) 2.29 (s, 3H).

Step 2: 3-chloro-4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin5 -yl)oxy)-5 - methylbenzonitrile.

To a stirred solution of 5-(4-bromo-2-chloro-6-methylphenoxy)-3-(4-methoxybenzyl)-6-(1,1,2,2tetrafluoroethyl)pyrimidin-4(3H)-one (800 mg, 1.49 mmol) in DMF (25 ml) under N2 atmosphere, dicyanozinc (193 mg, 1.64 mmol) and Pd(Ph ₃ P) ₄ (173 mg, 0.15 mmol) were added. The resulting mixture was stirred at 80°C for 2 hours and then diluted with EtOAc (25 ml). The mixture was washed with H ₂ O and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-50% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDCI3): δ 7.98 (s, 1H) 7.43-7.50 (m, 2H) 7.22 (d, J=8.68

Hz, 2H) 6.87-6.93 (m, 2H) 6.19-6.52 (m, 1H) 4.94-5.05 (m, 2H) 3.82 (s, 3H) 2, 35 (s, 3H).

Intermediate AB30.

CN

3-Cyclopropyl-5-methyl-4-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 3-cyclopropyl-4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)- 5-methylbenzonitrile

To a stirred solution of 3-chloro-4-(( 1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-5- methylbenzonitrile, AB29 (150 mg, 0.31 mmol), cyclopropylboronic acid (134 mg, 1.56 mmol), tribasic potassium phosphate (396 mg, 1.868 mmol) and di((3S,5S,7S)adamantan-1-yl )(butyl)phosphine (67.0 mg, 0.19 mmol) in toluene (5 ml) and H ₂ O (1 ml) under N2 atmosphere was added Pd(OAc) ₂ (20.97 mg, 0.093 mmol). The resulting mixture was stirred at 130°C for 16 hours and then passed through CELITE®. The filter cake was washed with DCM (10 ml) and MeOH (10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative plate TLC (33% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, CDC13): δ 7.89 (s, 1H) 7.27 (s, 1H) 7.14 (d, J=8.56 Hz, 2H) 7.01 (s, 1H) 6 .81 (d, J=8.56 Hz, 2H) 6.14-6.48 (m, 1H) 4.78-5.00 (m, 2H) 3.74 (s, 3H) 2.17 ( s, 3H) 1.65-1.73 (m, 1H) 0.64-0.79 (m, 2H) 0.39-0.51 (m, 1H) 0.20 (lat. dd, J= 9.90, 4.16 Hz, 1H).

Step 4: 3-cyclopropyl-5-methyl-4-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

A solution of 3-cyclopropyl-4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5- methylbenzonitrile (130 mg, 0.27 mmol) in TFA (2 ml) and TFAA (1 ml) was stirred at 110°C for 3 hours and then cooled to room temperature, carefully quenched by adding saturated aqueous NaHCO ₃ solution (10 ml ) and extracted with EtOAc (3x5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 368.1 (M+1). 'and NMR (400 MHz, CDC13): δ.80 (s, 1H) 7.78-7.83 (m, 1H) 7.33 (s, 1H) 7.11 (s, 1H) 6.28- 6.57 (m, 1H) 2.26 (s, 3H) 1.80-1.86 (m, 1H) 0.86-0.92 (m, 1H) 0.68-0.84 (m, 2H) 0.39-0.52 (m, 1H).

Intermediate connection AB31.

CN

F F

3-(Difluoromethyl)-5 -methyl-4-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

Step 1: 4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)-3-methyl-5- vinylbenzonitrile.

To a stirred solution of 3-chloro-4-(( 1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-5- methylbenzonitrile, AB29 (370 mg, 0.77 mmol), in 1,4-dioxane (5 ml) and H ₂ O (1 ml) under N2 was added potassium trifluoro(vinyl) borate (514 mg, 3.84 mmol) , K2CO3 (637 mg, 4.61 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (146 mg, 0.307 mmol) and diacetoxypalladium (34 .5 mg 0.154 mmol). The resulting mixture was stirred at 120°C for 18 hours and then filtered through CELITE®. The filter cake was washed with MeOH (10 ml) and DCM (10 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (10-50% EtOAc/PE) to give the title compound. 1H NMR (400 MHz,

- 55 045274

CDCI3): δ 7.95 (s, 1H) 7.54 (d, J=2.08 Hz, 1H) 7.41 (d, J=1.83 Hz, 1H) 7.16-7.19 ( m, 2H) 6.86-6.89 (m, 2H) 6.69 (dd, J=17.48, 11.00 Hz, 1H) 6.19-6.54 (m, 1H) 5.53 (d, J=17.48 Hz, 1H) 5.17-5.28 (m, 1H) 4.81-5.04 (m, 2H)

3.81 (s, 3H) 2.24 (s, 3H).

Step 2: 3-formyl-4-(( 1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5 yl)oxy)-5 -methylbenzonitrile.

To a stirred solution of 4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-3-methyl-5- vinylbenzonitrile (100 mg, 0.21 mmol) in 1,4-dioxane (1 ml) and water (0.33 ml), 2,6-dimethylpyridine (45.3 mg, 0.42 mmol), sodium periodate (136 mg, 0.63 mmol) and osmium oxide (OS) (2.69 mg, 10.56 µmol). The resulting mixture was stirred at 15°C for 1 hour and then quenched with saturated aqueous Na ₂ SO ₃ (15 ml) and extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. ^1H NMR (400 MHz, CDCl3): δ 10.16 (s, 1H) 7.99 (s, 1H) 7.68 (s, 1H) 7.42-7.46 (m, 1H) 7.17 -7.20 (m, 2H) 6.886.91 (m, 2H) 6.13-6.55 (m, 1H) 4.95 (d, J=3.18 Hz, 2H) 3.81 (s, 3H) 2.25 (s, 3H).

Step 3: 3 -(difluoromethyl)-4-(( 1 -(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5 -yl)oxy)- 5-methylbenzonitrile.

To a stirred solution of 3-formyl-4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5-yl)oxy)-5 -methylbenzonitrile (90 mg, 0.19 mmol) in DCM (1.5 ml) under N ₂ was added with diethylaminosulfotrifluoride (30.429 mg, 1.89 mmol). The resulting mixture was stirred at 15°C for 2 hours and then carefully poured into saturated aqueous NaHCO ₃ solution (20 ml) and extracted with DCM (3x20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. MS: 498 (M+1).

Step 4: 3-(difluoromethyl)-5-methyl-4-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

Solution of 3-(difluoromethyl)-4-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-5- Methylbenzonitrile (60 mg, 0.072 mmol) in TFA (2 ml) and TFAA (1 ml) was stirred at 110°C for 1 hour. The mixture was quenched by adding saturated aqueous NaHCO3 (15 ml) and extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 378 (M+1).

Intermediate connection AB32.

5-(Difluoromethyl)-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methoxybenzonitrile.

Step 1: 6-acetyl-5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)pyrimidin4(3H)-one.

3-Bromo-5- (difluoromethyl)-2-methoxyphenol, A08 (463 mg, 1.83 mmol), and K ₂ CO ₃ (460 mg, 3.33 mmol). The resulting reaction mixture was stirred at 60°C for 4 hours and then quenched with saturated NH ₄ Cl solution and extracted with EtOAc (3x25 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. MS: 511.1 (M+1).

Step 2: 6-acetyl-5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)-2,3dihydropyrimidin-4(1H)-one.

To a solution of 6-acetyl-5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)pyrimidin4(3H)-one (650 mg, 1.28 mmol) in MeOH (3 ml) at 0°C, NaBH ₄ (121 mg, 3.19 mmol) was added over 10 min, then quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (3x25 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 513.2 (M+1).

Step 3: 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

To a solution of 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)- 56 045274

2,3-Dihydropyrimidin-4(1H)-one (480 mg, 0.94 mmol) in THF (2 ml) at 25°C was added with DDQ (425 mg, 1.87 mmol) over 1 h, and control with TLC (50% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was diluted with H ₂ O (20 ml), extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 513.2 (M+1).

Step 4: 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

To a solution of 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (280 mg, 0.55 %). mmol) in DCM (4 ml) at 25°C was added DAST (0.739 ml, 5.59 mmol). The resulting mixture was stirred at 25°C for 1 hour and then carefully quenched with water (100 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column chromatography (50% EtOAc/PE) to give the title compound. MS: 513.2 (M+1).

Step 5: 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin5-yl)oxy)-2-methoxybenzonitrile.

To a solution of 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (60 mg, 0.12 mmol) in DMF (2 ml) under N2 atmosphere, add dicyanozinc (68.6 mg, 0.58 mmol), zinc (22.93 mg, 0.35 mmol) and bis(tri-tert-butylphosphine)palladium(0) (59.7 mg, 0.12 mmol). The resulting mixture was stirred at 140°C for 16 hours. TLC (50% EtOAc/PE) indicated that the starting material was consumed. The mixture was diluted with water (40 ml) and extracted with EtOAc (3x20 ml).

The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. MS: 460.2 (M+1).

Step 6. 5-(Difluoromethyl)-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methoxybenzonitrile.

A solution of 5-(3-bromo-5-(difluoromethyl)-2-methoxyphenoxy)-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one (50 mg, 0.088 mmol) in TFAA (0.5 ml, 3.54 mmol) and TFA (1 ml) were stirred at 110°C for 2 hours. TLC (50% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (3x10 ml). The combined organic compounds were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: 340.2 (M+1).

Intermediate AB33.

5-(Difluoromethyl)-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 6-acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

Solution of 6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B11 (3 g, 10.86 mmol), 3-bromo5-chloro-2-fluorophenol, A05 (3, 37 g, 11.95 mmol), and K2CO3 (4.50 g, 32.6 mmol) in DMF (30 ml) were stirred at 50°C for 1 hour and then diluted with water (50 ml) and extracted with EtOAc ( 3x50 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, DMSO- _d6 ): δ 2.49 (s, 3H) 2.49-2.49 (m, 1H) 3.73 (s, 3H) 5.08 (s, 2H) 6 .91 (d, J=8.68 Hz, 2H) 7.21 (dd, J=6.91, 2.38 Hz, 1H) 7.33 (lat, J=8.68 Hz, 2H ) 7.54 (dd, J=5.14, 2.45 Hz, 1H) 8.78 (s, 1H).

Step 2: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-2,3dihydropyrimidin-4(1H)-one.

To a solution of 6-acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (3 g, 6.23 mmol) in MeOH (10 ml) and THF (20 ml) NaBH ₄ (0.236 g, 6.23 mmol) was added. The resulting mixture was stirred at 20°C for 1 hour. TLC (50% EtOAc/PE) and LC-MS showed that the desired product was obtained. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous

- 57 045274

Na ₂ SO ₄ was filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 487.1 (M+1).

Step 3: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

Mixture of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)-2,3-dihydropyrimidin-4(III)-one (2.7 g 5.56 mmol) and CAN (6.09 g, 11.12 mmol) in ACN (20 ml) and water (5 ml) were stirred at 20°C for 20 min. TLC (50% EtOAc/PE) indicated that the desired product was obtained. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/PE) to give the title compound. MS: 485.0 (M+1).

Step 4: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one.

A solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin4(3H)-one (1.7 g, 3.51 mmol) and DAST (4.64 mL, 35.1 mmol) in DCM (17 mL) was stirred at 20°C for 1 hour. TLC (100% EtOAc) indicated the desired product was obtained. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-20% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, DMSO-d ₆ ): δ 1.49-1.59 (m, 3H) 3.73 (s, 3H) 5.06 (d, J=2.87 Hz, 2H) 5, 65-5.84 (m, 1H) 6.90 (d, J=8.60 Hz, 2H) 7.15 (dd, J=6.84, 2.21 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.55 (dd, J=5.07, 2.43 Hz, 1H) 8.74 (s, 1H).

Step 5: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)benzonitrile.

A solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)one (1.4 g, 2.88 mmol) and cyanocopper (2.58 g, 28.8 mmol) in NMP (25 ml) were stirred at 180°C for 3.5 hours. TLC (50% EtOAc/PE) and LC-MS showed that the desired product was obtained. The reaction mixture was diluted with EtOAc (50 ml) and passed through a filter. The filter cake was washed with EtOAc (20 ml) and H ₂ O (50 ml). The filtrate was extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/PE) to give the title compound. MS: 432.1 (M+1).

Step 6: 2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)5-vinylbenzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)benzonitrile (200 mg, 0.46 mmol) in 1,4-dioxane (4 ml) and water (0.8 ml) under a nitrogen atmosphere was added potassium trifluoro(vinyl)borate (93 mg, 0.70 mmol), di((3S,5S, 7S)-adamantan-1yl)(butyl)phosphine (66.4 mg, 0.185 mmol), K ₃ PO ₄ (197 mg, 0.926 mmol) and diacetoxypalladium (20.80 mg, 0.093 mmol). The resulting mixture was stirred at 110°C for 2 hours. TLC (50% EtOAc/PE) and LC-MS indicated completion of the reaction. The mixture was diluted with water (25 ml) and extracted with EtOAc (3x25 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (1% MeOH/DCM) to give the title compound. MS: 424.2 (M+1).

Step 7: 2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)5-formylbenzonitrile.

To a solution of 2-fluoro-3-((4-( 1 -fluoroethyl)-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-5-vinylbenzonitrile (300 mg, 0. 71 mmol) in 1,4-dioxane (10 ml) and water (3 ml), osmium oxide (VIII) (4.50 mg, 0.018 mmol) and 2,6-dimethylpyridine (213 mg, 1.98 mmol) were added . The resulting mixture was stirred at 20°C for 0.5 h, then sodium periodate (561 mg, 2.62 mmol) was added. The mixture was stirred at 20°C for an additional 3 hours. TLC (50% EtOAc/PE) and LC-MS showed complete conversion of the starting material. The reaction was quenched with saturated aqueous Na ₂ SO ₃ (10 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative plate TLC (2% MeOH/DCM) to give the title compound. MS: 426.2 (M+1).

Step 8: 5-(difluoromethyl)-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 2-fluoro-3-((4-( 1 -fluoroethyl)-1 -(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-5-formylbenzonitrile (300 mg, 0. 71 mmol) in DCM (0.5 ml) was added DAST (0.932 ml, 7.05 mmol). The resulting mixture was stirred at 20°C for 2 h, and TLC (50% EtOAc/PE) and LC-MS showed complete conversion of the starting material. The reaction was quenched with saturated aqueous NaHCO ₃ (10 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE),

- 58 045274 receiving the connection specified in the header. MS: 448.2 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 1.51-1.62 (m, 3H) 3.73 (s, 3H) 4.98-5.15 (m, 2H) 5.67-5, 93 (m, 1H) 6.80-7.12 (m, 3H) 7.31 (d, J=8.68 Hz, 2H) 7.57 (lat.

d., J=6.48 Hz, 1H) 7.91 (br., J=3.55 Hz, 1H) 8.79 (s, 1H).

Step 9: 5-(difluoromethyl)-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

A solution of 5-(difluoromethyl)-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (160 mg, 0.36 mmol) in TFA (7 ml) and TFAA (3.5 ml) were stirred at 100°C for 3 hours. TLC (50% EtOAc/PE) and LC-MS showed complete conversion of the starting material. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (2 ml), then washed with saturated aqueous NaHCO ₃ and brine and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 328.0 (M+1).

Intermediate connection AB34.

F

5-Chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile.

Step 1: Methyl 5-fluoro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate.

Potassium carbonate (16.11 g, 117 mmol) was added to a mixture of methyl 5-fluoro-1-(4-methoxybenzyl)-6-oxo1,6-dihydropyrimidine-4-carboxylate, B14 (21.29 g, 72.9 mmol), and 5-chloro-2-fluoro-3hydroxybenzonitrile, A06 (10 g, 58.3 mmol), in dimethylacetamide (350 ml) at 25°C. The resulting mixture was stirred at 90°C overnight. LC-MS showed the formation of the desired product and the purity of the reaction. Water (500 ml) was added to obtain a precipitate. The mixture was filtered, the solid was washed with water (100 ml) and hexane (200 ml), and dried overnight under high vacuum to give the title compound. MS: 444 (M+1).

Step 2: 5-(5-chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4carboxylic acid.

Potassium trimethylsilanolate (9.97 g, 78 mmol) was added to the stirred mixture of methyl 5-(5-chloro-3cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4 -carboxylate (23 g, 51.8 mmol) in THF (345 ml). The resulting mixture was stirred at 25°C for 1 hour. LC-MS showed the formation of only the desired product. HCl (1N aq, 300 mL) was slowly added to the mixture to form a white solid. The mixture was concentrated under reduced pressure to remove THF. The mixture was filtered and the white solid was washed with water and dried in vacuo to give the title compound. MS: 430.0 (M+1).

Step 3: 5-(5-chloro-3-cyano-2-fluorophenoxy)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-6-oxo-1,6dihydropyrimidine-4-carboxamide.

Into a flask containing 5-(5-chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6dihydropyrimidine-4-carboxylic acid (20 g, 46.5 mmol) and N, Odimethylhydroxylamine hydrochloride (4.99 g, 51.2 mmol) in DMF (200 ml), triethylamine (25.9 ml, 186 mmol) was added at 25°C followed by EDC (9.81 g, 51.2 mmol) and HOBt (7.84 g, 51.2 mmol). The resulting mixture was stirred at 25°C overnight. LC-MS indicated completion of the reaction. Water (300 ml) was added and the resulting precipitate was filtered and washed with water and dried in vacuo to give the title compound. MS: 473.1 (M+1).

Step 4: 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2fluorobenzonitrile.

Methylmagnesium bromide (3 M in THF, 40 ml, 120 mmol) was added dropwise to a cooled (-78°C) mixture of 5-(5-chloro-3-cyano-2-fluorophenoxy)-N-methoxy-1-(4 -methoxybenzyl)-N-methyl-6-oxo-1,6dihydropyrimidine-4-carboxamide (16.5 g, 34.9 mmol) in THF (350 ml). The resulting mixture was stirred at -78°C for 3 hours. LC-MS showed the presence of the desired product, but also the starting material. The reaction mixture was then heated to 0°C and stirred for 30 minutes. LC-MS indicated completion of the reaction. The reaction was quenched with saturated aqueous NH ₄ Cl (500 ml) and diluted with EtOAc (200 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x200 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 428.0

- 59 045274 (M+1).

Step 5: 5-chloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-2-fluorobenzonitrile.

Into a vessel containing 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)5-chloro-2-fluorobenzonitrile (7 g, 16.36 mmol) and dichloroethane (9.35 ml) DEOXOFLUOR® (15.08 ml, 82 mmol) was added at 25°C. The vessel was sealed and stirred at 70°C for 3 hours. LC-MS indicated the formation of the desired product. The reaction mixture was cooled to room temperature and very slowly and carefully poured into a saturated NaHCO ₃ solution. The organic layer was then separated and the aqueous layer was extracted with dichloromethane (2x100 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 450.0 (M+1).

Step 6: 5-Chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2fluorobenzonitrile.

A flask containing a mixture of 5-chloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile (7 g, 15.56 mmol) in trifluoroacetic acid (58.4 ml) and trifluoroacetic anhydride (19.45 ml) was stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and hexane (100 ml) was added slowly until a white solid formed. After stirring for 30 minutes, the white solid was collected on a filter and dried in vacuo to give the title compound. MS: 330.0 (M+1).

Intermediate connection AB35.

3-((4-Bromo-1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-1,6-d ihydropyrimidin-5 -yl) hydroxy)-2,5-dimethylbenzonitrile.

Step 1: Dimethyl 2-(5-chloro-3-cyano-2-methylphenoxy)malonate To a solution of 5-chloro-3-hydroxy-2methylbenzonitrile, A07 (12 g, 71.6 mmol), add potassium carbonate (19, 79 g, 143 mmol). The resulting mixture was stirred for 15 minutes before dimethyl 2-chloromalonate (13.12 g, 79 mmol) was added. The reaction mixture was heated at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, then diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (6% EtOAc/PE) to give the title compound.

Step 2: 5-chloro-3-((4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To a solution of formamidine acetate (9.09 g, 87 mmol) in MeOH (120 ml) was added sodium methoxide (9.44 g, 175 mmol) and the reaction mixture was stirred at room temperature for 5 min, and then dimethyl-2 was added portionwise -(5-chloro-3-cyano-2-methylphenoxy)malonate (13 g, 43.7 mmol). The reaction mixture was heated at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was dissolved in water (50 ml) and acidified to pH 5 using 1.5 M HCl. The precipitate was collected on a filter, washed with EtOAc to obtain the crude title compound, which was used in the next step without further purification.

Step 3: 5-chloro-3-((1-(4-methoxybenzyl)-4-((4-methoxybenzyl)oxy)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-2-methylbenzonitrile.

To a solution of 5-chloro-3-((4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (9 g, 32.4 mmol) in DMF (300 ml) was added potassium carbonate (13.44 g, 97 mmol) followed by the addition of 1-(chloromethyl)-4-methoxybenzene (12.69 g, 81 mmol) after 15 minutes of initial stirring at room temperature. The reaction mixture was heated at 80°C for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ice water and EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-40% EtOAc/PE) to give the title compound. MS: 518.4 (M+1).

Step 4: 5-chloro-3-((4-hydroxy-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile.

To a solution of 5-chloro-3-(( 1 -(4-methoxybenzyl)-4-((4-methoxybenzyl)oxy)-6-oxo-1,6-dihydropyrimi- 60 045274 din-5-yl)oxy)- 2-methylbenzonitrile (10.2 g, 19.69 mmol) in DCM (85 ml) at 0°C was added dropwise

TFA (7.59 ml, 98 mmol) and the reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was triturated with methanol and the solid was collected on a filter to give the title compound. MS: 398.2 (M+1).

Step 5: 3-((4-hydroxy-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5dimethylbenzonitrile.

To a solution of 5-chloro-3-((4-hydroxy-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile (1.45 g, 3.64 mmol ) in THF (15 ml) and water (2 ml) were added methyl boronic acid (0.436 g, 7.29 mmol) and potassium phosphate (2.321 g, 10.93 mmol). After purging with nitrogen, chloro(2dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) was added ( 0.287 g, 0.364 mmol), then the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (3% MeOH/DCM) to give the title compound. MS: 378.2 (M+1).

Step 6: 3-((4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile.

To a solution of 3-((4-hydroxy-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5dimethylbenzonitrile (1.0 g, 2.65 mmol) in trifluoroacetic acid (10 ml, 130 mmol) at 0°C, trifluoroacetic anhydride (5 ml, 35.4 mmol) and anisole (0.289 ml, 2.65 mmol) were added. The reaction mixture was stirred at 100°C for 3 hours and then concentrated under reduced pressure. The residue was purified by silica column chromatography (3% MeOH/DCM) to give the title compound.

Step 7: 3-((4,6-dibromopyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile.

To a solution of 3-((4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile (500 mg, 1.944 mmol) in ACN (10 ml) at 0°C was added phosphorus oxybromide (2229 mg, 7.77 mmol) followed by the addition of triethylamine (0.542 ml, 3.89 mmol). The reaction mixture was stirred at 80°C for 16 hours and then concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (7% EtOAc/PE) to give the title compound.

Step 8: 3-((4-bromo-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile.

Potassium acetate (272 mg, 2.77 mmol). The reaction mixture was stirred at 80°C for 16 hours and then concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (50% EtOAc/PE) to give the title compound. MS: 639.0 (2M+1).

Aircraft intermediate connections.

Intermediate connection BC01.

F F

5-Fluoro-3-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-(perfluoroethyl)pyrimidin-4(3H)-one.

A mixture of 5-fluoro-6-(perfluoroethyl)pyrimidin-4(3H)-one, B02 (420 mg, 1.81 mmol), potassium carbonate (625 mg, 4.52 mmol) and 5-(chloromethyl)-4- methoxy-2,6-dimethylpyrimidine, C14 (405 mg, 2.17 mmol), in DMA (9 ml) was stirred at room temperature for 16 hours. LC-MS showed good conversion of starting material to product. The mixture was filtered. The filtrate was collected using EtOAc (200 ml) and washed with water (3x50 ml), brine (50 ml), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% MeOH/DCM) to give the title compound. MS: 383.1 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 8.79 (s, 1H), 4.86 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.18 (c, 3H).

- 61 045274

Intermediate connection BC02.

ABOUT

Methyl 5-fluoro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate.

Mixture of 5-fluoro-6-(perfluoroethyl)pyrimidin-4(3H)-one, B02 (50 mg, 0.22 mmol), 5-(chloromethyl)-4methoxy-2-methylpyrimidine, C15 (55.8 mg, 0 .32 mmol) and potassium carbonate (89 mg, 0.65 mmol) in NMP (431 µl) were stirred at 23°C for 16 h. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water, the precipitate was collected on a filter, washed with water (3x) and air dried to give the title compound. MS: 369.1 (M+1).

Intermediates listed in table. 10 was prepared using the procedure described above for the synthesis of intermediate BC02, using the corresponding intermediates B described in the Intermediates B section.

Table 11

Prom. conn. Structure IUPAC name MS (M+1) WSOP ABOUT F I Ν O N F F । 5 -fluoro-3-((4-methoxy-2methylpyrimidin-5 -yl)methyl)-6(1,1,2,2- tetrafluoroethyl)pyrimidin-4(3N)one 351.2 VS04 Z )=o ^z —°\ I 5-fluoro-3-((4-methoxy-2,6- d imethylpyrimide in- 5 -yl)methyl)- 6-(trifluoromethyl)pyrimidine- 4(ZN)-on 333.2 VS05 ⁰ 1 f^ JU A. F 'Ts N || ^N FFI 5 -fluoro-3-((4-methoxy-6methylpyrimidin-5 -yl)methyl)-6(1,1,2,2- tetrafluoroethyl)pyrimidine-4(ZN)- He 351.2

Intermediate connection BC06.

5-Fluoro-3-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin4(3H)-one.

Mixture of 5-fluoro-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one, B01 (123 mg, 0.57 mmol), 5(chloromethyl)-4-methoxy-2,6 -dimethylpyrimidine, C15 (107 mg, 0.57 mmol), and potassium carbonate (238 mg, 1.72 mmol) in NMP (1147 μl) were stirred at 23°C for 16 h. LC-MS indicated that the reaction was complete . The reaction mixture was filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 365.1 (M+1).

Example 1.

F

5-(Difluoromethyl)-2-methoxy-3-((1-((2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4- 62 045274 (1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 5-(difluoromethyl)-2-methoxy-3-((1-((4-((4-methoxybenzyl)oxy)-2-methylpyrimidin5-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 5-(difluoromethyl)-2-methoxy-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile, AB18 (46 mg , 0.12 mmol), 5-(chloromethyl)-4-((4methoxybenzyl)oxy)-2-methylpyrimidine, C15 (48.9 mg, 0.175 mmol), K2CO3 (48.5 mg) was added to DMF (1 ml) , 0.351 mmol) and LiBr (10.16 mg, 0.117 mmol). The resulting reaction mixture was stirred at 50°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (66% EtOAc/PE) to give the title compound. MS: 634.4 (M-1).

Step 2: 5-(difluoromethyl)-2-methoxy-3-((1-((2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-( 1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 5 -(difluoromethyl)-2-methoxy-3 -((1 -((4-((4-methoxybenzyl)oxy)-2-methylpyrimidin-5 yl)methyl)-6-oxo-4-(1, 1,2,2-Tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (15 mg, 0.024 mmol) in DCM (1 ml), TFA (1 ml, 12.98 mmol) was added and the resulting mixture was stirred under N2 atmosphere at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 516.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.40 (s, 1H), 6.69 -7.03 (m, 2H), 4.85 (s, 2H), 4.02 (s, 3H), 2.26 (s, 3H).

Example 2.

3-(Difluoromethyl)-5-((1-((2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

This compound was prepared in the same manner as described above for the synthesis of Example 1 using intermediate AB01 and intermediate C15. MS: 486 (M+1).

Example 3.

2,5-Dichloro-3-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 5-chloro-3-((4-(1,1-difluoroethyl)-1 -((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile.

Mixture of 2,5-dichloro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB01 (30 mg, 0.079 mmol ), 5-(chloromethyl)-4-methoxy-2,6-dimethylpyrimidine, C14 (29.3 mg, 0.157 mmol), lithium bromide (13.64 mg, 0.157 mmol) and K2CO3 (76 mg, 0.550 mmol) in DMFA (4 ml) was stirred at 50°C for 2 hours. TLC indicated that the reaction was complete. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (20 ml) and extracted with EtOAc (2x10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 532 (M+1).

Step 2: 2,5-dichloro-3-((4-(1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6- oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 2,5-dichloro-3-((4-(1,1-difluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile (40 mg, 0.081 mmol) in ACN (3.0 ml) was added with KI (40.1 mg, 0.242 mmol) and TMS-Cl (0.031 ml, 0.242 mmol). The resulting mixture was stirred at 70°C for 1.5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (5 ml) and

- 63 045274 extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 548.2 (M+1). ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.70 (s, 1H) 7.37 (d, J=2.20 Hz, 1H)

6.79 (d, J=2.21 Hz, 1H) 5.02 (s, 2H) 2.60 (s, 3H) 2.50 (s, 3H) 1.97 (t, J=18.85 Hz, 3H).

The following examples shown in table. 12 was prepared in a similar manner as described above for the synthesis of Example 3 using the appropriate intermediates AB and C.

Table 12

Note No. (AB#, C#) Structure IUPAC name MS (M+1) 4 (AB01, C14) 1J ⁰ 1 X Ν ⁰ FF ^H 5 -chloro-3 -((4-(1,1 -d iforoethyl)- 1 -((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-1,6- Dihydropyrimidin-5-yl)oxy)2-methylbenzonitrile 462 5 (AB04, C14) 5 -(difluoromethyl)-3 -((1-((2,6dimethyl-4-oxo-4,5 dihydropyrimide in-5yl)methyl)-6-oxo-4-(1,1,2trifluoroethyl)-1,6dihydropyrimidine -5-yl)oxy)2-methylbenzonitrile 496.2 F 1 f M E L A F χ N CT Ν FF ^Η 6 (AB03, C14) N. J x j Ll FX Ν Ο Ν ' FF ^Η 3 -((4-( 1,1-d iforoethyl)-1 -((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-1,6- Dihydropyrimidin-5-yl)oxy)5-(difluoromethyl)-2methylbenzonitrile 478 7 (AB13, C14) Ύ Τ ⁰ 1 ο. Α χΧ F γ Ν Ν ιΐ Μα F Ν SG Ν FF ^Η 3-bromo-5-(( 1 -((2,4-dimethyl-6oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6dihydropyrimidine -5yl)oxy)benzonitrile 529 and 530

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F 5 -(difluoromethyl)-3 -((1-((2,4- ^N 4 Xf dimethyl-6-oxo-1,6- 8 (AB05, /0 °\ Λ Dihydropyrimidin-5yl)methyl)-6-oxo-4- 482.1 C14) 0 u γΥ^Ν £1 (trifluoromethyl)-1,6- fY F Ν O' H dihydropyrimidin-5-yl)oxy)- 2-methylbenzonitrile F 3 -((4-( 1,1-difluoroethyl)-1 -((2,4- ^F dimethyl-6-oxo-1,6- 9 T J o Dihydropyrimidine-5- (AB20, C14) Ck Ti Xi' X yl)methyl)-6-oxo-1,6- dihydropyrimidin-5-yl)oxy)- 494.0 fH F N Cr H 5 -(difluoromethyl)-2methoxybenzonitrile F 5 -(difluoromethyl)-3 -((1-((2,4- IL 1 -T dimethyl-6-oxo-1,6- 10 II 1 0 Dihydropyrimidine-5- (AB18, C14) c ¹ ΛX Χή h yl)methyl)-6-oxo-4-( 1,1,2,2- tetrafluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)- 530.2 F F 2-methoxybenzonitrile CN 4-((4-( 1,1-difluoroethyl)-1 -((2,4- 11 (AB17, C14) % 0 0 Ύ' X^N dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-1,6- 442.1 T L X dihydropyrimidin-5-yl)oxy)- FY F N 0 NH 3,5-dimethylbenzonitrile

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12 (AB21, C14) O \ 3 -chloro-4-((4-(1,1-d iforoethyl)- 1 -((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-1,6- Dihydropyrimidin-5-yl)oxy)5-methylbenzonitrile 462.2 13 (AB19, C14) % O 3,5-dichloro-4-((4-( 1,1difluoroethyl)-1-((2,4-dimethyl-6oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxobdihydropyrimidin-5yl)oxy)benzonitrile 482 14 (AB23, C14) Ha ^F | ^F o about XXXx 3 -((4-( 1,1-d iforoethyl)-1 -((2,4dimethyl-6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)2,4,5-trifluorobenzonitrile 468.1 15 (AB15, C14) o ) ιζ^ S-- A 3 -((4-( 1,1-d iforoethyl)-1 -((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-1,6- Dihydropyrimidin-5-yl)oxy)5 -(difluoromethyl)-2fluorobenzonitrile 482.1 16 (AB22, C14) CN _F J(\ X O 1 F 1 1 II F XX Ax. XNN AA A A US Ν CU N ' FF ^N 4-((4-(1,1-d iforoethyl)-1 -((4hydroxy-2,6- dimethylpyrimidin-5yl)methyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)- 3-methyl-5- (trifluoromethyl)benzonitrile 496.2

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17 (AB25, C14) CN ^С1 ^ ^С о 1 Οόοήι i ^H (S) or (R)-3,5-dichloro-4-((1((2,4-d imethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-4-(1-fluoroethyl)-6oxo -1,6-dihydropyrimidin-5yl)oxy)benzonitrile single enantiomer (isomer A with faster elution) 464.0 18 (AB28, C14) CN ^X AA cAA ⁴ F (S) or (R)-3-chloro-4-((1-((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-4-(1-fluoroethyl)-6oxo-1,6 -dihydropyrimidin-5yl)oxy)-5-methylbenzonitrile single enantiomer (isomer A with faster elution) 444.2 19 (AB 30, C14) CN F Af NN /1/ Λα F A< N CT N FF ^H 3-cyclopropyl-4-(( 1-((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)5-methylbenzonitrile 504.0 20 (AB31, C14) N. ^F <a1 FX Ν 'AN +D / Λ AF Af N ΟΝ^ FF ^H 3 -(difluoromethyl)-4-(( 1-((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6 - Dihydropyrimidin-5-yl)oxy)5-methylbenzonitrile 514 21 (AB14, C14) F N.C. /x T.A. Cl-^y 0 I 00TAa f—An 2-chloro-5-(difluoromethyl)-3-((1((2,4-d imethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4-( 1,1,2, 2tetrafluoroethyl)-1,6dihydropyrimidin-5yl)oxy)benzonitrile 534.2

Example 22.

F F

5-(Difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1-fluoroethyl)-6oxo-1,6 -dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 5-chloro-3-((4-(1,1-difluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo1,6-dihydropyrimidin- 5-yl)oxy)-2-fluorobenzonitrile.

- 67 045274

To a stirred solution of 5-chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-2-fluorobenzonitrile, AB34 (50 mg, 0.152 mmol), and 5-(chloromethyl)-4-methoxy-2,6dimethylpyrimidine, C14 (31.1 mg, 0.167 mmol), K ₂ CO ₃ (41.9 mg, 0.303 mmol) was added to DMF (758 μl). The resulting mixture was stirred at room temperature overnight. The mixture was filtered to obtain the title compound, which was directly used in the next step.

Step 2: 5-chloro-3-((4-(1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo- 1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile.

To a solution of 5-chloro-3-((4-(1,1-difluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidine-5 -yl)oxy)-2-fluorobenzonitrile (72.9 mg, 0.152 mmol) to NMP (758 μl) was added pyridine hydrochloride (88 mg, 0.76 mmol). The resulting mixture was heated at 120°C in a microwave oven for 20 minutes. LC-MS showed the formation of the desired product. The reaction mixture was diluted with water (100 μl) and DMSO (300 μl), and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 466.0 (M+1). 1H NMR (600 MHz, DMSO- _d6 ): δ 8.72 (s, 1H), 7.81 (dd, J=4.3, 2.3 Hz, 1H), 7.61 (dd, J= 7.4, 2.3 Hz, 1H), 4.90 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 1.92 (t, J=19.6 Hz, 3H).

The following examples shown in table. 13 was prepared in a similar manner as described above for the synthesis of Example 22 using the appropriate intermediates AB and C.

Table 13

Note No. (AB#, C#) Structure IUPAC name MS (M+1) 23 (AB08, C14) •A ABOUT Z 3 -((4-( 1,1-difluoroethyl)-1-((2,4d imethyl-6-oxo-1,6- d ihydropyrimidin-5 yl)methyl)-6-oxo-1,6- d ihydropyrimidin-5 yl)oxy)-5- (difluoromethyl)benzo-nitrile 464.1 24 (AB34, C25) y d Z %o o o / ιζ^ С- s o ό 5 -chloro-3 -((4-(1,1-difluoroethyl)1 -((4-methyl-6-oxo-2- ((pyrimidine-2- yloxy)methyl)-1,6- d ihydropyrimidin-5 yl)methyl)-6-oxo-1,6d ihydropyrimidin-5 yl)oxy)-2-fluorobenzonitrile 559.9 25 (AVOS, S25) FNC. ^F °I 3-((4-(1,1-difluoroethyl)-1-((4methyl-6-oxo-2-((pyrimidin2-yloxy)methyl)-1,6- d ihydropyrimidin-5 yl)methyl)-6-oxo-1,6d ihydropyrimidin-5 yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile 572.0 26 (AB35, C14) IJ ° 1 Χ X7 H 3 -((4-bromo-1 -((2,4-dimethyl-6oxo-1,6-d ihydropyrimidin5-yl)methyl)-6-oxo-1,6- d ihydropyr imidine-5 - yl)oxy)-2,5- dimethylbenzonitrile 458.1

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Example 27.

2-Amino-5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1, 2,2tetrafluoroethyl)-1,6-dihydropyrimidin-5 -yl)oxy)benzonitrile.

A solution of 5-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile, example 23 (800 mg, 1.594 mmol), in EtOH (280 ml) was stirred at 60°C under NH ₃ for 30 hours, and then concentrated with N ₂ flushing to give a crude residue. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 499.1 (M+1).

Examples 28 (isomer A) and 29 (isomer B).

(S)-5-(Difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1fluoroethyl)-6-oxo -1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile, and (R)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6 -dihydropyrimidin-5-yl)methyl)-4-(1fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile.

To a stirred solution of 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5yl)oxy)-2-methylbenzonitrile, AB27 (200 mg, 0.619 mmol), in DMF (2 ml) was added 5-(chloromethyl)-4methoxy-2,6-dimethylpyrimidine, C14 (115 mg, 0.619 mmol), K ₂ CO ₃ (171 mg, 1.237 mmol) and lithium bromide (53.7 mg, 0.619 mmol). The resulting mixture was stirred at 25°C for 1 hour. TLC (50% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give a racemic mixture of the title compound. MS: 474.1 (M+1).

Step 2: 5-(difluoromethyl)-3-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1-fluoroethyl)6-oxo -1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To a stirred solution of 5-(difluoromethyl)-3-((4-(1-fluoroethyl)-1-((4-methoxy-2,6dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile (180 mg, 0.380 mmol) in ACN (4 ml) was added with KI (189 mg, 1.141 mmol) and TMS-Cl (0.146 ml, 1.141 mmol). The resulting reaction mixture was stirred at 70°C for 12 hours. TLC (66% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give a racemic mixture of the title compound. MS: 460.2 (M+1).

The racemic mixture was purified by chiral SFC (IC-H column, 25% EtOH/CO ₂ with 0.1% NH4OH) to give isomer A of Example 28 (faster elution): MS: 460.2 (M+1); and isomer B of Example 29 (slower elution): MS: 460.2 (M+1).

Examples 30 (isomer A) and 31 (isomer B).

- 69 045274 (S)-5-Chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1-fluoroethyl)- 6-oxo1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile, and (R)-5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6- Dihydropyrimidin-5-yl)methyl)-4-(1-fluoroethyl)-6-oxo1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile.

Step 1: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6- Dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB24 (152 mg, 0.488 mmol), in DMF (5 ml) was added K2CO3 (202 mg, 1.46 mmol), lithium bromide (85 mg, 0.98 mmol) and then 5-(chloromethyl)-4-methoxy-2,6-dimethylpyrimidine, C14 (202 mg, 0.975 mmol). The resulting reaction mixture was stirred at 20°C for 30 minutes. TLC (33% EtOAc/PE) and LC-MS indicated that the reaction was complete. The mixture was diluted with water (5.0 ml) and extracted with EtOAc (3x5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 462.2 (M+1).

Step 2: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((4-hydroxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6- Dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 5-chloro-2-fluoro-3-((4-( 1 -fluoroethyl)-1 -((4-methoxy-2,6-dimethylpyrimidin-5 -yl)methyl)-6oxo-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile (150 mg, 0.325 mmol) in ACN (3 ml), KI (67.9 mg, 0.409 mmol) and TMS-Cl (0.136 ml, 1.065 mmol) were added. The resulting reaction mixture was stirred at 70°C for 5 hours. TLC (20% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was then purified by reverse phase HPLC (ACN/water with 0.1% TFA) to obtain a racemic mixture of the title compounds. MS: 448.2 (M+1). A mixture of two stereoisomers was purified using chiral SFC (IC-H, 35% IPA/SOD, giving Example 30 isomer A (faster elution): MS: 448.2 (M+1), 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 7.81 (lat d, J=2.3 Hz, 1H), 7.55-7.46 (m, 1H), 5.82-5.61 (m, 1H), 4.87 (br s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 1.59-1.47 (m, 3H); and isomer B of Example 31 (slower elution): MS: 448.2 (M+1), 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 7.81 (dd, J=2 ,3, 4.4 Hz, 1H), 7.51 (dd, J=2.3, 7.3 Hz, 1H), 5.835.62 (m, 1H), 4.87 (lat s, 2H) , 2.33 (s, 3H), 2.23 (s, 3H), 1.59-1.45 (m, 3H).

The following compounds shown in table. 14 was prepared as a racemate followed by purification to obtain the indicated isomers in a manner similar to that described above for the synthesis of Example 30 using the indicated intermediates AB and C described in the appropriate sections.

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Table 14

Note No. (AB#, C#) Structure IUPAC name MS (M+1) 32 (AVZZ, S14) F Dx XV ⁰ 1 F (S) or (I)-5-(difluoromethyl)3-((1 -((2,4-d imethyl-6-oxo1,6-dihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl) -6oxo-1,6-d ihydropyrimidin5-yl)oxy)-2fluorobenzonitrile single enantiomer (isomer A with faster elution) 464.1 33 (AVZZ, S14) FNC. XV f^^V ⁰ 1 o. XX XX NN VV Λ A >VN Cr N 1 H F (R) or (8)-5-(difluoromethyl)3-((1 -((2,4-d imethyl-6-oxo1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl )-6oxo-1,6-d ihydropyrimidin5-yl)oxy)-2fluorobenzonitrile single enantiomer (isomer B with slower elution) 464.1 34 (AB26, C14) Λ J CI^V^ 0 I F (S) or (R)-2,5-dichloro-3-((1((2,4-dimethyl-6-oxo-1,6d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl) -6oxo-1,6-d ihydropyrimidin5-yl)oxy)benzonitrile single enantiomer (isomer A with faster elution) 464.0

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35 (AB32, C14) FNC. Yj ^F Ο ί Vyxx ί ⁿ (S) or (K)-5-(difluoromethyl)3-((1 -((2,4-d imethyl-6-oxo1,6-dihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl) -6oxo-1,6-d ihydropyrimidin5-yl)oxy)-2methoxybenzonitrile single enantiomer (isomer A with faster elution) 476.0 36 (AB32, C14) “χ+ ⁰ I ^ο υ5 ^ν ΧΧϊ F (R) or (8)-5-(difluoromethyl)3-((1 -((2,4-d imethyl-6-oxo1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl )-6oxo-1,6-d ihydropyrimidin5-yl)oxy)-2methoxybenzonitrile single enantiomer (isomer B with slower elution) 476.0

Example 37.

F F F

3-((1-((4-Amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl )oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

Step 1: 3-((1-((4-(bis(4-methoxybenzyl)amino)-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a cooled (0°C) solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile, AB06 (100 mg, 0.253 mmol), and (4-(bis(4methoxybenzyl)amino)-6-methoxy-2-methylpyrimidin-5-yl)methanol, C13 (104 mg, 0.253 mmol), triphenylphosphine (66.4 mg, 0.253 mmol) and DIAD (49.2 μl, 0.253 mmol). The resulting solution was stirred at 23°C for 16 hours, then purified directly by silica column chromatography (0-50% EtOAc/hexane) to give the title compound. MS: 787.2 (M+1).

Step 2: 3-((1-((4-amino-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy) -5-(difluoromethyl)-2-methylbenzonitrile.

3-((1-((4-(Bis(4-methoxybenzyl)amino)-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidin- 5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (130 mg, 0.165 mmol) was dissolved in TFA (2 ml) and heated at 100°C for 1 hour. The solution was concentrated under reduced pressure. The residue was further dried by azeotropic evaporation with toluene to isolate the title compound. MS: 547.1 (M+1).

Step 3: 3-((1 -((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidine -5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a cooled (0°C) solution of 3-((1-((4-amino-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimidin-5 -yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (90 mg, 0.165 mmol) in ACN (824 μl), TMS-I (448 μl, 3.29 mmol) was added. The resulting reaction mixture was stirred at 23°C for 1 hour. The reaction was neutralized by adding Na ₂ SO ₃ (500 μl), then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.05% NH4OH) to give the title compound. MS: 410.3 (M+1). 1H NMR (600 MHz, DMSO-72 045274 d6) δ 11.66 (s, 1H), 8.57 (s, 1H), 7.74 (s, 1H), 7.35 (s, 1H), 6 .88 (t, J=55.3 Hz, 1H), 6.58 (s, 2H), 4.74 (s, 2H),

3.28 (s, 3H), 2.10 (s, 3H).

The following compounds shown in table. 15 was prepared in a manner similar to that described above for the synthesis of Example 37 using the indicated intermediates AB and

C, described in the relevant sections.

Table 15

Note No. (AB #, WITH#) Structure IUPAC name MS (M+1) 38 (AB12, C13) 1 t F O NH ₂ X ⁿ F 3 -((1 -((4-amino-2-methyl-6oxo-1,6-dihydropyrimidin5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-5-chloro -2fluorobenzonitrile 521.1 39 (AB10, C13) T J F'^T O NH ₂ 1 ⁿ F^F 3 -((1 -((4-amino-2-methyl-6oxo-1,6-dihydropyrimidin5-yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidine-5- yl)oxy)-5-chloro-2fluorobenzonitrile 503.1

Example 40.

3-((1-((2,4-Dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1, 6-dihydropyrimidin-5-yl)oxy)-2-fluoro-5-methylbenzonitrile.

Step 1: 5-chloro-2-fluoro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a mixture of 5-chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile AB10 (153 mg, 0.418 mmol ), K ₂ CO ₃ (133 mg, 0.964 mmol) and LiBr (27.9 mg, 0.321 mmol) in DMF (3 ml) was added 5-(chloromethyl)-4-methoxy-2,6-dimethylpyrimidine, C14 (60 mg, 0.321 mmol). The resulting reaction mixture was stirred at 20°C for 3 hours and then concentrated under reduced pressure. The residue was purified by silica column chromatography (033% EtOAc/PE) to give the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H) 7.85 (dd, J=4.82, 2.63 Hz, 1H) 7.69 (dd, J=7.24 , 2.41 Hz, 1H) 6.68-7.01 (m, 2H) 5.06 (s, 2H) 3.88 (s, 3H) 2.48 (s, 3H) 2.45 (s, 3H).

Step 2: 2-fluoro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile.

To a mixture of 5-chloro-2-fluoro-3-(( 1 -((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl) _{K 2 CO 3} (144 .68 mg, 1.05 mmol), 2,4,6-trimethyl-1,3,5,2,4,6trioxatriborinan (131.42 mg, 1.05 µmol), X-Phos (83.18 mg, 174.48 µmol) and Pd(OAc) ₂ (7.83 mg, 34.9 µmol). The resulting mixture was stirred at 110°C under N2 for 2 hours and then purified by silica column chromatography (0-33% EtOAc/PE) to give the title compound. MS: 496.2 (M+1).

Step 3: 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)) -1,6-dihydropyrimidin-5-yl)oxy)-2-fluoro-5-methylbenzonitrile.

To a solution of 2-fluoro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile (100 mg, 201.85 µmol) in ACN (5 ml) was added TMS-Cl (65.79 mg, 605.56 µmol) and KI (100.52 mg , 605.56 µmol). The resulting reaction mixture was stirred at 70°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 482.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H) 7.42 (br d, J=3.75 Hz, 1H)

7.21-7.27 (m, 1H) 6.70-7.01 (m, 1H)) 4.91 (s, 2H) 2.35 (s, 3H) 2.28 (s, 3H) 2 .23 (s, 3H).

The following compounds shown in table. 16 was prepared in a manner similar to that described above for the synthesis of Example 40 using the indicated intermediates AB and C described in the appropriate sections.

Table 16

Note No. (AB#, C#) Structure IUPAC name MS (M+1) 41 (AB34, C14) NC,/// 1 t ⁰ 1 τι ^F F ^H 3 -((4-( 1,1-difluoroethyl)-1 ((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-1,6dihydropyrimidin-5yl)oxy)-2 -fluoro-5methylbenzonitrile 446.2 42 (AB10, C14) - 7 7 o\A- 3 -((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6dihydropyrimidin-5yl)oxy )-5-ethyl-2fluorobenzonitrile 496.2

Example 43 (isomer A).

CN

F (S) or (R)-4-(( 1 -((2,4-Dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-( 1 -fluoroethyl)-6- oxo1,6-dihydropyrimidin-5-yl)oxy)-3,5-dimethylbenzonitrile.

Step 1: 4-((4-acetyl-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3,5-dimethylbenzonitrile.

To a solution of 4-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3,5dimethylbenzonitrile, AB16 (650 mg, 1.45 mmol), to TFA (5 ml, 64.9 mmol) TFAA (2.5 ml, 17.70 mmol) was added. The resulting reaction mixture was stirred at 110°C for 6 hours. Then the reaction mixture was concentrated under reduced pressure, alkalinized to pH ~9 sat. aq. NaHCO ₃ solution. (10.0 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (MS: 284.1 (M+1), 589.1 (2M+23)), which was used directly without further purification.

Step 2: 4-((4-acetyl-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3 ,5-dimethylbenzonitrile.

To a solution of 4-((4-acetyl-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3,5-dimethylbenzonitrile (500 mg) (crude) and lithium bromide (307 mg, 3.53 mmol ) in DMA (5 ml) was added 5-(chloromethyl)-4methoxy-2,6-dimethylpyrimidine, C14 (366 mg, 1.765 mmol), and K ₂ CO ₃ (488 mg, 3.53 mmol). The resulting reaction mixture was stirred at 20°C for 30 minutes. Upon completion of the reaction, water (5.0 ml) was added. The reaction mixture was extracted with EtOAc (3x5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified using preparative TLC plates (10% MeOH/DCM) to give the title compound.

Step 3: 4-((4-(1-hydroxyethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6- 74 045274 dihydropyrimidin-5- yl)oxy)-3,5-dimethylbenzonitrile

To a solution of 4-((4-acetyl-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-3, 5-dimethylbenzonitrile (200 mg, 0.438 mmol) in MeOH (1.0 ml) was added to a 1 M solution of Zn(BH ₄ ) ₂ in THF (0.110 ml, 0.110 mmol) at -10-0°C. The resulting reaction mixture was stirred at -10-0°C for 0.5 hours. TLC (10% MeOH/DCM) indicated that the reaction was complete. The reaction mixture was diluted with water (5 ml) and extracted with EtOAc (4x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

Step 4: 4-((4-(1-fluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy) -3,5-dimethylbenzonitrile.

To a solution of 4-((4-(1-hydroxyethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)- 3,5-dimethylbenzonitrile (130 mg, 0.269 mmol) in DCM (5 mL) at 0°C, DAST (0.082 mL, 0.618 mmol) was added and the resulting mixture was stirred at 0°C for 1 h. TLC (10% MeOH /DCM) indicated that the reaction was complete. The reaction mixture was diluted with water (5 ml) and extracted with DCM (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 438.1 (M+1).

Step 5: 4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-( 1 -fluoroethyl)-6-oxo-1,6-dihydropyrimidin- 5-yl)oxy)-3,5-dimethylbenzonitrile.

To a solution of 4-((4-(1-fluoroethyl)-1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-1,6dihydropyrimidin-5-yl)oxy)- 3,5-dimethylbenzonitrile (150 mg, 0.261 mmol) in ACN (2 ml) was added with KI (216 mg, 1.303 mmol) and TMS-Cl (0.167 ml, 1.303 mmol). The resulting reaction mixture was stirred at 70°C for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give a racemic mixture of the title compound. MS: 424.1 (M+1). The racemic mixture was purified by chiral SFC (IC-H column, 40% 1PA/ _CO2 with 0.1% NH4OH) to give isomer A of Example 43 (faster elution) MS: 424.1 (M+1). ¹ H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 8.42 (s, 1H), 7.49 (d, J=7.24, 2H), 6.06 ( d, J=6.00, 0.5H), 5.94 (d, J=6.80, 0.5H) 4.77 (s, 2H). 2.22 (d, J=10.4, 6H), 2.06 (s, J=7.2, 6H), 1.58 (m, 3H).

Example 44 (isomer B).

(S) or (R)-5-Chloro-2-fluoro-3-((1-((2-(1-hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl) -2-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile.

Step 1: 3-((1 -((2-acetyl-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1,6 -dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile, AB10 (307 mg, 0.839 mmol), K ₂ CO ₃ (193 mg, 1.398 mmol), lithium bromide (91 mg, 1.048 mmol) and 1-(5-(chloromethyl)-4-methoxy-6methylpyrimidine-2- yl)ethanone, C21 (150 mg, 0.00 mmol). The resulting mixture was stirred at 20°C for 16 hours. TLC (50% EtOAc/PE) indicated completion of the reaction. The reaction mixture was diluted with water (15 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-66% EtOAc/PE) to give the title compound. MS: 544 (M+1).

Step 2: 5-chloro-2-fluoro-3-((1-((2-(1-hydroxyethyl)-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a stirred solution of 3-((1-((2-acetyl-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1, 6 -d ihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile (95 mg, 0.175 mmol) in DCM (5 ml), a solution of zinc borohydride (0.175 ml, 0.175 mmol) in DCM (1 ml) was added and the resulting mixture was stirred at 20°C for 5 minutes. TLC (25% EtOAc/PE) indicated completion of the reaction. The reaction mixture was quenched with 1N. aqueous HCl (5 ml) and water (20 ml) and then extracted with DCM (3x50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. MS: 546 (M+1).

- 75 045274

Step 3: 5-chloro-2-fluoro-3-((1-((2-(1-hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo- 4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((1-((2-(1-hydroxyethyl)-4-methoxy-6methylpyrimidin-5-yl)methyl)-2-oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,2-dihydropyridin-3yl)oxy)benzonitrile (80 mg, 0.147 mmol) in ACN (0.5 ml) was added KI (73.1 mg, 0.440 mmol) and TMS-Cl ( 0.056 ml, 0.440 mmol). The resulting mixture was stirred at 70°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give a racemic mixture of the title compound. MS: 532 (M+1). The racemic mixture was purified by chiral SFC (IC-H column, 25% 1PA/CO ₂ with 0.1% NH4OH) to give isomer B of Example 44 (slower elution) as the title compound. MS: 532 (M+1). 1H NMR (400 MHz, DMSO-d ₆ ): δ ppm 8.82 (s, 1H), 7.83-7.90 (m, 1H), 7.72 (dd, J=7.40, 2.38 Hz, 1H), 6.72-7.02 ( m, 1H), 5.67 (br s, 1H), 4.91 (s, 2H), 4.41-4.51 (m, 1H), 2.38 (s, 3H), 1.33 (d, J=6.72 Hz, 3H).

Example 45.

5-Chloro-2-fluoro-3-((1-((2-(hydroxymethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 5-chloro-2-fluoro-3-((1-((4-methoxy-6-methyl-2-vinylpyrimidin-5-yl)methyl)-6-oxo-4(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile, AB10 (442 mg, 0.967 mmol), 5-(chloromethyl)-4-methoxy-6methyl-2-vinylpyrimidine, C24 (240 mg, 0.967 mmol), K ₂ CO ₃ (267 mg, 1.933 mmol) and lithium bromide were added to DMF (8 ml) (126 mg, 1.450 mmol). The resulting mixture was stirred at 15°C for 1 hour. TLC (50% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-50% EtOAc/PE) to give the title compound. MS: 528 (M+1).

Step 2: 5-chloro-2-fluoro-3-((1-((2-formyl-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((1-((4-methoxy-6-methyl-2-vinylpyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2 -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (270 mg, 0.512 mmol) in 1,4-dioxane (10 ml) and water (3 ml), add 2,6-dimethylpyridine (110 mg , 1.023 mmol), osmium oxide (OS) (6.50 mg, 0.026 mmol) and sodium periodate (328 mg, 1.535 mmol). The resulting mixture was stirred at 15°C for 30 minutes. TLC (50% EtOAc/PE) indicated that the reaction was complete. The reaction mixture was quenched with saturated aqueous Na ₂ SO ₃ (15 ml) and extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step. MS: 529.9 (M+1).

Step 3: 5-chloro-2-fluoro-3-((1-((2-(hydroxymethyl)-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 5-chloro-2-fluoro-3-((1-((2-formyl-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2 -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (80 mg, 0.151 mmol) in EtOAc (3 ml) was added a 1 M solution of Zn(BH ₄ ) ₂ in DCM (0.151 ml, 0.151 mmol). mmol). The resulting mixture was stirred at 15°C for 3 minutes. TLC (66% EtOAc/PE) indicated completion of the reaction. The reaction mixture was quenched with H ₂ O (10 ml), extracted with EtOAc (3x10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step. MS: 532 (M+1).

Step 4: 5-chloro-2-fluoro-3-((1-((2-(hydroxymethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((1-((2-(hydroxymethyl)-4-methoxy-6-methylpyrimidin-5yl)methyl)-6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (70 mg, 0.132 mmol) in ACN (1.5 ml) under N2 was added KI (65.5 mg, 0.395 mmol) and TMS -Cl (0.050 ml, 0.395 mmol). The resulting mixture was stirred at 70°C for 2 hours and then purified directly by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 518

- 76 045274 (M+1). ^1H NMR (400 MHz, DMSO-d6): 8.81 (s, 1H), 7.85 (dd, J=4.52, 2.54 Hz, 1H), 7.71 (dd, J=7 ,28, 2.43 Hz,

1H), 6.69-7.03 (m, 1H), 4.92 (s, 2H), 4.29 (s, 2H), 2.38 (s, 3H).

Example 46.

5-(Difluoromethyl)-3-((1-((2-(3-hydroxypropyl)-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 3-((1-((2-chloro-4-methoxypyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile, AB07 (1 g , 2.65 mmol), K ₂ CO ₃ (0.733 g, 5.30 mmol) and 2-chloro-5-(chloromethyl)-4-methoxypyrimidine, C19 (0.537 g, 2 .78 mmol). The resulting mixture was stirred at room temperature overnight. LC-MS analysis showed the desired product and no starting material. The reaction mixture was diluted with water and stirred at room temperature for 30 minutes. The white precipitate was collected on a filter and washed with water (3x), then air dried to give the title compound. MS: 534.2 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((2-(3-hydroxypropyl)-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

Mixture of 3-((1-((2-chloro-4-methoxypyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl) hydroxy)-5-(difluoromethyl)-2-methylbenzonitrile (30 mg, 0.056 mmol), potassium trifluoro(3hydroxypropyl)borate (37.3 mg, 0.225 mmol), cesium carbonate (18.31 mg, 0.056 mmol) and chloro[ (di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(I) (cataCXimum A Pd G2 precatalyst) (3.76 mg, 5.62 µmol) was purged with N ₂ and then added 1,4-dioxane (1.6 ml) and water (0.4 ml). The reaction mixture was heated at 120°C in a microwave oven for 10 min. LC-MS showed the formation of the desired product. The reaction mixture was diluted with Et ₂ O, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was again treated with ACN (1.5 ml) and then treated with potassium iodide (28.0 mg, 0.169 mmol) and chlorotrimethylsilane (0.071 ml, 0.562 mmol). The resulting reaction mixture was heated at 100°C for 10 min and then purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 544.2 (M+1).

Example 47.

5-(Difluoromethyl)-2-methyl-3-((1-((2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6 -oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

This compound was prepared as described in Example 46, but using (1-methyl-1H-pyrazol-4yl)boronic acid. MS: 566.3 (M+1).

Example 48.

5-(Difluoromethyl)-3-((1-((2-(hydroxymethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

- 77 045274

Step 1: 3-((1-((2-chloro-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1, 6dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a stirred solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile, AB07 (1 .5 g, 3.98 mmol), and (2-chloro-4-methoxy-6methylpyrimidin-5-yl)methanol, C20 (0.750 g, 3.98 mmol), in toluene (30 ml) was added at 0°C triphenylphosphine (1.564 g, 5.96 mmol) and then DIAD (1.160 mL, 5.96 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours and then diluted with water (100 ml) and extracted with EtOAc (3x80 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-35% EtOAc/PE) to give the title compound. MS: 548.2 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((2-(hydroxymethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-(1 ,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To the N ₂ purged mixture of 3-((1-((2-chloro-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl))-1 ,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (50 mg, 0.091 mmol), potassium trifluoro(((4-methoxybenzyl)oxy)methyl)borate (47.1 mg, 0.183 mmol) and cataCXimum A Pd G2 precatalyst (12.20 mg, 0.018 mmol) in 1,4-dioxane (1 ml) and water (500 μl), a 2 M aqueous solution of cesium carbonate (500 μl, 1,000 mmol) was added. The resulting reaction mixture was heated at 150°C in a microwave oven for 10 minutes. LC-MS showed the formation of the desired product. The reaction mixture was extracted with Et ₂ O (2x). The combined organic layers were concentrated under reduced pressure. The residue was treated with ACN (1 ml) and then treated with potassium iodide (45.5 mg, 0.274 mmol) and chlorotrimethylsilane (116 μl, 0.913 mmol). The mixture was heated at 100°C for 10 minutes. LC-MS showed the formation of the desired product. The mixture was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 530.3 (M+1).

The following compounds shown in table. 17 was prepared in a manner similar to that described above for the synthesis of Example 48 using the indicated intermediates AB and C described in the appropriate sections and the appropriate boronic acid or potassium trifluoroborate for Step 2.

Table 17

Note No. (AB#, C#) Structure Name according to IU PAK MS (M+1) 49 (AB07, C20) %'/ 5-(difluoromethyl)-3-((1-((2(3-hydroxypropyl)-4methyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2- tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-2methylbenzonitrile 558.2

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50 (AB11, C20) O □Z 4-((1-((2-(3hydroxypropyl)-4-methyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-3,5dimethylbenzonitrile 522.2 51 (AB07, C20) / O Z 5-(difluoromethyl)-3-((1-((2(methoxymethyl)-4-methyl-6oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-2methylbenzonitrile 544.3 52 (AB07, C20) ’ Z 5-(difluoromethyl)-2-methyl3-((1 -((4-methyl-2-(2methylprop-1-ey-1-yl)-6oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)benzonitrile 554.3

Examples 53 (mixture of isomers) and 54 (isomer A). F

5-(Difluoromethyl)-3-(( 1 -((2-( 1 -hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (53, racemic mixture), and

5-(difluoromethyl)-3-((1-((2-(1-hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (54, single S- or R-isomer).

Step 1: 5-(difluoromethyl)-3-((1-((4-methoxy-6-methyl-2-vinylpyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Mixture of 3-((1-((2-chloro-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidine -5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (title compound from Step 1 of Example 48) (230 mg, 0.420 mmol), potassium vinyl trifluoroborate (169 mg, 1.259 mmol), PdCl ₂ (dppf ) (92 mg, 0.126 mmol) and cesium carbonate (850 mg, 2.61 mmol) in 1,4-dioxane (1679 µl) and water (420 µl) were purged with N2 and heated at 150°C in a microwave oven for 15 min. LC-MS showed the formation of the desired product as a major peak. The reaction mixture was partitioned between water and EtOAc (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (40-100% EtOAc/hexane) to give the title compound. MS: 540.2 (M+1).

Step 2: 5-(difluoromethyl)-3 -((1 -((2-formyl-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4- 79 045274 (1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-(difluoromethyl)-3-((1-((4-methoxy-6-methyl-2-vinylpyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2 -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (118 mg, 0.219 mmol), osmium tetroxide (274 μl, 0.022 mmol), 2,6-dimethylpyridine (51.0 μl, 0.437 mmol) and sodium periodate (140 mg, 0.656 mmol) in 1,4-dioxane (1641 µl) and water (547 µl). The resulting reaction mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with EtOAc (50 ml), then washed with saturated aqueous NH ₄ Cl (2x20 ml), water (20 ml), brine (20 ml), and then dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 542.2 (M+1).

Step 3: 5-(difluoromethyl)-3-((1-((2-(1-hydroxyethyl)-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6oxo-4-( 1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-ethylbenzonitrile.

To a cooled (-78°C) solution of 5-(difluoromethyl)-3-((1-((2-formyl-4-methoxy-6-methylpyrimidin5-yl)methyl)-6-oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (38 mg, 0.070 mmol) in THF (351 μl) was added dropwise to a 3 M solution of methylmagnesium bromide in Et ₂ O (28 .1 µl, 0.084 mmol). The resulting mixture was stirred at -78°C until LC-MS indicated complete consumption of the starting material. The reaction mixture was diluted with water, then extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used for the next step without further purification. MS: 558.3 (M+1).

Step 4: 5-(difluoromethyl)-3-((1-((2-(1-hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To a mixture of 5-(difluoromethyl)-3-((1-((2-( 1 -hydroxyethyl)-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6oxo-4-(1,1,2, 2-Tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (34 mg, 0.061 mmol) in ACN (2 ml) was added with KI (10 mg, 0.060 mmol) and TMS-Cl (66 μl , 0.516 mmol). The resulting mixture was heated at 100°C for 10 min in a microwave oven. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water, then filtered and purified by reverse phase HPLC (CN/water with 0.1% TFA) to give the title compound, Example 53 (racemic mixture) MS: 544.2 (M+1). This racemic mixture was purified by chiral SFC (AD-H column, 15% MeOH/CO ₂ with 0.1% DEA) to give the title compound, isomer A of Example 54 (faster eluting isomer A). MS: 544.4 (M+1). 1H NMR (600 MHz, acetone-d ₆ ) δ 8.77 (s, 1H), 7.64 (s, 1H), 7.21 (s, 1H), 6.80 (t, J=48 Hz, 1H), 5.02 (s, 2H), 2.56 (s, 3H), 2.43 (s, 3H), 1.44 (d, J=6.7 Hz, 3H).

Example 55.

5-Chloro-2-fluoro-3-((1-((2-(3-methoxypropyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-( perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 5-chloro-3-((1-((2-chloro-4-methoxy-6-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidine-5 -yl)oxy)-2-fluorobenzonitrile.

To a stirred solution of 5-chloro-2-fluoro-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile, AB12 (0.73 g, 1.903 mmol), and 2 -chloro-5-(chloromethyl)-4-methoxy-6methylpyrimidine, C20 (0.433 g, 2.093 mmol), K2CO3 (0.526 g, 3.81 mmol) was added to NMP (9.51 ml). The resulting mixture was stirred at room temperature overnight. LC-MS showed the formation of the desired product. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (10 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 554.1 (M+1).

Step 2: 5-chloro-2-fluoro-3-((1-((2-(3-methoxypropyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo- 4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Degassed DME (474 μl) was added to the vessel containing 5-chloro-3-((1-((2-chloro-4-methoxy-6methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile (35 mg, 0.063 mmol), tris(trimethylsilyl)silane (21.43 μl, 0.069 mmol), hexafluorophosphate [4,4'-bis(1, 1dimethylethyl)-2,2'-bipyrudin-N 1,N1 ']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-nirudinyl-N]phenylC]iridium(III), (Ir[dF (CF ₃ )ppy] ₂ (dtbpy))PF ₆ (0.708 mg, 0.632 µmol), 1-bromo-3-methoxypropane (6.00 mg,

- 80 045274

0.063 mmol) and anhydrous Na ₂ CO ₃ (13.39 mg, 0.126 mmol). The vessel was purged and filled with N2, and 250 μl of nickel stock solution [obtained by sonicating a mixture of NiCl ₂ DME (35 mg) and 4,4'-di-tert-butyl-2,2'-dipyridyl for 10 min was added (40 mg) in degassed DME (10 ml)]. The resulting mixture was sealed and irradiated with a 34 W Kessil® LED lamp (at a distance of 7 cm, with a cooling fan to maintain the temperature at 25°C) overnight. The reaction was quenched by exposure to air. The reaction mixture was diluted with water (2 ml) and EtOAc (2 ml). The organic layer was separated and concentrated under reduced pressure. The resulting crude product was dissolved in DMF (1 ml) and pyridine hydrochloride (36.2 mg) was added. The resulting mixture was stirred at 120°C for 30 minutes. The reaction mixture was diluted with DMSO (1 ml) and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 578.2 (M+1). ^1H NMR (600 MHz, DMSO-d6): δ 8.81 (d, J=5.6 Hz, 1H), 7.85 (m, 1H), 7.81 (m, 1H), 4.92 (s, 2H), 4.43 (t, J=6.1 Hz, 1H), 3.42 (t, J=6.1 Hz, 1H), 2.63 (t, J=7.4 Hz , 1H), 2.57 (t, J=7.4 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H), 2.08 (m, 1H), 1.78 (m, 1H).

Example 56.

Methyl-3 -(5 -((5 -(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4-(perfluoroethyl)pyrimidin-1 (6H)yl)methyl)-4-methyl-6 -oxo-1,6-dihydropyrimidin-2-yl)propanoate.

This compound was prepared as described in Example 56, but using methyl 3-bromopropanoate. MS: 592.2 (M+1).

Example 57.

F

3-(( 1 -((2-Amino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidine -5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

Step 1: 3-((1-((2-chloro-4-methoxypyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a cooled (0°C) suspension of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy) benzonitrile, AB07 (1.4 g, 3.71 mmol), and K2CO3 (0.513 g, 3.71 mmol) in DMF (18.56 ml) was added 2-chloro-5-(chloromethyl)-4-methoxypyrimidine, C19 (0.860 g, 4.45 mmol). The resulting suspension was stirred at room temperature for 10 min, and LC-MS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-80% EtOAc/hexane) to give the title compound. MS: 534.1 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((4-methoxy-2-((4-methoxybenzyl)amino)pyrimidin-5-yl)methyl)-6oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To a solution of 3-((1-((2-chloro-4-methoxypyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl )oxy)-5-(difluoromethyl)-2-methylbenzonitrile (95 mg, 0.178 mmol) in THF (890 μl) was added 4-methoxybenzylamine (48.8 mg, 0.356 mmol). The resulting reaction mixture was stirred at 60°C overnight. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (10 ml), washed with saturated aqueous NaHCO ₃ solution, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 635.2 (M+1).

Step 3: 3-((1-((2-amino-4-methoxypyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5- yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-3-((1-((4-methoxy-2-((4-methoxybenzyl)amino)pyrimidin-5-yl)methyl)6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (0389804- 81 045274

0171) (110 mg, 0.173 mmol) to DCM (867 µl) was added TFA (134 µl, 1.734 mmol) and TFAA (24.49 µl,

0.173 mmol). The resulting reaction mixture was heated at 100°C for 1 hour. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. MS: 515.2 (M+1).

Step 4: 3-((1-((2-amino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1 ,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a solution of 3-((1 -((2-amino-4-methoxypyrimidin-5 -yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl )oxy)-5-(difluoromethyl)-2-methylbenzonitrile (85 mg, 0.165 mmol) in ACN (826 μl) was added TMS-I (225 μl, 1.652 mmol). The resulting reaction mixture was heated at 110°C in a microwave oven until LC-MS indicated that the reaction was complete. The reaction solution was diluted with EtOAc (10 ml) and washed with saturated aqueous Na ₂ SO ₃ solution, filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 501.2 (M+1).

Example 58.

3-(( 1 -((4-Amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1,1-difluoroethyl)-6-oxo-1,6dihydropyrimidine -5 -yl)oxy)-5-chloro-2-fluorobenzonitrile.

Step 1: 5-chloro-3 -((1 -((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-4-(1,1-difluoroethyl)-6oxo-1,6- Dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile.

To a solution of 5-chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2fluorobenzonitrile, AB34 (100 mg, 0.303 mmol), in DMF (3 ml) added 4-chloro-5-(chloromethyl)-6methoxy-2-methylpyrimidine, C22 (69?1 mg, 0.334 mmol), potassium carbonate (126 mg, 0.910 mmol) and lithium bromide (26.3 mg, 0.303 mmol). The resulting mixture was stirred at 25°C for 8 hours and then concentrated under reduced pressure. The residue was purified by preparative plate TLC (50% EtOAc/PE) to give the title compound. MS: 500.1 (M+1).

Step 2: 5-chloro-3-((9-(1,1-difluoroethyl)-4-methoxy-11-(4-methoxybenzyl)-2-methyl-7-oxo7,10,10a, 11-tetrahydro-5H -dipyrimido[1,2-a:4',5'-pyrimidin-8-yl)oxy)-2-fluorobenzonitrile.

To a solution of 5-chloro-3 -((1 -((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-4-(1,1-difluoroethyl)-6oxo-1,6-dihydropyrimidine -5-yl)oxy)-2-fluorobenzonitrile (60 mg, 0.120 mmol) and (4methoxyphenyl)methanamine (16.45 mg, 0.120 mmol) in DMA (2 ml) was added with TEA (0.033 ml, 0.240 mmol). The resulting mixture was stirred at 80°C for 4 hours and then concentrated under reduced pressure. The residue was purified by silica column chromatography (0-20% EtOAc/PE) to give the title compound. MS: 601 (2M+1).

Step 3: 3-((1 -((4-amino-6-methoxy-2-methylpyrimidin-5-yl)methyl)-4-(1,1-difluoroethyl)-6-oxo-1,6dihydropyrimidin-5 - yl)oxy)-5-chloro-2-fluorobenzonitrile.

To a solution of 5-chloro-3 -((4-(1,1-difluoroethyl)-1 -((4-methoxy-6-((4-methoxybenzyl)amino)-2methylpyrimidin-5-yl)methyl))-6 -oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile (30 mg, 0.050 mmol) in TFA (3 ml) was added TFAA (7.05 μl, 0.050 mmol). The resulting reaction solution was stirred at 80°C for 0.5 hour and then concentrated under reduced pressure to obtain the title compound. MS: 481.1 (M+1).

Step 4: 3-((1 -((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1,1-difluoroethyl)-6oxo-1, 6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile.

To a solution of 3-((1 -((4-amino-6-methoxy-2-methylpyrimidin-5-yl)methyl)-4-(1,1-difluoroethyl)-6-oxo1,6-dihydropyrimidin-5-yl )oxy)-5-chloro-2-fluorobenzonitrile (15 mg, 0.031 mmol) in ACN (3 ml) was added KI (15.54 mg, 0.094 mmol) and TMS-Cl (0.012 ml, 0.094 mmol). The resulting mixture was stirred at 70°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 481.1 (M+1). 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (br s, 1H) 8.58 (s, 1H) 7.79-7.89 (m, 1H) 7.66 (dd, J= 7.34, 2.32 Hz, 1H) 6.65 (br. s, 2H) 4.78 (s, 2H) 2.15 (s, 3H) 1.93 (t, J=19.44 Hz, 3H).

The following compounds shown in table. 18 was prepared in a manner similar to that described above for the synthesis of Example 58 using the indicated intermediates AB.

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Table 18

Note No. (AB #) Structure Name according to IU PAK MS (M+1) 59 (AB07) F М.^ Ί ^F О nh ₂ st JU X Ν I _Ν \ 1 i F~γ Ν Cr Ν 1 Η Ff 3-((1 -((4-amino-2-methyl-6oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-5-(difluoromethyl)2-methylbenzonitrile 515.2 60 (AB05) jOt ^f ο nh ₂ XN I ν уА-У ₀ X _N % F 1 Н F 3-((1 -((4-amino-2-methyl-6oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(trifluoromethyl)-1,6dihydropyrimidin-5yl)oxy)-5-(difluoromethyl)2-methylbenzonitrile 483.2

F

Example 61.

F

5-(Difluoromethyl)-3-((1-((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 3-((1-((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1, 6dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile, AB07 (392 mg , 1.039 mmol), and 4-chloro-5-(chloromethyl)-6-methoxy-2methylpyrimidine, C22 (323 mg, 1.56 mmol), K ₂ CO ₃ (287 mg, 2.078 mmol) was added to DMF (3464 μl ). The resulting reaction mixture was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water and then extracted with EtOAc (3x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 548.2 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Mixture of 3-((1-((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidine -5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (10.9 mg, 0.020 mmol), ethylboronic acid (21 mg, 0.284 mmol), Cs ₂ CO ₃ (19.45 mg, 0.060 mmol) and cataCXium A precatalyst Pd G2 (5.32 mg, 7.96 µmol) were purged with N2 and then treated with 1,4-dixoane (500 µl) and water (50 µl). The resulting mixture was heated at 150°C in a microwave oven for 10 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was extracted with Et ₂ O (2x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in ACN (1 ml), then KI (9.91 mg, 0.060 mmol) and TMS-Cl (25.4 μl, 0.199 mmol) were added. The resulting mixture was heated at 100°C for 2 hours. The reaction mixture was filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 528.2 (M+1).

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2-((1-((4-Cyclopropyl-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin- 5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile.

This compound was prepared as described in Example 61 using cyclopropylboronic acid. MS: 540.2 (M+1).

Example 63.

Example 62.

5-(Difluoromethyl)-3-((1-((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 3-((1-((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy) -5-difluoromethyl)-2-methylbenzonitrile.

To the solution

5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5 yl)oxy)benzonitrile, AB06 (1200 mg, 3.04 mmol), and 4 -chloro-5-(chloromethyl)-6-methoxy-2methylpyrimidine, C22 (711 mg, 3.43 mmol), K ₂ CO ₃ (839 mg, 6.07 mmol) was added to DMF (15.2 ml). The resulting reaction mixture was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The reaction mixture was poured into EtOAc (20 ml), washed with water (2x10 ml) and brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-75% EtOAc/hexane) to give the title compound. MS: 566.0 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((4-ethyl-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)-2-methylbenzonitrile.

Mixture of 3-((1-((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-5 -difluoromethyl)-2-methylbenzonitrile (50 mg, 0.088 mmol), ethylboronic acid (9.79 mg, 0.133 mmol), chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2aminobiphenyl)]palladium( P) (5.91 mg, 8.84 µmol) and Cs ₂ CO ₃ (86 mg, 0.265 mmol) were purged with N ₂ , then dissolved in water (80 µl) and 1,4-dioxane (803 µl). The resulting mixture was heated at 100°C for 16 hours and then filtered through CELITE®. The filtrate was diluted with EtOAc (10 ml) and washed with water (2x3 ml). The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 560.1 (M+1).

Step 3: 5-(difluoromethyl)-3-((1-((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-3-((1-((4-ethyl-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile (18 mg, 0.032 mmol) in DMF (1000 μl) was added pyridine hydrochloride (18.59 mg, 0.161 mmol). The resulting mixture was heated at 120°C for 15 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with DMSO (1 ml) and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 546.1 (M+1).

- 84 045274

Example 64.

F

F

5-(Difluoromethyl)-3-((1-((4-(fluoromethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 3-((1-((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy) -5-(difluoromethyl)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile, AB06 (1750 mg, 4.43 mmol), and 4-chloro-5-(chloromethyl)-6-methoxy-2methylpyrimidine, C22 (1 g, 4.83 mmol), in DMF (22.14 ml) was added K ₂ CO ₃ (1.224 g, 8.86 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The solution was poured into EtOAc (20 ml), washed with water (2x10 ml) and brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-75% EtOAc:hexane) to give the title compound. MS: 566.1 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((4-methoxy-6-(((4-methoxybenzyl)oxy)methyl)-2-methylpyrimidin5-yl)methyl)-6-oxo-4- (perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

3-((1-((4-Chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)- 5-(difluoromethyl)-2-methylbenzonitrile (150 mg, 0.265 mmol) was dissolved in water (241 μl) and 1,4-dioxane (2410 μl) and degassed. CataCXium A precatalyst Pd G2 (17.73 mg, 0.027 mmol), potassium trifluoro(((4-methoxybenzyl)oxy)methyl)borate (103 mg, 0.398 mmol) and Cs ₂ CO ₃ (259 mg, 0.795 mmol) were then added. . The resulting reaction mixture was degassed and heated at 100°C for 1 hour, then filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 682.1 (M+1).

Step 3: 5-(difluoromethyl)-3-((1-((4-(hydroxymethyl)-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-3-((1-((4-methoxy-6-(((4-methoxybenzyl)oxy)methyl)-2-methylpyrimidin-5yl)methyl)-6-oxo-4-( perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (123 mg, 0.180 mmol) in CH ₂ Cl ₂ (1805 μl) was added TFA (139 μl, 1.805 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The material was concentrated under reduced pressure to give the title compound. MS: 562.1 (M+1).

Step 4: 5-(difluoromethyl)-3-((1-((4-(fluoromethyl)-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

A solution of 5-(difluoromethyl)-3-((1-((4-(hydroxymethyl)-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile (101 mg, 0.180 mmol) in DCM (900 µl) was treated with DAST (59.4 µl, 0.450 mmol) and stirred at 55°C for 72 h. The solution was diluted with DCM (10 ml) and slowly quenched with a saturated aqueous solution of NaHCO ₃ to pH ~7. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: 564.1 (M+1).

Step 5: 5-(difluoromethyl)-3-((1-((4-(fluoromethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

A solution of 5-(difluoromethyl)-3-((1-((4-(fluoromethyl)-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimidin- 5-yl)oxy)-2-methylbenzonitrile (100 mg, 0.177 mmol) in DMF (1775 μl) was treated with pyridine hydrochloride (103 mg, 0.887 mmol). The resulting reaction mixture was heated at 120°C in a microwave oven for 15 minutes. The reaction mixture was filtered and purified by reverse phase HPLC (ACN/water with 0.05% NH ₄ OH) to give the title compound. MS: 550.1 (M+1). ^1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.73 (s, 1H), 7.25 (s, 1H), 6.86 (t, J=55.3 Hz, 1H), 5.38 (d, J=46.8 Hz, 2H), 4.96 (s, 2H), 2.43 (s, 3H), 2.27 (s, 3H).

- 85 045274

Example 65.

5-(Difluoromethyl)-3-((1-((4-(difluoromethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 5-(difluoromethyl)-3-((1-((6-methoxy-2-methyl-4-vinyl-1,6-dihydropyrimidin-5-yl)methyl)6-oxo-4-(perfluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Mixture of 3-((1-((4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-5 -(difluoromethyl)-2-methylbenzonitrile, (the title compound from Step 1 of Example 63) (200 mg, 0.353 mmol), tributyl(vinyl)stannane (208 μL, 0.707 mmol) and bis(triphenylphosphone)palladium(I) dichloride (49.6 mg, 0.071 mmol) in toluene (3535 μl) was stirred at 100°C for 16 hours. The mixture was partitioned between EtOAc and saturated KF solution. The resulting solution was stirred for 30 minutes, then filtered, the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-80% EtOAc/hexane) to give the title compound. MS: 558.1 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((4-formyl-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)-2-methylbenzonitrile.

To a solution of 5-(difluoromethyl)-3-((1 -((6-methoxy-2-methyl-4-vinyl-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (100 mg, 0.179 mmol) in a mixture of dioxane (1345 μl) and water (448 μl) was added 2.5% (by weight) solution of osmium oxide (OS) in tert-butanol (225 µl, 0.018 mmol), 2,6-dimethylpyridine (41.6 µl, 0.359 mmol) and sodium periodate (115 mg, 0.538 mmol). The resulting reaction mixture was stirred at 25°C for 24 hours.

The mixture was diluted with EtOAc (50 ml) and washed with saturated aqueous NH ₄ Cl (2x20 ml), water (20 ml), brine (20 ml), dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/hexane) to give the title compound. MS: 560.1 (M+1).

Step 3: 5-(difluoromethyl)-3-((1-((4-(difluoromethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-(perfluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Solution of 5-(difluoromethyl)-3-((1-((4-formyl-6-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidine-5 -yl)oxy)-2-methylbenzonitrile (40 mg, 0.072 mmol) in DCM (358 μl) was treated with DAST (23.62 μl, 0.179 mmol). The resulting reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was treated with DMF (1 ml), pyridine hydrochloride (83 mg, 0.715 mmol) and heated at 120°C for 15 min until all starting material was consumed. The reaction mixture was filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 568.1 (M+1). 1H NMR (500 MHz, DMSO- _d6 ) δ 12.98 (s, 1H), 8.80 (s, 1H), 7.75 (s, 1H), 7.48-6.65 (m, 3H ), 5.05 (s, 2H), 2.49 (p, J=1.8 Hz, 3H), 2.31 (s, 3H).

Example 66.

5-(Difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2, 2tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Step 1: 5-(difluoromethyl)-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)) -1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

Mixture of 5-fluoro-3-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin- 86 045274

4(3H)-one, BC05 (23 mg, 0.063 mmol), 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (11.56 mg,

0.063 mmol) and potassium carbonate (26.2 mg, 0.189 mmol) in NMP (210 µl) were heated at 80°C until LCMS showed complete conversion of the starting material. The reaction mixture was diluted with water, the precipitate was collected on a filter and washed with water (3x), then air dried to give the title compound. MS: 528.2 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile.

A mixture of 5-(difluoromethyl)-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl))- 1,6-Dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile and potassium iodide (10.48 mg, 0.063 mmol) in ACN (2 ml) were treated with TMS-Cl (48.4 μl, 0.379 mmol), then heated at 100°C for 10 min. The reaction mixture was filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 514.2 (M+1). ^1H NMR (600 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 7.44 (s, 1H), 6.73 (s, 1H), 4.99 (s, 2H), 2.59 (s, 3H), 2.55 (s, 3H), 2.49 (s, 3H).

Example 67.

F

F

5-(Difluoromethyl)-2-methyl-3-((1-((2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 5-(difluoromethyl)-3-((1-((4-methoxy-2-methylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidin-5-yl )oxy)-2-methylbenzonitrile.

Mixture of 5-fluoro-3-((4-methoxy-2-methylpyrimidin-5-yl)methyl)-6-(perfluoroethyl)pyrimidin-4(3H)-one, BC02 (16 mg, 0.043 mmol), 5-( difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (7.96 mg, 0.043 mmol) and potassium carbonate (18.02 mg, 0.130 mmol) in NMP (145 μl) were heated at 80°C for 1 h. the mixture was diluted with water, the precipitate was collected on a filter, washed with water (2x) and air dried to obtain the title compound, which was used for the next step without purification. MS: 532.2 (M+1).

Step 2: 5-(difluoromethyl)-2-methyl-3-((1-((2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

The above crude material and KI (21.64 mg, 0.130 mmol) in ACN (2 mL) were treated with TMS-Cl (70 μL, 0.548 mmol), then heated at 100 °C until LC-MS indicated the reaction was complete. The reaction mixture was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 518.2 (M+1).

1H NMR (600 MHz, methanol^) δ 8.67 (s, 2H), 8.04 (s, 2H), 7.60 (s, 2H), 7.03 (s, 2H), 6.68 ( s, 1H), 3.30 (s, 19H), 2.54 (s, 6H), 2.45 (s, 6H), 1.93 (s, 1H).

The following compounds shown in table. 19 was prepared in a manner similar to that described above for the synthesis of Example 67 using the indicated intermediates BC and A.

- 87 045274

Table 19

Note No. (BC#, A#) Structure Name according to IU PAK MS (M+1) 68 (BC05, A 10) BA xv 0 0 F^F 2-chloro-3 -((1 -((2,4-d imethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-5methylbenzonitrile 498.0 69 (BC05, A01) F ba 1 Tj ^{F 0} 1 XNN UA a A AC NON · FH F 3-(difluoromethyl)-5-((1((2,4-d imethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl) 1,6-dihydropyrimidin-5yl)oxy)benzonitrile 500.1 70 (VSOZ, A02) Z )=o )—“P 5-(difluoromethyl)-2-methyl3-((1 -((2-methyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)benzonitrile 500.2

-88045274

71 (VSO, A17) jO ^F [X o. IL 1 F γ NN M II JJ If FF ^H 3-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2,4difluorobenzonitrile 504.2 72 (BC01, A07) XJ ⁰ I 0h A. AXNN U/ 1 A F^ N SG NXFH 4 5 -chloro-3 -((1 -((2,4-d imethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2methylbenzonitrile 516.2 73 (BC01, A18) X. Ο χ A x\ A γ N N X X X F% N SG N H fA F 3-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2- methylbenzonitrile 502.1 74 (BC01, A19) AX ⁰ 1 o. AA FXNN ^F >ul L l FN CT N FF ^H 3-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2methylbenzonitrile 482.2

- 89 045274

75 (BC05, A20) N 4-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-3,5dimethylbenzonitrile 477 1 1 XX T ⁰ 1 °\ XX Ν VN \ L d 1 IF—γ N Cr N 1 h f'^t 76 (BC01, A21) J F ₄ No. 11 _ 1 - n y+n Q L l US N SG N ' FF ^H 4-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-3-methoxy-5 methylbenzonitrile 512.3 77 (BC04, A20) h 1 J J 1 ⁰ 1 XyA (Г V ^x F 4-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(trifluoromethyl)-1,6dihydropyrimidin-5yl)oxy)-3,5- dimethylbenzonitrile 446.2 78 (BC01, A20) 1 1 f < F ^F XF^ F 1 G ⁰ I e. 11 i YNN 1 d A 1 X Ν Ο NF ^H 4-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-3,5- dimethylbenzonitrile 496.2 79 (BC06, A02) Xj ^F ° 1 O^N F 5-(difluoromethyl)-2-methyl3-((1 -((4-methyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)benzonitrile 500.2

- 90 045274

Example 80.

2,5-Dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6- Dihydropyrimidin-5-yl)oxy)benzonitrile.

Step 1: 2,5-dichloro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5- yl)oxy)benzonitrile.

To a solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile, BC01 (200 mg, 0.523 mmol), in ACN ( 2616 µl) potassium carbonate (72.3 mg, 0.523 mmol) and 2,5-dichloro-3-hydroxybenzonitrile, A04 (118 mg, 0.628 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours and then filtered. The filtrate was diluted with EtOAc (200 ml) and hexane (20 ml), washed with water (3x50 ml), brine (50 ml), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-70% EtOAc/hexane) to give the title compound. MS: 550.2 (M+1).

Step 2: 2,5-dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitrile.

To a solution of 2,5-dichloro-3-((1 -((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidin-5- yl)oxy)benzonitrile (154 mg, 0.280 mmol) in ACN (2799 µl) was added TMSI (381 µl, 2.80 mmol). The resulting reaction mixture was stirred at room temperature for 2 days. LC-MS showed complete conversion. The reaction was quenched with saturated aqueous Na ₂ SO ₃ (300 μl) and purified by reverse phase HPLC (ACN/water with 0.05% NH4OH) to give the title compound. MS: 536.1 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H ), 4.89 (s, 2H), 2.31 (s, 3H), 2.22 (s, 3H).

The following compounds shown in table. 20 was prepared in a manner similar to that described above for the synthesis of Example 80 using the indicated intermediates BC and A.

Table 20

Note No. (BC#, A#) Structure IUPAC name MS (M+1) 81 (BC05, A06) J T ^F ^T ⁰ 1 τΧίχΧ. CT 'N'''' Λ ⁿ 5 -chloro-3 -((1 -((2,4-d imethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-2fluorobenzonitrile 502.1 82 (VS01, AAZ) ^.v _g IJ 0 I F-f'N X ^H F 5 -bromo-2-chloro-3 -((1 -((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy) benzonitrile 580.1 and 582.1

- 91 045274

83 (BC01, A02) AJ ^{F 0} 1 CX Ν Ύ% N \ 1 a X Λ N 0 NH fX F 5-(difluoromethyl)-3-((1-((4methoxy-2,6dimethylpyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2methylbenzonitrile 532.2 84 (BC01, AOI) F ^N 4 i LJ ^F Y ⁰ 1 ^Τχτχ Λ ^H F 3-(methyl difluoro)-5-((1 -((4methoxy-2,6- dimethylpyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)benzonitrile 518.2 85 (BC01, All) γ z Vo ^z X 3-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2fluorobenzonitrile 486.1 86 (BC01, A12) ..Br T T XX O I F^^N X f4+ F 3-bromo-5-((1-((2,4-dimethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)benzonitrile 546.1 and 548.1

- 92 045274

87 (BC01, A06) Υ Y ⁰ 1% XI X ^H F 5-chloro-3-((1 -((2,4-dimethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-2fluorobenzonitrile 520.2 88 (BC01, A13) YY ⁰ 1 0. X- γ NN dU 1 A F^ N CY N [ H FIT F 3-((1 -((4-methoxy-2,6dimethylpyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)-5methylbenzonitrile 482.1 89 (BC04, A03) 1J ci^V ο ι .YrxY Ur'N θ'' Ν ^ F 1 H F 5 -bromo-2-chloro-3 -((1 -((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(trifluoromethyl)-1,6dihydropyrimidin-5yl)oxy) benzonitrile 530.1 and 532.1 90 (BC04, A04) I T CI^^Y 0 I f TxT i Xk O'^N F Y H 2,5-dichloro-3-((1-((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(trifluoromethyl)-1,6dihydropyrimidin-5yl)oxy)benzonitrile 486.1 91 (BC05, A14) NC./x/ T T o 0 i°xVi^ fT\X F F 3-((1 -((2,4-dimethyl-6-oxo1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-2,5- dimethylbenzonitrile 477.2 92 (BC04, A06) nc.^-^.ci YY F^X O I fOT^xx F 1 H F 5 -chloro-3 -((1 -((2,4-d imethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(trifluoromethyl)-1,6dihydropyrimidin-5yl)oxy)-2fluorobenzonitrile 470.1

- 93 045274

Example 93.

3-((1-((2,4-Dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy )-2-fluoro-5-methylbenzonitrile.

Step 1: 5-chloro-2-fluoro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidine -5-yl)oxy)benzonitrile.

To a solution of 5-fluoro-3-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-(perfluoroethyl)pyrimidin4(3H)-one, BC01 (115 mg, 0.301 mmol), in ACN (1504 µl) potassium carbonate (83 mg, 0.602 mmol) and 5-chloro-2-fluoro-3-hydroxybenzonitrile, A05 (61.9 mg, 0.361 mmol) were added. The resulting reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was diluted with EtOAc (200 ml) and hexane (20 ml), then washed with water (3x50 ml), brine (50 ml), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-70% EtOAc/hexane) to give the title compound. MS: 534.2 (M+1).

Step 2: 5-methyl-2-fluoro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)benzonitrile.

To the degassed mixture of 5-chloro-2-fluoro-3-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin- 5-yl)oxy)benzonitrile (90 mg, 0.169 mmol) in water (211 µl) and 1,4-dioxane (632 µl), add chloro[(di(1-adamantyl)-n-butylphosphine)-2-( 2aminobiphenyl)]palladium(P) (11.27 mg, 0.017 mmol), potassium methyl trifluoroborate (30.8 mg, 0.253 mmol) and Cs ₂ CO ₃ (165 mg, 0.506 mmol). The resulting reaction mixture was heated at 130°C for 30 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-80% EtOAc/hexane) to give the title compound. MS: 514.2 (M+1).

Step 3: 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)1,6-dihydropyrimidin-5 -yl)oxy)-2-fluoro-5-methylbenzonitrile.

Solution of 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl) oxy)-2-fluoro-5-methylbenzonitrile (32 mg, 0.062 mmol) in ACN (312 μl) was treated with TMS-I (42.4 μl, 0.312 mmol). The resulting reaction mixture was heated at 40°C for 4 hours. LC-MS indicated that the reaction was complete. The reaction was quenched with a saturated aqueous solution of Na ₂ SO ₃ (100 μl) and stirred for 30 minutes. DMSO (2 mL) was added to the solution and purified by reverse phase HPLC (ACN/water with 0.05% NH4OH) to give the title compound. MS: 500.2 (M+1). 1H NMR (600 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 7.41 (d, J=3.9 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 5.05 (s, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H).

Example 94.

2-Chloro-3-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-( 1,1,2,2- tetrafluoroethyl)1,6-dihydropyrimidin-5-yl)oxy)-5-(trifluoromethyl)benzonitrile.

Step 1: 5-(3-bromo-2-chloro-5-(trifluoromethyl)phenoxy)-3-((4-methoxy-2,6-dimethylpyrimidin-5yl)methyl)-6-(1,1,2, 2-tetrafluoroethyl)pyrimidin-4(3H)-one.

To a stirred solution of 5-fluoro-3-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-(1,1,2,2tetrafluoroethyl)pyrimidin-4(3H)-one, BC05 ( 50 mg, 0.137 mmol), and 3-bromo-2-chloro-5(trifluoromethyl)phenol (41.6 mg, 0.151 mmol) in DMFA (1 ml) was added K ₂ CO ₃ (37.9 mg, 0.275 mmol). The resulting mixture was stirred at 120°C overnight. LC-MS showed the formation of the desired product. The reaction mixture was diluted with water (5 ml) and extracted

EtOAc (5 ml). The organic layer was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 621.0 (M+1).

Step 2: 2-chloro-3-((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-( 1,1,2 ,2tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(trifluoromethyl)benzonitrile.

A mixture of 5-(3-bromo-2-chloro-5-(trifluoromethyl)phenoxy)-3-((4-methoxy-2,6-dimethylpyrimidin-5ul)methyl)-6-(1,1,2,2- tetrafluoroethyl)pyrimidin-4(3H)-one (37 mg, 0.060 mmol), Zn(CN) ₂ (4.21 mg, 0.036 mmol) and Pd(PPh ₃ ) ₄ (6.90 mg, 5.97 μmol) in DMF (600 µl) was degassed for 5 min and then heated at 120°C overnight. LC-MS showed the formation of the desired product. The reaction mixture was diluted with DMF (1 ml) and then filtered and treated with pyridine hydrochloride (20.70 mg, 0.179 mmol). The resulting mixture was stirred at 120°C for 20 minutes. LC-MS showed the final product. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 552.1 (M+1). 1H NMR (500 MHz, DMSO- _d6 ) δ 8.81 (s, 1H), 8.23 (s, 1H), 7.78 (s, 1H), 3.84 (s, 2H), 2. 32 (s, 3H), 2.27 (s, 3H).

Example 95.

Ν

II

3-Chloro-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5 -yl)oxy)-5-methylbenzonitrile.

Step 1: 5-(2-chloro-4-methoxy-6-methylphenoxy)-3-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)6-(perfluoroethyl)pyrimidine-4(3H) -He.

2-chloro-4-methoxy-6-methylphenol (45.2 mg, 0.262 mmol), 5-fluoro-3-((4-methoxy2,6-dimethylnirimidin-5-yl)methyl)-6-( perfluoroethyl)pyrimidin-(3H)-one, BC01 (100 mg, 0.26 mmol), potassium carbonate (90 mg, 0.65 mmol) and DMF (2.6 ml). The resulting reaction mixture was heated at 100°C for 15 hours, cooled to ambient temperature, and then filtered through a syringe filter. The crude solution was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to give the title compound. MS: 535.3 (M+1).

Step 2: 5-(2-chloro-4-hydroxy-6-methylphenoxy)-3-((4-methoxy-2,6-dimethylpyrimidin-5yl)methyl)-6-(perfluoroethyl)pyrimidin-4(3H)- He.

To an ice-cooled solution of 5-(2-chloro-4-methoxy-6-methylphenoxy)-3-((4-methoxy-2,6dimethylpyrimidin-5-yl)methyl)-6-(perfluoroethyl)pyrimidin-4(3H )-one (87 mg, 0.16 mmol) in DCM (3 ml) was added dropwise to a 1 M solution of BBr ₃ in DCM (0.34 ml, 0.34 mmol). The resulting reaction mixture was allowed to warm to ambient temperature, stirred for 15 hours and then quenched by adding methanol (2 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane followed by 10% MeOH/DCM) to give the title compound. MS: 521.2 (M+1).

Step 3: 3-chloro-4-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl) oxy)-5-methylphenyltrifluoromethanesulfonate.

To a solution of 5-(2-chloro-4-hydroxy-6-methylphenoxy)-3-((4-methoxy-2,6-dimethylpyrimidin-5ul)methyl)-6-(perfluoroethyl)pyrimidin-4(3H)-one (100 mg, 0.19 mmol), triethylamine (0.04 mL, 0.29 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (82 mg, 0.23 mmol) were added to DCM (3 mL). The resulting reaction mixture was allowed to stir at ambient temperature for 2 hours and then quenched by adding saturated aqueous sodium bicarbonate (10 ml). The reaction mixture was extracted with DCM (3x10 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 653.2 (M+1).

Step 4: 3-chloro-4-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl) hydroxy)-5-methylbenzonitrile.

A mixture of 3-chloro-4-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6dihydropyrimidin-5-yl)oxy) -5-methylphenyltrifluoromethanesulfonate (62 mg, 0.10 mmol), tbuXPhos Pd G3 precatalyst (30.2 mg, 0.038 mmol) and zinc cyanide (7.36 mg, 0.063 mmol) were purged three times

- 95 045274 nitrogen before adding water (1.5 ml) and THF (0.38 ml). The resulting reaction mixture was heated at

65°C for 15 hours, cooled to ambient temperature, filtered through a pad of

CELITE® and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 530.2 (M+1).

Step 5: 3-chloro-4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile.

To a stirred solution of 3-chloro-4-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) oxy)-5-methylbenzonitrile (16 mg, 0.030 mmol) and potassium iodide (15.04 mg, 0.091 mmol) in ACN (302 μl) was added to TMS-Cl (11.58 μl, 0.091 mmol). The resulting mixture was heated at 50°C overnight. LC-MS showed complete and pure conversion. The reaction mixture was cooled, quenched with MeOH (1 ml) and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA) to obtain fractions containing the desired product, which were combined, diluted with saturated aqueous NaHCO ₃ and extracted with DCM (3x). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 516.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.5 (s, 1H), 7.4 (s, 2H), 5.0-4.8 (dd, 2H), 2.55 (s, 3H), 2.5 (s, 3H), 2.3 (s, 3H).

The following compounds shown in table. 21 was prepared in a manner similar to that described above for the synthesis of Example 95 using the indicated intermediates BC and A.

Table 21

Note No. (BC#, A#) Structure IUPAC name MS (M+1) 96 (BC01, A15) N o U 1 F Af Ν _N % IJFN SG NFF ^N 3,5-dichloro-4-(( 1 -((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(perfluoroethyl)-1,6dihydropyrimidin-5yl)oxy)benzonitrile 536.2 97 (BC05, A15) O ^: L. - 3,5-dichloro-4-(( 1 -((2,4dimethyl-6-oxo-1,6dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)- 1,6-dihydropyrimidin-5yl)oxy)benzonitrile 518.2 98 (BC05, A16) /U Chao 3 -chloro-4-(( 1 -((2,4-dimethyl6-oxo-1,6- dihydropyrimidin-5yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)1,6-dihydropyrimidin-5yl)oxy)-5methylbenzonitrile 498.2

Anti-cell death activity assay (TACK HIV).

PBMCs obtained from healthy donors were grown in complete medium (RPMI 1640 with L-glutamine, 10% heat-inactivated fetal bovine serum; 100 U/ml penicillin streptomycin) containing 5 μg/ml phytohemagglutinin (PHA) and approximately 2.5 x 106 cells /ml, for 3 days at 5% CO ₂ , 37°C and 90% humidity. On day 4, PHA-stimulated cells were washed and resuspended at approximately 20 x ^{10 6} cells/ml in complete medium with IL-2 (10 U/ml), with the original pseudotyped HIV virus VSV-G (VSV-G/pNLGl- P2A-AEnv - 20 μg/ml p24) and incubated for 4 hours at 37°C, 5% CO ₂ and 90% humidity. VSV-G/pNLG1-P2A-ΔEnv is a VSV-G pseudotype virus derived from the pNL43 virus with an egfp insertion at the 5' end of nef, and eGFP expression driven by normal spliced RNA transcripts. The virus contains Vif truncated by 50 amino acids due to a single nucleotide deletion causing a frameshift, and does not express Nef due to a stop codon after gfp. In this virus, Env is not expressed due to a frameshift that results in multiple stop codons. Infected cells were then washed 3 times in complete medium supplemented with 10 U/ml IL-2 by centrifugation at 200 g for 3 min at 22°C. Cells were resuspended at 5x106 cells/ml in complete medium supplemented with 10 U/ml IL-2 and incubated overnight at 37°C, 5% CO2 and 90% humidity. To treat infected PBMCs with compounds of the invention, cells were diluted to a concentration of 4x105 cells/ml in RPMI 1640 medium supplemented with L-glutamine, 5.0% normal human serum (NHS), 100 U/ml penicillin-streptomycin and IL-2 (10 U /ml). 20,000 cells were placed in each well of 384-well poly-D-lysine coated plates, wherein each well treated contained the compound of the invention and DMSO at a final concentration of <0.5%. Testing of compounds was carried out by 10-point 3-fold titration. The plates were analyzed in an Acumen EX3 reader using a Blue Laser 488 nm, and the amount of GFP loss reflecting the death of infected cells was assessed in GFP-positive subjects. Titration curves and EC ₅₀ values were calculated using a four-parameter logistic approximation. The results are presented in table. 22.

Table 22

Note No. TASK ec ₅₀ (nM) Note No. TASK ec ₅₀ (nM) Note No. TASK ec ₅₀ (nM) Note No. TASK ec ₅₀ (nM) 1 431.0 26 413.0 51 394.8 76 498.0 2 411.4 27 450.7 52 456.0 77 409.4 3 416.9 28 208.4 53 391.5 78 155.9 4 411.5 29 312.0 54 212.9 79 459.8 5 186.8 thirty 205.7 55 276.0 80 340.0 6 201.2 31 396.8 56 161.4 81 156.3 7 353.3 32 170.8 57 493.3 82 530.9 8 251.7 33 208.1 58 252.1 83 251.8 9 287.0 34 474.0 59 134.6 84 291.0 10 146.2 35 350.8 60 227.9 85 440.7 AND 267.0 36 72.3 61 485.2 86 472.8 12 199.5 37 114.1 62 406.3 87 217.5 13 395.0 38 480.6 63 276.5 88 397.1 14 343.0 39 265.1 64 162.0 89 433.7 15 244.7 40 198.4 65 382.3 90 489.1 16 199.4 41 363.1 66 262.5 91 325.3 17 282.4 42 307.8 67 174.4 92 283.6 18 128.6 43 437.7 68 477.9 93 172.0 19 315.3 44 333.3 69 340.5 94 491.9 20 364.9 45 257.2 70 202.6 95 179.2 21 131.8 46 303.3 71 148.6 96 366.6 22 181.0 47 393.9 72 377.2 97 182.4 23 428.7 48 341.8 73 450.0 98 183.0 24 338.8 49 277.8 74 483.8 25 353.2 50 249.6 75 208.6

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Claims (19)

CLAIM 1. A connection that is selected from the group consisting of: 5 -(difluoromethyl)-2-methoxy-3 -((1 -((2-methyl-6-oxo-1,6-dihydropyrimide in-5 yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile; 3 -(difluoromethyl)-5 -((1 -((2-methyl-6-oxo-1,6-d ihydropyrimidin-5 -yl)methyl)6-oxo-4-( 1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 2,5-dichloro-3 -((4-(1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-1 ,6-dihydropyrimidin-5yl)oxy)benzonitrile; 5 -chloro-3 -((4-( 1,1 -difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin5-yl)methyl)-6-oxo-1,6 -dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((2,6-dimethyl-4-oxo-4,5-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(1,1,2- trifluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2·methylbenzonitrile; 3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5 -yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile; 3 -bromo-5 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 -yl)methyl)-6oxo-4-(1,1,2,2-tetrafluoroethyl )-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; 3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5 -yl)oxy)-5-(difluoromethyl)-2methoxybenzonitrile; 5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methoxybenzonitrile; 4-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimide in- 5 -yl)oxy)-3,5-dimethylbenzonitrile; - 98 045274 3-chloro-4-((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1, 6-d ihydropyrimidin 5 -yl)methyl)-6-oxo- 1, 6-d ihydropyrimidin-5 -yl)oxy)-5-methylbenzonitrile; 3,5-dichloro-4-((4-(1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-1 ,6-dihydropyrimide in-5yl)oxy)benzonitrile; 3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimide in- 5-yl)oxy)-2,4,5-trifluorobenzonitryl; 3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimide in- 5-yl)oxy)-5-(difluoromethyl)-2fluorobenzonitrile; 4-((4-( 1,1-difluoroethyl)-1 -((4-hydroxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidin-5-yl)oxy)- 3-methyl-5-(trifluoromethyl)benzonitrile; 3 -cyclopropyl-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-5methylbenzonitrile; 3 -(difluoromethyl)-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5methylbenzonitrile; 2-chloro-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile; 5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)-6-oxo-1 ,6-d ihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; 3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimide in- 5-yl)oxy)-5-(difluoromethyl)benzonitryl; 5 -chloro-3 -((4-( 1,1 -difluoroethyl)-1 -((4-methyl-6-oxo-2-((pyrimidin-2yloxy)methyl)-1,6-d ihydropyrimidine-5 - yl)methyl)-6-oxo-1,6-dihydropyrimide in-5 yl)oxy)-2-fluorobenzonitrile; 3 -((4-( 1,1-difluoroethyl)-1 -((4-methyl-6-oxo-2-((pyrimidin-2-yloxy)methyl)1,6-dihydropyrimidin-5-yl)methyl) -6-oxo-1,6-dihydropyrimide in-5-yl)oxy)-5(difluoromethyl)-2-methylbenzonitrile; 3-((4-bromo-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-1,6-dihydropyrimidin-5-yl)oxy)- 2,5-dimethylbenzonitrile; - 99 045274 2-amino-5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5yl)methyl)-6-oxo-4-( 1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile; (5)-5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; (7?)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5yl)methyl)-4-(1-fluoroethyl)-6 -oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; (S)-5 -chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-4(1-fluoroethyl)-6-oxo -1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile; (7?)-5-chloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4(1-fluoroethyl)-6-oxo -1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile; (S)-5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2fluorobenzonitrile, (7?)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1 ,6-dihydropyrimide in-5yl)methyl)-4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2fluorobenzonitrile; (5)-5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-4-(1-fluoroethyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2methoxybenzonitrile; (7?)-5-(difluoromethyl)-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5yl)methyl)-4-(1-fluoroethyl)-6 -oxo-1,6-dihydropyrimidin-5 -yl)oxy)-2methoxybenzonitrile; 3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4 (perfluoroethyl)-1,6-dihydropyrimidine- 5-yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile; 3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4 (perfluoroethyl)-1,6-dihydropyrimidine- 5-yl)oxy)-5-chloro-2-fluorobenzonitrile; 3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4 (1,1,2,2-tetrafluoroethyl )-1,6-dihydropyrimidin-5 -yl)oxy)-5-chloro-2 fluorobenzonitrile; - 100 045274 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-2-fluoro-5 methylbenzonitrile; 3 -((4-( 1,1-difluoroethyl)-1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5yl)methyl)-6-oxo-1,6-dihydropyrimidin-5 -yl)oxy)-2-fluoro-5-methylbenzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-5-ethyl-2 fluorobenzonitrile; 5-chloro-2-fluoro-3 -((1 -((2-(hydroxymethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile; 5 -(difluoromethyl)-3 -((1 -((2-(3-hydroxypropyl)-6-oxo-1, 6-dihydropyrimidin 5-yl)methyl)-6-oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; 5 -(difluoromethyl)-2-methyl-3 -((1 -((2-( 1 -methyl-I H-p-irazol-4-yl)-6-oxo-1,6dihydropyrimidin-5-yl)methyl) -6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile; 5 -(difluoromethyl)-3 -((1 -((2-(hydroxymethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((2-(3-hydroxypropyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 4-(( 1 -((2-(3-hydrox-ipropyl)-4-methyl-6-oxo-1, 6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-3,5dimethylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((2-(methoxymethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5 -(difluoromethyl)-2-methyl-3 -((1 -((4-methyl-2-(2-methylprop-1-ey-1-yl)-6-oxo1,6-dihydropyrimidin-5-yl) methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)benzonitrile; - 101 045274 5-chloro-2-fluoro-3 -((1 -((2-(3-methoxypropyl)-4-methyl-6-oxo-1,6dihydropyrimide in-5 -yl)methyl)-6-oxo-4- (perfluoroethyl)-1,6-d ihydropyrimidin-5 yl)oxy)benzonitrile; methyl-3 -(5 -((5 -(5-chloro-3-cyano-2-fluorophenoxy)-6-oxo-4(perfluoroethyl)pyrimidin-1 (6H)-yl)methyl)-4-methyl-6 -oxo-1,6-d ihydropyr imidin-2 yl)propanoate; 3 -((1 -((2-amino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1,1,2,2tetrafluoroethyl)-1,6-d ihydropyrimidin-5 -yl)oxy)-5 -(diforomethyl)-2methylbenzonitrile; 3-((1 -((4-amino-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1,1 difluoroethyl)-6-oxo-1,6- dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile; 3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl) -1,6-d ihydropyrimidin-5 -yl)oxy)-5 -(methyl difluoro)-2methylbenzonitrile; 3-((1-((4-amino-2-methyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(trifluoromethyl)-1,6-dihydropyrimidine-5 -yl)oxy)-5-(difluoromethyl)-2methylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimide in-5 yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; 2-(( 1 -((4-cyclopropyl-6-methoxy-2-methylpyrimidin-5 -yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1,6-d ihydropyrimidine -5 -yl)oxy)-5 -(difluoromethyl)-2methylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimide in-5 yl)methyl)-6-oxo-4-(perfluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((4-(fluoromethyl)-2-methyl-6-oxo-1,6dihydropyrimide in-5 -yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-d ihydropyrimidin-5 yl)oxy)-2-methylbenzonitrile; 5 -(difluoromethyl)-3 -((1 -((4-(d iforomethyl)-2-methyl-6-oxo-1,6dihydropyrimide in-5 -yl)methyl)-6-oxo-4-(perfluoroethyl) -1,6-d ihydropyrimidin-5 yl)oxy)-2-methylbenzonitrile; - 102 045274 5 -(difluoromethyl)-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2methylbenzonitrile; 5 -(difluoromethyl)-2-methyl-3 -((1 -((2-methyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 2-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo 4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile; 3 -(difluoromethyl)-5 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile; 5 -(difluoromethyl)-2-methyl-3 -((1 -((2-methyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) oxy)-2,4-difluorobenzonitrile; 5 -chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo 4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)-2-methylbenzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) hydroxy)-2-methylbenzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) hydroxy)-2-methylbenzonitrile; 4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-3,5-d imethylbenzonitrile; 4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) oxy)-3-methoxy-5-methylbenzonitrile; 4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(trifluoromethyl)-1,6-d ihydropyrimidin-5-yl )oxy)-3,5-dimethylbenzonitrile; 4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl) hydroxy)-3,5-dimethylbenzonitrile; 5 -(difluoromethyl)-2-methyl-3 -((1 -((4-methyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-( 1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5yl)oxy)benzonitrile; 2,5-dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile; - 103 045274 5 -chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile; 5 -bromo-2-chloro-3 -((1 -((2,4-d imethyl-6-oxo-1,6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5 -(difluoromethyl)-3 -((1 -((4-methox and-2,6-d imethylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidine-5- yl)oxy)-2-methylbenzonitrile; 3-(difluoromethyl)-5-((1-((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy )benzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-2-fluorobenzonitrile; 3 -bromo-5 -((1 -((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5 -yl)methyl)-6oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin- 5-yl)oxy)benzonitrile; 5 -chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimidin-5 -yl)oxy)-2-fluorobenzonitrile; 3-((1 -((4-methoxy-2,6-dimethylpyrimidin-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile ; 5 -bromo-2-chloro-3 -((1 -((2,4-d imethyl-6-oxo-1, 6-d ihydropyrimidin-5 yl)methyl)-6-oxo-4-(trifluoromethyl)- 1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 2,5-dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6oxo-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(1,1,2,2-tetrafluoroethyl)-1 ,6-d ihydropyrimidin-5 -yl)oxy)-2,5-d immethylbenzonitrile; 5 -chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5 -yl)methyl)-6-oxo4-(trifluoromethyl)-1,6-dihydropyrimidin-5 -yl)oxy)-2-fluorobenzonitrile; 3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6-oxo-4(perfluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)-2-fluoro-5-methylbenzonitrile; 2-chloro-3 -((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-5(trifluoromethyl)benzonitrile; 3-chloro-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo4-(perfluoroethyl)-1,6-dihydropyrimide in- 5 -yl)oxy)-5-methylbenzonitrile; 3,5-dichloro-4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6oxo-4-(perfluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)benzonitrile; 3,5-dichloro-4-((1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimide in-5-yl)methyl)-6oxo-4-( 1,1,2,2 -tetrafluoroethyl)-1,6-d ihydropyrimidin-5 -yl)oxy)benzonitrile; 3 -chloro-4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo 4-( 1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile; or a pharmaceutically acceptable salt thereof. - 104 045274 2. A compound according to claim 1, representing:_______________________________________ (3,5-dichloro-4-(( 1 -((2,4-d imethyl-6-oxo-1,6-d ihydropyrimidin-5 -yl)methyl )-4-(1 fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitriles, its (S) and (R) stereoisomers; (3-chloro-4-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1fluoroethyl)-6-oxo-1,6- d ihydropyrimidin-5-yl)oxy)-5-methylbenzonitre or its (5) and (K) stereoisomers; 2,5-dichloro-3-((1-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(1fluoroethyl)-6-oxo-1,6 -d ihydropyrimidin-5-yl)oxy)benzonitriles its (5) and (R) stereoisomers; 4-(( 1 -((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-( 1 -fluoroethyl)-6oxo-1,6-dihydropyrimidin-5-yl )oxy)-3,5-dimethylbenzonitrile and its (S) and (R) stereoisomers; 5-chloro-2-fluoro-3-((1-((2-(1-hydroxyethyl)-4-methyl-6-oxo-1,6-dihydropyrimidin 5-yl)methyl)-2-oxo-4 -(1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridin-3 yl)oxy)benzonitrile and its (5) and (R) stereoisomers; And 5-(difluoromethyl)-3 -((1 -((2-( 1 -hydroxyethyl)-4-methyl-6-oxo-1,6dihydropyrimidin-5-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile and its (S) and (R) stereoisomers; or a pharmaceutically acceptable salt thereof. 3. The connection according to claim 1, which is or a pharmaceutically acceptable salt thereof. 4. The connection according to claim 3, which is or a pharmaceutically acceptable salt thereof. 6. The connection according to claim 5, which is - 105 045274 or a pharmaceutically acceptable salt thereof. 8. The connection according to claim 7, which is or a pharmaceutically acceptable salt thereof. 10. The connection according to claim 9, which is or a pharmaceutically acceptable salt thereof. - 106 045274 12. The connection according to claim 11, which is 13. A pharmaceutical composition containing an effective amount of a compound according to any one of claims 1 to 3, 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12, and pharmaceutically acceptable carrier. 14. A method of treating or preventing an infection caused by HIV, or treating, preventing or delaying the onset of progression of AIDS or AIDS-associated complex (ARC) in a person in need thereof, which comprises administering to the person an effective amount of a compound according to any one of claims 1 to 3 , 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12. 15. A method of inducing GAG-POL dimerization in HIV-infected cells of a human in need thereof, which comprises administering to the human an effective amount of a compound according to any one of claims 1 to 3, 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or connections according to any one of paragraphs 4, 6, 8, 10 or 12. 16. A method for selectively killing HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to non-HIV-infected cells in a human, which comprises administering to the human an effective amount of a compound according to any one of claims 1-3, 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12. 17. The method according to any one of claims 14 to 16, further comprising administering to a person an effective amount of one or more additional compatible antiviral agents active against HIV selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside reverse transcriptase inhibitors HIV, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors and downstream inhibitors. 18. A method of enhancing the suppression of HIV viremia in a human, wherein the viremia is suppressed by administration of one or more compatible antiviral agents active against HIV, which further includes administering to the human an effective amount of a compound according to any one of claims 1-3, 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12. 19. Use of a compound according to any one of claims 1-3, 5, 7, 9 or I, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12, for the treatment or prevention of HIV infection , or to treat, prevent, or delay the onset or progression of AIDS or ARC in a person. 20. Use of a compound according to any one of claims 1-3, 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12, for the selective destruction of HIV-infected cells, expressing GAG-POL, without concomitant cytotoxicity to non-HIV-infected cells in humans. 21. Use of a compound according to any one of claims 1-3, 5, 7, 9 or 11, or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 4, 6, 8, 10 or 12 for enhancing the suppression of HIV viremia in humans , where viremia is suppressed by one or more compatible antiviral agents active against HIV. 22. The method according to any one of claims 14, 15, 16 or 18, wherein HIV is HIV-1. 23. Use according to any one of claims 19, 20 or 21, wherein HIV is HIV-1. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 107-