RU2816090C2 - Pyridinone compounds as selective cytotoxic agents against hiv-infected cells - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to pyridinone derivatives of formula I or a pharmaceutically acceptable salt thereof and pharmaceutical compositions based thereon, having cell killing activity, activated by small molecules (SMACK), and having activity for selective destruction of HIV-infected cells expressing GAG-POL.

EFFECT: using the invention enables treating HIV infections, as well as treating and preventing or delaying the onset or progression of AIDS or AIDS-associated complex (ARC).

16 cl, 16 tbl, 43 ex

Description

BACKGROUND OF THE ART

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 debilitating 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 that make the virus in their body resistant to available treatments, and there is a rapid rebound of viremia when therapy is stopped, indicating that current treatment regimens are not curative.

HIV is a retrovirus whose life cycle involves the reverse transcription of the viral RNA genome into DNA through an enzyme known as reverse transcriptase, and the subsequent integration of a copy of the DNA into the host chromosomal DNA using a virally 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 in the GAG and GAG-POL proteins, with GAG containing structural proteins and GAG-POL resulting from a frameshift near the carboxy terminus of GAG and containing the viral enzymes protease (PR), reverse transcriptase (RT) and integrase (IN), in addition to structural proteins. GAG and GAG-POL are cleaved into individual proteins during the maturation process that occurs during the budding of virions from an infected cell. At this time, GAG-POL dimerizes, and the dimeric HIV PR in the GAG-POL dimer now forms an active enzyme that can be cleaved from the polyprotein and catalyze further cleavage to form the remaining 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 not infectious. Once integration has occurred, the cell is infected until it dies, either through normal cell death pathways, 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 therapy 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 USA, 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 has the potential to reduce low-grade viremia in frail patients and may also play a role in HIV treatment strategies.

SUMMARY OF THE INVENTION

The present disclosure relates to pyridinone derivatives and their use as small molecule activated cell killing (SMACK) agents that accelerate the death of cells expressing HIV GAG-POL without concomitant cytotoxicity to HIV-naïve cells. Accordingly, the compounds described herein are useful for treating HIV infection, or for treating, preventing, or delaying the onset or progression of AIDS or AIDS-associated complex (ARC). In addition, the compounds are useful for selectively killing HIV-infected cells expressing GAG-POL in a subject infected with HIV. Also provided are compositions and methods of use comprising the compounds disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pyridinone-derived compounds and their use to accelerate the death of cells expressing HIV GAG-POL without concomitant cytotoxicity to non-HIV-infected cells. In the absence of compounds such as those of the present invention, PR activation occurs during virus maturation and the concentration of mature PR in the cytoplasm is limited. In contrast, the present compounds promote the desired phenotype by catalyzing GAG-POL dimerization within the infected cell by binding to the immature RT binding site and triggering premature activation of the HIV PR enzyme within the infected host cell prior to budding. 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, demonstrating the role of HIV protease in this process.

The compounds described herein also have activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to the homology between the mature and immature RT pocket of HIV, which allows the compounds to bind to the mature hydrophobic pocket adjacent to the active site of the viral RT enzyme. Binding to mature RT results in inhibition of enzymatic activity and proviral DNA production, which prevents infection of naïve CD4+ T cells.

Although the effect of NNRTI on RT and GAG-POL dimerization has been documented (Tachedjian et al. Proc. Natl. Acad. Sci. USA 2001, 98(13):7188; Tachedjian et al. FEBS Lett. 2005, 579:379; Figueiredo et al. PLOS Path. 2006, 2(11):1051; Sudo et al. J. Virol. 2013, 87(6):3348), selective killing of HIV-infected cells as a result of enhanced dimerization was first reported by Jochmans et al. (Jochmans et al. Retrovirology 2010, 7:89). The authors 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-targeted killing of 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 saw a significant reduction in virus production for some NNRTIs compared to 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.

The present description relates to a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is H, halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1 -7 F, or -OC _1-3 alkyl, substituted or unsubstituted 1-7 F;

R ² is CN and R ³ is H; or R ² is H and R ³ is CN;

R ⁴ is -H, halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1-7 F, or -OC _1-3 alkyl, substituted or unsubstituted with 1-7 F;

R ⁵ is -H, halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1-7 F, or -OC _1-3 alkyl, substituted or unsubstituted with 1-7 F;

R ⁶ is halogen or -C _1-6 alkyl substituted with 1-9 -F;

R ⁷ is -H or -C _1-3 alkyl;

R ⁸ is -H, halogen or -C _1-3 alkyl; And

R ⁹ is -H, pyrazolyl or -C _1-6 alkyl, substituted or unsubstituted -OH or -OC _1-3 alkyl.

Embodiment 1 of the present disclosure provides compounds of formula I having structural formula II (where R ² is CN and R ³ is H):

or pharmaceutically acceptable salts thereof, wherein ^R1 , ^R4 , ^R6 , ^R7 , ^R8 and ^R9 are as defined in Formula I.

Embodiment 2 of the present disclosure provides compounds of Formula I or Formula II, or pharmaceutically acceptable salts of each of the above, wherein:

R ⁴ is halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1-7 F, or -OC _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 1, R ⁴ is halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 2, R ⁴ is halogen, -CH ₃ or -CH ₃ substituted with 1-3 F.

Embodiment 3A of the present disclosure provides compounds of Formula I, Formula II, Embodiment 2, or any class thereof, or pharmaceutically acceptable salts of each of the foregoing, wherein R ¹ is -H.

Embodiment 3B of the present disclosure provides compounds of Formula I, Formula II, Embodiment 2, or any class thereof, or pharmaceutically acceptable salts of each of the above, wherein R ¹ is halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1-7 F, or -OC _1-3 alkyl, substituted or unsubstituted 1-7 F In their class 1, R1 is halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 2, R1 is halogen or _CH3 .

Embodiment 4 of the present specification provides compounds of formula I having structural formula III (where R ² is H and R ³ is CN):

or pharmaceutically acceptable salts thereof, wherein ^R1 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 are as defined in Formula I.

Embodiment 5A of the present specification provides compounds of formula I or formula III, or pharmaceutically acceptable salts of each of the above, wherein:

R ¹ is halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1-7 F, or -OC _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 1, R ¹ is halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 2, R ¹ is halogen or CH ₃ .

Embodiment 5B of the present specification provides compounds of formula I or formula III, or pharmaceutically acceptable salts of each of the above, wherein:

R ⁵ is halogen, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, -C _1-3 alkyl, substituted or unsubstituted 1-7 F, or -OC _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 1, R ⁵ is halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F. In their class 2, R ⁵ is halogen, -CH ₃ or -CH ₃ substituted with 1-3 F.

Embodiment 6 of the present disclosure provides compounds of Formula I, Formula II, Formula III, or Embodiment 2, 3A, 3B, 5A, or 5B, or any class thereof, or pharmaceutically acceptable salts of each of the above, wherein R ⁶ is halogen or -C _1-4 alkyl substituted with 1-9 -F. In their class 1, R ⁶ is halogen or -C _1-3 alkyl substituted with 1-7 -F. In their class 2, R ⁶ is halogen or -C _1-2 alkyl substituted with 1-5 -F.

Embodiment 7 of the present disclosure provides compounds of Formula I, Formula II, Formula III, or Embodiment 2, 3A, 3B, 5A, 5B, or 6, or any class thereof, or pharmaceutically acceptable salts of each of the foregoing, wherein R ⁷ is H or -CH ₃ .

Embodiment 8 of the present disclosure provides compounds of Formula I, Formula II, Formula III, Embodiment 2, 3A, 3B, 5A, 5B, 6 or 7, or any class thereof, or pharmaceutically acceptable salts of each of the foregoing, wherein R ⁸ is -H or halogen.

Embodiment 9 of the present disclosure provides compounds of Formula I, Formula II, Formula III, Embodiment 2, 3A, 3B, 5A, 5B, 6, 7 or 8, or any class thereof, or pharmaceutically acceptable salts of each of the foregoing, wherein R ⁹ is -H, pyrazolyl or -C _1-4 alkyl, substituted or unsubstituted -OH or -OC _1-3 alkyl. In their class 1, R ⁹ is -H, pyrazolyl or -C _1-3 alkyl, substituted or unsubstituted -OH or -OC _1-3 alkyl. In their class 2, R ⁹ is -H, pyrazolyl or -C _1-3 alkyl, substituted or unsubstituted -OH or -OCH ₃ .

Embodiment 10 of the present disclosure provides compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein

R ¹ is H, halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F; for example, R ¹ is H, halogen or CH ₃ ;

R ⁴ is halogen, -CH ₃ or -CH ₃ substituted with 1-3 F;

R ⁶ is halogen or -C _1-3 alkyl substituted with 1-7 -F, for example, R ⁶ is -C _1-2 alkyl substituted with 1-5 -F;

R ⁷ is -H or -C _1-3 alkyl, for example, R ⁷ is H or -CH ₃ ;

R ⁸ is -H, halogen or -C _1-3 alkyl, for example, R ⁸ is -H or halogen; And

R ⁹ is -H, pyrazolyl or -C _1-6 alkyl, substituted or unsubstituted -OH or -OC _1-3 alkyl, for example, R ⁹ is -H, pyrazolyl, or -C _1-3 alkyl, substituted or unsubstituted substituted -OH or -OCH ₃ .

Embodiment 11 of the present disclosure provides compounds of formula I or III, or pharmaceutically acceptable salts thereof, wherein

R ¹ is halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F, for example, R ¹ is halogen or CH ₃ ;

R ⁵ is halogen or -C _1-3 alkyl, substituted or unsubstituted with 1-7 F, e.g. R ⁵ is halogen, -CH ₃ or -CH ₃ substituted with 1-3 F, e.g. R ₅ is -CH ₃ ;

R ⁶ is halogen or -C _1-3 alkyl substituted with 1-7 -F, for example, R ⁶ is -C _1-2 alkyl substituted with 1-5 -F;

R ⁷ is -H or -C _1-3 alkyl, for example, R ⁷ is H or -CH ₃ ;

R ⁸ is -H, halogen or -C _1-3 alkyl, for example, R ⁸ is -H or halogen; And

R ⁹ is -H, pyrazolyl or -C _1-6 alkyl, substituted or unsubstituted -OH or -OC _1-3 alkyl, for example, R ⁹ is -H, pyrazolyl, or -C _1-3 alkyl, substituted or unsubstituted substituted -OH or -OCH ₃ .

Reference to compounds of formula I herein includes compounds of formula I, II and III, as well as embodiments and classes thereof. The compounds of formula I may be neutral compounds or in salt form, if such salts are possible, including pharmaceutically acceptable salts.

The term "for example" means "for example". When the terms “for example” or “for example” are used herein, the examples provided are for illustrative purposes and are not intended to be an exhaustive list of all relevant examples.

As used herein, the term “alkyl” refers to saturated aliphatic hydrocarbon groups, both branched and straight chain, having a certain number of carbon atoms within a certain range.

For example, the term "C _1-6 alkyl" means straight or branched chain alkyl groups, including all possible isomers having 1, 2, 3, 4, 5 or 6 carbon atoms, and also includes each of the hexyl and pentyl isomers, and also n- , iso- , sec- and tert -butyl (butyl, and -butyl, b -butyl, t -butyl, together “C ₄ alkyl”, Bu=butyl), n- and iso -propyl (isopropyl, and -propyl together "C ₃ alkyl"; Pr=propyl), ethyl (Et) and methyl (Me). "C _1-4 alkyl" has 1, 2, 3 or 4 carbon atoms and includes each of n- , i- , b- and t -butyl, n- and i -propyl, ethyl and methyl. "C _1-3 alkyl" has 1, 2 or 3 carbon atoms, and includes each of n -propyl, n -propyl, ethyl and methyl.

"Cycloalkyl" refers to a cyclized alkyl ring having a specified number of carbon atoms in a specified range. Thus, for example, “C _3-6 cycloalkyl” includes each of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and “C _3-4 cycloalkyl” includes each of cyclopropyl and cyclobutyl.

"Halo" or "halogen" means chlorine, fluorine, bromine or iodine. Chlorine, fluorine and bromine are a class of halogens of interest, particularly chlorine and fluorine.

“HIV-naïve cells” are cells that are not infected with HIV.

“Compatible anti-HIV agents” are anti-HIV agents other than HIV protease inhibitors.

A "stable" compound is one 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 present invention are limited to the stable compounds covered by Formula I and its variations. For example, certain moieties as defined in Formula I may be unsubstituted or substituted, and the latter term is intended to cover substitution patterns (ie, the number and type of substituents) that are chemically possible for a group and that result in a stable compound.

The present description includes 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 present disclosure also includes mixtures of diastereomers, especially mixtures of epimers, in all proportions. The present description covers compounds of formula I having either an ( R ) or ( S ) stereoconfiguration at the asymmetric center and at any additional asymmetric centers that may be present in the compound of formula I, as well as stereoisomeric mixtures thereof. Embodiments of the present disclosure also include a mixture of enantiomers enriched in 51% or more of one enantiomer, including, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer. A single epimer is preferred. Single or single enantiomers refer to enantiomers 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 enantiomers. Thus, the individual enantiomers are the subject of this description in pure form, both levorotary and dextrorotatory antipodes, in the form of racemates and as mixtures of the two enantiomers in all proportions. In the case of cis/trans isomerism, this description includes 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 means, for example, chromatography or crystallization, using stereochemically homogeneous starting materials for the synthesis, or stereoselective synthesis. Optionally, derivatization can be carried out before the separation of stereoisomers. The separation of the mixture of stereoisomers can be carried out at an intermediate stage during the synthesis of the compound of formula I, or it can be carried out on 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 description includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

As will be appreciated by one skilled in the art, some of the compounds of the present disclosure may exist as tautomers. All tautomeric forms of such compounds, whether isolated individually or in mixtures, are included within the scope of the present description. For example, in cases where an oxo (=O) substituent is allowed on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent may actually be present, in whole or in part, in the -OH form.

The atoms in a compound of formula I may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present specification is intended to include all suitable isotopic variants of the compounds of Formula I; for example, the different isotopic forms of hydrogen (H) include protium ( ^1H ) and deuterium ( ^2H ). Protium is the predominant isotope of hydrogen found in nature. Deuterium enrichment may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may provide a compound used as a standard for characterizing biological samples. Isotopically enriched compounds of formula I can be prepared without undue experimentation by conventional methods well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, using suitable isotope-enriched reagents and/or intermediates .

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 its recipient). When the compounds of formula I contain one or more acidic groups or basic groups, the invention includes the corresponding pharmaceutically acceptable salts.

Thus, compounds of formula I which contain acidic groups (eg -COOH) can be used in accordance with the invention in the form of, for example, but not limited to, 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 of formula I which 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, such as, but not limited to, hydrochloride, hydrobromide, salts with phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acids, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid acid, pivalic 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, etc. If the compounds of formula I simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). Salts can be prepared from compounds of formula I 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 of formula I 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.

The present description covers any composition consisting of a compound of formula I or a compound that is a salt thereof, including, for example, but not limited to, a composition consisting of the said compound bound together with one or more additional molecular and/or ionic components that may be called a "cocrystal". As used herein, the term “cocrystal” refers to a solid phase (which may or may not be crystalline) where two or more different molecular and/or ionic components (usually in a stoichiometric ratio) are held together by nonionic interactions, including but not limited to them, hydrogen bonds, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces (Van der Waals). There is no proton transfer between dissimilar components, and the solid phase is neither a simple salt nor a solvate. A discussion of cocrystals can be found, for example, in S. Aitipamula et al., Crystal Growth and Design , 2012, 12(5), pp. 2147-2152.

In addition, the compounds of the present invention may exist in amorphous form and/or in one or more crystalline forms, and as such, all amorphous and crystalline forms and mixtures thereof of the compounds of formula I and their salts are intended to be included within the scope of this specification. In addition, some of the compounds herein may form solvates with water (ie, hydrates) or common organic solvents. Such solvates and hydrates, especially the pharmaceutically acceptable solvates and hydrates of the compounds herein, are also included within the scope of the compounds defined by Formula I and their pharmaceutically acceptable salts, along with non-solvated and anhydrous forms of such compounds.

Accordingly, the compounds of Formula I or salts thereof, including pharmaceutically acceptable salts thereof, embodiments thereof, and specific compounds described and claimed herein include all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), cocrystalline forms, solvate and hydrate forms, and any combinations of the above forms, where such forms are possible.

Another embodiment of the present disclosure provides a compound of formula I, wherein the compound or a salt thereof is in substantially pure form. As used herein, the term “substantially pure” means at least about 60% by weight, typically at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% of the mass. (for example, from about 90% by weight to about 99% by weight), even more preferably, at least about 95% by weight. (for example, from about 95 wt.% to about 99 wt.% or from about 98 wt.% to 100 wt.%), and most preferably, at least about 99 wt.%. (eg, 100% by weight) of a product containing a compound of Formula I or a salt thereof (eg, a product isolated from a reaction mixture yielding the compound or salt) constitutes the compound or salt. The level of purity of the compounds and salts can be determined using standard analytical methods such as high performance liquid chromatography and/or mass spectrometry or NMR methods. If more than one analytical method is used and the methods provide experimentally significant differences in a given level of purity, then the method providing the highest level of purity takes precedence. A compound or salt with 100% purity is a compound or salt that does not contain detectable impurities as determined by a standard method of analysis. With respect to a compound of the invention that has one or more asymmetric centers and may occur 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 of formula I herein and their pharmaceutically acceptable salts are useful for inducing GAG-POL dimerization in HIV-infected cells and thereby selectively killing HIV-infected cells expressing GAG-POL without the concomitant cytotoxicity to HIV-naïve cells, referred to as herein, small molecule activated cell killing activity (SMACK). Thus, the compounds of formula I and their pharmaceutically acceptable salts are useful for:

(i) A method of treating HIV infection or treating, preventing or delaying the onset or progression of AIDS or ARC in a human in need thereof, which comprises administering to the human an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof;

(ii) A method of causing dimerization of GAG-POL in HIV-infected cells in a human in need thereof, which comprises administering to the human an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and/or

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

In addition, the compounds of formula I and their pharmaceutically acceptable salts are useful in any of methods (i), (ii) or (iii) above, further comprising administering to a human an effective amount of one or more compatible HIV antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors. In methods (i), (ii) and (iii) immediately above, a person is treated with a compound of formula I or a pharmaceutically acceptable salt thereof in addition to treatment with one or more compatible HIV antiviral agents.

The compounds of Formula I and their pharmaceutically acceptable salts are also useful for a method of enhancing suppression of HIV viremia in a human whose viremia is suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the human an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Other embodiments of the present disclosure include the following:

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

(b) A pharmaceutical composition that contains a product obtained by combining (eg, mixing) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(c) The pharmaceutical composition of claim (a) or (b), further comprising an effective amount of one or more compatible anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents.

(d) The pharmaceutical composition of claim (c), wherein the compatible anti-HIV agent is selected from one or more antivirals selected from the group consisting of nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase translocation inhibitors, non-nucleoside reverse transcriptase inhibitors HIV transcriptase, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.

(e) A combination which is (i) a compound of formula I or a pharmaceutically acceptable salt thereof and (ii) one or more compatible anti-HIV agents selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound and a compatible anti-HIV agent are each used in an amount that makes the combination effective for treating HIV infection, or for treating, preventing, or delaying the onset or progression of AIDS or ARC.

(f) Combination (e), wherein the compatible anti-HIV agent is an antiviral drug selected from the group consisting of nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, inhibitors fusions of HIV, HIV entry inhibitors and HIV maturation inhibitors.

(g) A method of causing dimerization of GAG-POL in HIV-infected cells, a method of selectively killing HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to HIV-naïve cells, and/or a method of treating HIV infection, or treating, preventing or delaying it. the onset or progression of AIDS or ARC, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

(h) The method of (g), wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one other compatible HIV antiviral agent selected from nucleoside or nucleotide reverse transcriptase inhibitors of HIV, nucleoside reverse translocation inhibitors transcriptase, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.

(i) Method (g) or (h), comprising administering to a subject a pharmaceutical composition (a), (b), (c) or (d) or a combination of (e) or (f).

(j) Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for (1) inducing GAG-POL dimerization in HIV-infected cells in a subject; (2) selectively killing HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to HIV-naïve cells in the subject; (3) treating HIV infection in the subject; (4) treating, preventing or delaying the onset or progression of AIDS or ARC in a subject; and/or (5) enhancing suppression of HIV viremia in a subject being treated with a compatible anti-HIV agent.

(k) A compound of formula I or a pharmaceutically acceptable salt thereof for use in (1) inducing GAG-POL dimerization in HIV-infected cells; (2) selective killing of HIV-infected cells expressing GAG-POL without concomitant cytotoxicity to HIV-naïve cells; (3) treatment of HIV infection; (4) treating, preventing or delaying the onset or progression of AIDS or ARC; and/or (5) enhancing suppression of HIV viremia in a subject being treated with a compatible anti-HIV agent.

Additional embodiments of the present invention include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of Formula I or a salt thereof used therein is in substantially pure form. With respect to a pharmaceutical composition containing a compound of Formula I 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 of Formula I or a salt thereof as such.

Another embodiment of the present disclosure includes 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 of Formula I means providing the compound to an individual in need of treatment or prophylaxis, and includes both self-administration and administration to a patient by another person. When a compound is presented in combination with one or more other active agents (for example, antiviral agents useful in the treatment or prevention of HIV infection or AIDS), "administration" and variations thereof are each understood to include providing the compound and other agents at the same time time or at different times. When the combination agents are administered simultaneously, they may be administered together in one composition or they may be administered separately.

As used herein, the term “composition” is intended to cover 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.

The term "subject" or "patient" as used herein refers to an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation or experiment.

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 HIV-naïve 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, treat HIV infection, or is effective to treat or delay the onset or progression of AIDS, or ARC in a patient infected with HIV. Another embodiment of an “effective amount” is a “prophylactically effective amount”, which is an amount of a compound effective to prevent 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, for treating HIV infection, and a prophylactically effective amount, for example, for preventing or reducing the risk of developing AIDS or ARC in a subject infected with HIV. As used herein, the term “prevention” refers to reducing the likelihood or severity of AIDS following HIV infection.

In the combination therapies of the present invention, the effective amount may refer to each individual agent or to the combination as a whole, where the amounts of all agents administered in the combination are collectively effective, but where the component agent of the combination may or may not be present individually in an effective amount relative to that considered effective for a given component of the agent when administered alone.

In the methods of the present invention (i.e., selectively killing HIV-infected cells expressing GAG-POL, treating HIV infection or treating, preventing or delaying the onset or progression of AIDS or ARC), the compounds of this invention or salts thereof can be administered by means of , ensuring contact of the active agent 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 in combinations of therapeutic agents. The compound can be administered alone, but is typically administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. The compounds of the present invention can, for example, be administered orally (for example, in the form of a tablet or capsule), parenterally (including, for example, subcutaneous injection, intravenous, intramuscular or intrasternal injection or infusion methods), by inhalation spray, or rectally, in unit dosage the form of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and delivery devices. The compound may also be administered via an implantable drug delivery device adapted to provide an effective amount of the compound or pharmaceutical composition of the compound over an extended period of time.

COMPOSITIONS

Solid preparations suitable for oral administration (eg, powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can use solid excipients such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like. Liquid preparations suitable for oral administration (for example, suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can use any of the usual vehicles such as water, glycols, oils, alcohols and the like . 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, wherein 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, where the carrier includes the active chemical ingredient with polymers as suitable excipients, or using an implantable drug delivery device. Further description of methods suitable for use in the preparation of pharmaceutical compositions for use in the present invention, and ingredients suitable for use in said compositions, is presented in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6 and previous editions.

Formulations of compounds of Formula I that result in supersaturation and/or rapid dissolution of the drug can be used to facilitate oral absorption of the drug. Formulation approaches that cause supersaturation and/or rapid dissolution of the drug 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 reviews (eg, A.T.M. Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticle systems based on both depletion and direct synthesis are also described in reviews such as Wu et al (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

The compounds of Formula I can be administered at a dosage range, for example, 1 to 20 mg/kg, or 1 to 10 mg/kg, or about 5 mg/kg body weight of a mammal (eg, human) per day, or at other time intervals , depending on the situation, once or in several doses. The compounds of formula I can be administered in a dosage range of 0.001 to 2000 mg per day, either 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, administered orally or by other routes of administration as a single dose or divided doses.

For oral (e.g., tablets or capsules) or other routes of administration, dosage units may contain from 100 mg to 1500 mg of active ingredient, for example, but not limited to, 100, 150, 200, 250, 300, 350, 400, 450, 500 , 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 milligrams of the active ingredient for symptomatic dosage adjustments for the patient being treated. In addition, the compound may be formulated into oral formulations for immediate or modified release, such as sustained or controlled release. When a compound of Formula I is administered as a salt, reference to the amount of compound in milligrams or grams is based on 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 more than one dose at different times (divided daily doses) every 24 hours. Each dose can be administered using one or more dosage units, depending on the situation.

The specific dose level and dosing frequency for any given patient may vary and will depend on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, route and time of administration. , rate of elimination, combination of drugs, severity of the specific condition and the host undergoing therapy. In some cases, depending on the potency of the compound or individual response, deviations up or down from this dose may be necessary. 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 suppressing HIV, treating or preventing HIV infection and/or treating, preventing or delaying the onset or progression of AIDS or ARC. It is understood that an anti-HIV agent is effective for treating, preventing or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions resulting from or associated therewith. The present description is further directed to the use of a compound of formula I with one or more compatible anti-HIV agents, that is, anti-HIV agents other than HIV protease inhibitors. For example, compounds of formula I can be administered in combination with effective amounts of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infectives or vaccines useful for the treatment of HIV infection or AIDS. Suitable compatible HIV antiviral drugs for use in combination with the compounds herein include, but are not limited to, those listed in Table A, as follows:

Table A : Antiviral agents for the treatment of HIV infection or AIDS

Name Type abacavir, ABC, ZIAGEN® NRTI abacavir +lamivudine, EPZICOM® NRTI abacavir+lamivudine+zidovudine, TRIZIVIR® NRTI AZT, zidovudine, azidothymidine, RETROVIR® NRTI capravirine NNRTI ddC, zalcitabine, dideoxycytyline, HIVID ® NRTI ddI, didanosine, dideoxyinosine, VIDEX® NRTI ddI (enteric-coated), VIDEX EC® NRTI delavirdine, DLV, RESCRIPTOR® NNRTI dolutegravir, TIVICAY® InSTI 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) NRTTI Elvitegravir InSTI emtricitabine, FTC, EMTRIVA® NRTI emtricitabine+tenofovir DF, TRUVADA® NRTI emivirine, COACTINON® NNRTI enfuvirtide, FUZEON® FI enteric-coated didanosine, VIDEX EC® NRTI etravirine, TMC-125 NNRTI lamivudine, 3TC, EPIVIR® NRTI lamivudine+zidovudine, COMBIVIR® NRTI maraviroc, SELZENTRY® EI nevirapine, NVP, VIRAMUNE® NNRTI raltegravir, MK-0518, ISENTRESS™ InSTI Rilpivirine NNRTI stavudine, d4T, didehydrodeoxythymidine, ZERIT® NRTI tenofovir disoproxil fumarate, VIREAD® NRTI tenofovir alafenamide fumarate NRTI vikrivirok EI

EI=entry inhibitor; FI=fusion inhibitor; InSTI=integrase inhibitor; NRTI=nucleoside or nucleotide reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTTI=nucleoside reverse transcriptase translocation inhibitor. Some of the drugs listed in the table are used in salt form, for example, abacavir sulfate, delavirdine mesylate.

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

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

The following acronyms and abbreviations have the meanings indicated:

ACN=acetonitrile AcOH=acetic acid; Ac=acetyl=-C(O)CH ₃ ; aq.=water aq.=water B ₂ Pin ₂₌ bis(pinacolato)diborone BPO=benzoyl peroxide CNA=ceric ammonium nitrate cataCXium® A Pd G2 precatalyst=chloro[(di(1-adamantyl) -N -butylphosphine)-2-(2-aminobiphenyl)]palladium(II) TDAS=(diethylamino)sulfur trifluoride DCE=1,2-dichloroethane DCM=dichloromethane DDC=2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD=diisopropyl azodicarboxylate DHP=3,4-dihydro- 2H -pyran DIBAL-H=diisobutylaluminum hydride DIPEA-diisopropylethylamine DME=dimethoxyethane DMF= N, N -dimethylformamide Dess-Martin periodinan=1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one DMA=dimethylacetamide DMSO=dimethyl sulfoxide DMSO _- d6 ₌ deuterated dimethyl sulfoxide for example=for example, but not limited to EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTA=ethylenediaminetetraacetic acid EtOAc=ethyl acetate EtOH=ethanol FBS=fetal bovine serum GFP=Green Fluorescent Protein HIV=human immunodeficiency virus HOBt=hydroxybenzotriazole HPLC=high performance liquid chromatography h=hour KI=potassium iodide Ir [(Ome)(1,5-COD)] ₂ =(1,5-cyclooctadiene)(methoxy)iridium(I) dimer l=liter; g=gram DPLC=liquid chromatography area fraction LC-MS, LCMS=liquid chromatography - mass spectroscopy DAL=lithium diisopropylamide AHL=lithium aluminum hydride m-CPBA=3-chloroperbenzoic acid Me=methyl MeI=methyl iodide MeOH=methanol Me-THF=2-metaltetrahydrofuran MTBE=methyl tert-butyl ether min=minute MS=mass spectroscopy MsCl, Mesyl-Cl=methanesulfonyl chloride NaIO ₄ = sodium periodate NBS= N -bromoscynimide n-BuLi=n-butyllithium NCS= N -chlorosuccinimide HSS=healthy human serum NMP= N -methyl-2-pyrrolidinone NMR=nuclear magnetic resonance PBMC=peripheral blood mononuclear cells PBS=phosphate buffered saline Pd ₂ (dba) ₃ = tris(dibenzylideneacetone)dipalladium(0) PdCl ₂ (dppf)=[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc) ₂ = palladium(II) acetate Pd(Ph ₃ P) ₄₌ tetrakis(triphenylphosphine)palladium(0) PE, P.E.=petroleum ether PHA=phytohemamaglutinin PMB=4-methyloxybenzyl PMBCl=4-methoxybenzyl chloride PPTS=4-toluenesulfonic acid RT=room temperature saturated=saturated SMACK - small molecule activated cell killing SN _Ar =nucleophilic aromatic substitution FTBA=tetrabutylammonium fluoride Tc=thiophene carboxylate t -BuOH= tert -butanol t -BuOK= potassium tert -butoxide t -BuONO= tert -butyl nitrite TEA=triethylamine TFA=trifluoroacetic acid TFAA=trifluoroacetic anhydride THF=tetrahydrofuran TLC=thin layer chromatography TMS-Cl=trimethylsilyl chloride X-Phos=2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

Several methods for preparing the compounds of the present invention are described in the following schemes and examples. Starting materials and intermediates are purchased or prepared using known procedures, or as otherwise illustrated in the five Intermediate sections ( A, B, C, AB, and BC ) that follow. A frequently used method for preparing compounds of formula I is described in the following schemes.

SCHEME 1

Scheme 1 depicts the method for preparing compounds of formula I. Intermediate AB is prepared by the procedures illustrated in the section "Intermediate AB ". The Mitsunobu reaction or alkylation using a suitable benzyl alcohol or pyridinone halide (intermediate C ) gives intermediate ABC . Intermediate C typically has a protected (PG') pyridinone group, designated Z in Scheme 1. The synthesis of C is illustrated in the section "Intermediate C ". The resulting ABC intermediate may optionally be subject to further modification followed by a deprotection step to produce compounds of formula I.

SCHEME 2

Scheme 2 illustrates another method for preparing compounds of formula I. The SN _Ar reaction between intermediate A (commercially available or prepared using the procedures described in the "Intermediate A " section) and intermediate BC (prepared using the procedures illustrated in the "Intermediate" section connection BC "). used to create an ABC intermediate. The C ring of pyridinone is usually protected by a protecting group (PG'), such as methyl or a PMB group. The resulting ABC intermediate may then optionally be subjected to further modification followed by a deprotection step to produce compounds of Formula I.

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

The progress of the reactions is determined either by analytical thin layer chromatography (TLC), typically performed with E. Merck precoated TLC plates, silica gel 60F-254, 0.25 mm layer thickness, or by analytical liquid chromatography-mass spectrometry (LC-MS). Typically, the LC-MS analytical system used consists of a Waters ZQ™ platform with electrospray ionization in positive ion mode using an Agilent 1100 Series HPLC with autosampler. The column is typically Waters Xterra MC C18, 3.0 x 50 mm, 5 µm or Waters Acquity UPLC® BEH C18, 1.0 x 50 mm, 1.7 µm. The flow rate is 1 ml/min and the injection volume is 10 μL. UV determination is carried out in the range of 210-400 nm. The mobile phase consists 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 moving to 100% solvent B over 3. 75 min, held for 1.1 min, then switching to 100% solvent A for 0.2 min. LC/MS determinations are performed on a Waters Classing Aquity system equipped with TUV and MS detectors and a Waters SQD mass spectrometer, Shimadzu 20 UV 254 and 220 nm with a Shimadzu 2010 or 2020 mass spectrometer or an Agilent 1200 HPLC with DAD/ELSD and G6110 MSD with 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 in acetonitrile with gradient from 90:10 (A:B) to 5:95 (A:B) over 6 minutes at a flow rate of 1.8 ml/min, UV detection at 210 nm; 2) Aquity BEH C18, (1.0 x 50 mm) 1.7 µm column 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 minutes at a flow rate of 0.3 ml/min, UV detection at 215 nm; 3) Agilent YMC J'Sphere H-80 (3x50 mm) 5 µm column 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 quadrupole mass spectrometer 1100; 4) Agilent TC-C18 (2.1 x 50 mm) 5 µm column 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 to 90:10 to 0:100 (A:B) for 3 min and 10:90 (A:B) for 0.6 min at 0.8 ml flow rate /min, UV detection at 254 and 220 nm and an Agilent 6110 quadrupole mass spectrometer.

Preparative HPLC purification is typically performed using either a mass spectrometry-guided system or a non-mass spectrometry-guided system. It is typically performed on a Waters Chromatography Workstation configured with an LC-MS system consisting of: Waters ZQ™ Single Quadrupole Electrospray Ionization MS System, Waters 2525 Gradient Pump, Waters 2767 Injector/Collector, Waters 996 PDA Detector, MS Conditions: 150-750 amu, positive electrospray, MS-triggered assembly and Waters SUNFIRE® c-18 5 micron, 30 mm (ID) x 100 mm column. Mobile phases consist of mixtures of acetonitrile (10-100%) in water containing 0.1% TFA. The flow rate is maintained at 50 mL/min, the injection volume is 1800 μL, and the UV detection range is 210–400 nm. An alternative is to use a preparative HPLC system with a Gilson Workstation consisting of: Gilson GX-281 injector/manifold, Gilson UV/VIS-155 sensor, Gilson 333 and 334 pumps and equipped with a column selected from the following: Phenomenexd Synergi C18 (150 mm x 30 mm x 4 microns), YMC-Actus Pro C18 (150 mm x 30 mm x 5 microns), Xtimate C18 (150 mm x 25 mm x 5 microns), Boston Green ODS (150 mm x 30 mm x 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 (0-100% acetonitrile/water eluent 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 TPA). The injection volume is from 1000 to 8000 µL, and the UV detection range is 210-400 nm. Mobile phase gradients are optimized for individual compounds.

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

Chiral SLC separations are performed on Sepiate Prep SFC 100, Multigram II (MG II), THAR80 Prep SFC, or Waters SFC (80, 200, or 350) using the conditions described in the experimental section.

Proton or ¹ H NMR is recorded using a Varian Unity-Inova 400 MHz NMR spectrometer equipped with a Varian 400 ATB PFG 5 mm, Nalorac DBG 400-5 or Nalorac IDG 400-5, Varian-400 MHz MR spectrometer equipped with an Auto X ID PFG Probe 5 mm, a Varian 400MHz VNMR spectrometer equipped with a PFG 4Nuc Probe 5 mm, or a Bruker AvanceIII 500MHz spectrometer equipped with a PABBO Probe 5 mm, in accordance with standard analytical methods, unless otherwise specified, and present the results of the spectral analysis. ¹ H NMR spectra were recorded in CDCl ₃ solutions unless otherwise indicated. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) is used as an internal standard in CD ₃ Cl solutions, and the residual peak of CH ₃ OH or TMS is used as an internal standard in CD ₃ OD solutions. Combination constants (J) are expressed in Hertz (Hz).

It is understood that the chiral center in a compound can exist in the " S " or " R " stereoconfiguration, or as a mixture of both. Within a molecule, each bond, drawn as a straight line from the chiral center, spans each of the ( R ) and ( S ) stereoisomers, as well as mixtures thereof, unless otherwise noted. Compounds in Examples 32 , 33 , and 34 contain a chiral center. The mixture of isomers obtained as described in each of the experiments for these compounds is separated to give one or both of isomer A (the faster eluting isomer) and isomer B (the slower eluting isomer) based on their observed elution order obtained in the result of the division, as done in the Example. Elution times and/or order of separated isomers may differ if performed under conditions other than those used here. The absolute stereochemistry ( R or S ) of the chiral center in each of the separated "A" and/or "B" stereoisomers in Examples 32 , 33 , and 34 is not determined, and "A" and "B" refer only to the order of elution resulting from the conditions met cleaning. An asterisk (*) may be used in corresponding chemical structure drawings of example compounds to indicate the chiral center.

Intermediate A section

Intermediate connection A01

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) add PMBCl (34 g, 0.21 mol) and K₂CO₃ (55 g, 0.4 mmol), then the mixture was stirred at 70°C for 4 hours. The reaction mixture was filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica (2% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃): 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) add 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 is filtered and extracted with EtOAc (3 x 400 ml). The combined organic layers are washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (1-2% EtOAc/petroleum ether) 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) add 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 RT for 3 hours. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc (3×200 ml). The organic layer is washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (2-10% EtOAc/petroleum ether) 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) add TDAS (106 g, 0.6 mol) at 0°C under N ₂ atmosphere, then the mixture is stirred for 3 hours at RT. After completion of the reaction, the mixture is quenched with water and extracted with DCM (3 x 200 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/TFUA (100 ml/50 ml) was stirred at 110°C for 3 hours. Once complete reactions, the resulting mixture is quenched sat. aq. NaHCO ₃ (100 ml) and extracted with EtOAc (3 x 150 ml). The combined organic layers are 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).

Intermediate connection A02

5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile

Step 1: 5-formyl-2-methylbenzonitrile

In a 20 L 4-neck round bottom flask, purged and kept under an inert nitrogen atmosphere, place a solution of 5-bromo-2-methylbenzonitrile (750 g, 38.26 mol) in tetrahydrofuran (6 L), n-BuLi (1.54 L , 38.26 mol) was added dropwise at -78°C, the resulting solution was stirred for 30 minutes, N,N-dimethylformamide (295 g, 4.04 mol, 1.05 equiv.) was added dropwise. And the reaction mixture is stirred at -78°C for 30 minutes in a liquid nitrogen bath, and then quenched by adding 5 L of sat. NH ₄ Cl aq. the resulting solution is extracted with EtOAc (3 x 5 L). The organic layer was washed with brine, dried over Na ₂ SO4, 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) is placed in a 3-liter, 4-neck round-bottom flask, purged and kept in an inert atmosphere of nitrogen, and the reaction mixture is stirred at 60° C,1-bromopyrrolidine-2,5-dione (300 g, 1.69 mol) was added in 3 batches. The resulting solution is stirred at 60°C for 30 minutes. The reaction mixture was then quenched by adding 5 L of water/ice and stirred for 1 hour. The solids were collected by filtration and dried under vacuum to give the title compound and used as is in the next step.

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

A solution of 3-bromo-5-formyl-2-methylbenzamide (500 g (crude product from step 2, 2.07 mol) in dichloromethane (10 l), pyridine (524.5 g, 6.63 mol). While the resulting solution was stirred at 0°C, 2,2,2-trifluoroacetate (1305 g, 6.21 mol) was added dropwise. The resulting solution was stirred for 30 min at RT, then quench with water/ice (5 L) and extract with DCM (3 x 5 L). The organic layers are combined and dried over anhydrous Na ₂ SO ₄ , filter and concentrate under reduced pressure. The residue is purified by flash chromatography on dioxide silicon (20% EtOAc/hexane) to obtain 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), TDAS (260 g, 1.61 mol, 1.00 equiv.) was added dropwise with CT. The resulting solution was stirred at RT for 1 hour and then quenched with water/ice (3 L). The resulting solution is extracted with DCM (3 x 5 L). The organic layers are combined and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound and used as is 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), add 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 (3×) and stirred at 90°C for 1 hour, and then partitioned between ice water (4 L) and EtOAc (3×2 L). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (33% EtOAc/hexane) to give the title compound. MS: 182 (M+1). ^1H NMR (400 MHz, DMSO- d6 ): 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

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) add 1-chloropyrrolidine-2,5-dione (5.15 g, 38.6 mmol) and the resulting mixture stir at 60°C for 6 hours. The mixture is divided between water (200 ml) and EtOAc (2×150 ml). The combined organic layers were washed with brine (3×300 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 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), add tert-butyl nitrite (17.34 ml, 146 mmol) at 25°C for 1 hour. The reaction mixture is diluted with water (180 ml) and extracted with EtOAc (3 x 120 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (10-100% EtOAc/petroleum ether) to give the title compound. ^1H NMR (400 MHz, chloroform- d ): δ ppm. 7.51 (dd, J = 2.26, 1.65 Hz, 1 H), 7.44-7.47 (m, 1 H).

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

To a stirred solution of (4-methoxyphenyl)methanol (2.75 g, 19.89 mmol) in DMF (40 ml) was added NaH (1.034 g, 25.9 mmol) 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 (3 x 150 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , 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), TFA (20 ml) and then stirred at 25°C for 1 hour. After completion, the reaction mixture is poured into sat. aq. NaHCO ₃ (30 ml), extract with DCM (3 x 60 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).

Intermediate connection A04

3-bromo-5-chloro-2-fluorophenol

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

To a solution of 2-bromo-4-chloro-1-fluorobenzene (300 g, 1.43 mol) in hexane (4.5 L), add B ₂ Pin ₂ (363.7 g, 1.43 mol), Ir [ (Ome) (1,5-COD)] ₂ (14.2 g, 21.42 mmol), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (11.5 g, 42.85 mmol), then purged with nitrogen three times. The resulting solution was stirred at RT overnight and then concentrated in vacuo. The residue is purified by flash chromatography on silica (0-100% EtOAc/petroleum ether) 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), add a solution of sodium hydroxide (138 g, 3.45 mol) in water (3 l), 35% aq. hydrogen peroxide (390 g, 3.44 mol) at 0°C. the resulting solution is stirred at 0°C for 2 hours, and quenched with sat. aqueous solution of Na ₂ SO ₃ . After adjusting the pH of the solution to 3-4 with HCl (1 M), the resulting solution is extracted with EtOAc (3 x 3 L). The combined organic layers are washed with brine, then concentrated under reduced pressure. The residue is purified by flash chromatography on silica (0-90% EtOAc/petroleum ether) to give the title compound. ^1H NMR (400 MHz, CDCl ₃ ): δ 11.31 (bs, 1H), 7.47 (dd, J =2.4, 4.4 Hz, 1H), 7.30 (dd, J =2 ,4, 7.6 Hz, 1H).

Intermediate connection A05

5-chloro-2-fluoro-3-hydroxybenzonitrile

To a solution of 3-bromo-5-chloro-2-fluorophenol (86 g, 343 mmol) in NMP (860 ml), add CuCN (154 g, 1.72 mol) in one portion. The resulting reaction mixture was stirred at 180°C for 2 hours, then partitioned between ice water (1 L) and EtOAc (3 x 800 ml). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (2-33% EtOAc/petroleum ether) to give the title compound. ^1H NMR (400 MHz, DMSO- d6 ): δ 11.33 (bs, 1H), 7.49 (dd, J =2.5, 4.5 Hz, 1H) _, 7.30 (dd, J =2.5, 7.6 Hz, 1H).

Intermediate connection A06

5-chloro-3-hydroxy-2-methylbenzonitrile

Stage 1: 2,3-difluorobenzaldehyde

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

Stage 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 DMF (10 L) was stirred at 20°C for 3 hours, then divided between (6 L) and EtOAc (3 × 8 L). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (2% EtOAc/petroleum ether) 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 DMF (11 L) was treated with POCl ₃ (5688 g, 37.10 mol). The resulting solution was stirred at 25°C for 3 hours, then divided between (6 L) and EtOAc (3 x 6 L). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (2% EtOAc/petroleum ether) 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 into NH ₃ (gas). The resulting solution was stirred at 140°C for 8 hours, cooled to RT, then concentrated under reduced pressure. The remainder is divided between (5 L) and MTBE (3 × 8 L). The combined organic layers were washed with water, brine and 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 DMF (14 L) was treated with NCS (1008 g, 7.55 mol). The resulting solution was stirred at 45°C for 2 hours, then partitioned between ice water (20 L) and EtOAc (3 × 12 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (3% EtOAc/petroleum ether) 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), add a solution of 2-amino-5-chloro-3-fluorobenzonitrile (747 g, 4.38 mol) in ACN (7 L) dropwise with stirring for 90 minutes. The resulting mixture was stirred at RT for 10 h, and diluted with water (15 L), and then extracted with EtOAc (3 x 10 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (3% EtOAc/petroleum ether) 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 1,4-dioxane (4500 ml) and water (450 ml) was stirred at 100°C for 60 min and then diluted with water (4 l), and extract with EtOAc (3 x 6 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (3% EtOAc/petroleum ether) to give the title compound.

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

Under a nitrogen atmosphere, to a solution of 4-methoxybenzyl alcohol (410 g, 2.97 mol) in DMF (3200 ml), add sodium hydride (128 g, 5.33 mol), then add a solution of 5-chloro-3-fluoro- 2-methylbenzonitrile (418 g, 2.46 mol) in DMF (800 ml) dropwise. The resulting solution was stirred at 25°C for 12 hours, then diluted with ice water (2 L), and extracted with EtOAc (3 x 3 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting solid was washed with petroleum ether and collected at the top of the 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 at the top of the filter to give the title compound. MS: 166 (M-1). ^1H NMR (400 MHz, DMSO- d6 ): 10.67 (s, 1H), 7.32-7.33 (d, 1H), 7.07-7.08 (d, 1H) _, 2. 24 (s, 3H).

Intermediate connection A07

5-fluoro-3-hydroxy-2-methylbenzonitrile

Step 1: 3-bromo-5-fluoro-2-methylaniline

To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (23 g, 98 mmol) in ethanol (390 ml), add ammonium hydrochloride (26.3 g, 491 mmol) and water (38.3 ml , 2126 mmol) then add iron solution (27.4 g, 491 mmol). The resulting mixture was stirred at 90°C for 6 hours. After completion of the reaction, monitored by TLC, the reaction mixture was filtered through a sintered funnel. The filtrate is evaporated under reduced pressure. The residue was purified by silica column chromatography (5% EtOAc/petroleum ether) to give the title compound. MS: 204.2 and 206.2 (M+1).

Step 2: 3-bromo-5-fluoro-2-methylphenol

To a solution of sulfuric acid (145 ml, 2729 mmol) in water (21.73 ml, 1206 mmol) add 3-bromo-5-fluoro-2-methylphenol (7 g, 31.1 mmol). The resulting mixture is cooled in an ice bath to 0°C. A solution of sodium nitrate (6.66 g, 78 mmol) in water is then added dropwise. After stirring at this temperature for 30 minutes, the reaction mixture is heated at 100°C for 30 minutes, and then diluted with water and extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (4-10% EtOAc/petroleum ether) to give the title compound. MS: 203.2 and 205.2 (M-1).

Step 3: 5-fluoro-3-hydroxy-2-methylbenzonitrile

To a stirred solution of 3-bromo-5-fluoro-2-methylphenol (7 g, 34.1 mmol) in DMA (140 ml), add zinc powder (4.46 g, 68.3 mmol) and dppf (3.79 g, 6.83 mmol). The resulting mixture was degassed with nitrogen for 10 minutes and then Pd ₂ (dba) ₃ (1.563 g, 1.707 mmol) and zinc cyanide (8.02 g, 68.3 mmol) were added. The reaction vessel is hermetically sealed. And the resulting mixture is heated to 140°C for 6 hours, and then diluted with water (200 ml), and filtered through a layer of CELITE®. The filter cake is washed with EtOAc (400 ml). The filtrate layers are separated. The aqueous layer was then extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine (2×200 ml) and dried over sodium filtrate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography over silica (5-15% EtOAc/petroleum ether) to give the title compound. MS: 150.2 (M-1).

The following intermediates in Table 1 are purchased from commercial sources.

TABLE 1

Intermediate connection no. Structure IUPAC name CAS No. A08 4-hydroxy-3,5-dimethylbenzonitrile 4198-90-7 A09 3-bromo-5-hydroxybenzonitrile 770718-92-8 A10 3-chloro-5-hydroxybenzonitrile 473923-97-6

Section "Intermediate B"

Intermediate connection B01

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

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

To a solution of potassium heptaoxodichrome (1782 g, 6.06 mol) in sulfuric acid (2097 g, 21.38 mol) and water (2400 ml), add 2,2,3,3-tetrafluoropropan-1-ol (800 g, 6.06 mol) drop by drop with stirring at 100°C. The resulting solution was stirred at 100°C for 5 hours at reflux, and then extracted with MTBE (4×2L). The organic layer was dried with anhydrous sodium filtrate and concentrated under reduced pressure to obtain the title compound and used as is in the next step.

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), add sulphuroyl dichloride (787.2 g, 6.62 mol) dropwise at 0°C, then add DMF (753.4 g, 10.31 mol) dropwise. After stirring at RT for 45 min, the reaction mixture was cooled to 0°C, and then treated with methoxy(methyl)amine hydrochloride (1222.5 g, 12.53 mol), and TEA (1913 g, 18.91 mol) drops. The resulting mixture was stirred at RT for 5 hours and then quenched with ice water (2 L) and extracted with MTBE (3 L). The organic layer is washed with sat. aq. NaHCO ₃ , brine, dried over anhydrous sodium filtrate, 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), add ethyl 2-fluoroacetate (316.2 g, 2.98 mol ), 1M solution of LiHMDS in THF (3729 ml, 3.73 mol) at -78°C. 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 is extracted with MTBE (3x2L). The organic layer was washed with brine, dried over anhydrous sodium filtrate, 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), add formamidine acetate (1185.1 g, 11.38 mol), and sodium methoxide (492 g, 9.11 mol). The resulting mixture was stirred at RT for 2 hours, then quenched with ice water (1.5 L). After adjusting the pH of the solution to 3 with HCl(2M), the resulting mixture is extracted with MTBE (3 × 1 L). The combined organic layers are dried over anhydrous sodium filtrate, 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, CD ₃ OD): δ 8.10 (1H, s), 6.67~6.38(1H, m).

The following intermediates in Table 2 are prepared according to Scheme C using the procedure described for the synthesis of intermediate B01 using a known fluorinated alkyl alcohol or its corresponding acid or methyl ester.

TABLE 2

Intermediate connection No. Structure IUPAC name MS B02 5-fluoro-6-(pentafluoroethyl)-3,4-dihydropyrimidin-4-one 231.0 (M-1) B03 6-(1,1-difluoroethyl)-5-fluoropyrmidin-4(3H)-one 177.1 (M-1) B04 5-fluoro-6-(trifluoromethyl)pyrmidin-4(3H)-one 183.0 (M+1)

Intermediate connection B05

4-chloro-5-fluoro-6-methoxypyrmidine

To a solution of 4,6-dichloro-5-fluoropyrmidine (8.0 g, 47.9 mmol) in MeOH (80 ml) add sodium methoxide (3.05 g, 56.5 mmol) at 0°C. The resulting reaction mixture was stirred at 20°C for 2 hours, then quenched with water (20 ml) and then extracted with EA (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 connection B06

4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrmidine

To a solution of 4-chloro-5-fluoro-6-methoxypyrmidine (5.2 g, 28.8 mmol), tributyl (1-ethoxyvinyl) stannane (12.48 g, 34.5 mmol) in DMF (50 ml) Pd(Ph ₃ P) ₄ (0.5 g, 0.433 mmol). The resulting reaction mixture was stirred at 100°C for 4 hours under N ₂ atmosphere. Once complete, the reaction mixture is diluted with water (30 ml), extracted with EtOAc (3×100 ml). The combined organic layers are treated with sat. aq. KF (80 ml) and stirred at RT for 0.5 h, then passed through a layer of CELITE® filter. The filtrate is washed with water, brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is 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 connection B07

6-acetyl-5-fluoropyrmidin-4(3H)-one

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

Intermediate connection B08

1-(5-fluoro-6-methoxypyrmidin-4-yl)ethanone

To a stirred solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrmidine, B06 (12 g, 60.5 mmol) in ACN (100 ml) at 0°C, add dropwise 4M hydrochloric acid in 1. 4-dioxane (30 ml, 120 mmol). The resulting solution was stirred at room temperature for 1 hour and then carefully quenched with ice water (200 ml) and extracted with EtOAc. The combined organic layers are dried over anhydrous sodium filtrate, filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-20% EtOAc/petroleum ether) to give the title compound. MS: 171.4 (M+1).

Intermediate connection B09

5-fluoro-6-(1,1,2-trifluoroethyl)pyrmidin-4(3H)-one

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

A solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrmidine, B06 (0.2 g, 0.86 mmol) in ACN (3 ml) was added dropwise to a suspension of 1-chloromethyl-4-bis(tetrafluoroborate) fluoro-1,4-diazoniabicyclo[2,2,2]octane (0.456 g, 1.29 mmol) in ACN (2 ml) and water (1 ml) over 4 h, maintaining the temperature below 15°C. The reaction mixture is then quenched with sat. aq. NaHCO ₃ (10 ml) and stir for 10 minutes. Once complete, the mixture is extracted with EA (3×10 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)pyrmidine

To a solution of 2-fluoro-1-(5-fluoro-6-methoxypyrmidin-4-yl)ethanone (0.15 g, 0.60 mmol) in DCM (2 ml) add diethylaminosulfur trifluoride (0.578 g, 3.59 mmol ). The resulting reaction mixture was stirred at 20°C for 4 hours and then diluted with water and extracted with EtOAc (3×50 ml). The combined organic layers are concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/PE) to give the title compound. ¹ H 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)pyrmidin-4(3H)-one

To a mixture of 5-fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrmidine (0.05 g, 0.238 mmol) and KI (0.119 g, 0.714 mmol) in ACN (15 ml), add chlorotrimethylsilane ( 0.078 g, 0.714 mmol) at CT. 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 B10

5-fluoro-6-methoxypyrmidine-4-carboxylate

In a 20 L hermetically sealed test tube, purged with N ₂ , place a solution of 4-chloro-5-fluoro-6-methoxypyrmidine, 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). A CO cylinder is then placed for carbonylation at 2 bar and heated at 50° C. for 16 hours. The solids are filtered off. The filtrate is concentrated under reduced pressure to remove MeOH, and then diluted with EtOAc (4 L). Solids are filtered off. The filtrate is concentrated again under reduced pressure. The residue was purified by silica column chromatography (10% EtOAc/hexane) and then recrystallized (propan-2-ol:H ₂ O=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 connection B11

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

Trimethylsilyl chloride (25.7 mL, 201 mmol) was added slowly to a stirred suspension of methyl 5-fluoro-6-methoxypyrmidine-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 indicated completion of the reaction. The reaction mixture was quenched with methanol (100 ml) and concentrated to obtain the title compound, which was used in the next step without further purification. MS: 173.0 (M+1). ^1H NMR (400 MHz, DMSO- _d6 ) 8.12 (s, 1H), 2.59 (s, 3H).

Intermediate B12

5-bromo-6-(trifluoromethyl)pyrmidin-4(3H)-one

This intermediate is prepared by bromination of 6-(trifluoromethyl)pyrmidin-4(3H)-one using the procedures described in US20140100231(A1).

Intermediate B13

6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrmidin-4(3H)-one

To a solution of 6-acetyl-5-fluoropyrmidin-4(3H)-one, B07 (1.0 g, 5.44 mmol) in DMF (10 ml) add K ₂ CO ₃ (2.257 g, 16.33 mmol). The resulting reaction mixture was stirred at 20°C for 10 minutes, then 1-(chloromethyl)-4-methoxybenzene (1.023 g, 6.53 mmol) was added. The reaction mixture was stirred at 20°C for a further 6 hours and then diluted with water (50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers are washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (50% EtOAc/PE) to give the title compound. MS: 277.1 (M+1). ^1H NMR (400 MHz, CDCl ₃ ): 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 following intermediates in TABLE 3 are prepared under similar conditions to the above synthetic procedure described for the synthesis of intermediate B13 using the corresponding intermediate B.

TABLE 3

Intermediate connection Source material B Structure IUPAC name MS (M+1) B14 B03 6-(1,1-difluoroethyl)-5-fluoro-3-(4-methoxybenzyl)pyrmidin-4( 3H )-one 299.0 B15 B11 Methyl 5-fluoro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate 293.0 B16 B01 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrmidin-4(3H)-one 335.1 B17 B02 5-fluoro-3-(4-methoxybenzyl)-6-(perfluoroethyl)pyrmidin-4(3H)-one 353.1 B18 B04 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one 325.1 (M+23)

Intermediate connection B19

5-bromo-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one

This intermediate is prepared using the procedures described in US20140100231(A1).

Intermediate B20

5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrmidin-4(3H)-one

This intermediate is prepared using the procedures described in US20140100231(A1).

Intermediate C Section

Intermediate C01

(6-chloro-2-methoxypyridin-3-yl)methanol

Step 1: 6-chloro-2-methoxynicotinaldehyde

To a stirred mixture of t -BuLi (23.94 ml, 38.3 mmol) in THF (100 ml) at -78°C, add 2-chloro-6-methoxypyridine (5 g, 34.8 mmol). The resulting mixture was stirred at -78°C for 1 hour, and then DMF (3.51 ml, 45.3 mmol) was added and the reaction mixture was stirred at -78°C for 1.5 hours, and then quenched with acetic acid ( 3.99 ml, 69.7 mmol) at -78°C. The mixture is then heated to 20°C for 30 minutes. The mixture is neutralized with saturated aqueous NaHCO ₃ (200 ml) and extracted with EtOAc (3×50 ml). The combined organic fractions are washed with brine (3 x 50 ml), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (1-2% EtOAc/isohexane) to give the title compound.

Step 2: (6-chloro-2-methoxypyridin-3-yl)methanol

To a suspension of 6-chloro-2-methoxynicotinaldehyde (1 g, 5.83 mmol) in MeOH (12 ml) at 0°C, add sodium borohydride (0.140 g, 3.70 mmol) in portions over 20 minutes. The resulting mixture was stirred at 0°C for 40 minutes, then quenched with water and extracted with DCM (3x5 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used as is in the next step. MS: 174.1 (M+1).

Intermediate C02

(6-bromo-2-methoxypyridin-3-yl)methanol

Step 1: 6-bromo-2-methoxynicotinic acid

To a stirred solution of 2,2,6,6-tetramethylpiperidine (3.76 g, 26.6 mmol) in THF (50 ml) at -78°C, add a 2.5 M solution of n-BuLi in THF (10.64 ml, 26.6 mmol) drop by drop. The resulting mixture was stirred at the same temperature for 60 minutes, then a solution of 2-bromo-6-methoxypyridine (5 g, 26.6 mmol) in THF was added dropwise. The reaction mixture is stirred at the same temperature for 60 minutes and treated with crushed dry ice, added and stirred for 3 hours at -78°C, and then slowly warmed to room temperature and diluted with water. And then the pH of the mixture is adjusted to 3-4 using conc. HCl. The mixture is extracted with EtOAc (2×250 ml). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (50% EtOAc/petroleum ether) to give the title compound. MS: 230.2 and 232.0 (M-1).

Step 2: (6-bromo-2-methoxypyridin-3-yl)methanol

To a stirred solution of 6-bromo-2-methoxynicotinic acid (2.3 g, 9.91 mmol) in THF (20 ml), add a 1M solution of AHL in THF (19.82 ml, 19.82 mmol) dropwise at - 20°C. The resulting mixture was stirred at room temperature for 60 minutes, and then quenched with water (0.5 ml), 10% NaOH aqueous solution and water. The resulting mixture is stirred for 30 minutes and filtered through a layer of CELITE®. The filter cake is washed with EtOAc. The filtrate is concentrated under reduced pressure. The residue was purified first by silica column chromatography (30% EtOAc/petroleum ether) then using reverse phase HPLC (ACN/water with 0.1% TFA modifier) to give the title compound. MS: 217.4 and 219.4 (M+1).

Intermediate C03

(2-methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-3-yl)methanol

Mixture of 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (113 mg, 0.406 mmol ), (6-chloro-2-methoxypyridin-3-yl)methanol, C01 (47 mg, 0.271 mmol), and tribasic potassium phosphate (172 mg, 0.812 mmol) in 1,4-dioxane (2 ml) and water ( 1.0 mL) was purged with nitrogen for 5 minutes and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.81 mg, 0.027 mmol) was added. The resulting mixture was stirred at 80°C for 15 hours and then passed through a filter. The filtrate is concentrated under reduced pressure. The residue is purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 290.1 (M+1).

The following intermediates in TABLE 4 are prepared using a procedure similar to that described for the synthesis of intermediate C03 using the appropriate commercially available boronic acid or boronate.

TABLE 4

Intermediate connection Structure IUPAC name MS (M+1) C04 (2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)methanol 206.2 C05 (2-methoxy-6-(methoxymethyl)pyridin-3-yl)methanol 184 C06 (2-methoxy-6-methylpyridin-3-yl)methanol 154.4 C07 (2-methoxy-6-vinylpyridin-3-yl)methanol 166.0

Intermediate C08

1-(5-(chloromethyl)-6-methoxypyridin-2-yl)ethanone

Step 1: (6-(1-ethoxyvinyl)-2-methoxypyridin-3-yl)methanol and 1-(5-(hydroxymethyl)-6-methoxypyridin-2-yl)ethanone

To a solution of (6-chloro-2-methoxypyridin-3-yl)methanol, C01 (1 g, 5.76 mmol) and tributyl(1-ethoxyvinyl)stannane (4.16 g, 11.52 mmol) in DMF (5 ml) add Pd(Ph ₃ P) ₄ (0.200 g, 0.173 mmol). The resulting mixture was stirred at 100°C for 4 hours under a N ₂ atmosphere, and then cooled to room temperature and diluted with water (20 ml), and extracted with EtOAc (3×30 ml). The combined organic layers were treated with saturated aqueous KF (45 ml) and 4M HCl aqueous solution, stirred at 20°C for 0.5 h, then washed with brine (2 x 75 ml), dried over anhydrous Na ₂ SO ₄ , filter and concentrate under reduced pressure. The residue is purified by silica column chromatography (1-25% EtOAc/petroleum ether) to give the title compound. MS: 182.1 (M+1).

Intermediate C09

(4-chloro-6-methoxy-2-methylpyrmidin-5-yl)methanol

Step 1: Methyl 2-chloro-4,6-dimethylnicotinate

Thionyl chloride (20 mL, 275 mmol) was slowly added to 2-chloro-4,6-dimethylnicotinic acid (2 g, 10.78 mmol). The resulting mixture was stirred at 80°C for 2 hours and then concentrated under reduced pressure. The residue was treated with MeOH (20 ml) at 0°C, and then the reaction mixture was stirred at 20°C for 16 hours and concentrated under reduced pressure to obtain the title compound, which was used in the next step without further purification. MS: 200.1 (M+).

Step 2: Methyl 2-methoxy-4,6-dimethylnicotinate

To a solution of methyl 2-chloro-4,6-dimethylnicotinate (2.206 g, 11.05 mmol) in MeOH (20 ml) add sodium methanolate (3.58 g, 66.3 mmol) at 0°C. The resulting mixture was stirred at 60°C for 24 hours and then quenched with water (20 ml) and then extracted with DCM (3x20 ml). The combined organic layers were washed with brine (3×10 ml), 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: 196.1 (M+1).

Step 3: 2-methoxy-4,6-dimethylpyridin-3-yl)methanol

To a solution of methyl 2-methoxy-4,6-dimethylnicotinate (500 mg, 2.56 mmol) in THF (5 ml) add AHL (97 mg, 2.56 mmol) at 0°C. The resulting mixture was stirred at 20°C for 1 hour and then quenched with saturated ammonium chloride solution and extracted with DCM (3 x 10 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (25% EtOAc/petroleum ether) to give the title compound. MS: 168.3 (M+1).

Intermediate C10

(5-fluoro-2-methoxypyridin-3-yl)methyl methanesulfonate

Stage 1: 5-fluoro-2-methoxynicotinic acid

A mixture of sodium methoxide (5.70 g, 106 mmol) and methyl 2-chloro-5-fluoronicotinate (2 g, 10.55 mmol) in THF (15 ml) was stirred at 100 °C for 48 h, and then diluted with H ₂ O (30 ml) and acidified with HCl (1 M) to pH=3-4, and then extracted with EtOAc (3x20 ml). The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound, which is used directly in the next step without further purification. MS: 170 (M-1).

Step 2: (5-fluoro-2-methoxypyridin-3-yl)methanol

To a solution of 5-fluoro-2-methoxynicotinic acid (800 mg, 4.67 mmol) in THF (10 ml) was added AHL (266 mg, 7.01 mmol). The resulting mixture was stirred at 25°C for 5 minutes, then quenched with water (0.27 ml) and aqueous NaOH (0.27 ml). The mixture is filtered. The filtrate is extracted with EtOAc (3×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound, which is used in the next step without purification. MS: 158 (M+1).

Intermediate C11

(2-methoxypyridin-3-yl)methanol

Step 1: Methyl 2-methoxynicotinate

To a stirred solution of 2-methoxynicotinic acid (1 g, 6.53 mmol) in methanol (10 ml), add H ₂ SO ₄ (0.696 ml, 13.06 mmol) at 0°C. The resulting mixture was stirred at 65°C for 6 hours, and then concentrated under reduced pressure to obtain the title compound. MS: 168.4 (M+1).

Step 2: (2-methoxypyridin-3-yl)methanol

To a stirred solution of methyl 2-methoxynicotinate (500 mg, 2.99 mmol) in THF (6 mL), a 1M solution of AHL in THF (5.98 mL, 5.98 mmol) was slowly added at 0°C. The resulting mixture is warmed to room temperature and stirred for 6 hours, and then cooled and quenched with a saturated aqueous solution of Na ₂ SO ₄ and EtOAc. The reaction mixture is filtered through a pad of CELITE®. The filter cake is washed with excess EtOAc. The filtrate is separated. The organic layer is concentrated under reduced pressure to obtain the title compound. MS: 140.4 (M+1).

Intermediate C12

(2-chloro-4,6-dimethylpyridin-3-yl)methanol

To a solution of 2-chloro-4,6-dimethylnicotinic acid (300 mg, 1.616 mmol) dissolved in THF (3 ml), add 1M AHL solution in THF (1.616 ml, 1.616 mmol) dropwise over 10 minutes at 0°C . The resulting mixture is stirred at 0°C for 2 hours, and then warmed to ambient temperature and stirred over the weekend. LCMS showed complete conversion to the desired product. The reaction mixture is diluted with water (~1 ml) very slowly, and the organic solvent is evaporated under reduced pressure, and then partitioned between EtOAc (10 ml) and water (5 ml). The aqueous layer was then extracted with EtOAc (2×10 ml). The combined organic layers are dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 172.0 (M+1).

Intermediate C13

6-chloro-3-(chloromethyl)-2-methoxypyridine

A solution of (6-chloro-2-methoxypyridin-3-yl)methanol, C01 (500 mg, 2.88 mmol) in DCM (14 ml) was treated with triethylamine (0.803 ml, 5.76 mmol) and then Mesyl-Cl (0.247 ml, 3.17 mmol) drop by drop. The resulting reaction mixture was stirred at 23°C overnight, and then partitioned between DCM and saturated aqueous NaHCO ₃ solution. The organic layers are separated and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-20% EtOAc/Hexane) to give the title compound. MS: 192.0 (M+1). ¹ H NMR (600 MHz, Chloroform-d) δ 7.58 (d, J=7.7 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 4.53 (s, 2H), 3.99 (s, 3H).

The following intermediates in TABLE 5 are prepared using a procedure similar to that described for the synthesis of intermediate C12 with the appropriate intermediate (6-methoxypyrimidin-5-yl)methanol C as starting material described in table C12 .

TABLE 5

Intermediate connection Source material C Structure IUPAC name MS (M+1) C14 C03 3-(chloromethyl)-2-methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridine 308.1 C15 C05 3-(chloromethyl)-2-methoxy-6-(methoxymethyl)pyridine 202.0 C16 C09 3-(chloromethyl)-2-methoxy-4,6-dimethylpyridine 186.5 C17 C06 3-(chloromethyl)-2-methoxy-6-methylpyridine 172.1 C18 C11 3-(chloromethyl)-2-methoxypyridine 158.2 C19 C07 3-(chloromethyl)-2-methoxy-6-vinylpyridine 184.1 C20 C10 3-(chloromethyl)-5-fluoro-2-methoxypyridine 175.9 C21 C08 2,4-dichloro-5-(chloromethyl)-6-methoxypyrmidine 200.1 C23 C12 2-chloro-3-(chloromethyl)-4,6-dimethylpyridine 192.1

Intermediate C24

5-bromo-3-(chloromethyl)-2-methoxypyridine

Intermediate C24 is synthesized using a procedure similar to intermediate C12 by replacing intermediate C01 with commercially available (5-bromo-2-methoxypyridin-3-yl)methanol.

AB Intermediate Section

Intermediate AB01

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

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

To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrmidin-4(3H)-one, B16 (7 g, 20.94 mmol) in NMP (46 .5 ml) add 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (4.22 g, 23.04 mmol) and K ₂ CO ₃ (8.68 g, 62.8 mmol). The resulting mixture was stirred at 80°C overnight. LCMS showed complete conversion. The reaction mixture is cooled to room temperature, then diluted with water. The precipitate is collected at the top of the filter and washed with water (3×), then air dried to give the title compound. MS: 498.1 (M+1).

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

Solution of 5-(difluoromethyl)-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)- 2-methylbenzonitrile (9.89 g, 19.88 mmol) in TFA (66.3 ml) and TFUA (33.1 ml) was stirred at 50°C overnight. LCMS showed complete conversion. The reaction mixture is concentrated under reduced pressure. The residue is triturated with hexane and the solid is collected at the top of the filter, washed with hexane, then air dried to give the title compound, which is used directly in the next step without further purification. MS: 378.3 (M+1).

The following intermediates in TABLE 6 are prepared in a similar manner to the preparation of intermediate AB01 described above: SN _Ar reaction using the appropriate intermediate A and intermediate B , then deprotected to remove the PMB group using TFA/TFAA.

TABLE 6

Intermediate connection
(A#, B#) Structure IUPAC name MS (M+1) AB02
(A02, B18) 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 346.1 AB03
(A02, B17) 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 396.1 AB04
(A06, B16) 5-chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 366.1 AB05
(A08, B16) 3,5-dimethyl-4-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 341.9 AB06
(A05, B17) 5-chloro-2-fluoro-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 384.0 AB07
(A09, B16) 3-bromo-5-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 392.0 AB08
(A10, B16) 3-chloro-5-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 346.2
(M-1) AB09
(A06, B16) 5-chloro-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 362.0 AB10
(A03, B16) 2,5-dichloro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 382.0 AB11
(A07, B16) 5-fluoro-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 346.1

Intermediate AB12

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)pyrmidin-4(3H)-one

To a solution of 6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrmidin-4(3H)-one, B13 (2 g, 7.24 mmol) in DMF (10 ml) add 3-bromo-5-chloro -2-fluorophenol, A04 (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 (3×50 ml). The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is 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)pyrmidin-4(3H)-one

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

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

To a solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrmidin-4(3H)-one (680 mg, 1.406 mmol) in DCM (10 ml) add TDAS (0.427 ml, 3.23 mmol) at 0°C. The resulting reaction mixture was stirred at 0°C for 1 hour and then diluted with water (5 ml), extracted with DCM (3 x 10 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-5-yl)oxy)benzonitrile

To a stirred solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrmidin-4(3H)-one (340 mg, 0.700 mmol) in NMP (3 ml) add copper cyano (217 mg, 2.423 mmol) under N ₂ . 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 is filtered through a CELITE® funnel. The filtrate is extracted with EA (3×30 ml). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was triturated with MeOH (20 ml) to obtain 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-5-yl)oxy)benzonitrile (0.217 g , 0.503 mmol) to TFA (1.5 ml) add TFUA (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 obtain the title compound.

Intermediate AB13

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-oxo-1,6-dihydropyrimidine-4-carboxylate, B15 (21.29 g, 72. 9 mmol) and 5-chloro-2-fluoro-3-hydroxybenzonitrile, A05 (10 g, 58.3 mmol) in dimethylacetamide (350 ml) at 25°C. The resulting mixture was stirred at 90°C overnight. LCMS showed the desired product and a clear reaction mixture. Water (500 ml) is added and a precipitate forms. The mixture is filtered and the solid is 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-4-carboxylic acid

Potassium trimethylsilanolate (9.97 g, 78 mmol) was added to the stirred mixture of methyl 5-(5-chloro-3-cyano-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. LCMS showed only the desired product. HCl (1N aq, 300 ml) was added slowly and a white substance formed. The mixture is concentrated under reduced pressure to remove THF. The mixture is filtered and the white solid is washed with water and dried under vacuum 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-1,6-dihydropyrimidine-4-carboxamide

Into a flask containing 5-(5-chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (20 g, 46.5 mmol ) and N,O -dimethylhydroxylamine hydrochloride (4.99 g, 51.2 mmol) in DMF (200 ml), add triethylamine (25.9 ml, 186 mmol), then EDC (9.81 g, 51.2 mmol ) and HOBt (7.84 g, 51.2 mmol) at 25°C. The resulting mixture was stirred at 25°C overnight. LCMS indicates completion of the reaction. Water (300 ml) was added and the resulting precipitate was filtered and washed with water and dried under vacuum 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-2-fluorobenzonitrile

Methylmagnesium bromide (3M in THF, 40 ml, 120 mmol) is 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-1,6-dihydropyrimidine-4-carboxamide (16.5 g, 34.9 mmol) in THF (350 ml). The resulting mixture was stirred at -78°C for 3 hours. LCMS showed the desired product but also the starting material. The reaction mixture is then heated to 0°C and stirred for 30 minutes. LCMS shows completion of the reaction. The reaction mixture is 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 (2×200 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 428.0 (M+1).

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

Deoxofluor® (15.08 ml, 82 mmol) is added to the vial 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) at 25°C. The resulting vial was sealed and stirred at 70°C for 3 hours. LCMS indicated the desired product. The reaction mixture is cooled to room temperature and poured into a saturated NaHCO ₃ solution very slowly and carefully. Then, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 ml). The combined organic layers are dried over MgSO ₄ , filtered and concentrated. The residue is 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)-2-fluorobenzonitrile

A flask containing a mixture of 5-chloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-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, a white solid was collected at the top of the filter, and dried under vacuum to give the title compound. MS: 330.0 (M+1).

Intermediate AB14

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

Step 1: 3-((4-acetyl-6-methoxypyrmidin-5-yl)oxy)-5-chloro-2-methylbenzonitrile

To a solution of 1-(5-fluoro-6-methoxypyrmidin-4-yl)ethanone, B08 (2.8 g, 16.46 mmol) in DMF (20 ml), add potassium carbonate (6.82 g, 49.4 mmol) and 5-chloro-3-hydroxy-2-methylbenzonitrile, A06 (3.31 g, 19.75 mmol) under nitrogen. The resulting mixture was heated at 40°C for 2 hours and then diluted with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (20-60% EtOAc/petroleum ether) to give the title compound. MS: 318.4 (M+1).

Step 2: 5-chloro-3-((4-(1-hydroxyethyl)-6-methoxypyrmidin-5-yl)oxy)-2-methylbenzonitrile

To a stirred solution of 3-((4-acetyl-6-methoxypyrmidin-5-yl)oxy)-5-chloro-2-methylbenzonitrile (1.8 g, 5.67 mmol) in methanol (50 ml), add chloride heptahydrate cerium(iii) (3.17 g, 8.50 mmol), then sodium borohydride (0.214 g, 5.67 mmol) was added slowly. The resulting suspension is stirred at 0°C for 1 hour and then quenched with ice water and extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (40-80% EtOAc/petroleum ether) to give the title compound. MS: 320.0 (M+1).

Step 3: 5-chloro-3-((4-(1-fluoroethyl)-6-methoxypyrmidin-5-yl)oxy)-2-methylbenzonitrile

To a stirred solution of 5-chloro-3-((4-(1-hydroxyethyl)-6-methoxypyrmidin-5-yl)oxy)-2-methylbenzonitrile (1.4 g, 4.38 mmol) in DCM (5 ml) , add Deoxofluor (1.615 ml, 8.76 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours and then diluted with DCM and washed with saturated aqueous NaHCO ₃ and brine. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (10-40% EtOAc/petroleum ether) to give the title compound. MS: 322.4 (M+1).

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

To a stirred solution of 5-chloro-3-((4-(1-fluoroethyl)-6-methoxypyrmidin-5-yl)oxy)-2-methylbenzonitrile (1.2 g, 3.73 mmol) in ACN (20 mL) was added sodium iodide (1.118 g, 7.46 mmol) and TMS-Cl (0.953 ml, 7.46 mmol) under nitrogen. The resulting mixture was heated at 80°C for 2 hours and then concentrated under reduced pressure. The residue is purified by silica column chromatography (40-80% EtOAc/petroleum ether) to give the title compound. MS: 306.4 (M-1).

Intermediate AB15

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

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

To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one, B18 (9.0 g, 29.8 mmol), 5-chloro-3-hydroxy-2 -methylbenzonitrile, A06 (4.99 g, 29.8 mmol) in DMF (60 ml), add potassium carbonate (8.23 g, 59.6 mmol). The reaction mixture was stirred at 100°C for 16 hours and then diluted with water (85 ml) and extracted with EtOAc (100 ml). The organic layer was washed with brine (40 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-35% EtOAc/petroleum ether) to give the title compound. MS: 450.8 (M+1).

Step 2: 5-chloro-2-methyl-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

To a solution of 5-chloro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (3 g, 6. 67 mmol) in ACN (70 ml) and water (5 ml), add ceric ammonium nitrate (18.28 g, 33.3 mmol). The reaction mixture was stirred at room temperature for 24 hours and then diluted with water (10 ml) and extracted with EtOAc (200 ml). The organic layer was washed with brine (70 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-35% EtOAc/petroleum ether) to give the title compound. MS: 328.0 (M-1).

Intermediate AB16

5-chloro-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one

To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one, B18 (1 g, 3.31 mmol) in DMF (10 ml), add 3-bromo- 5-chloro-2-fluorophenol, A04 (0.821 g, 3.64 mmol) and K ₂ CO ₃ (16.54 mg, 0.120 mmol) at 25°C. The reaction mixture was stirred at 80°C for 1 hour and then diluted with water (3 ml) and extracted with EtOAc (3×2 ml). The combined organic layers were washed with brine (3 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (25% EtOAc/petroleum ether) to give the title compound. MS: 507.2 (M+1). ^1H NMR (400 MHz, Chloroform- d ) δ=8.03 (d, J=4.4 Hz, 1H), 7.34-7.24 (m, 3H), 7.04-6.89 ( m, 2H), 6.86 (dd, J=2.4, 6.6 Hz, 1H), 5.07 (s, 2H), 3.81 (s, 3H).

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

Stirred solution of a mixture of 5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one (300 mg, 0.591 mmol) and copper cyanide (I) (265 mg, 2.95 mmol) in NMP (3 ml) was stirred at 170°C for 7 hours, then diluted with water (30 ml), and then extracted with EtOAc (3 x 5 ml). The solid precipitate was washed with a mixed solvent of DCM:MeOH:MeCN=1:1:1 (5 ml). The combined organic layers were washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/petroleum ether) to give the title compound. ^1H NMR (400 MHz, Chloroform- d ) δ=8.17 (s, 1H), 7.35-7.30 (m, 1H), 7.25 (d, J=8.7 Hz, 2H) , 7.14 (dd, J=2.4, 7.0 Hz, 1H), 6.98-6.86 (m, 2H), 5.06 (s, 2H), 3.79 (s, 3H ).

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

To a solution of 5-chloro-2-fluoro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (200 mg, 0.176 mmol) in TFA (2 ml), add TFUA (1 ml). The resulting mixture was stirred at 110°C for 2 hours, then quenched by adding saturated aqueous NaHCO ₃ solution (5 ml) and extracted with EtOAc (3x5 ml). The combined organic layers were washed with brine (10 mL), 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: 375.0 (M+ACN+1).

Intermediate AB17

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

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

To a mixture of the compound 5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrmidin-4(3H)-one, B20 (20 g, 55.7 mmol), 3-chloro-5- hydroxybenzonitrile, A10 (17.10 g, 111 mmol) in NMP (140 ml), add K ₂ CO ₃ (15.39 g, 111 mmol). The resulting mixture was stirred at 140°C for 24 hours. 3-chloro-5-hydroxybenzonitrile (17.10 g, 111 mmol) was added to the mixture. The resulting mixture was stirred at 140°C for another 16 hours, then diluted with water and extracted with EtOAc. The organic layer is washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (6.25-50% EtOAc/petroleum ether) to give the title compound. MS: 432.1 (M+1).

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

A mixture of 3-chloro-5-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (1.0 g, 2.316 mmol), chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (155 mg, 0.232 mmol), potassium methyltrifluoroborate (424 mg, 3.47 mmol) and Cs ₂ CO ₃ (2264 mg, 6.95 mmol)) in water (5.79 ml) and 1,4-dioxane (17.4 ml) were purged with N ₂ and then heated to 130°C. After 30 minutes, the mixture is passed through a layer of CELITE® filter. The filtrate is diluted with EtOAc (10 ml) and washed with water. The organic layer is dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-70% EtOAc/Hexane) to give the title compound. MS: 412.1 (M+1). ¹ H NMR (600 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.17 (s, 1H), 7.01 ( s, 1H), 6.89 (d, J=8.6 Hz, 3H), 5.05 (s, 2H), 3.80 (s, 3H), 2.35 (s, 3H), 1, 93 (t, J=18.8 Hz, 3H).

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

To a solution of 3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile (841.5 mg, 2.045 mmol) to TFA (9297 μl) add anisole (223 μl, 2.045 mmol) and TFUA (930 μl). The resulting mixture is heated to 110°C for 15 minutes, and concentrated under reduced pressure. The residue is taken up in DCM (20 ml) and washed with saturated aqueous NaHCO ₃ solution (2×5 ml) and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-10% MeOH/DCM) to give the title compound. MS: 292.1 (M+1). ^1H NMR (600 MHz, Chloroform- d ) δ 8.08 (s, 1H), 7.20 (s, 1H), 7.02 (s, 1H), 6.93 (s, 1H), 2, 38 (s, 3H), 1.96 (t, J=18.8 Hz, 3H).

BC Intermediate Section

Intermediate connection BC01

5-fluoro-3-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrmidin-4(3H)-one

To a mixture of 5-fluoro-6-(1,1,2,2-tetrafluoroethyl)pyrmidin-4(3H)-one, B01 (48 mg, 0.224 mmol), lithium bromide (19.47 mg, 0.224 mmol) and K ₂ CO ₃ (77 mg, 0.561 mmol) in DMF (2242 µl), add 3-(chloromethyl)-2-methoxy-4,6-dimethylpyridine, C16 (41.6 mg, 0.224 mmol). The resulting mixture was heated to 50°C overnight and then filtered and purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 363.9 (M+1). ^1H NMR (500 MHz, Chloroform- d ) δ 8.18 (s, 1H), 6.65 (s, 1H), 5.08 (s, 2H), 3.94 (s, 3H), 2. 46 (s, 3H), 2.40 (s, 3H).

The following intermediates in TABLE 7 are prepared under conditions such as those described above in the procedure for the synthesis of intermediate BC01 using the appropriate intermediate B and intermediate C.

TABLE 7

Intermediate connection
(B#, C#) Structure IUPAC name MS (M+1) BC02
(B04, C23) 3-((2-chloro-4,6-dimethylpyridin-3-yl)methyl)-5-fluoro-6-(trifluoromethyl)pyrmidin-4(3H)-one 336.0 BC03
(B01, C17) 5-fluoro-3-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrmidin-4(3H)-one 350.1

Intermediate connection BC04

5-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-(trifluoromethyl)pyrmidin-4(3H)-one

To a stirred solution of 5-fluoro-6-(trifluoromethyl)pyrmidin-4(3H)-one, B04 (0.207 g, 1.139 mmol) and 3-(chloromethyl)-5-fluoro-2-methoxypyridine, C20 (0.2 g , 1.139 mmol) in NMP (5.70 ml) at room temperature, add potassium carbonate (0.315 g, 2.278 mmol). The resulting mixture was stirred at room temperature overnight, and diluted with water (3 ml) and EtOAc (3 ml). The organic layer is separated and concentrated under reduced pressure to obtain the title compound, which is used in the next step without further purification. MS: 322.1 (M+1).

The following intermediates in TABLE 8 are prepared under conditions such as those described above in the procedure for the synthesis of intermediate BC04 using the appropriate intermediate B and intermediate C.

TABLE 8

Intermediate connection
(B#, C#) Structure IUPAC name MS (M+1) BC05
(B02, C20) 5-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-(perfluoroethyl)pyrmidin-4(3H)-one 372.1 BC06
(B08, C16) 5-fluoro-3-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1,1,2-trifluoroethyl)pyrmidin-4(3H)-one 346.4

EXAMPLE 1

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

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

To a stirred solution of 3-(chloromethyl)-2-methoxy-6-(methoxymethyl)pyridine, C15 (30 mg, 0.149 mmol), 5-chloro-2-fluoro-3-((6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB04 (35 mg, 0.086 mmol) in DMF (1 ml), add K ₂ CO ₃ (23.81 mg, 0.172 mmol) and lithium bromide (11.22 mg, 0.129 mmol). The resulting mixture was stirred at 15°C for 1 hour. TLC indicated completion of the reaction and the mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/petroleum ether) to give the title compound. MS: 531 (M+1).

Step 2: 5-chloro-2-fluoro-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-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-((2-methoxy-6-(methoxymethyl)pyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (25 mg, 0.047 mmol) in ACN (0.5 ml), add KI (23.45 mg, 0.141 mmol) and TMS-Cl ( 0.018 ml, 0.141 mmol) under N ₂ . The resulting mixture was stirred at 70°C for 1 hour. TLC showed completion of the reaction. The mixture was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 517 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.79 (s, 1 H) 8.78 (s, 1 H) 7.69 (d, J = 6.84 Hz, 1 H) 7.31 ( m, J =4.41, 2.43 Hz, 1 H) 7.07 (dd, J =6.84, 2.43 Hz, 1 H) 6.15-6.45 (m, 1 H) 6 .10 (d, J =6.84 Hz, 1 H) 4.94 (s, 2 H) 4.36 (s, 2 H) 3.45 (s, 3 H).

The following examples in TABLE 9 were prepared using the same procedure as described above for the synthesis of Example 1 using the appropriate intermediate AB and intermediate C.

TABLE 9

EXAMPLE
(AB No., C No.) Structure IUPAC name MS (M+1) 2
(AB13, C16) 5-chloro-3-((4-(1,1-difluoroethyl)-1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1 ,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile 465.0 3
(AB13, C17) 5-chloro-3-((4-(1,1-difluoroethyl)-1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1,6 -dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile 451.1 4
(AB16, C17) 5-chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile 455.0 5
(AB01, C16) 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 513.2 6
(AB08, C16) 3-chloro-5-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 483.0 7
(AB07, C16) 3-bromo-5-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 527.0
And
529.0 8
(AB10, C18) 2,5-dichloro-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitrile 489.0 9
(AB11, C17) 5-fluoro-2-methyl-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 467.2 10
(AB05, C16) 4-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-3,5-dimethylbenzonitrile 477.4 eleven
(AB01, C24) 3-((1-((5-bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile 565.2
And
567.2 12
(AB14, C14) 5-chloro-3-((4-(1-fluoroethyl)-6-oxo-1-((2-oxo-6-(1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl) methyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 481.1 13
(AB15, C14) 5-chloro-2-methyl-3-((6-oxo-1-((2-oxo-6-(1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl)methyl)-4 -(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 503.1

EXAMPLE 14

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

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

To a stirred solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB01 (30 mg, 0.080 mmol) and 3-(chloromethyl)-5-fluoro-2-methoxypyridine, C20 (15.36 mg, 0.087 mmol) in NMP (795 µl) at room temperature, add potassium carbonate (21.98 mg , 0.159 mmol). The resulting mixture was stirred at room temperature overnight and then diluted with water (3 ml) and extracted with EtOAc (3 ml). The organic layer is concentrated under reduced pressure to obtain the title compound, which is used in the next step without further purification. MS: 517.1 (M+1).

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

To a solution of 5-(difluoromethyl)-3-((1-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (40 mg, 0.077 mmol) in ACN (775 µl), add TMS-I (10.54 µl, 0.077 mmol) dropwise at room temperature. After addition, the resulting mixture was heated to 60°C for 1 hour and then diluted with EtOAc (2 ml) and quenched with saturated aqueous NaHCO ₃ (1 ml) and saturated aqueous Na ₂ S ₂ O ₃ (1 ml). The organic layer is separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 503.1 (M+1). ^1H NMR (600 MHz, DMSO- d6 ) δ 8.73 (s, 1H), _7.73 (s, 1H), 7.61-7.56 (m, 2H), 7.31 (s, 1H), 6.94 (d, J =16.0 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 4.87 (s, 2H), 2.47 ( s, 3H).

The following examples in TABLE 10 were prepared using the same procedure as described above for the synthesis of Example 14 using the appropriate intermediate AB and intermediate C.

TABLE 10

EXAMPLE
(AB No., C No.) Structure IUPAC name MS (M+1) 15
(AB17, C16) 3-((4-(1,1-difluoroethyl)-1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1,6-dihydropyrimidine -5-yl)oxy)-5-methylbenzonitrile 427.2 16
(AB02, C18) 5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile 453.1 17
(AB01, C18) 5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 485.1 18
(AB02, C20) 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 471.1 19
(AB15, C20) 5-chloro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5 -yl)oxy)-2-methylbenzonitrile 455.1 20
(AB06, C20) 5-chloro-2-fluoro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile 509.1

EXAMPLE 21

5-chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile

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

To an ice-cold solution of 5-chloro-2-fluoro-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB06 (50 mg, 0.130 mmol) and (2 -methoxy-6-methylpyridin-3-yl)methanol, C17 (20.0 mg, 0.13 mmol) in DCM (1303 µl) add DIAD (25.3 µl, 0.130 mmol) dropwise. The resulting mixture was warmed to room temperature and then diluted with saturated aqueous NaHCO ₃ and extracted with DCM. The organic layer is dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 519.1 (M+1).

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

To a solution of 5-chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidine-5 -yl)oxy)benzonitrile (39 mg, 0.075 mmol) and potassium iodide (37.4 mg, 0.226 mmol) in ACN (752 μl), add TMS-Cl (28.8 μl, 0.226 mmol). The resulting mixture was heated to 50°C for 1 hour and then cooled to room temperature, then diluted with MeOH (1 ml) and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 505.0 (M+1). ^1H NMR (500 MHz, Chloroform- d ) δ 8.78 (s, 1H), 7.68 (d, J =6.9 Hz, 1H), 7.33 (s, 1H), 7.10 ( d, J =6.8 Hz, 1H), 6.12 (d, J =7.5 Hz, 1H), 4.94 (s, 2H), 2.36 (s, 3H).

The following example, Example 22 in TABLE 11, was prepared using a procedure similar to that described above for the synthesis of Example 21 using the appropriate intermediate AB and intermediate C.

TABLE 11

EXAMPLE
(AB No., C No.) Structure IUPAC name MS (M+1) 22
(AB01, C17) 5-(difluoromethyl)-2-methyl-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 499.1

EXAMPLE 23

5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile

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

To a solution of 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB03 (50 mg, 0.127 mmol) in THF (633 µl), add (2-methoxypyridin-3-yl)methanol, C18 (19.36 mg, 0.139 mmol) and triphenylphosphine (127 mg, 0.380 mmol), then add (E)-di-tert-butyl diazene- 1,2-dicarboxylate (64.1 mg, 0.278 mmol). The resulting mixture was stirred overnight, filtered and concentrated under reduced pressure to give the title compound. MS: 517.1 (M+1).

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

To a solution of 5-(difluoromethyl)-3-((1-((2-methoxypyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)- 2-methylbenzonitrile (65 mg, 0.126 mmol) in DMA (629 μl), add pyridine hydrochloride (43.6 mg, 0.378 mmol). The resulting mixture was stirred at 120°C for 60 minutes and then purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 503.1 (M+1). ^1H NMR (500 MHz, DMSO- d6 ) δ 11.80 (s, 1H), 8.77 (s, 1H), _7.73 (s, 1H), 7.42 (d, J =6, 8 Hz, 1H), 7.37 (s, 2H), 6.12 (t, J =6.7 Hz, 1H), 4.85 (s, 2H), 2.44 (s, 3H).

EXAMPLE 24

3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

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

To a stirred solution of 5-chloro-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB09 (90 mg, 0.249 mmol) and 3-(chloromethyl)-2-methoxy-4,6-dimethylpyridine, C16 (46.2 mg, 0.249 mmol) in DMF (3 ml) then add potassium carbonate solution (68.8 mg, 0.498 mmol). The resulting mixture was stirred at RT for 5 hours and then diluted with water (30 ml) and extracted with EtOAc (2×30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (0-60% EtOAc/PE) to give the title compound. MS: 510.8 (M+1).

Step 2: 3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

To a stirred solution of 5-chloro-3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (70 mg, 0.137 mmol) in THF (3 ml) add cesium carbonate (134 mg, 0.411 mmol) and PdCl ₂ (dppf) (22.38 mg , 0.027 mmol) and trimethylboroxine (25.8 mg, 0.206 mmol). The resulting mixture was heated to 100°C overnight and then quenched with water (10 ml) and extracted with EtOAc (2×20 ml). The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash silica chromatography (0-40% EtOAc/PE) to give the title compound. MS: 490.8 (M+1).

Step 3: 3-((1-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6- Dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

To a stirred ice solution of 3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile (60 mg, 0.122 mmol) to ACN (3 ml) add sodium iodide (36.7 mg, 0.245 mmol) and TMS-Cl (0.031 ml, 0.245 mmol ). The resulting mixture was heated to 80°C for 1 hour and then quenched with water (10 ml) and extracted with EtOAc (2×20 ml). The combined organic layers are 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 as modifier) to isolate the title compound. MS: 477.2 (M+1).

EXAMPLE 25

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

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

To a stirred solution of 6-chloro-3-(chloromethyl)-2-methoxypyridine, C13 (244 mg, 1.272 mmol) and 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1.1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB01 (480 mg, 1.272 mmol) in NMP (3181 µl) at room temperature, add K ₂ CO ₃ (352 mg, 2 .54 mmol). The resulting mixture was stirred at 25°C overnight and then diluted with water (50 ml), and stirred at room temperature for 30 minutes. The precipitate is collected at the top of the filter, washed with water (3×), then air dried to give the title compound. MS: 533.3 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)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-((6-chloro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (20 mg, 0.038 mmol), potassium trifluoro(((4-methoxybenzyl)oxy)methyl)borate (14.53 mg, 0.056 mmol) and cataCXium® A Pd G2 (5.02 mg, 7.51 µmol) in 1,4-dioxane (1 ml), add 2 M aqueous cesium carbonate (0.5 ml, 1.0 mmol). The resulting mixture was heated at 150°C in a microwave oven for 15 minutes, and then extracted with EtOAc. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is taken up with ACN (1 ml), and treated with KI (6.23 mg, 0.038 mmol) and TMS-Cl (40 μl, 0.313 mmol). The resulting mixture was heated at 100°C in a microwave oven for 10 minutes and then purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 515.2 (M+1).

The following examples in TABLE 12 were prepared following the same procedure as described above for the synthesis of Example 25 using the intermediate from Step 1 in the synthesis of Example 25 with a suitable heteroaryl or alkyl boronate in the second column.

TABLE 12

Example No. Commercial starting material Structure IUPAC name MS (M+1) 26 potassium methoxymethyl trifluoroborate 5-(difluoromethyl)-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 529.3 27 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 5-(difluoromethyl)-3-((1-((2-hydroxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)methyl)-6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 551.0 28 potassium trifluoro(3-hydroxypropyl) borate 5-(difluoromethyl)-3-((1-((6-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 543.2

EXAMPLE 29

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

Step 1: 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine- 5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile

A mixture of 3-((1-((6-chloro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5- yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (intermediate from Step 1 of Example 25 ) (100 mg, 0.188 mmol), bis(triphenylphosphine)palladium(II) dichloride (26.3 mg, 0.038 mmol) , and tributyl(1-ethoxyvinyl)tin (127 µl, 0.375 mmol) in toluene (1877 µl) were stirred at 100°C overnight, and then diluted with EtOAc and saturated aqueous KF, and treated with concentrated HCl (1 ml). The mixture is stirred at room temperature. overnight and passed through CELITE® in a funnel. The filtrate is extracted with EtOAc (2X). The combined organic layers are concentrated under reduced pressure. The residue is purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 541.4 (M+1).

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

To a solution of 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5 -yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (30 mg, 0.056 mmol) in THF (278 µl) at -78°C, add a 3 M solution of methylmagnesium bromide in Et ₂ O (37.0 µl, 0.111 mmol) drop by drop. Once LCMS showed complete conversion, the mixture was quenched with MeOH and water, and then partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was taken up with ACN (2 mL) and treated with KI (9.22 mg, 0.056 mmol) and TMS-Cl (20 μL, 0.156 mmol). The resulting mixture is heated at 100°C in a microwave oven for 10 minutes. The mixture was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 543.4 (M+1). ^1H NMR (600 MHz, Acetone- d6 ) δ 8.77 (s, 1H), 7.67-7.54 (m, 2H) _, 7.22 (s, 1H), 6.77 (d, J= 11.9 Hz, 1H), 6.70-6.65 (m, 1H), 6.26 (d, J = 7.2 Hz, 1H), 4.94 (s, 2H), 2, 03 (s, 3H), 1.62 (s, 1H), 1.53 (s, 6H).

EXAMPLE 30

3-chloro-5-((6-oxo-1-((2-oxo-6-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)methyl)-4-(trifluoromethyl) -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 3-((1-((6-bromo-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5 -chlorobenzonitrile

To a stirred solution of 3-chloro-5-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (2.27 g, 7.19 mmol) in toluene (30 ml ), add (6-bromo-2-methoxypyridin-3-yl)methanol C02 (1.3 g, 5.96 mmol), triphenylphosphine (3.15 g, 12.01 mmol) and DIAD (2.337 ml, 12. 02 mmol). The resulting mixture was stirred at room temperature overnight and then diluted with EtOAc. The organic layer is washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (30% EtOAc/PE) to give the title compound.

Step 2: 3-((1-((6-bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5- yl)oxy)-5-chlorobenzonitrile

To a stirred solution of 3-((1-((6-bromo-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5 -chlorobenzonitrile (1.8 g, 3.49 mmol) to ACN (20 ml) add sodium iodide (1.046 g, 6.98 mmol) and TMS-Cl (0.892 ml, 6.98 mmol). The reaction mixture is stirred at 80°C overnight, then cooled to room temperature and more ACN is added, stirred and filtered. The filter cake is washed with ACN. The filtrate is concentrated under reduced pressure to obtain the title compound. MS: 501.2 and 503.2 (M+1).

Step 3: 3-chloro-5-((6-oxo-1-((2-oxo-6-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)methyl)-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Mixture of 3-((1-((6-bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl) oxy)-5-chlorobenzonitrile (20 mg, 0.040 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.28 mg, 0.048 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (3.26 mg, 3.99 µmol), tribasic potassium phosphate (22.85 mg, 0.108 mmol) in 1,4-dioxane (53.2 µl) and water (26.6 µl) degass and flush with N ₂ . The resulting mixture was stirred at 80°C for 3 hours. LCMS showed that the reaction mixture was complete. The solvent is evaporated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 489.0 (M+1).

EXAMPLE 31

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

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

To a solution of 5-chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB04 (150 mg , 0.410 mmol) and K ₂ CO ₃ (283 mg, 2.051 mmol) in DMF (2 ml), add 3-(chloromethyl)-2-methoxy-6-vinylpyridine, C19 (75 mg, 0.410 mmol) and lithium bromide ( 42.8 mg, 0.492 mmol). The resulting mixture was stirred at 20°C for 20 hours and then quenched with H ₂ O (5 ml), extracted with EtOAc (3×5 ml). The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (25% EtOAc/PE) to give the title compound. MS: 513.1 (M+1).

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

To a mixture of 5-chloro-2-fluoro-3-((1-((2-methoxy-6-vinylpyridin-3-yl) methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (80 mg, 0.156 mmol) and 2,6-lutidine (0.051 ml, 0.438 mmol) in 1,4-dioxane (3 ml) and H ₂ O (1 ml), add osmium tetroxide (1.224 µl, 3.90 µmol) dissolved in t -BuOH (0.1 ml). The resulting mixture was stirred at 20°C for 30 minutes, and sodium periodate (122 mg, 0.571 mmol) was added to the mixture. The resulting mixture was stirred at 20°C for 1.5 hours and then diluted with EtOAc (10 ml) and carefully poured into water (10 ml). The organic layer was washed with saturated aqueous Na ₂ S ₂ O ₃ (10 ml) and brine (10 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the title compound. MS: 515.1 (M+1).

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

To a solution of 5-chloro-2-fluoro-3-((1-((6-formyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (70 mg, 0.136 mmol) in EtOAc (1 ml) and MeOH (3 ml), add Zn(BH ₄ ) ₂ (0.136 ml, 0.136 mmol). The resulting mixture was stirred at 20°C for 0.25 h, and then quenched with 1N HCl (10 ml), extracted with EtOAc (3×10 ml). The combined organic layers are dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound, which is used directly in the next step. MS: 517.1 (M+1).

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

To a solution of 5-chloro-2-fluoro-3-((1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (60 mg, 0.116 mmol) in ACN (3.00 ml) add KI (57.8 mg, 0.348 mmol) and TMS-Cl (0.045 ml, 0.348 mmol). The resulting 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 as modifier) to isolate the title compound. MS: 503.0 (M+1). ^1H NMR (400 MHz, DMSO- d6 ): δ11.75 (s, 1H), 8.79 ( _s , 1H), 7.86-7.84 (m, 1H), 7.69-7 .50 (m, 1H), 7.48-7.46 (d, 1H), 6.87-6.74 (m, 1H), 6.17-6.15 (m, 1H), 5. 42 (s, 1H), 4.86(s, 2H), 4.27 (s, 2H).

EXAMPLE 32 (isomer A) and 33 (isomer B)

( S )-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6 -oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile and

( R )-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6 -oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((2-methoxy-6-vinylpyridin-3-yl)methyl)-6-oxo-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, AB12 (0.3 g, 0.963 mmol) in DMF (5 ml) add 3-(chloromethyl)-2-methoxy-6-vinylpyridine, C19 (0.177 g, 0.963 mmol), K ₂ CO ₃ (0.399 g, 2.89 mmol) and lithium bromide (0.167 g, 1.925 mmol). The resulting mixture was stirred at 20°C for 1 hour and then extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is triturated with MeOH to give the title compound and used directly without further purification.

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

To a mixture of 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((2-methoxy-6-vinylpyridin-3-yl)methyl)-6-oxo-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile (200 mg, 0.436 mmol) in 1,4-dioxane (1.5 ml) and water (0.5 ml), add 2,6-dimethylpyridine (131 mg, 1.220 mmol) and a solution of osmium tetroxide (0.1 ml, 0.436 mmol) in t-BuOH (0.1 ml). The resulting mixture was stirred at 20°C for 15 minutes. Sodium periodate (336 mg, 1.569 mmol) is then added. The reaction mixture was stirred at 20°C for 1.5 h and then diluted with water (15 ml) and extracted with EtOAc (3×15 ml). The combined organic layers are dried over anhydrous Na ₂ SO ₄ and concentrated. The residue is purified by silica column chromatography (0-20% EtOAc/petroleum ether) to give the title compound. MS: 461.1 (M+1).

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

To a solution of 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-formyl-2-methoxypyridin-3-yl)methyl)-6-oxo-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile (55 mg, 0.107 mmol) in THF (3 ml) and EtOAc (2 ml), add 1M Zn(BH ₄ ) ₂ solution in THF (0.021 ml, 0.021 mmol) at -30° C. The resulting mixture was stirred at -30°C for 0.5 h. The reaction mixture was quenched with water (1 drop) and then concentrated under reduced pressure to obtain the title compound. MS: 463.1 (M+1).

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

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

(R)-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl) -6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

To a solution of 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile (49 mg, 0.106 mmol) to ACN (3 ml) add KI (22.14 mg, 0.133 mmol). TMS-Cl (0.044 ml, 0.347 mmol). The resulting mixture was stirred at 70°C for 5 hours and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the racemic title compound. MS: 449 (M+1). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm. 4.27 (bd, J=4.63 Hz, 2 H) 4.83 (s, 2 H) 5.46 (s, 1 H) 5.63-5.88 (m, 1 H) 6.15 (shd, J =7.28 Hz, 1 H) 7.42 (d, J =7.06 Hz, 1 H) 7.58 (shd, J =5.73 Hz, 1 H) 7.82 (shs , 1 H) 8.68 (s, 1 H). The rcemic mixture is purified by chiral SLC (Chiralpak IC-H column, 250 x 30 mm ID, 5 µm, IPA/CO _{2 =} 35%) to obtain Example 32 of isomer A (faster elution) and Example 33 of isomer B (slower elution) .

EXAMPLE 34 (isomer A)

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

Step 1: 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine- 5-yl)oxy)-5-chloro-2-fluorobenzonitrile

To a solution of 5-chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB04 (247 mg , 0.676 mmol) in DMF (4 ml), add 1-(5-(chloromethyl)-6-methoxypyridin-2-yl)ethanone, C21 (135 mg, 0.676 mmol) and K ₂ CO ₃ (187 mg, 1.352 mmol ) and lithium bromide (88 mg, 1.014 mmol). The resulting mixture was stirred at 30°C for 5 hours, and diluted with H ₂ O (15 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine (40 ml) and 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: 529.2 (M+1).

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

To a solution of 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5 -yl)oxy)-5-chloro-2-fluorobenzonitrile (144 mg, 0.272 mmol) in EtOAc (21 ml) add 1M Zn(BH ₄ ) ₂ solution in THF (0.272 ml, 0.272 mmol) at 20°C. The resulting solution was stirred at 15-20°C for 0.5 h, and then quenched with 4N HCl aqueous solution (5 ml), and diluted with H ₂ O (15 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS: 531.2 (M+1).

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

To a solution of 5-chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (185 mg, 0.349 mmol) in ACN (32 ml) add KI (174 mg, 1.046 mmol) and TMS-Cl (0.134 ml, 1.046 mmol ). The resulting mixture was stirred at 70°C for 2 hours and then diluted with water (15 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine (30 ml), 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 as modifier) to isolate the racemic title compound. The racemic mixture was purified by chiral SLC (ChiralPak AD-H column, 250 x 30 mm ID, 5 µm, 25% IPA/CO ₂ with 0.1% NH ₄ OH modifier) to give Example 34 (isomer A, faster elution ). MS: 517.0 (M+1). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm. 1.29 (d, J= 6.58 Hz, 3 H) 4.49 (shd, J= 4.39 Hz, 1 H) 4.86 (s, 2 H) 5.49 (shd, J = 3 .51 Hz, 1 H) 6.17 (d, J= 7.45 Hz, 1 H) 6.68-7.07 (m, 1 H) 7.47 (d, J= 7.02 Hz, 1 H) 7.76 (dd, J =7.24, 2.41 Hz, 1 H) 7.85 (dd, J =4.38, 2.63 Hz, 1 H) 8.80 (s, 1 H ).

EXAMPLE 35

3-(difluoromethyl)-5-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile

Potassium carbonate (34.4 mg, 0.249 mmol) was added to a stirred solution of 5-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-(trifluoromethyl)pyrmidin-4(3H)- she, BC04 (40 mg, 0.125 mmol) and 3-(difluoromethyl)-5-hydroxybenzonitrile, A01 (25.3 mg, 0.149 mmol) in DMF (623 μl) at room temperature. The resulting mixture was stirred at 100°C overnight, and then diluted with water (2 ml) and EtOAc (2 ml). The organic layer is separated and concentrated under reduced pressure. The residue was dissolved in ACN (2 mL) and TMS-I (85 μL, 0.623 mmol) was added dropwise at room temperature. After addition, the resulting mixture was heated to 60°C for 2 hours. The reaction mixture was diluted with EtOAc (2 ml) and quenched with saturated aqueous NaHCO ₃ (1 ml) and saturated aqueous Na ₂ S ₂ O ₃ (1 ml). The organic layer is separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 457.1 (M+1). ^1H NMR (600 MHz, DMSO- d6 ) δ 8.75 (s, 1H), 7.88 (s, 1H), 7.79 (s _, 1H), 7.66 (s, 1H), 7 .62-7.55 (m, 2H), 7.00 (t, J =55.2 Hz, 1H), 4.88 (s, 2H).

The following examples in TABLE 13 were prepared using the same procedure as described above for the synthesis of Example 35 using the appropriate intermediate A and intermediate BC .

TABLE 13

EXAMPLE
(A No., BC No.) Structure IUPAC name MS (M+1) 36
(A03,BC04) 2,5-dichloro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile 476.0 37
(A05,BC04) 5-chloro-2-fluoro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile 459.0 38
(A02,BC05) 5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)-2-methylbenzonitrile 521.1

EXAMPLE 39

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

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

Mixture of 5-fluoro-3-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrmidin-4(3H)-one, BC03 (60 mg , 0.172 mmol), 5-chloro-2-fluoro-3-hydroxybenzonitrile, A05 (30.9 mg, 0.180 mmol), potassium carbonate (47.5 mg, 0.344 mmol) in DMF (859 µl) heated to 80°C overnight and then at 100°C for the second night. The crude product was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 501.2 (M+1).

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

To a solution of 5-chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (11.5 mg, 0.023 mmol) and potassium iodide (11.44 mg, 0.069 mmol) in ACN (230 μl), add TMS-Cl (8.80 µl, 0.069 mmol). The resulting mixture was heated to 50°C for 4 hours and then quenched with MeOH (1 ml). The crude product was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 487.2 (M+1).

The following examples in TABLE 14 were prepared using the same procedure as described above for the synthesis of Example 39 using the appropriate intermediate A and intermediate BC .

TABLE 14

EXAMPLE
A#, BC# Structure IUPAC name MS (M+1) 40
(A01,BC01) 3-(difluoromethyl)-5-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile 499.1 41
(A02,BC06) 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2- trifluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile 495.4

EXAMPLE 42

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

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

Mixture of 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (118 mg, 0.643 mmol), ((2-chloro-4,6-dimethylpyridin-3-yl)methyl)-5-fluoro-6-( trifluoromethyl)pyrmidin-4(3H)-one, BC02 (180 mg, 0.536 mmol), potassium carbonate (148 mg, 1.072 mmol) in DMF (2 ml) was stirred at 80°C for 15 h, passed through a filter bed. The filter cake is washed with EtOAc (10 ml). The filtrate is partitioned between EtOAc and water. The layers are separated. And the aqueous layer was further extracted with EtOAc (3×10 ml). The combined organic layers are dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica column chromatography (0-100% EtOAc/hexane) to give the title compound. MS: 499.1 (M+1).

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

Solution of 3-((1-((2-chloro-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5 -(difluoromethyl)-2-methylbenzonitrile (140 mg, 0.281 mmol) in AcOH (32.100 ml, 561 mmol) is heated at 100°C for 4 nights until LCMS shows complete conversion. The mixture is concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 481.1 (M+1). ^1H NMR (500 MHz, Chloroform- d ) δ 8.77 (s, 1H), 7.45 (s, 1H), 7.26 (d, J =1.8 Hz, 3H), 6.73 ( s, 1H), 6.51 (t, J =55.9 Hz, 1H), 6.16 (s, 1H), 5.02 (s, 2H), 2.64 (s, 1H), 2, 59 (s, 3H), 2.43 (d, J =1.4 Hz, 3H), 2.35 (s, 3H).

EXAMPLE 43: Determination of cell killing activity (SMACK):

PBMCs obtained from healthy donors are 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 at approximately 2.5 × 106 cells /ml for 3 days at 5% CO ₂ , 37°C and 90% humidity. On day 4, PHA-stimulated cells are washed and resuspended at approximately 20 x 106 cells/ml in complete medium with IL-2 (10 U/ml) with the original VSV-G pseudotyped HIV virus (VSV-G/pNLG1-P2A-∆ Env-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 pseudotyped virus derived from pNL43 with an egfp insertion 5' nef and eGFP expression driven by normal spliced RNA transcripts. A virus containing Vif truncated by 50 amino acids due to a single nucleotide deletion causing a frameshift does not express Nef due to the stop codon after gfp . HIV Env is not expressed due to frameshifting, which produces multiple stop codons. infected cells are then washed with complete medium plus 10 U/ml IL-2 3 times by centrifugation at 200 x g for 3 minutes at 22°C. Cells are resuspended at 5x106 cells/ml in complete medium plus 10 U/ml IL-2 and incubated overnight at 37°C, 5% CO ₂ and 90% humidity. For compound treatment, infected PBMCs are diluted to 4 x 105 cells/ml RPMI 1640 with L-glutamine, 50% healthy human serum (HHS), 100 U/ml penicillin-streptomycin plus IL-2 (10 U/ml), and 20,000 cells are transferred to each well of a 384-well poly-D-lysine-coated plate containing compounds with a final DMSO of <0.5%. Compounds are tested with a 10-point 3-fold titration. The plates are analyzed on an Acumen ex3 imager using a Blue Laser 488 nm, and the number of GFP-positive objects is collected with the loss of GFP representing the death of infected cells. Titration curves and EC ₅₀ values are calculated using a four-parameter logistic fitting model. The results are shown in Table 15.

TABLE 15

Example SMACK EC ₅₀ _50% SZN (nM) Viking EC ₅₀ _50% SZN (nM) 1 257.7 29.55 2 293.5 37.37 3 87.63 14.05 4 197.3 41.15 5 160.8 47.11 6 262.7 37.51 7 433.3 29.11 8 495.4 26.93 9 281 15.67 10 245.9 --- eleven 401.8 --- 12 374.5 127.4 13 295.5 342.9 14 101.4 29.5 15 384.2 21.9 16 268.1 7,077 17 217.5 17.14 18 148.2 32.84 19 375.6 30.69 20 99.04 83.72 21 152 76.75 22 131.2 48.92 23 233.8 53.02 24 346.5 168.1 25 72.69 19.55 26 90.06 29.26 27 292.3 77.24 28 73.8 --- 29 187.2 29.83 thirty 414.6 30.14 31 86.78 20.66 32 377 18.25 33 389 23.15 34 270.3 43.15 35 313.7 15.61 36 369.3 49.96 37 412.8 32.36 38 190.8 96.81 39 162.4 33.55 40 282.6 39.23 41 283.4 59.8 42 222.1 43.13

Claims (76)

1. Compound of formula I or a pharmaceutically acceptable salt thereof, where R ¹ is H, halogen or -C _1-3 alkyl, unsubstituted or substituted with 1-7 F; R ² is CN and R ³ is H; or R ² is H and R ³ is CN, or R ² is -C _1-3 alkyl, unsubstituted or substituted with 1-7 F, and R ³ is H; R ⁴ is -H, halogen, -C _1-3 alkyl, unsubstituted or substituted by 1-7 F, -OC _1-3 alkyl, unsubstituted or substituted by 1-7 F, or CN; R ⁵ is –H or -C _1-3 alkyl, unsubstituted or substituted with 1-7 F; R ⁶ is halogen or -C _1-6 alkyl substituted with 1-9 -F; R ⁷ is -H or -C _1-3 alkyl; R ⁸ is -H, halogen or -C _1-3 alkyl; And R ⁹ is -H, pyrazolyl or -C _1-6 alkyl, unsubstituted or substituted -OH or -OC _1-3 alkyl. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ⁶ is halogen or -C _1-3 alkyl substituted with 1-7 -F. 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that R ⁷ is H or -CH ₃ . 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that R ⁸ is -H or halogen. 5. Connection according to any one of paragraphs. 1-4, having structural formula II or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is -H. 7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is halogen or -C _1-3 alkyl, unsubstituted or substituted with 1-7 F. 8. Connection according to any one of paragraphs. 1-4, having structural formula III or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is halogen or -C _1-3 alkyl, unsubstituted or substituted with 1-7 F. 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, characterized in that R ⁵ is halogen or -C _1-3 alkyl, unsubstituted or substituted with 1-7 F. 11. The connection according to claim 1, which is: 5-chloro-2-fluoro-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-chloro-3-((4-(1,1-difluoroethyl)-1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1 ,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile; 5-chloro-3-((4-(1,1-difluoroethyl)-1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1,6 -dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile; 5-chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 3-chloro-5-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 3-bromo-5-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 2,5-dichloro-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-fluoro-2-methyl-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 4-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-3,5-dimethylbenzonitrile; 3-((1-((5-bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile; 5-chloro-3-((4-(1-fluoroethyl)-6-oxo-1-((2-oxo-6-(1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl) methyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5-chloro-2-methyl-3-((6-oxo-1-((2-oxo-6-(1H-pyrazol-3-yl)-1,2-dihydropyridin-3-yl)methyl)-4 -(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 3-((4-(1,1-difluoroethyl)-1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1,6-dihydropyrimidine -5-yl)oxy)-5-methylbenzonitrile; 5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile; 5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(1,1,2,2- tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5-chloro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5 -yl)oxy)-2-methylbenzonitrile; 5-chloro-2-fluoro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile; 5-chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-2-methyl-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile; 3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile; 5-(difluoromethyl)-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5-(difluoromethyl)-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5-(difluoromethyl)-3-((1-((2-hydroxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)methyl)-6-oxo-4-(1,1,2 ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5-(difluoromethyl)-3-((1-((6-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 5-(difluoromethyl)-3-((1-((6-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-( 1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; 3-chloro-5-((6-oxo-1-((2-oxo-6-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)methyl)-4-(trifluoromethyl) -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-chloro-2-fluoro-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1, 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; ( S ) 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)- 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; ( R )-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl) -6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, isomer A; 3-(difluoromethyl)-5-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile; 2,5-dichloro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)benzonitrile; 5-chloro-2-fluoro-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6 -dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidine -5-yl)oxy)-2-methylbenzonitrile; 5-chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 3-(difluoromethyl)-5-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2- trifluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; or 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile; or a pharmaceutically acceptable salt thereof. 12. The connection according to claim 1, which is or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition having small molecule-activated cell killing (SMACK) activity, containing an effective amount of a compound according to any one of claims. 1-12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition according to claim 13, further containing an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, entry inhibitors HIV and HIV maturation inhibitors. 15. Connection according to any one of paragraphs. 1-12 for therapy. 16. A pharmaceutical composition having the activity of selectively destroying HIV-infected cells expressing GAG-POL, containing an effective amount of a compound according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.