Pyridone derivatives as selective cytotoxic agents against HIV-infected cells

Abstract

The present disclosure relates to pyridone derivatives of formula I and their use for selectively killing HIV-infected GAG-POL-expressing cells without concomitant cytotoxicity to HIV-naive cells, and for treating HIV infection, or treating, preventing, or delaying the onset or progression of AIDS or AIDS-related complex (ARC).

Description

Background of the Invention

[0002] Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, people infected with HIV exhibit severe immunodeficiency, which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. A variety of clinically approved antiretroviral drugs are available that demonstrate multi-log reductions in viral load. Treated patients are at risk of acquiring mutations that render the virus in their bodies resistant to available therapies, and rapid rebound of viremia is seen upon release of treatment, indicating that current regimens are incurable.

[0003] HIV is a retrovirus, and its life cycle involves reverse transcription of viral RNA genome into DNA by an enzyme called reverse transcriptase, and then the DNA copy is integrated into the host chromosome DNA by the integrase of the virus encoding. The host cell mechanism is used to transcribe viral RNA and translate viral proteins together with viral auxiliary proteins. Many viral proteins are contained in GAG and GAG-POL protein, wherein GAG comprises structural protein, and GAG-POL is produced by the frameshift near the carboxyl terminal of GAG and also comprises protease (PR), reverse transcriptase (RT) and integrase (IN) viral enzyme in addition to structural protein. GAG and GAG-POL are cracked into single protein by maturation process, and this process occurs during virion budding from infected cells. Now GAG-POL dimerization, and the dimerization HIV PR in the present GAG-POL dimer forms active enzyme, which can be cracked out of polyprotein by itself and catalyze further cracking to form remaining viral enzyme and structural protein.

[0004] Available antiretroviral drugs work by blocking viruses at different stages of the viral life cycle. For example, reverse transcriptase inhibitors target viral reverse transcriptase and prevent RNA genomes from being copied into DNA, integrase inhibitors block the ability of replicated DNA to be integrated into host cells, and protease inhibitors prevent viral maturation so that the virions produced from cells treated with protease inhibitors are immature and non-infectious. Once integration has occurred, the cell will be infected until it dies through normal cell death pathways, accelerated death caused by viral factors, or targeted by the immune system. Although most infected cells are expected to die within about 2 days after being infected, the rapid rebound of viremia after treatment is released, indicating that infected cells will still exist even after many years of treatment (see, e.g., JB Dinoso). et al.,Proc. Natl. Acad. Sci. USA, 2009, 106(23):9403-9408). Therefore, new therapies 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 the patient's body has the potential to reduce low-level viremia in suppressed patients and may also play a role in HIV cure strategies. SUMMARY OF THE INVENTION

[0006] The present disclosure relates to pyridone derivatives and their use as small molecule activated cell killing (SMACK) agents, which accelerate the death of HIV GAG-POL expressing cells without cytotoxicity to HIV naive cells. Therefore, the compounds disclosed herein can be used to treat HIV infection, or to treat, prevent, or delay the onset or progression of AIDS or AIDS-related complex (ARC). In addition, the compounds can be used to selectively kill HIV-infected GAG-POL expressing cells in HIV-infected subjects. Compositions and methods of use comprising compounds of the present disclosure are also provided. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present disclosure relates to pyridone derivative compounds and their use for accelerating the death of HIV GAG-POL expressing cells without accompanying cytotoxicity to HIV primary cells. In the absence of compounds such as those from the present invention, PR activation occurs during viral maturation and the concentration of mature PR in the cytoplasm is limited. In contrast, the compounds of the present invention promote the desired phenotype as follows: by binding to immature RT binding sites and triggering premature activation of HIV PR enzymes in host infected cells before budding, catalyzing GAG-POL dimerization in infected cells. As a result, PR cleaves host substrates in cells, leading to cytotoxicity and cell death. This effect can be blocked in the presence of HIV protease inhibitors such as indinavir or darunavir, demonstrating the role of HIV protease in this process.

[0009] The compounds currently disclosed herein also have activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to the homology between the mature and immature RT pockets in HIV, which allows the compounds to bind to the mature hydrophobic pocket near the active site of the viral RT enzyme. Binding to mature RT results in inhibition of enzyme activity and production of DNA provirus, which prevents infection of naive CD4+ T-cells.

[0010] Although the effects of NNRTIs on dimerization of RT and GAG-POL have 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), Jochmans et al. first reported selective killing of HIV-infected cells due to enhanced dimerization (Jochmans et al. Retrovirology 2010, 7:89). The authors generated data showing these effects in chronically infected MT-4 cells, PBMCs, and CD4+ cells. Based on the potency of the tested molecules, they concluded: "These data are proof of concept for targeted drug-induced elimination of HIV-producing cells. Although NNRTIs themselves may not be effective enough for therapeutic applications, 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 the activity of NNRTIs in primary cell models of HIV latency. They found that some NNRTIs significantly reduced viral production compared to other classes of antiretroviral drugs and inferred that this was due to the ability of these compounds to eliminate cells expressing the HIV GAG-POL protein.

[0011] The present disclosure relates to compounds of Formula I or pharmaceutically acceptable salts thereof:

[0012]

[0013] in:

[0014] R 1 H, halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 alkyl;

[0015] R 2 is CN and R 3 is H; or R 2 is H and R3 It is CN;

[0016] R 4 Yes -H, halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 alkyl;

[0017] R 5 Yes -H, halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 alkyl;

[0018] R 6 is halogen or -C substituted with 1-9 -F 1-6 alkyl;

[0019] R 7 Is -H or -C 1-3 alkyl;

[0020] R 8 is -H, halogen or -C 1-3 alkyl; and

[0021] R 9 is -H, pyrazolyl or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-6 alkyl.

[0022] In embodiment 1 of the present disclosure, a compound having structural formula II (wherein R 2 is CN and R 3 H) is a compound of formula I or a pharmaceutically acceptable salt thereof:

[0023]

[0024] Where R 1 , R 4 , R 6 , R 7 , R 8 and R 9 As defined in Formula I.

[0025] In embodiment 2 of the present disclosure is a compound of Formula I or Formula II, or a pharmaceutically acceptable salt of each of the foregoing, wherein:

[0026] R 4 It is halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 Alkyl. In its class 1, R 4 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 Alkyl. In its class 2, R 4 It is halogen, -CH 3 or -CH substituted by 1-3 F 3 .

[0027] In embodiment 3A of the present disclosure is a compound of Formula I, Formula II, Embodiment 2, or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing, wherein R 1 Yes -H.

[0028] In embodiment 3B of the present disclosure is a compound of Formula I, Formula II, Embodiment 2, or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing, wherein R 1 It is halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 Alkyl. In its class 1, R 1 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 Alkyl. In its class 2, R 1 is a halogen or CH 3 .

[0029] In embodiment 4 of the present disclosure is a compound having structural formula III (wherein R 2 is H and R 3 CN) is a compound of formula I or a pharmaceutically acceptable salt thereof:

[0030]

[0031] Where R 1 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in Formula I.

[0032] In embodiment 5A of the present disclosure is a compound of Formula I or Formula III, or a pharmaceutically acceptable salt of each of the foregoing, wherein:

[0033] R 1 It is halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 Alkyl. In its class 1, R 1 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 Alkyl. In its class 2, R 1 Is a halogen or CH 3 .

[0034] In embodiment 5B of the present disclosure is a compound of Formula I or Formula III, or a pharmaceutically acceptable salt of each of the foregoing, wherein:

[0035] R 5 It is halogen, -NH 2 、-NH-C 1-3 Alkyl, -N(C 1-3 alkyl) 2 , -C 3-6 Cycloalkyl, unsubstituted or substituted by 1-7 F 1-3 Alkyl, or unsubstituted or substituted by 1-7 F -OC 1-3 Alkyl. In its class 1, R 5 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 Alkyl. In its class 2, R 5 It is halogen, -CH 3 or -CH substituted by 1-3 F 3 .

[0036] In embodiment 6 of the present disclosure is a compound of Formula I, Formula II, Formula III, or Embodiment 2, 3A, 3B, 5A or 5B or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing, wherein R6 is halogen or -C substituted with 1-9 -F 1-4 Alkyl. In its class 1, R 6 is halogen or -C substituted with 1-7 -F 1-3 Alkyl. In its class 2, R 6 is halogen or -C substituted with 1-5 -F 1-2 alkyl.

[0037] In embodiment 7 of the present disclosure is a compound of Formula I, Formula II, Formula III, or Embodiments 2, 3A, 3B, 5A, 5B or 6 or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing, wherein R 7 is H or -CH 3 .

[0038] In embodiment 8 of the present disclosure is a compound of Formula I, Formula II, Formula III, Embodiment 2, 3A, 3B, 5A, 5B, 6 or 7 or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing, wherein R 8 is -H or halogen.

[0039] In embodiment 9 of the present disclosure is a compound of Formula I, Formula II, Formula III, Embodiment 2, 3A, 3B, 5A, 5B, 6, 7 or 8 or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing, wherein R 9 is -H, pyrazolyl or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-4 Alkyl. In its class 1, R 9 is -H, pyrazolyl, or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-3 Alkyl. In its class 2, R 9 is -H, pyrazolyl, or unsubstituted or substituted with -OH or -OCH 3 Replaced-C 1-3 alkyl.

[0040] In embodiment 10 of the present disclosure is a compound of formula I or II, or a pharmaceutically acceptable salt thereof, wherein

[0041] R 1 is H, halogen or -C which is unsubstituted or substituted by 1-7 F 1-3 Alkyl; for example, R 1 is H, halogen or CH 3 ;

[0042] R 4 It is halogen, -CH 3 or -CH substituted by 1-3 F3 ;

[0043] R 6 is halogen or -C substituted with 1-7 -F 1-3 Alkyl groups, such as R 6 It is -C replaced by 1-5 -F 1-2 alkyl;

[0044] R 7 Is -H or -C 1-3 Alkyl groups, such as R 7 is H or -CH 3 ;

[0045] R 8 is -H, halogen or -C 1-3 Alkyl groups, such as R 8 is -H or halogen; and

[0046] R 9 is -H, pyrazolyl or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-6 Alkyl groups, such as R 9 is -H, pyrazolyl, or unsubstituted or substituted with -OH or -OCH 3 Replaced-C 1-3 alkyl.

[0047] In embodiment 11 of the present disclosure is a compound of formula I or III, or a pharmaceutically acceptable salt thereof, wherein

[0048] R 1 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 Alkyl groups, such as R 1 Is a halogen or CH 3 ;

[0049] R 5 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 Alkyl groups, such as R 5 It is halogen, -CH 3 or -CH substituted by 1-3 F 3 , for example R 5 Yes-CH 3 ;

[0050] R 6 is halogen or -C substituted with 1-7 -F 1-3 Alkyl groups, such as R 6 It is -C replaced by 1-5 -F 1-2 alkyl;

[0051] R 7Is -H or -C 1-3 Alkyl groups, such as R 7 is H or -CH 3 ;

[0052] R 8 is -H, halogen or -C 1-3 Alkyl groups, such as R 8 is -H or halogen; and

[0053] R 9 is -H, pyrazolyl or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-6 Alkyl groups, such as R 9 is -H, pyrazolyl, or unsubstituted or substituted with -OH or -OCH 3 Replaced-C 1-3 alkyl.

[0054] References herein to compounds of Formula I encompass compounds of Formula I, II and III and embodiments and classes thereof. The compounds of Formula I may be neutral compounds or in the form of salts (where such salts are possible), including pharmaceutically acceptable salts.

[0055] The term “eg” means “for example.” When the term “eg” or “for example” is used herein, the listed example or examples are intended to be illustrative and are not intended to be an exhaustive list of all relevant examples.

[0056] As used herein, "alkyl" refers to branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms within a specified range. 1-6 The term "alkyl" refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms (including all possible isomers), and includes each of the hexyl and pentyl isomers as well as n-butyl, isobutyl, sec-butyl and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively referred to as "C 4 alkyl"; Bu = butyl), n-propyl and isopropyl (propyl, i-propyl, collectively referred to as "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-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, ethyl and methyl. "C 1-3 The "alkyl" group has 1, 2 or 3 carbon atoms and includes each of n-propyl, isopropyl, ethyl and methyl.

[0057] "Cycloalkyl" means a cyclized alkyl ring having a specified number of carbon atoms within 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.

[0058] "Halo" or "halogen" means chlorine, fluorine, bromine or iodine. Chlorine, fluorine and bromine are one class of halogens of interest, and more particularly chlorine and fluorine.

[0059] "HIV naive cells" are cells that have not been infected with HIV.

[0060] A "compatible anti-HIV agent" is an anti-HIV agent that does not include an HIV protease inhibitor.

[0061] A "stable" compound is one that can be prepared and isolated and whose structure and properties remain or can be caused to remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and its embodiments. For example, certain moieties defined in Formula I may be unsubstituted or substituted, and the latter is intended to cover substitution patterns (i.e., the number and type of substituents) for the moieties that are chemically possible and that result in stable compounds.

[0062] The present disclosure includes single diastereomers, particularly diastereomers, i.e. compounds with the same chemical formula but different spatial arrangements around a single atom. The present disclosure also includes mixtures of diastereomers of all ratios, particularly mixtures of diastereomers. The present disclosure encompasses compounds of formula I having (R) or (S) stereoconfiguration at asymmetric centers and at any additional asymmetric centers that may be present in compounds of formula I, as well as stereoisomer mixtures thereof. Embodiments of the present disclosure also include enantiomeric mixtures 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). Single diastereomers are preferred. Single or single enantiomers represent enantiomers obtained by chiral synthesis and / or using known separation and purification techniques, and it can be 100% of one enantiomer or can contain a small amount (e.g., 10% or less) of the opposite enantiomer. Therefore, the individual enantiomers are the subject of the present disclosure in pure form (as levorotatory and dextrorotatory enantiomers), in the form of racemates, and in the form of mixtures of the two enantiomers in all ratios. In the case of cis / trans isomerism, the present disclosure includes both the cis-form and the trans-form and mixtures of all ratios of these forms.

[0063] If desired, by separating the mixture by conventional methods (e.g., chromatography or crystallization), by using stereochemically uniform synthetic starting materials, or by stereoselective synthesis, the preparation of each stereoisomer can be carried out. Optionally, derivatization can be performed before separating the stereoisomers. The separation of the stereoisomer mixture can be performed in an intermediate step during the synthesis of the compound of Formula I, or it can be performed on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, if necessary, the crystalline product or crystalline intermediate is derivatized with a reagent containing a stereocenter of known configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy analysis. The present disclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0064] As will be appreciated by those of ordinary skill in the art, certain compounds of the present disclosure may be capable of existing as tautomers. All tautomeric forms of such compounds, whether individually isolated or in mixtures, are within the scope of the present disclosure. For example, where oxo (=O) substituents are allowed on heteroaromatic rings and keto-enol tautomerism is possible, it will be understood that the substituents may actually exist in whole or in part as -OH forms.

[0065] The atoms in the compounds of Formula I may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominantly occurs in nature. The present disclosure is intended to include all suitable isotopic variants of the compounds of Formula I; for example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the dominant hydrogen isotope present in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as standards for characterization of biological samples. Isotopically enriched compounds of formula I can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by methods similar to those described in the schemes and embodiments herein, using appropriate isotopically enriched reagents and / or intermediates.

[0066] The compounds can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts that have the effectiveness of the parent compound and are not biologically or otherwise undesirable (e.g., non-toxic and otherwise harmless to its recipient). When the compound of Formula I contains one or more acidic or basic groups, the present invention includes the corresponding pharmaceutically acceptable salts.

[0067] Therefore, the compound of formula I containing acidic groups (e.g., -COOH) can be used according to the present invention, such as but not limited to as alkali metal salts, alkaline earth metal salts or ammonium salts. Examples of such salts include but are not limited to sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. The compound of formula I containing one or more basic groups (i.e., groups that can be protonated) can be used according to the present invention in the form of acid addition salts with inorganic or organic acids, such as but not limited to salts with the following acids: hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compound of formula I contains both acidic and basic groups in the molecule, the invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. Salts can be obtained from compounds of formula I by conventional methods known to those skilled in the art, for example by combination with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts. The invention also includes all such salts of compounds of formula I: they are not directly suitable for use in medicines due to their low physiological compatibility, but they can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0068] The present disclosure encompasses any composition comprising a compound of Formula I or a compound as a salt thereof, including, for example, but not limited to, a composition comprising the compound combined with one or more additional molecular and / or ionic components, which may be referred to as a "co-crystal". As used herein, the term "co-crystal" refers to a solid phase (which may or may not be crystalline) in which two or more different molecular and / or ionic components (usually in stoichiometric ratios) are held together by non-ionic interactions, including, but not limited to, hydrogen bonding, dipole-dipole interactions, dipole-quadrupole interactions, or dispersion forces (van der Waals forces). There is no proton transfer between the different components, and the solid phase is neither a simple salt nor a solvate. A discussion of co-crystals can be found, for example, in S. Aitipamula et al., Crystal Growth and Design, 2012, 12 (5), pp. 2147-2152.

[0069] In addition, the compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and therefore all amorphous and crystalline forms of the compounds of Formula I and their salts and mixtures thereof are intended to be included within the scope of the present disclosure. In addition, some compounds of the present disclosure may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates of the compounds of the present disclosure, particularly pharmaceutically acceptable solvates and hydrates, together with the non-solvated and anhydrous forms of such compounds, are also encompassed within the scope of the compounds defined by Formula I and their pharmaceutically acceptable salts.

[0070] Therefore, the compounds of Formula I or salts thereof (including pharmaceutically acceptable salts thereof), embodiments and specific compounds thereof described and claimed herein encompass all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms), co-crystal forms, solvates and hydrate forms, as well as any combination of the foregoing forms (when such forms are possible).

[0071] Another embodiment of the present disclosure is a compound of formula I, wherein the compound or its salt is in substantially pure form. "Substantially pure" used herein appropriately refers to, at least about 60% by weight, usually at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% by weight (for example, about 90% by weight to about 99% by weight), even more preferably at least about 95% by weight (for example, about 95% by weight to about 99% by weight, or about 98% by weight to 100% by weight) and most preferably at least about 99% by weight (for example, 100% by weight) of the compound containing formula I or its salt product (for example, the product separated from the reaction mixture providing the compound or salt) is composed of the compound or salt. Using standard analytical methods such as high performance liquid chromatography and / or mass spectrometry or NMR technology, it is possible to determine the purity level of compound and salt. If more than one analytical method is used and these methods provide experimentally significant differences in the purity level determined, then the method providing the highest purity level is defined. A 100% pure compound or salt is one that contains no detectable impurities as determined by standard analytical methods. With respect to compounds of the invention that have one or more asymmetric centers and that may exist as a mixture of stereoisomers, a substantially pure compound may be a substantially pure mixture of stereoisomers or a substantially pure individual stereoisomer.

[0072] The compounds of formula I herein and their pharmaceutically acceptable salts can be used to induce GAG-POL dimerization in HIV-infected cells, and thereby selectively kill HIV-infected GAG-POL-expressing cells without accompanying cytotoxicity to HIV-naive cells, which is referred to herein as small molecule activated cell killing (SMACK) activity. Therefore, the compounds of formula I and their pharmaceutically acceptable salts can be used for:

[0073] (i) a method for treating HIV infection, or treating, preventing, or delaying the onset or progression of AIDS or ARC in a human subject in need thereof, the method comprising administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof;

[0074] (ii) a method for inducing GAG-POL dimerization in HIV-infected cells of a human subject in need thereof, the method comprising administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and / or

[0075] (iii) A method for selectively killing HIV-infected GAG-POL-expressing cells in a human subject without concomitant cytotoxicity to HIV-naive cells, the method comprising administering to the human subject an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

[0076] In addition, the compounds of Formula I and their pharmaceutically acceptable salts can be used in any of the above methods (i), (ii) or (iii), further comprising administering to a human subject an effective amount of one or more compatible HIV antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors. In the methods of (i), (ii) and (iii) just above, in addition to treatment with one or more compatible HIV antiviral agents, the human subject is treated with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0077] The compounds of formula I and their pharmaceutically acceptable salts can also be used in a method of enhancing the suppression of HIV viremia in a human subject whose viremia is suppressed by administration of one or more compatible HIV antiviral agents, the method comprising additionally administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

[0078] Other embodiments of the present disclosure include the following:

[0079] (a) A pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0080] (b) A pharmaceutical composition comprising a product prepared by combining (eg, mixing) an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0081] (c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators and anti-infective agents.

[0082] (d) The pharmaceutical composition of (c), wherein the compatible anti-HIV agent is selected from one or more antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.

[0083] (e) A combination of (i) a compound of Formula I or a pharmaceutically acceptable salt thereof and (ii) one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound and the compatible anti-HIV agent are each used in a specific amount that makes the combination effective in treating HIV infection, or in treating, preventing or delaying the onset or progression of AIDS or ARC.

[0084] (f) The combination of (e), wherein the compatible anti-HIV agent is an antiviral agent 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, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.

[0085] (g) a method for inducing GAG-POL dimerization in HIV-infected cells, a method for selectively killing HIV-infected GAG-POL-expressing cells without concomitant cytotoxicity to HIV-naive cells, and / or a method for treating HIV infection, or treating, preventing AIDS or ARC, or delaying the onset or progression of AIDS or ARC, the method 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.

[0086] (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 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.

[0087] (i) The method of (g) or (h), comprising administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).

[0088] (j) Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for (1) inducing GAG-POL dimerization in HIV-infected cells of a subject; (2) selectively killing HIV-infected GAG-POL-expressing cells in a subject without concomitant cytotoxicity to HIV-naive cells; (3) treating HIV infection in a subject; (4) treating, preventing, or delaying the onset or progression of AIDS or ARC in a subject; and / or (5) enhancing the suppression of HIV viremia in a subject receiving treatment with a compatible anti-HIV agent.

[0089] (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) selectively killing HIV-infected GAG-POL-expressing cells without concomitant cytotoxicity to HIV-naive cells; (3) treating HIV infection; (4) treating, preventing, or delaying the onset or progression of AIDS or ARC; and / or (5) enhancing the suppression of HIV viremia in subjects receiving compatible anti-HIV agents.

[0090] Additional embodiments of the present invention include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of formula I or its salt used therein is substantially pure. With respect to pharmaceutical compositions comprising a compound of formula I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it should be understood that the term "substantially pure" refers to the compound of formula I or its salt itself.

[0091] Another embodiment of the present disclosure is the above-mentioned pharmaceutical composition, method and purposes, wherein the HIV of interest is HIV-1. The term "administering" and variants thereof (e.g., "administering" compound) of the compound of Formula I refer to providing the compound to an individual in need of treatment or prevention, and include self-administration and administration to the patient by another person. When the compound is provided in combination with one or more other activating agents (e.g., an antiviral agent that can be used to treat or prevent HIV infection or AIDS), "administering" and variants thereof are each understood to include providing the compound and other medicaments simultaneously or not simultaneously. When the medicaments of the combination are administered simultaneously, they can be administered together in a single composition, or they can be administered separately.

[0092] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product resulting from combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0093] As used herein, the term "subject" or "patient" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0094] The term "effective amount" as used herein refers to the amount of a compound that is sufficient to induce GAG-POL dimerization in HIV-infected cells and selectively kill HIV-infected GAG-POL-expressing cells without cytotoxicity to HIV-naive cells; and / or to exert a therapeutic effect and / or a preventive effect after administration. One embodiment of an "effective amount" is a "therapeutically effective amount," which is the amount of such a compound: in HIV-infected patients, it effectively selectively kills HIV-infected GAG-POL-expressing cells, effectively treats HIV infection, or effectively treats AIDS or ARC or delays the onset or progression of AIDS or ARC. Another embodiment of an "effective amount" is a "preventive effective amount," which is the amount of a compound that effectively prevents AIDS or ARC in HIV-infected patients. It should be understood that an effective amount can be both a therapeutically effective amount (e.g., for treating HIV infection) and a preventive effective amount (e.g., for preventing the occurrence of AIDS or ARC or reducing the risk of AIDS or ARC in HIV-infected subjects). The term "prevention" as used herein means reducing the likelihood or severity of AIDS after HIV infection.

[0095] In the combination therapies of the present invention, an effective amount may refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered in the combination are effective together, but wherein the component agents of the combination may or may not be present individually in an effective amount with reference to the amount of the component agent considered effective when administered alone.

[0096] In the method of the present invention (i.e., selectively killing HIV-infected GAG-POL expressing cells, treating HIV infection, or treating, preventing AIDS or ARC or delaying the onset or progression of AIDS or ARC), the compound of the present invention or its salt can be administered in a manner that the active agent is in contact with the site of action of the agent. They can be administered in a conventional manner that can be used in combination with a drug, as a single therapeutic agent or a combination of therapeutic agents. The compound can be administered by itself, but is usually administered together with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice. The compound of the present invention can be administered, for example, as follows: in a unit dosage form of a pharmaceutical composition containing an effective amount of the compound and a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and vehicle, orally (e.g., by tablets or capsules), parenterally (including, for example, subcutaneous injection, intravenous, intramuscular or intrasternal injection or infusion technology), by inhalation spray, or rectally. The compound can also be administered by an implantable drug delivery device, which is suitable for providing an effective amount of the compound or a pharmaceutical composition of the compound over an extended period of time.

[0097] preparation

[0098] Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art, and solid excipients such as starch, sugar, kaolin, lubricants, adhesives, disintegrants, etc. can be used. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art, and any common medium such as water, glycols, oils, alcohols, etc. can be used. Parenteral compositions can be prepared according to techniques known in the art, and sterile water (as a carrier) and optional other ingredients, such as dissolution aids, are generally used. Injectable solutions can be prepared according to methods known in the art, wherein the carrier comprises a solution of a saline solution, a glucose solution or a mixture containing saline and glucose. Implantable compositions can be prepared according to methods known in the art, wherein the carrier comprises an active chemical component and a polymer as a suitable excipient, or an implantable device is utilized for drug delivery. Further description of methods suitable for preparing pharmaceutical compositions for use in the present invention and ingredients suitable for such compositions is provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6 and previous editions.

[0099] The preparation of the compound of formula I that causes drug supersaturation and / or rapid dissolution can be used to promote oral drug absorption. The formulation scheme that causes drug supersaturation and / or rapid dissolution includes, but is not limited to nanoparticle system, amorphous system, solid solution, solid dispersion and lipid system. Such formulation scheme and the technology for preparing them are known in the art. For example, solid dispersion can be prepared using the excipient and process described in the review (for example, ATM Serajuddin, JPharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticle system based on attrition and direct synthesis has also been described in the review such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

[0100] The compound of formula I can be administered, for example, in a dosage range of 1-20 mg / kg, or 1-10 mg / kg, or about 5 mg / kg of mammal (e.g., human) body weight per day, or at other time intervals as appropriate, in single or divided doses. The compound of formula I can be administered in a dosage range of 0.001-2000 mg per day in single or divided doses. An example of a dosage range is 0.01-1500 mg / day, or 0.1-1000 mg / day, administered orally in single or divided doses or by other routes of administration.

[0101] For oral (e.g., tablets or capsules) or other routes of administration, the dosage unit can contain 100 mg to 1500 mg of active ingredient, such as, but not limited to, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400 or 1500 mg of active ingredient, for adjusting the dosage of the patient to be treated according to the symptoms. In addition, the compound can be formulated into an oral formulation for immediate or modified release, such as extended or controlled release. When the compound of Formula I is used as a salt, the amount of the compound in milligrams or grams mentioned is based on the free form (i.e., non-salt form) of the compound.

[0102] Daily administration may be by any suitable route of administration, but is preferably by oral administration, and may be a single dose or more than one dose (divided daily doses) at staggered times within each 24 hour period. Each dose may be administered using one or more dosage units as appropriate.

[0103] The specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the specific condition and the host to be treated. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upward or downward from a given dose. The amount and frequency of administration will be adjusted according to the judgment of the attending clinician considering these factors.

[0104] An "anti-HIV agent" is any agent that is effective, directly or indirectly, in inhibiting HIV, treating or preventing HIV infection, and / or treating, preventing AIDS or ARC, or delaying the onset or progression of AIDS or ARC. It should be understood that anti-HIV agents are effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and / or diseases or conditions caused or associated therewith. The present disclosure further relates to the use of compounds of Formula I together with one or more compatible anti-HIV agents (i.e., anti-HIV agents that do not include HIV protease inhibitors). For example, a compound of Formula I may be administered in combination with an effective amount of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infective agents, or vaccines that can be used to treat HIV infection or AIDS. Suitable compatible HIV antiviral agents for use in combination with the compounds of the present disclosure include, but are not limited to, those listed in Table A below:

[0105] Table A: Antiviral Agents Used to Treat HIV Infection or AIDS

[0106] name type Abacavir, ABC, ZIAGEN® NRTI Abacavir + Lamivudine, EPZICOM® NRTI Abacavir + Lamivudine + Zidovudine, Sanxiewei® NRTI AZT, zidovudine, azidothymidine, RETROVIR® NRTI Capevirin NNRTI ddC, zalcitabine, dideoxycytidine, HIVID® NRTI ddI, didanosine, didanosine, VIDEX® NRTI ddI (enteric coated), VIDEX EC® NRTI Delavirdine, DLV, RESCRIPTOR® NNRTI Dolutegravir, TIVICAY® InSTI <![CDATA[Doravirine, PIFELTRO TM > NNRTI <![CDATA[Doravirine / Lamivudine / Tenofovir Disoproxil Fumarate, DELSTRIGO TM > 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 Ivitegravir 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, Shuangtaizhi® NRTI Maraviroc, SELZENTRY® EI Nevirapine, NVP, VIRAMUNE® NNRTI <![CDATA[Raltegravir, MK-0518, ISENTRESS TM > InSTI Rilpivirine NNRTI Stavudine, d4T, didehydrothymidine, ZERIT® NRTI Tenofovir disoproxil fumarate, VIREAD® NRTI Tenofovir Alafenamide Fumarate NRTI Virivero EI

[0107] EI = entry inhibitor; FI = fusion inhibitor; InSTI = integrase inhibitor; NRTI = nucleoside or nucleotide reverse transcriptase inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTTI = nucleoside reverse transcriptase translocation inhibitor. Some of the drugs listed in the table are used in salt form; e.g., abacavir sulfate, delavirdine mesylate.

[0108] It should be understood that the scope of the combination of the compounds of the present invention with compatible anti-HIV agents is not limited to the HIV antiviral agents listed in Table A, but in principle includes any combination with any pharmaceutical composition that can be used to treat or prevent HIV AIDS or ARC, but with the exception of HIV protease inhibitors. Compatible HIV antiviral agents and other active agents are generally used in these combinations with their conventional dosage ranges and regimens 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 versions. The dosage ranges of the compounds of the present disclosure in these combinations may be the same as those described above.

[0109] The compounds of the invention can also be used to prepare and perform screening assays for antiviral compounds. For example, the compounds of the invention can be used to isolate enzyme mutants, which are excellent screening tools for more potent antiviral compounds. In addition, the compounds of the invention can be used to establish or determine the binding site of other antiviral agents to the reverse transcriptase region within GAG-POL, for example, by competitive inhibition.

[0110] The following acronyms and abbreviations have the meanings indicated:

[0111] ACN = Acetonitrile <![CDATA[AcOH = acetic acid; Ac = acetyl = -C(O)CH 3 ; aq. = aqueous]]> aq. = water-based <![CDATA[B 2 Pin 2 = Bis(pinacol)diboron]]> BPO = Benzoyl Peroxide CAN = Cerium Ammonium Nitrate cataCXium®A Pd G2 procatalyst = chloro[(di(1-adamantyl)-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) DAST = (diethylamino)sulfur trifluoride DCE = 1,2-dichloroethane DCM = dichloromethane DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD = diisopropyl azodicarboxylate DHP = 3,4-dihydro-2-pyran DIBAL-H = Diisobutylaluminum hydride DIPEA - Diisopropylethylamine DME = dimethoxyethane DMF = ,-dimethylformamide Dess-Martin periodinane = 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one DMA = dimethylacetamide DMSO = dimethyl sulfoxide <![CDATA[DMSO- d 6 = Deuterated dimethyl sulfoxide]]> eg = 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 = hours KI = Potassium iodide <![CDATA[Ir [(Ome)(1,5-COD)] 2 = (1,5-cyclooctadiene)(methoxy)iridium(I) dimer]]> L = liter; g = gram LCAP = Liquid Chromatography Area Percent LC-MS, LCMS = Liquid chromatography-mass spectrometry LDA = lithium diisopropylamide LAH = Lithium Aluminum Hydride m-CPBA = 3-Chlorobenzene Me = Methyl MeI = Methyl iodide MeOH = Methanol Me-THF = 2-methyltetrahydrofuran MTBE = Methyl tert-butyl ether min = minutes MS = mass spectrometry MsCl, mesyl-Cl = methanesulfonyl chloride <![CDATA[NaIO 4 = Sodium Periodate]]> NBS = -bromosuccinimide n-BuLi = n-Butyllithium NCS = -chlorosuccinimide NHS = Normal human serum NMP = -methyl-2-pyrrolidone NMR = Nuclear Magnetic Resonance PBMC = peripheral blood mononuclear cells PBS = Phosphate Buffered Saline <![CDATA[Pd 2 (dba) 3 = Tris(dibenzylideneacetone)dipalladium(0)]]> <![CDATA[PdCl 2 (dppf) = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride]]> <![CDATA[Pd(OAc) 2 = Palladium(II) acetate<!-- 13 --> ]]> <![CDATA[Pd(Ph 3 P) 4 = Tetrakis(triphenylphosphine)palladium(0)]]> PE, PE = Petroleum ether PHA = Phytohemagglutinin PMB = 4-methoxybenzyl PMBCl = 4-methoxybenzyl chloride PPTS = 4-Toluenesulfonic acid RT = Room temperature sat. = saturated SMACK - Small molecule activated cell killing <![CDATA[SN Ar = Nucleophilic Aromatic Displacement]]> TBAF = Tetrabutylammonium fluoride Tc = Thiophene carboxylate -BuOH = tert-Butanol -BuOK = Potassium tert-butoxide -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

[0112] Several methods for preparing the compounds of the invention are described in the following schemes and examples. Starting materials and intermediates were purchased or prepared using known procedures, or otherwise illustrated in the following five intermediates (A, B, C, AB and BC). Common routes for compounds of Formula I are described in the following schemes.

[0113] Solution 1

[0114]

[0115] Scheme 1 depicts a method for preparing compounds of Formula I. Intermediate AB is prepared using the procedure exemplified in the Intermediate AB section. Mitsunobu reaction or alkylation using an appropriate pyridone benzyl alcohol or halide (Intermediate C) provides intermediate ABC. Intermediate C typically has a protected (PG') pyridone moiety, as shown in Scheme 1 as Z. The synthesis of C is exemplified in the Intermediate C section. The resulting intermediate ABC can optionally be subjected to additional modifications, followed by a deprotection step, to obtain a compound of Formula I.

[0116] Solution 2

[0117]

[0118] Scheme 2 illustrates another method for preparing compounds of Formula I. The SN reaction between Intermediate A (commercially available or prepared using the procedure in the Intermediate A section) and Intermediate BC (prepared by the procedure exemplified in the Intermediate BC section) is Ar The reaction is used to prepare the intermediate ABC. The pyridone C ring is usually protected with a protecting group (PG') such as a methyl or PMB group. The resulting intermediate ABC can then optionally undergo additional modifications followed by a deprotection step to obtain a compound of formula I.

[0119] Reactions that are sensitive to moisture or air are performed under nitrogen or argon using anhydrous solvents and reagents. Reactions performed using microwave irradiation are typically performed using an Emrys Optimizer manufactured by Personal Chemistry or an Initiator manufactured by Biotage. Concentration of solutions is performed on a rotary evaporator under reduced pressure.

[0120] The progress of the reaction was determined by analytical thin layer chromatography (TLC) or analytical liquid chromatography-mass spectrometry (LC-MS), usually using E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Typically, the analytical LC-MS system used was a Waters ZQ ™ The column is usually a Waters Xterra MS C18, 3.0×50 mm, 5 μ m or Waters Acquity UPLC ® BEH C18 1.0 x 50 mm, 1.7 μ The flow rate was 1 mL / min and the injection volume was 10 μL. UV detection was in the range of 210-400 nm. The mobile phase consisted of solvent A (water + 0.05% TFA) and solvent B (acetonitrile + 0.05% TFA) with a gradient of 100% solvent A for 0.7 min, 3.75 min to 100% solvent B, held for 1.1 min, and then returned to 100% solvent A for 0.2 min. LC / MS assays were performed on a Waters Classifying Aquity system equipped with TUV and MS detectors and a Waters SQD mass spectrometer, a Shimadzu 20 UV 254 and 220 nM with a Shimadzu 2010 or 2020 mass spectrometer, or an Agilent 1200 HPLC equipped with a DAD / ELSD and a G6110 MSD using one of the following conditions: 1) an Ascentis Express C18 (3 x 50 mm) 2.7 μm column using a mobile phase consisting of A: 0.05% trifluoroacetic acid in water and B: 0.05% trifluoroacetic acid in acetonitrile with a gradient from 90:10 (A:B) to 5:95 (A:B) over 6 min at a flow rate of 1.8 mL / min with UV detection at 210 nm; 2) an Aquity BEH C18, (1.0 x50 mm) 1.7 μm column using a mobile phase consisting of A: 1) Agilent YMC J'Sphere H-80 (3 x 50 mm) 5 μm column, using a mobile phase containing A: 0.1% trifluoroacetic acid in water and B: acetonitrile, with a gradient from 90:10 (A:B) to 5:95 (A:B) in 2 min, a flow rate of 0.3 mL / min, and UV detection at 215 nm; 2) Agilent YMC J'Sphere H-80 (3 x 50 mm) 5 μm column, using a mobile phase containing A: 0.1% trifluoroacetic acid in water and B: acetonitrile, with a gradient from 95:5 (A:B) to 0:100 (A:B) in 3.6 min and a hold at 0:100 (A:B) for 0.4 min, a flow rate of 1.4 mL / min, UV detection at 254 and 220 nm, and an Agilent 1100 quadrupole mass spectrometer; 3) Agilent TC-C18 (2.1 x 50 mm) 5 μm column, using a mobile phase consisting of A: 0.0375% trifluoroacetic acid in water and B: 0.01875% trifluoroacetic acid in acetonitrile, a gradient of 90:10 (A:B) for 0.4 min, 90:10 to 0:100 (A:B) over 3 min, and 10:90 (A:B) for 0.6 min, a flow rate of 0.8 mL / min, UV detection at 254 and 220 nm, and an Agilent 6110 quadrupole mass spectrometer.

[0121] Preparative HPLC purifications are usually performed using either mass spectrometry-oriented systems or non-mass-oriented systems. Typically, they are performed on a Waters chromatography workstation equipped with an LC-MS system consisting of a Waters ZQ ™ Single quadrupole MS system, Waters 2525 stepper pump, Waters 2767 Injecto / Collector, Waters 996 PDA detector, MS conditions: 150-750 amu, positive electrospray, MS triggered collection and Waters SUNFIRE ® C-18 5 micron, 30 mm (id) x 100 mm column. The mobile phase consisted of a mixture of acetonitrile (10-100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL / min and the injection volume was 1800 μ L, and the UV detection range was 210-400 nm. An alternative preparative HPLC system used was a Gilson workstation consisting of a Gilson GX-281 injector / collector, a Gilson UV / VIS-155 detector, Gilson 333 and 334 pumps, and equipped with a column selected from the following: Phenomenex 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 mm x 30 mm x 5 microns). Conditions included 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% acetonitrile / water eluent with 0.1% v / v TFA). Injection volume range 1000-8000 μ L, and the UV detection range was 210-400 nm. The mobile phase gradient was optimized for individual compounds.

[0122] Biotage is commonly used ®Flash chromatography was performed on silica gel (32-63 μm, 60Å pore size) using a Flash Chromatography Apparatus (Dyax Corp.), an ISCO CombiFlash® Rf Apparatus, or an ISCO CombiFlash® Companion XL in prepacked cartridges of the dimensions indicated.

[0123] SFC chiral resolutions were performed on a Sepiate Prep SFC 100, Multigram II (MGII), THAR80 prep SFC or Waters SFC (80, 200 or 350) using the conditions described in the experimental section.

[0124] Unless otherwise noted, proton or ion spectra were acquired according to standard analytical techniques 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 probe, a Varian-400 MHz MR spectrometer equipped with an Auto X ID PFG Probe 5 mm, a Varian 400 MHz VNMRS spectrometer equipped with a PFG 4Nuc Probe 5 mm, or a Bruker AvanceIII 500 MHz spectrometer equipped with a PABBO Probe 5 mm. 1 H NMR and report the spectral analysis results. 3 Obtained in solution 1 H NMR spectra, unless otherwise indicated. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as CD 3 Cl solution, and the residual CH 3 OH peak or TMS is used as CD 3 Internal reference in OD solution. Coupling constants (J) are reported in Hertz (Hz).

[0125] It is understood that chiral centers in a compound can be represented by " S "or" R " stereoconfiguration, or as a mixture of both. Within a molecule, unless otherwise indicated, each bond drawn as a straight line from a chiral center encompasses ( R )and( S) stereoisomers and mixtures thereof. The compounds in Examples 32, 33 and 34 contain chiral centers. The isomeric mixtures prepared as described in the individual experiments for these compounds were separated based on their observed elution order (resulting from the separations performed as in the Examples) to provide one or both of Isomer A (the faster eluting isomer) and Isomer B (the slower eluting isomer). If carried out under conditions different from those used herein, the elution times and / or order of the separated isomers may be different. The absolute stereochemistry of the chiral centers of each of the "A" and / or "B" separated stereoisomers in Examples 32, 33 and 34 was not determined ( R or S ), and "A" and "B" simply represent the elution order resulting from the purification conditions performed. Asterisks (*) may be used in the relevant chemical structure diagrams of the example compounds to indicate chiral centers.

[0126] Intermediate Part A

[0127] Intermediate A01

[0128]

[0129] 3-(Difluoromethyl)-5-hydroxybenzonitrile

[0130] Step 1: 3-Chloro-5-((4-methoxybenzyl)oxy)benzonitrile

[0131] To a solution of 3-chloro-5-hydroxybenzonitrile (30 g, 0.20 mol) in ACN (300 mL) was added PMBCl (34 g, 0.21 mol) and K 2 CO 3 (55 g, 0.4 mmol) and the mixture was then stirred at 70°C for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (2% EtOAc / petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ 7.33 (d, J= 8.0 Hz, 2H), 7.23 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.94 (d, J= 8.0 Hz, 2H), 5.00 (s, 2H), 3.83 (s, 3H).

[0132] Step 2: 3-((4-methoxybenzyl)oxy)-5-vinylbenzonitrile

[0133] In N 23-Chloro-5-((4-methoxybenzyl)oxy)benzonitrile (50 g, 0.18 mol) was added to a solution of dioxane / H 2 Potassium vinyl trifluoroborate (25 g, 0.18 mol), K 2 CO 3 (50g, 0.36 mol), X-phos (17 g, 36 mmol) and Pd(OAc) 2 (4.1 g, 18 mmol), the mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the resulting mixture was filtered and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (1-2% EtOAc / petrol ether) to give the title compound. 1 H 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= 8.4Hz, 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).

[0134] Step 3: 3-Formyl-5-((4-methoxybenzyl)oxy)benzonitrile

[0135] The compound 3-((4-methoxybenzyl)oxy)-5-vinylbenzonitrile (28 g, 0.1 mol) was reacted in dioxane / H 2 O (180 mL / 60 mL) was added to the stirred solution of 2,6-lutidine (22 g, 0.2 mol), OsO 4 (1.3 g, 5 mmol) and NaIO 4 (43 g, 0.2 mol), and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (3×200 mL). The organic layer was washed with water and brine, and then purified by Na 2 SO4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (2-10% EtOAc / petroleum ether) to give the title compound. 1 H NMR (400 MHz, DMSO- d 6 ): 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).

[0136] Step 4: 3-(Difluoromethyl)-5-((4-methoxybenzyl)oxy)benzonitrile

[0137] At 0°C in N 2 To a stirred solution of 3-formyl-5-((4-methoxybenzyl)oxy)benzonitrile (22 g, 82 mmol) in DCM (250 mL) was added DAST (106 g, 0.6 mol) under atmosphere, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was quenched with water and extracted with DCM (3×200 mL). The organic layer was washed with water and brine, and then purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound.

[0138] Step 5: 3-(Difluoromethyl)-5-hydroxybenzonitrile

[0139] A solution of 3-(difluoromethyl)-5-((4-methoxybenzyl)oxy)benzonitrile (23.7 g, 82 mmol) in TFA / TFAA (100 mL / 50 mL) was stirred at 110 °C for 3 h. When the reaction was complete, the resulting mixture was treated with saturated NaHCO 3 The mixture was quenched with aqueous solution (100 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. 1 H NMR (400 MHz, DMSO- d 6 ): 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).

[0140] Intermediate A02

[0141]

[0142] 5-(Difluoromethyl)-3-hydroxy-2-methylbenzonitrile

[0143] Step 1: 5-Formyl-2-methylbenzonitrile

[0144] Into a 20-L 4-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, a solution of 5-bromo-2-methylbenzonitrile (750 g, 38.26 mol) in tetrahydrofuran (6 L) was placed, n-BuLi (1.54 L, 38.26 mol) was added dropwise at -78°C, the resulting solution was stirred for 30 min, N,N-dimethylformamide (295 g, 4.04 mol, 1.05 equivalents) was added dropwise. The reaction mixture was stirred at -78°C in a liquid nitrogen bath for 30 min, and then 5 L of saturated NH 4 The resulting solution was extracted with EtOAc (3 × 5 L). The organic layer was washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound.

[0145] Step 2: 3-Bromo-5-formyl-2-methylbenzamide

[0146] Into a 3-L 4-neck round bottom flask purged and maintained with a nitrogen inert atmosphere, a solution of 5-formyl-2-methylbenzonitrile (245 g, 1.69 mol) in sulfuric acid (980 mL) was placed, the reaction mixture was stirred at 60°C, and 1-bromopyrrolidine-2,5-dione (300 g, 1.69 mol) was added in 3 batches. The resulting solution was stirred at 60°C for 30 min. The reactants were then quenched by adding 5 L of water / ice and stirred for 1 h. The solids were collected by filtration and dried under vacuum to give the title compound and used as is in the next step.

[0147] Step 3: 3-Bromo-5-formyl-2-methylbenzonitrile

[0148] Into a 20-L 4-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 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 at room temperature for 30 min, then quenched with water / ice (5 L), and extracted with DCM (3×5 L). The organic layers were combined and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (20% EtOAc / hexanes) to give the title compound.

[0149] Step 4: 3-Bromo-5-(difluoromethyl)-2-methylbenzonitrile

[0150] To a solution of 3-bromo-5-formyl-2-methylbenzonitrile (360 g, 1.61 mol) in dichloromethane (5.4 L) was added DAST (260 g, 1.61 mol, 1.00 equiv) dropwise at room temperature. The resulting solution was stirred at room temperature for 1 h and then quenched with water / ice (3 L). The resulting solution was extracted with DCM (3×5 L). The organic layers were combined and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound and use as such in the next step.

[0151] Step 5: 5-(Difluoromethyl)-3-hydroxy-2-methylbenzonitrile

[0152] To a solution of 3-bromo-5-(difluoromethyl)-2-methylbenzonitrile (320 g, 1.30 mol) in 1,4-dioxane (1.6 L) was added a solution of KOH (146 g, 2.60 mol) in water (1.6 L), Pd 2 (dba) 3 (67 g, 64.92 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (55 g, 129.53 mmol). The resulting mixture was purged with nitrogen (3×) and stirred at 90°C for 1 h, then partitioned between ice water (4 L) and EtOAc (3×2 L). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by flash chromatography on silica (33% EtOAc / hexanes) to give the title compound. MS: 182 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.65 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.26 (d, J =1.5 Hz, 1H), 6.99 (s, 1H), 2.34 (d, J = 1.3 Hz, 3H).

[0153] Intermediate A03

[0154]

[0155] 2,5-Dichloro-3-hydroxybenzonitrile

[0156] Step 1: 2-Amino-5-bromo-3-fluorobenzonitrile

[0157] To a stirred solution of 2-amino-3-fluorobenzonitrile (5 g, 36.7 mmol) in DMF (50 mL) was added 1-chloropyrrolidine-2,5-dione (5.15 g, 38.6 mmol) and the resulting mixture was stirred at 60 °C for 6 h. The mixture was partitioned between water (200 mL) and EtOAc (2×150 mL). The combined organic layers were washed with brine (3×300 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used in the next step without purification. MS: 171.1 (M+1).

[0158] Step 2: 2,5-Dichloro-3-fluorobenzonitrile

[0159] To a mixture of 2-amino-5-chloro-3-fluorobenzonitrile (6.217 g, 36.4 mmol), cuprous (I) chloride (10.82 g, 109 mmol) and cupric (II) chloride (17.15 g, 128 mmol) in ACN (60 mL) was added tert-butyl nitrite (17.34 ml, 146 mmol) at 25 °C for 1 h. The reaction mixture was diluted with water (180 mL) and extracted with EtOAc (3×120 mL). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (10-100% EtOAc / petroleum ether) to give the title compound. 1 H NMR (400 MHz, chloroform- d ): δ ppm 7.51 (dd, J =2.26, 1.65 Hz, 1H), 7.44 - 7.47 (m, 1H).

[0160] Step 3: 2,5-Dichloro-3-((4-methoxybenzyl)oxy)benzonitrile

[0161] 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 min, then 2,5-dichloro-3-fluorobenzonitrile (3.78 g, 19.89 mmol) was added, and then stirred at 25°C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×150 mL). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to give the title compound. MS: 308.1 (M+1).

[0162] Step 4: 2,5-Dichloro-3-hydroxybenzonitrile

[0163] To a stirred solution of 2,5-dichloro-3-((4-methoxybenzyl)oxy)benzonitrile (6.13 g, 19.89 mmol) in DCM (60 mL) was added TFA (20 mL) and then stirred at 25 °C for 1 h. After completion, the reaction mixture was poured into saturated NaHCO 3 The solution was added to an aqueous solution (30 mL) and extracted with DCM (3×60 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used directly without further purification. MS: 187.9 (M-1).

[0164] Intermediate A04

[0165]

[0166] 3-Bromo-5-chloro-2-fluorophenol

[0167] Step 1: 2-(3-Bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0168] To a solution of 2-bromo-4-chloro-1-fluorobenzene (300 g, 1.43 mol) in hexane (4.5 L) was added B 2 Pin 2 (363.7 g, 1.43 mol), Ir [(Ome) (1,5-COD)] 2 To the 4-(4-tert-butylpyridin-2-yl)-1-(4-tert-butylpyridin-1-yl)-pyridine (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 3 times. The resulting solution was stirred at room temperature overnight, and then concentrated under vacuum. Residue was purified by flash chromatography (0-100% EtOAc / petroleum ether) on silica to obtain title compound.

[0169] Step 2: 3-Bromo-5-chloro-2-fluorophenol

[0170] To a solution of 2-(3-bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (385 g, 1.15 mol) in THF (3.85 L) at 0°C, a solution of sodium hydroxide (138 g, 3.45 mol) in water (3 L), 35% aqueous hydrogen peroxide (390 g, 3.44 mol) were added. The resulting solution was stirred at 0°C for 2 h and quenched by heating with saturated Na 2 SO 3 The aqueous solution was quenched. After the pH of the solution was adjusted to 3-4 with HCl (1 M), the resulting solution was extracted with EtOAc (3×3 L). The combined organic layer was washed with brine and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica (0 - 90% EtOAc / petroleum ether) to obtain the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ11.31 (br. s., 1H), 7.47 (dd, J = 2.4, 4.4 Hz, 1H), 7.30 (dd, J = 2.4, 7.6 Hz, 1H).

[0171] Intermediate A05

[0172]

[0173] 5-Chloro-2-fluoro-3-hydroxybenzonitrile

[0174] To a solution of 3-bromo-5-chloro-2-fluorophenol (86 g, 343 mmol) in NMP (860 mL) was added CuCN (154 g, 1.72 mol) in one portion. The resulting reaction mixture was stirred at 180 °C for 2 h and then partitioned between ice water (1 L) and EtOAc (3×800 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (2-33% EtOAc / petroleum ether) to give the title compound. 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.33 (br. s., 1H), 7.49 (dd, J = 2.5,4.5 Hz, 1H), 7.30 (dd, J = 2.5, 7.6 Hz, 1H).

[0175] Intermediate A06

[0176]

[0177] 5-Chloro-3-hydroxy-2-methylbenzonitrile

[0178] Step 1: 2,3-Difluorobenzaldehyde

[0179] To a solution of 1,2-difluorobenzene (1668 g, 14.62 mol) in THF (16.7 L) cooled at -78°C, a solution of n-BuLi in THF (6.44 L, 16.08 mol) was added dropwise over 60 min with stirring. DMF (5340 g, 73.06 mol) was then added dropwise over 60 min at -78°C with stirring. The resulting solution was stirred at -78°C for 1 h. The reactants were then treated with saturated NH 4 The solution was quenched with aqueous Cl solution (10 L) and then extracted with EtOAc (3×10 L). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (2% EtOAc / petroleum ether) to give the title compound.

[0180] Step 2: E )-N-[(2,3-difluorophenyl)methylidene]hydroxylamine

[0181] 2,3-Difluorobenzaldehyde (2410 g, 16.96 mol) was dissolved in NH 2 A mixture of 70% solution of OH (672 g, 20.35 mol) in DMF (10 L) was stirred at 20 °C for 3 h and then partitioned between water (6 L) and EtOAc (3×8 L). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (2% EtOAc / petroleum ether) to give the title compound.

[0182] Step 3: 2,3-Difluorobenzonitrile

[0183] Will( E A solution of )-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 h and then partitioned between water (6 L) and EtOAc (3×6 L). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (2% EtOAc / petroleum ether) to give the title compound.

[0184] Step 4: 2-Amino-3-fluorobenzonitrile

[0185] In a sealed reactor, a solution of 2,3-difluorobenzonitrile (1273 g, 9.15 mol) in EtOH (13 L) was reacted with NH 3 The resulting solution was stirred at 140 °C for 8 h, cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between water (5 L) and MTBE (3 x 8 L). The combined organic layers were washed with water, brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound.

[0186] Step 5: 2-Amino-5-chloro-3-fluorobenzonitrile

[0187] 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 h and then partitioned between ice water (20 L) and EtOAc (3×12 L). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (3% EtOAc / petroleum ether) to give the title compound.

[0188] Step 6: 2-Bromo-5-chloro-3-fluorobenzonitrile

[0189] Towards t -BuONO (815 g, 7.88 mol) and CuBr 2 To a mixture of 2-amino-5-chloro-3-fluorobenzonitrile (1365 g, 6.13 mol) in ACN (8 L) was added dropwise a solution of 2-amino-5-chloro-3-fluorobenzonitrile (747 g, 4.38 mol) in ACN (7 L) with stirring over 90 min. The resulting mixture was stirred at room temperature for 10 h and diluted with water (15 L) and then extracted with EtOAc (3×10 L). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (3% EtOAc / petroleum ether) to give the title compound.

[0190] Step 7: 5-Chloro-3-fluoro-2-methylbenzonitrile

[0191] 2-Bromo-5-chloro-3-fluorobenzonitrile (768 g, 3.28 mol), 1,4-methylboric acid (297 g, 4.96 mol), potassium carbonate (913 g, 6.61 mol) and PdCl 2 A mixture of (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, then diluted with water (4 L) and extracted with EtOAc (3×6 L). The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash chromatography on silica (3% EtOAc / petroleum ether) to give the title compound.

[0192] Step 8: 5-Chloro-3-[(4-methoxyphenyl)methoxy]-2-methylbenzonitrile

[0193] Under nitrogen atmosphere, sodium hydride (128 g, 5.33 mol) was added to a solution of 4-methoxybenzyl alcohol (410 g, 2.97 mol) in DMF (3200 mL), followed by dropwise addition of a solution of 5-chloro-3-fluoro-2-methylbenzonitrile (418 g, 2.46 mol) in DMF (800 mL). The resulting solution was stirred at 25 °C for 12 h, then diluted with ice water (2 L) and extracted with EtOAc (3×3 L). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The resulting solid is washed with petroleum ether and collected on top of the filter to give the title compound.

[0194] Step 9: 5-Chloro-3-hydroxy-2-methylbenzonitrile

[0195] 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 h. The solid was collected on top of the filter to give the title compound. MS: 166 (M-1). 1 H NMR (400 MHz, DMSO- d 6 ): 10.67 (s,1H), 7.32-7.33 (d, 1H), 7.07-7.08 (d, 1H), 2.24 (s, 3H).

[0196] Intermediate A07

[0197]

[0198] 5-Fluoro-3-hydroxy-2-methylbenzonitrile

[0199] Step 1: 3-Bromo-5-fluoro-2-methylaniline

[0200] To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (23g, 98 mmol) in ethanol (390 mL), ammonium hydrochloride (26.3 g, 491 mmol) and water (38.3 ml, 2126 mmol) were added, followed by iron (27.4 g, 491 mmol). The resulting mixture was stirred at 90 ° C for 6 h. After the reaction was monitored by TLC, the reaction mixture was filtered through a sinter funnel. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (5% EtOAc / petroleum ether) on silica to obtain the title compound. MS: 204.2 and 206.2 (M+1).

[0201] Step 2: 3-Bromo-5-fluoro-2-methylphenol

[0202] To a solution of sulfuric acid (145 mL, 2729 mmol) in water (21.73 mL, 1206 mmol) was added 3-bromo-5-fluoro-2-methylphenol (7 g, 31.1 mmol). The resulting mixture was cooled to 0°C with an ice bath. A solution of sodium nitrate (6.66 g, 78 mmol) in water was then added dropwise. After stirring at this temperature for 30 minutes, the reaction mixture was heated at 100°C for 30 minutes, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and purified by evaporation over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (4-10% EtOAc / petroleum ether) to give the title compound. MS: 203.2 and 205.2 (M-1).

[0203] Step 3: 5-Fluoro-3-hydroxy-2-methylbenzonitrile

[0204] To a stirred solution of 3-bromo-5-fluoro-2-methylphenol (7 g, 34.1 mmol) in DMA (140 mL) were added 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 min, and then Pd 2 (dba) 3 (1.563 g, 1.707 mmol) and zinc cyanide (8.02 g, 68.3 mmol). The reaction vessel was sealed. The resulting mixture was heated to 140°C for 6 h, then diluted with water (200 mL) and filtered through a CELITE® bed. The filter cake was washed with EtOAc (400 mL). The filtrate layers were separated. The aqueous layer was further extracted with EtOAc (2×200mL). The combined organic layers were washed with brine (2×200 mL) and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (5-15% EtOAc / petroleum ether) to obtain the title compound. MS: 150.2 (M-1).

[0205] The following intermediates in Table 1 were purchased from commercial sources.

[0206]

[0207] Intermediate Part B

[0208] Intermediate B01

[0209]

[0210] 5-Fluoro-6-(1,1,2,2-tetrafluoroethyl)-3,4-dihydropyrimidin-4-one

[0211] Step 1: 2,2,3,3-Tetrafluoropropionic acid

[0212] To a solution of potassium heptaoxodichromium (1782 g, 6.06 mol) in sulfuric acid (2097 g, 21.38 mol) and water (2400 mL), 2,2,3,3-tetrafluoropropane-1-ol (800 g, 6.06 mol) was added dropwise with stirring at 100°C. The resulting solution was stirred at reflux at 100°C for 5 h and then extracted with MTBE (4×2 L). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, which was used as is in the next step.

[0213] Step 2: 2,2,3,3-Tetrafluoro-N-methoxy-N-methylpropionamide

[0214] To a solution of 2,2,3,3-tetrafluoropropionic acid (crude product from the previous step, 45% purity, 1007 g, 3.15 mol) in THF (4600 mL) was added sulfur dichloride (787.2 g, 6.62 mol) dropwise at 0°C followed by DMF (753.4 g, 10.31 mol) dropwise. After stirring at room temperature for 45 min, the reaction mixture was cooled to 0°C and then treated dropwise with methoxy(methyl)amine hydrochloride (1222.5 g, 12.53 mol) and TEA (1913 g, 18.91 mol). The resulting mixture was stirred at room temperature for 5 h and then quenched with ice water (2 L) and extracted with MTBE (3 L). The organic layer was washed with saturated NaHCO 3 The mixture was washed with aqueous solution, brine, dried over anhydrous sodium sulfate, filtered and distilled to give the title compound.

[0215] Step 3: Ethyl 2,4,4,5,5-pentafluoro-3-oxopentanoate

[0216] To a solution of 2,2,3,3-tetrafluoro-N-methoxy-N-methylpropionamide (470 g, 2.49 mol) in THF (4700 mL) was added ethyl 2-fluoroacetate (316.2 g, 2.98 mol) and a 1M solution of LiHMDS in THF (3729 mL, 3.73 mol) at -78°C. The resulting mixture was stirred at -78°C for 2 h and then washed with saturated NH 4The mixture was quenched with aqueous Cl solution (1 L). After the pH of the solution was adjusted to 3 with HCl (1 M), the reaction mixture was extracted with MTBE (3×2 L). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step.

[0217] Step 4: 5-Fluoro-6-(1,1,2,2-tetrafluoroethyl)-3,4-dihydropyrimidin-4-one

[0218] To a solution of ethyl 2,4,4,5,5-pentafluoro-3-oxopentanoate (533 g, 2.28 mol) in methanol (5330 mL) was added formamidine acetate (1185.1 g, 11.38 mol) and sodium methoxide (492 g, 9.11 mol). The resulting mixture was stirred at room temperature for 2 h and then quenched with ice water (1.5 L). After the pH of the solution was adjusted to 3 with HCl (2M), the resulting mixture was extracted with MTBE (3×1 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization from MTBE / PE (1:5) to give the title compound. MS: 212.9 (M-1). 1 HNMR: (300MHz, CD 3 OD): δ 8.10 (1H, s), 6.67~6.38 (1H, m).

[0219] The following intermediates in Table 2 were prepared according to Scheme C using the procedure outlined in the synthesis of Intermediate B01 using known fluorinated alkyl alcohols or their corresponding acids or methyl esters.

[0220]

[0221] Intermediate B05

[0222]

[0223] 4-Chloro-5-fluoro-6-methoxypyrimidine

[0224] To a solution of 4,6-dichloro-5-fluoropyrimidine (8.0 g, 47.9 mmol) in MeOH (80 mL) was added sodium methoxide (3.05 g, 56.5 mmol) at 0°C. The resulting reaction mixture was stirred at 20°C for 2 h, then quenched with water (20 ml) and then extracted with EA (3×20 mL). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. MS: 163.1 (M+1). 1H NMR (400 MHz, DMSO- d 6 ): δ 8.45(s, 1H), 4.03(s, 1H).

[0225] Intermediate B06

[0226]

[0227] 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine

[0228] To a solution of 4-chloro-5-fluoro-6-methoxypyrimidine (5.2 g, 28.8 mmol) and tributyl(1-ethoxyvinyl)stannane (12.48 g, 34.5 mmol) in DMF (50 ml) was added Pd(Ph 3 P) 4 (0.5 g, 0.433 mmol). The resulting reaction mixture was heated to 400 °C under N 2 Stir at 100 °C for 4 h under atmosphere. After completion, the reaction was diluted with water (30 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were treated with saturated aqueous KF solution (80 mL) and stirred at room temperature for 0.5 h, then passed through a CELITE® bed filter. The filtrate was washed with water, brine, and filtered through anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by column chromatography on silica (10-90% EtOAc / PE) to give the title compound. 1 H 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).

[0229] Intermediate B07

[0230]

[0231] 6-Acetyl-5-fluoropyrimidin-4(3H)-one

[0232] To a solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine (4.5 g, 20.43 mmol) in THF (30 ml) was added 6M aqueous HCl (20 mL, 120 mmol) dropwise at 0° C. The resulting reaction solution was stirred at 20° C. for 18 h and then concentrated under reduced pressure while maintaining the bath temperature at 40° C. to give the title compound. 1 H NMR (400MHz, d 6 -DMSO): δ 8.15(s, 1H), 2.50(s, 3H).

[0233] Intermediate B08

[0234]

[0235] 1-(5-Fluoro-6-methoxypyrimidin-4-yl)ethanone

[0236] To a stirred solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine, B06 (12 g, 60.5 mmol) in ACN (100 mL) at 0°C, a 4M solution of hydrochloric acid in 1,4-dioxane (30 mL, 120 mmol) was added dropwise. The resulting solution was stirred at room temperature for 1 h, then carefully quenched with ice-cold water (200 mL), and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-20% EtOAc / petroleum ether) to obtain the title compound. MS: 171.4 (M+1).

[0237] Intermediate B09

[0238]

[0239] 5-Fluoro-6-(1,1,2-trifluoroethyl)pyrimidin-4(3H)-one

[0240] Step 1: 2-Fluoro-1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone

[0241] A solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine, B06 (0.2 g, 0.86 mmol) in ACN (3 mL) was added dropwise over 4 h to a suspension of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (0.456 g, 1.29 mmol) in ACN (2 mL) and water (1 mL), maintaining the temperature below 15°C. The reaction mixture was then treated with saturated NaHCO 3The mixture was quenched with aqueous solution (10 mL) and stirred for 10 min. After completion, the mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine and purified by MgSO 4 Dry, filter and concentrate under reduced pressure to give the title compound. MS: 189.1 (M+1).

[0242] Step 2: 5-Fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrimidine

[0243] To a solution of 2-fluoro-1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone (0.15 g, 0.60 mmol) in DCM (2 mL) was added diethylaminosulfur trifluoride (0.578 g, 3.59 mmol). The resulting reaction mixture was stirred at 20 °C for 4 h, then diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc / PE) to give the title compound. 1 H NMR (400MHz, CDCl 3 ) δ8.56 (s, 1H), 4.99 (t, J=12.0 Hz, 1H), 4.88 (t, J=12.0 Hz, 1H), 4.12 (s, 3H).

[0244] Step 3: 5-Fluoro-6-(1,1,2-trifluoroethyl)pyrimidin-4(3H)-one

[0245] To a mixture of 5-fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrimidine (0.05 g, 0.238 mmol) and KI (0.119 g, 0.714 mmol) in ACN (15 mL) was added trimethylsilyl chloride (0.078 g, 0.714 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h, then diluted with EtOAc and washed with Na 2 S 2 O 3 The mixture was washed with aqueous solution and brine, and then with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. MS: 197.1 (M+1).

[0246] Intermediate B10

[0247]

[0248] 5-Fluoro-6-methoxypyrimidine-4-carboxylate

[0249] In use N 2In a purified 20-L sealed tube, 4-chloro-5-fluoro-6-methoxypyrimidine, B05 (410 g, 2.52 mol) in MeOH (8.2 L), triethylamine (1.247 kg, 12.32 mol), PdCl 2 (dppf) (201 g, 246.32 mmol) in a solution. Then set up in a gas bottle with CO at 2 bar for carbonylation and heated at 50 ° C for 16 h. Filter out the solid. The filtrate is concentrated under reduced pressure to remove MeOH and then diluted with EtOAc (4 L). Filter out the solid. The filtrate is concentrated under reduced pressure again. The residue is purified by column chromatography on silica (10% EtOAc / hexanes) and then recrystallized (propane-2-ol:H 2 (2:7) to give the title compound MS: 187 (M+1). 1 H NMR (400MHz, CDCl 3 ): δ5.587 (s, 1H), 4.109-4.075 (s, 3H), 4.003-3.935 (s, 3H).

[0250] Intermediate B11

[0251]

[0252] 5-Fluoro-6-hydroxypyrimidine-4-carboxylic acid methyl ester

[0253] Trimethylsilyl chloride (25.7 ml, 201 mmol) was slowly added to a stirring slurry of 5-fluoro-6-methoxypyrimidine-4-carboxylic acid methyl ester, 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 that the reaction was complete. The reaction was quenched with methanol (100 mL) and concentrated to give the title compound, which was used in the next step without further purification. MS: 173.0 (M+1). 1 HNMR (400 MHz, DMSO-d 6 ) 8.12 (s, 1H), 2.59 (s, 3H).

[0254] Intermediate B12

[0255]

[0256] 5-Bromo-6-(trifluoromethyl)pyrimidin-4(3H)-one

[0257] This intermediate was prepared by bromination of 6-(trifluoromethyl)pyrimidin-4(3H)-one using the procedure reported in US20140100231(A1).

[0258] Intermediate B13

[0259]

[0260] 6-Acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one

[0261] To a solution of 6-acetyl-5-fluoropyrimidin-4(3H)-one, B07 (1.0 g, 5.44 mmol) in DMF (10 mL) was added K 2 CO 3 (2.257 g, 16.33 mmol). The resulting reaction mixture was stirred at 20 °C for 10 min, then 1-(chloromethyl)-4-methoxybenzene (1.023 g, 6.53 mmol) was added. The reaction mixture was stirred at 20 °C for another 6 h, then diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (50% EtOAc / PE) to give the title compound. MS: 277.1 (M+1). 1 H 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).

[0262] The following intermediates in Table 3 were prepared using the corresponding intermediate B under similar conditions to the above synthetic procedure outlined in the synthesis of intermediate B13.

[0263]

[0264] Intermediate B19

[0265]

[0266] 5-Bromo-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

[0267] This intermediate was prepared using the procedure reported in US20140100231(A1).

[0268] Intermediate B20

[0269]

[0270] 5-Bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one

[0271] This intermediate was prepared using the procedure reported in US20140100231(A1).

[0272] Intermediate C

[0273] Intermediate C01

[0274]

[0275] (6-Chloro-2-methoxypyridin-3-yl)methanol

[0276] Step 1: 6-Chloro-2-methoxynicotinaldehyde

[0277] At -78℃ t To a stirred mixture of -BuLi (23.94 mL, 38.3 mmol) in THF (100 mL) was added 2-chloro-6-methoxypyridine (5 g, 34.8 mmol). The resulting mixture was stirred at -78 °C for 1 hour, then DMF (3.51 mL, 45.3 mmol) was added and the reaction mixture was stirred at -78 °C for 1.5 h, then quenched with acetic acid (3.99 mL, 69.7 mmol) at -78 °C. Next, the mixture was warmed to 20 °C over 30 minutes. The mixture was washed with saturated NaHCO 3 The aqueous solution (200 mL) was neutralized and extracted with EtOAc (3×50 mL). The combined organic fractions were washed with brine (3×50 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by column chromatography on silica (1-2% EtOAc / isohexane) to give the title compound.

[0278] Step 2: (6-Chloro-2-methoxypyridin-3-yl)methanol

[0279] To a suspension of 6-chloro-2-methoxynicotinaldehyde (1 g, 5.83 mmol) in MeOH (12 mL) at 0°C, sodium borohydride (0.140 g, 3.70 mmol) was added portionwise over 20 minutes. The resulting mixture was stirred at 0°C for 40 minutes, then quenched with water and extracted with DCM (3×5 mL). The combined organic layers were washed with brine and purified by anhydrous MgSO 4Dry, filter and concentrate under reduced pressure to give the title compound which was used as such in the next step. MS: 174.1 (M+1).

[0280] Intermediate C02

[0281]

[0282] (6-Bromo-2-methoxypyridin-3-yl)methanol

[0283] Step 1: 6-Bromo-2-methoxynicotinic acid

[0284] To a stirred solution of 2,2,6,6-tetramethylpiperidine (3.76 g, 26.6 mmol) in THF (50 mL) at -78°C, a 2.5 M solution of n-BuLi in THF (10.64 mL, 26.6 mmol) was added dropwise. The resulting mixture was stirred at the same temperature for 60 minutes, and then a solution of 2-bromo-6-methoxypyridine (5g, 26.6 mmol) in THF was added dropwise. The reaction mixture was stirred at the same temperature for 60 minutes, treated with crushed dry ice powder, and stirred at -78°C for 3 hours, then slowly warmed to room temperature and diluted with water. The pH of the mixture was then adjusted to 3-4 using concentrated HCl. The mixture was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (50% EtOAc / petroleum ether) to give the title compound. MS: 230.2 and 232.0 (M-1).

[0285] Step 2: (6-Bromo-2-methoxypyridin-3-yl)methanol

[0286] To a stirred solution of 6-bromo-2-methoxynicotinic acid (2.3 g, 9.91 mmol) in THF (20 mL) at -20 ° C, a 1M solution of LAH in THF (19.82 mL, 19.82 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 60 minutes, then quenched with water (0.5 mL), 10% NaOH aqueous solution and water. The resulting mixture was stirred for 30 minutes and passed through CELITE bed filtration. The filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. Residue was first purified by column chromatography (30% EtOAc / petroleum ether) on silica, then purified using reversed-phase HPLC (ACN / water containing 0.1% TFA regulator) to obtain the title compound. MS: 217.4 and 219.4 (M+1).

[0287] Intermediate C03

[0288]

[0289] (2-Methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-3-yl)methanol

[0290] A 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 tripotassium 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 h and then passed through a filter. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 290.1 ​​(M+1).

[0291] The following intermediates in Table 4 were prepared using similar procedures outlined in the synthesis of intermediate C03 using the corresponding commercially available boronic acids or boronic esters.

[0292]

[0293] Intermediate C08

[0294]

[0295] 1-(5-(Chloromethyl)-6-methoxypyridin-2-yl)ethanone

[0296] Step 1: (6-(1-ethoxyvinyl)-2-methoxypyridin-3-yl)methanol and 1-(5-(hydroxymethyl)-6- (methoxypyridin-2-yl)ethanone

[0297] 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) was added Pd(Ph 3 P) 4 (0.200 g, 0.173 mmol). The resulting mixture was stirred at N 2The mixture was stirred at 100 °C for 4 h under a 4% carbonyl atmosphere, then cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were treated with saturated aqueous KF solution (45 mL) and 4M aqueous HCl solution, stirred at 20 °C for 0.5 h, then washed with brine (2 × 75 mL), and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (1-25% EtOAc / petroleum ether) to give the title compound. MS: 182.1 (M+1).

[0298] Intermediate C09

[0299]

[0300] (4-Chloro-6-methoxy-2-methylpyrimidin-5-yl)methanol

[0301] Step 1: 2-Chloro-4,6-dimethylnicotinate

[0302] To 2-chloro-4,6-dimethylnicotinic acid (2 g, 10.78 mmol) was slowly added sulfur dichloride (20 mL, 275 mmol). The resulting mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The residue was treated with MeOH (20 mL) at 0 °C, then the reaction mixture was stirred at 20 °C for 16 h and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 200.1 (M+).

[0303] Step 2: 2-Methoxy-4,6-dimethylnicotinate

[0304] To a solution of methyl 2-chloro-4,6-dimethylnicotinate (2.206 g, 11.05 mmol) in MeOH (20 mL) was added sodium methoxide (3.58 g, 66.3 mmol) at 0°C. The resulting mixture was stirred at 60°C for 24 h, then quenched with water (20 mL) and then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (3×10 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used in the next step without further purification. MS: 196.1 (M+1).

[0305] Step 3: 2-methoxy-4,6-dimethylpyridin-3-yl)methanol

[0306] To a solution of 2-methoxy-4,6-dimethylnicotinate (500 mg, 2.56 mmol) in THF (5 ml) was added LAH (97 mg, 2.56 mmol) at 0°C. The resulting mixture was stirred at 20°C for 1 hour, then quenched with saturated ammonium chloride solution and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by preparative TLC plate (25% EtOAc / petroleum ether) to give the title compound. MS: 168.3 (M+1).

[0307] Intermediate C10

[0308]

[0309] Methanesulfonic acid (5-fluoro-2-methoxypyridin-3-yl)methyl ester

[0310] Step 1: 5-Fluoro-2-methoxynicotinic acid

[0311] 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 heated with H 2 O (30 mL) and acidified to pH = 3-4 with HCl (1 M), then extracted with EtOAc (3×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used directly in the next step without further purification. MS: 170 (M-1).

[0312] Step 2: (5-Fluoro-2-methoxypyridin-3-yl)methanol

[0313] To a solution of 5-fluoro-2-methoxynicotinic acid (800 mg, 4.67 mmol) in THF (10 ml) was added LAH (266 mg, 7.01 mmol). The resulting mixture was stirred at 25 °C for 5 minutes, then it was quenched with water (0.27 mL) and aqueous NaOH (0.27 mL). The mixture was filtered. The filtrate was extracted with EtOAc (3×30 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used in the next step without purification. MS: 158 (M+1).

[0314] Intermediate C11

[0315]

[0316] (2-Methoxypyridin-3-yl)methanol

[0317] Step 1: 2-Methoxynicotinate methyl ester

[0318] To a stirred solution of 2-methoxynicotinic acid (1 g, 6.53 mmol) in methanol (10 mL) was added H 2 SO 4 (0.696 mL, 13.06 mmol). The resulting mixture was stirred at 65 °C for 6 h and then concentrated under reduced pressure to give the title compound. MS: 168.4 (M+1).

[0319] Step 2: (2-methoxypyridin-3-yl)methanol

[0320] To a stirred solution of methyl 2-methoxynicotinate (500 mg, 2.99 mmol) in THF (6 mL) was slowly added 1 M LAH in THF (5.98 mL, 5.98 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 6 h, then cooled and washed with saturated Na 2 SO 4 The aqueous solution was quenched with EtOAc. The reaction mixture was filtered through a CELITE® bed. The filter cake was washed with excess EtOAc. The filtrate was separated. The organic layer was concentrated under reduced pressure to give the title compound. MS: 140.4 (M+1).

[0321] Intermediate C12

[0322]

[0323] (2-Chloro-4,6-dimethylpyridin-3-yl)methanol

[0324] To a solution of 2-chloro-4,6-dimethylnicotinic acid (300 mg, 1.616 mmol) dissolved in THF (3 mL) at 0°C, a 1M solution of LAH in THF (1.616 mL, 1.616 mmol) was added dropwise over 10 minutes. The resulting mixture was stirred at 0°C for 2 h, then warmed to ambient temperature and stirred over the weekend. LCMS showed complete conversion to the desired product. The reaction mixture was diluted very slowly with water (~1 mL), and the organic solvent was evaporated under reduced pressure and then partitioned between EtOAc (10 mL) and water (5 mL). The aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic layers were purified by filtration over anhydrous MgSO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 172.0 (M+1).

[0325] Intermediate C13

[0326]

[0327] 6-Chloro-3-(chloromethyl)-2-methoxypyridine

[0328] 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 with mesyl-Cl (0.247 mL, 3.17 mmol) dropwise. The resulting reaction mixture was stirred at 23 °C overnight and then heated in DCM and saturated NaHCO 3 The organic layer was separated and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-20% EtOAc / hexanes) 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).

[0329] The following intermediates in Table 5 were prepared using similar procedures outlined in the synthesis of Intermediate C12 with the appropriate (6-methoxypyrimidin-5-yl)methanol Intermediate C as the starting materials described in Table C12.

[0330]

[0331]

[0332] Intermediate C24

[0333]

[0334] 5-Bromo-3-(chloromethyl)-2-methoxypyridine

[0335] Intermediate C24 was synthesized using a similar procedure to Intermediate C12 by replacing Intermediate C01 with commercially available (5-bromo-2-methoxypyridin-3-yl)methanol.

[0336] Intermediate AB

[0337] Intermediate AB01

[0338]

[0339] 5-(Difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5- (4-(2-Methyl)oxy)benzonitrile

[0340] Step 1: 5-(difluoromethyl)-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)- 1,6-Dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0341] To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one, B16 (7 g, 20.94 mmol) in NMP (46.5 mL) was added 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 indicated complete conversion. The reaction mixture was cooled to room temperature and then diluted with water. The precipitate was collected on the top of the filter and washed with water (3×) and then air-dried to give the title compound. MS: 498.1 (M+1).

[0342] Step 2: 5-(Difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine (5-pyridin-5-yl)oxy)benzonitrile

[0343] A 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 TFAA (33.1 mL) was stirred at 50 °C overnight. LCMS indicated complete conversion. The reaction mixture was concentrated under reduced pressure. The residue was triturated with hexanes and the solid was collected on top of the filter, washed with hexanes, and then air-dried to give the title compound, which was used directly in the next step after further purification. MS: 378.3 (M+1).

[0344] The following intermediates in Table 6 were prepared in a similar manner to Intermediate AB01 described above: SN Ar The reaction was then deprotected using TFA / TFAA to remove the PMB group.

[0345]

[0346]

[0347]

[0348] Intermediate AB12

[0349]

[0350] 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0351] Step 1: 6-acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one

[0352] To a solution of 6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B13 (2 g, 7.24 mmol) in DMF (10 mL) was added 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 h and then poured into H 2 O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by column chromatography on silica (2-3.3% MeOH / DCM) to give the title compound.

[0353] Step 2: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidine-4-yl (3H)-Keto

[0354] To a solution of 6-acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (300 mg, 0.623 mmol) in THF (2 mL) was added 0.1 M Zn(BH 4 ) 2 A solution in THF (0.934 mL, 0.093 mmol) was added and the mixture was stirred for 10 min. To the reaction mixture was added water (1 drop) and then concentrated under reduced pressure to give the title compound.

[0355] Step 3: 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidine-4-yl (3H)-Keto

[0356] To a solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (680 mg, 1.406 mmol) in DCM (10 mL) was added DAST (0.427 mL, 3.23 mmol) at 0°C. The resulting reaction mixture was stirred at 0°C for 1 h, then diluted with water (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound.

[0357] Step 4: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine (5-pyridin-5-yl)oxy)benzonitrile

[0358] In N 2 To a stirred solution of 5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (340 mg, 0.700 mmol) in NMP (3 mL) was added cyanocopper (217 mg, 2.423 mmol). The resulting mixture was stirred at 170 °C for 12 h and then treated with H 2 O (30 mL) and EtOAc (30 mL). The mixture was filtered through a CELITE® funnel. The filtrate was extracted with EA (3×30 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was triturated with MeOH (20 mL) to give the title compound.

[0359] Step 5: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0360] 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) in TFA (1.5 mL) was added TFAA (0.75 mL). The resulting mixture was stirred at 100 °C for 6 h, then diluted with DCM (10 mL) and concentrated under reduced pressure to give the title compound.

[0361] Intermediate AB13

[0362]

[0363] 5-Chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile

[0364] Step 1: 5-fluoro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid methyl ester

[0365] 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 indicated the desired product and clean reaction. Water (500 mL) was added and a precipitate formed. The mixture was filtered and the solid was washed with water (100 mL) and hexanes (200 mL) and dried under high vacuum overnight to give the title compound. MS: 444 (M+1).

[0366] Step 2: 5-(5-chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine 4-pyridinecarboxylic acid

[0367] Potassium trimethylsilanolate (9.97 g, 78 mmol) was added to a stirred mixture of 5-(5-chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid methyl ester (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 aqueous solution, 300 mL) was added slowly and a white solid was formed. The mixture was concentrated under reduced pressure to remove THF. The mixture was filtered and the white solid was washed with water and dried under vacuum to obtain the title compound. MS: 430.0 (M+1).

[0368] Step 3: 5-(5-chloro-3-cyano-2-fluorophenoxy)- N -Methoxy-1-(4-methoxybenzyl)- N -methyl-6- Oxo-1,6-dihydropyrimidine-4-carboxamide

[0369] To a solution 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) was added to a flask, triethylamine (25.9 ml, 186 mmol), followed by EDC (9.81 g, 51.2 mmol) and HOBt (7.84 g, 51.2 mmol). The resulting mixture was stirred at 25 ° C overnight. LCMS indicated that the reaction was complete. Water (300 mL) was added and the resulting precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound. MS: 473.1 (M+1).

[0370] Step 4: 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)- 5-Chloro-2-fluorobenzonitrile

[0371] Methylmagnesium bromide (3M solution in THF, 40 mL, 120 mmol) was added dropwise to a cold (-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 h. LCMS indicated the desired product, but the starting material was still present. The reaction mixture was then warmed to 0 °C and stirred for 30 min. LCMS indicated the reaction was complete. The reaction was washed with saturated NH 4 The solution was quenched with aqueous Cl solution (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) and dried over anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 428.0 (M+1).

[0372] Step 5: 5-Chloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine (2-(2-pyridin-5-yl)oxy)-2-fluorobenzonitrile

[0373] Deoxofluor® (15.08 ml, 82 mmol) was added to a 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 h. LCMS indicated the desired product. The reaction was cooled to room temperature and very slowly and carefully poured into saturated NaHCO 3Then, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were filtered through MgSO 4 Dry, filter and concentrate. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 450.0 (M+1).

[0374] Step 6: 5-chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluoro Benzonitrile

[0375] 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 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and hexanes (100 mL) were added slowly until a white solid was formed. After stirring for 30 min, the white solid was collected on the top of the filter and dried under vacuum to give the title compound. MS: 330.0 (M+1).

[0376] Intermediate AB14

[0377]

[0378] 5-Chloro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0379] Step 1: 3-((4-acetyl-6-methoxypyrimidin-5-yl)oxy)-5-chloro-2-methylbenzonitrile

[0380] To a solution of 1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone, B08 (2.8 g, 16.46 mmol) in DMF (20 mL) under nitrogen was added potassium carbonate (6.82 g, 49.4 mmol) and 5-chloro-3-hydroxy-2-methylbenzonitrile, A06 (3.31 g, 19.75 mmol). The resulting mixture was heated at 40 °C for 2 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (20-60% EtOAc / petroleum ether) to give the title compound. MS: 318.4 (M+1).

[0381] Step 2: 5-Chloro-3-((4-(1-hydroxyethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0382] To a stirred solution of 3-((4-acetyl-6-methoxypyrimidin-5-yl)oxy)-5-chloro-2-methylbenzonitrile (1.8 g, 5.67 mmol) in methanol (50 mL) was added cerium (III) chloride heptahydrate (3.17 g, 8.50 mmol) followed by the slow addition of sodium borohydride (0.214 g, 5.67 mmol). The resulting suspension was stirred at 0 °C for 1 hour, then quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine solution and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (40-80% EtOAc / petroleum ether) to give the title compound. MS: 320.0 (M+1).

[0383] Step 3: 5-Chloro-3-((4-(1-fluoroethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0384] To a stirred solution of 5-chloro-3-((4-(1-hydroxyethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile (1.4 g, 4.38 mmol) in DCM (5 mL) was added deoxofluor (1.615 mL, 8.76 mmol) at 0°C. The resulting mixture was allowed to reach room temperature for 3 h, then diluted with DCM and washed with saturated NaHCO 3 The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (10 40% EtOAc / petroleum ether) to give the title compound. MS: 322.4 (M+1).

[0385] Step 4: 5-Chloro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0386] To a stirred solution of 5-chloro-3-((4-(1-fluoroethyl)-6-methoxypyrimidin-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 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica (40- 80% EtOAc / petroleum ether) to give the title compound. MS: 306.4 (M-1).

[0387] Intermediate AB15

[0388]

[0389] 5-Chloro-2-methyl-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0390] Step 1: 5-chloro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5-yl)- (2-Methyl)oxy)-2-methylbenzonitrile

[0391] To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-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) was added potassium carbonate (8.23 g, 59.6 mmol). The reaction mixture was stirred at 100 °C for 16 h and then diluted with water (85 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (40 mL) and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-35% EtOAc / petroleum ether) to give the title compound. MS: 450.8 (M+1).

[0392] Step 2: 5-Chloro-2-methyl-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0393] 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) was added cerium ammonium nitrate (18.28 g, 33.3 mmol). The reaction mixture was stirred at room temperature for 24 h, then diluted with water (10 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (70 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-35% EtOAc / petroleum ether) to give the title compound. MS: 328.0 (M-1).

[0394] Intermediate AB16

[0395]

[0396] 5-Chloro-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0397] Step 1: 5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidine-4-yl (3H)-Keto

[0398] To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one, B18 (1 g, 3.31 mmol) in DMF (10 mL) at 25 °C were added 3-bromo-5-chloro-2-fluorophenol, A04 (0.821 g, 3.64 mmol) and K 2 CO 3 (16.54 mg, 0.120 mmol). The reaction mixture was stirred at 80 °C for 1 h, then diluted with water (3 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was passed through a preparative-TLC plate (25% EtOAc / petroleum ether) to give the title compound. MS: 507.2 (M+1). 1 H NMR (400MHz, 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).

[0399] Step 2: 5-Chloro-2-fluoro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine (5-pyridin-5-yl)oxy)benzonitrile

[0400] A stirred solution of a mixture of 5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (300 mg, 0.591 mmol) and cuprous (I) cyanide (265 mg, 2.95 mmol) in NMP (3 mL) was stirred at 170 °C for 7 h, then diluted with water (30 mL), and then extracted with EtOAc (3×5 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by preparative-TLC plate (50% EtOAc / petroleum ether) to give the title compound. 1 H NMR (400MHz, 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).

[0401] Step 3: 5-Chloro-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0402] 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) was added TFAA (1 mL). The resulting mixture was stirred at 110 °C for 2 h and then quenched by the addition of saturated NaHCO 3 The solution was quenched with aqueous solution (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used directly in the next step. MS: 375.0 (M+ACN+1).

[0403] Intermediate AB17

[0404]

[0405] 3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile

[0406] Step 1: 3-Chloro-5-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine- 5-(5-yl)oxy)benzonitrile

[0407] To a mixture of compound 5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B20 (20 g, 55.7 mmol), 3-chloro-5-hydroxybenzonitrile, A10 (17.10 g, 111 mmol) in NMP (140 mL) was added K 2 CO 3 (15.39 g, 111 mmol). The resulting mixture was stirred at 140 °C for 24 h. 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 h, then diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (6.25-50% EtOAc / petroleum ether) to give the title compound. MS: 432.1 (M+1).

[0408] Step 2: 3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl) Oxy)-5-methylbenzonitrile

[0409] 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 A mixture of 1,4-dioxane (2264 mg, 6.95 mmol) in water (5.79 mL) and 1,4-dioxane (17.4 mL) was stirred with N 2 The mixture was purified and then heated to 130°C. After 30 minutes, the mixture was passed through a CELITE® filter bed. The filtrate was diluted with EtOAc (10 mL) and washed with water. The organic layer was purified by anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-70% EtOAc / hexanes) 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).

[0410] Step 3: 3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile

[0411] 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) in TFA (9297 µL) was added anisole (223 uL, 2.045 mmol) and TFAA (930 µL). The resulting mixture was heated to 110 °C for 15 min and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with saturated NaHCO 3 The residue was purified by column chromatography on silica (0-10% MeOH / DCM) to give the title compound. MS: 292.1 (M+1). 1 H 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).

[0412] Intermediate BC part

[0413] Intermediate BC01

[0414]

[0415] 5-Fluoro-3-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidine- 4(3H)-Keto

[0416] To 5-fluoro-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-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) was added to a mixture of 3-(chloromethyl)-2-methoxy-4,6-dimethylpyridine, C16 (41.6 mg, 0.224 mmol) in DMF (2242µL). The resulting mixture was heated to 50°C overnight, then filtered and purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 363.9 (M+1). 1 H 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).

[0417] The following intermediates in Table 7 were prepared using the corresponding Intermediate B and Intermediate C under similar conditions to the above synthetic procedure outlined in the synthesis of Intermediate BC01.

[0418]

[0419] Intermediate BC04

[0420]

[0421] 5-Fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

[0422] To a stirred solution of 5-fluoro-6-(trifluoromethyl)pyrimidin-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) was added potassium carbonate (0.315 g, 2.278 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight and diluted with water (3 mL) and EtOAc (3 mL). The organic layer was separated and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 322.1 (M+1).

[0423] The following intermediates in Table 8 were prepared using the corresponding Intermediate B and Intermediate C under similar conditions to the above synthetic procedure outlined in the synthesis of Intermediate BC04.

[0424]

[0425] Example 1

[0426]

[0427] 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

[0428] 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

[0429] 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) was added 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 h. TLC indicated that the reaction was complete and the mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by preparative TLC plate (50% EtOAc / petroleum ether) to give the title compound. MS: 531 (M+1).

[0430] 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

[0431] In N 2 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) was added KI (23.45 mg, 0.141 mmol) and TMS-Cl (0.018 ml, 0.141 mmol). The resulting mixture was stirred at 70° C. for 1 hour. TLC indicated that the reaction was complete. The mixture was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a regulator) to isolate the title compound. MS: 517 (M+1). 1 H NMR (400 MHz, CDCl3): 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, 1H) 6.10 (d,J =6.84 Hz, 1 H) 4.94 (s, 2 H) 4.36 (s, 2 H) 3.45 (s, 3 H).

[0432] The following Examples in Table 9 were prepared in a manner similar to that described above for the synthesis of Example 1 using the appropriate Intermediates AB and C.

[0433]

[0434]

[0435]

[0436]

[0437] Embodiment 14

[0438]

[0439] 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

[0440] 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

[0441] 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) was added potassium carbonate (21.98 mg, 0.159 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight, then diluted with water (3 mL) and extracted with EtOAc (3 mL). The organic layer was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 517.1 (M+1).

[0442] 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

[0443] 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) was added TMS-I (10.54 µL, 0.077 mmol) dropwise at room temperature. After addition, the resulting mixture was heated to 60 °C for 1 h, then diluted with EtOAc (2 mL) and washed with saturated NaHCO 3 Aqueous solution (1 mL) and saturated Na 2 S 2 O 3 The mixture was quenched with aqueous solution (1 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a regulator) to isolate the title compound. MS: 503.1 (M+1). 1 H NMR (600MHz, DMSO- d 6 ) 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).

[0444] The following Examples in Table 10 were prepared in a similar manner as described above for the synthesis of Example 14 using the appropriate Intermediates AB and Intermediates C.

[0445]

[0446]

[0447] Embodiment 21

[0448]

[0449] 5-Chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-( (fluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0450] Step 1: 5-chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(perfluoro (ethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0451] 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) was added DIAD (25.3 µL, 0.130 mmol) dropwise. The resulting mixture was warmed to room temperature and then treated with saturated NaHCO 3 The aqueous solution was diluted and extracted with DCM. The organic layer was washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 519.1 (M+1).

[0452] 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

[0453] To a solution of 5-chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (39 mg, 0.075 mmol) and potassium iodide (37.4 mg, 0.226 mmol) in ACN (752µL) was added TMS-Cl (28.8µl, 0.226 mmol). The resulting mixture was heated to 50°C for 1 hour and then cooled to room temperature before being diluted with MeOH (1 mL) and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 505.0 (M+1). 1 H 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).

[0454] The following Example 22 in Table 11 was prepared in a similar manner as described above for the synthesis of Example 21 using the appropriate Intermediate AB and Intermediate C.

[0455]

[0456] Embodiment 23

[0457]

[0458] 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

[0459] Step 1: 5-(difluoromethyl)-3-((1-((2-methoxypyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0460] 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 (633µL) was added (2-methoxypyridin-3-yl)methanol, C18 (19.36 mg, 0.139 mmol) and triphenylphosphine (127 mg, 0.380 mmol) followed by (E)-di-tert-butyldiazene-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).

[0461] 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

[0462] 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 (629µL) was added 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 containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 503.1 (M+1). 1 HNMR (500 MHz, DMSO- d 6 ) 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).

[0463] Embodiment 24

[0464]

[0465] 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

[0466] 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

[0467] 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) was added potassium carbonate (68.8 mg, 0.498 mmol). The resulting mixture was stirred at room temperature for 5 h, then diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by flash chromatography on silica (0-60% EtOAc / PE) to give the title compound. MS: 510.8 (M+1).

[0468] Step 2: 3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetramethyl (2-( ...

[0469] 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) was added cesium carbonate (134 mg, 0.411 mmol) and PdCl 2 (dppf) (22.38 mg, 0.027 mmol) and trimethylcyclotriboroxane (25.8 mg, 0.206 mmol). The resulting mixture was heated to 100 °C overnight, then quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue is purified by flash chromatography on silica (0-40% EtOAc / PE) to give the title compound. MS: 490.8 (M+1).

[0470] Step 3: 3-((1-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoro ethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

[0471] To a stirred and ice-cold 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) in ACN (3 mL) was added 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 h, then quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue is purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 477.2 (M+1).

[0472] Embodiment 25

[0473]

[0474] 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

[0475] Step 1: 3-((1-((6-chloro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethane 1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile

[0476] 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) was added K 2 CO 3 (352 mg, 2.54 mmol). The resulting mixture was stirred at 25 °C overnight, then diluted with water (50 mL) and stirred at room temperature for 30 minutes. The precipitate was collected on the top of the filter, washed with water (3×), and then air-dried to give the title compound. MS: 533.3 (M+1).

[0477] Step 2: 5-(Difluoromethyl)-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methane 6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0478] To N 2To a mixture of purified 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, 7.51µmol) in 1,4-dioxane (1 mL) was added 2 M aqueous cesium carbonate solution (0.5 mL, 1.0 mmol). The resulting mixture was heated at 150 °C in a microwave oven for 15 min and then extracted with EtOAc. The organic layer was purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was dissolved in ACN (1 mL) and treated with KI (6.23 mg, 0.038 mmol) and TMS-Cl (40µl, 0.313 mmol). The resulting mixture was heated in a microwave oven at 100°C for 10 minutes and then purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 515.2 (M+1).

[0479] The following Examples in Table 12 were prepared in a manner similar to that described above for the Synthesis of Example 25 using the intermediate in Step 1 of the Synthesis of Example 25 with the appropriate heteroaryl borate or alkyl borate in the second column.

[0480]

[0481] Embodiment 29

[0482]

[0483] 5-(Difluoromethyl)-3-((1-((6-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methane 6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0484] Step 1: 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoro ethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile

[0485] A 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 (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 (tol) (1877 µL) was stirred at 100 °C overnight, then diluted with EtOAc and saturated aqueous KF solution and treated with concentrated HCl (1 mL). The mixture was stirred at room temperature overnight and passed through CELITE® in a funnel. The filtrate was extracted with EtOAc (2X). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 541.4 (M+1).

[0486] Step 2: 5-(Difluoromethyl)-3-((1-((6-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydropyridine-3-yl)- 6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0487] To a solution of 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (30 mg, 0.056 mmol) in THF (278 µL) was added dropwise 3 M methylmagnesium bromide in Et 2 O (37.0 µL, 0.111 mmol). Once LCMS indicated complete conversion, the mixture was quenched with MeOH and water, and then quenched with EtOAc and saturated NaHCO 3 The organic layer was separated by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was dissolved in ACN (2 mL) and treated with KI (9.22 mg, 0.056 mmol) and TMS-Cl (20µL, 0.156 mmol). The resulting mixture was heated in a microwave oven at 100°C for 10 minutes. The mixture was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 543.4 (M+1). 1 H NMR (600 MHz, acetone- d 6) 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).

[0488] Embodiment 30

[0489]

[0490] 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

[0491] Step 1: 3-((1-((6-bromo-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dimethoxy- (5-(2-(2-pyrimidin-5-yl)oxy)-5-chlorobenzonitrile)

[0492] 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) was added (6-bromo-2-methoxypyridin-3-yl)methanol CO2 (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 was washed with water and brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by column chromatography on silica (30% EtOAc / PE) to give the title compound.

[0493] Step 2: 3-((1-((6-bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)- 1,6-dihydropyrimidin-5-yl)oxy)-5-chlorobenzonitrile

[0494] 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) in ACN (20 mL) was added sodium iodide (1.046 g, 6.98 mmol) and TMS-Cl (0.892 ml, 6.98 mmol). The reaction mixture was stirred at 80 °C overnight, then cooled to room temperature and some more ACN was added, stirred and filtered. The filter cake was washed with ACN. The filtrate was concentrated under reduced pressure to give the title compound. MS: 501.2 and 503.2 (M+1).

[0495] 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

[0496] 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 A mixture of the adduct (3.26 mg, 3.99 µmol), potassium phosphate tribasic (22.85 mg, 0.108 mmol) in 1,4-dioxane (53.2 µL) and water (26.6 µL) was degassed and heated with N 2 Purification. The resulting mixture was stirred at 80°C for 3h. LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure. The residue was subjected to reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 489.0 (M+1).

[0497] Embodiment 31

[0498]

[0499] 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

[0500] 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

[0501] 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 To a solution of 3-(chloromethyl)-2-methoxy-6-vinylpyridine (283 mg, 2.051 mmol) in DMF (2 mL) were added 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 h and then treated with H 2 O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by preparative TLC plate (25% EtOAc / PE) to give the title compound. MS: 513.1 (M+1).

[0502] 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

[0503] To a solution 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) was added to the mixture t -BuOH (0.1 mL) in osmium tetroxide (1.224 µL, 3.90 µmol). The resulting mixture was stirred at 20 °C for 30 min, and sodium periodate (122 mg, 0.571 mmol) was added to the mixture. The resulting mixture was stirred at 20 °C for 1.5 h, then diluted with EtOAc (10 mL) and carefully poured into water (10 mL). The organic layer was washed with saturated Na 2 S 2 O 3 The mixture was washed with aqueous solution (10 mL) and brine (10 mL), and then with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to give the title compound. MS: 515.1 (M+1).

[0504] 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

[0505] 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) was added Zn(BH 4 ) 2 (0.136 ml, 0.136 mmol). The resulting mixture was stirred at 20 °C for 0.25 h, then quenched with 1N HCl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound which was used directly in the next step. MS: 517.1 (M+1).

[0506] 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

[0507] 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) was added 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 containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 503.0 (M+1). 1 HNMR (400 MHz, DMSO- d 6 ): δ 11.75 (s, 1H), 8.79 (s, 1H), 7.86-7.84 (m, 1 H), 7.69-7.50 (m,1H), 7.48-7.46 (d, 1H), 6.87-6.74(m, 1H), 6.17-6.15 (m, 1 H), 5.42 (s, 1H), 4.86 (s, 2H), 4.27 (s, 2H).

[0508] Examples 32 (Isomer A) and 33 (Isomer B)

[0509]

[0510] ( S )-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine- 3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, and

[0511] ( R )-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine- 3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0512] Step 1: 5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((2-methoxy-6-vinylpyridin-3-yl)methane 6-Oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0513] 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) were added 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 were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was triturated with MeOH to give the title compound which was used without further purification.

[0514] 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

[0515] To a mixture of 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 (200 mg, 0.436 mmol) in 1,4-dioxane (1.5 mL) and water (0.5 mL) was added a solution of 2,6-lutidine (131 mg, 1.220 mmol) and 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) was then added. The reaction was stirred at 20 °C for 1.5 h, then diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with anhydrous Na 2 SO 4Dry and concentrate. The residue was purified by column chromatography on silica (0-20% EtOAc / petroleum ether) to give the title compound. MS: 461.1 (M+1).

[0516] Step 3: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl) 6-Oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0517] To a solution of 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 (55 mg, 0.107 mmol) in THF (3 mL) and EtOAc (2 mL) was added 1 M Zn(BH 4 ) 2 Solution in THF (0.021 mL, 0.021 mmol). The resulting mixture was stirred at -30 °C for 0.5 h. The reaction was quenched with water (1 drop) and then concentrated under reduced pressure to give the title compound. MS: 463.1 (M+1).

[0518] 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;

[0519] ( 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

[0520] (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

[0521] 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) in ACN (3 mL) was added 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 h and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the racemic title compound. MS: 449 (M+1). 1H NMR (400 MHz, DMSO- d 6 ) δppm 4.27 (br d, J=4.63 Hz, 2 H) 4.83 (s, 2 H) 5.46 (s, 1 H) 5.63 - 5.88 (m, 1H) 6.15 (br d, J =7.28 Hz, 1 H) 7.42 (d, J =7.06 Hz, 1 H) 7.58 (br d, J =5.73Hz, 1 H) 7.82 (br s, 1 H) 8.68 (s, 1 H). The racemic mixture was subjected to chiral SFC (ChiralpakIC-H column, 250×30 mm id, 5µm, IPA / CO 2 = 35%) to give Example 32 Isomer A (faster eluting) and Example 33 Isomer B (slower eluting).

[0522] Example 34 (Isomer A)

[0523]

[0524] ( 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

[0525] Step 1: 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoro ethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile

[0526] 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) was added 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 h and treated with H 2 O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (40 mL) and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue is purified by column chromatography on silica (50% EtOAc / PE) to give the title compound. MS: 529.2 (M+1).

[0527] 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

[0528] To a solution of 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile (144 mg, 0.272 mmol) in EtOAc (21 mL) was added 1 M Zn(BH 4 ) 2 The resulting solution was stirred at 15-20 °C for 0.5 h, then quenched with 4N aqueous HCl (5 mL) and washed with H 2 O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (40 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. MS: 531.2 (M+1).

[0529] Step 3: ( S )or( R )-5-chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-oxo-1,2-dihydropyridine- 3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0530] 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) was added 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 h, then diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4The mixture was dried, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the racemic title compound. The racemic mixture was purified by chiral SFC (ChiralPak AD-H column, 250×30 mm id, 5µm, 25% IPA / containing 0.1% NH 4 OH as a modifier for CO 2 ) to give Example 34 (Isomer A, faster eluting). MS: 517.0 (M+1). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 1.29 (d, J = 6.58 Hz, 3 H) 4.49 (br d, J = 4.39 Hz, 1 H)4.86 (s, 2 H) 5.49 (br d, 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).

[0531] Embodiment 35

[0532]

[0533] 3-(Difluoromethyl)-5-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)- (fluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0534] 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)pyrimidin-4(3H)-one, BC04 (40 mg, 0.125 mmol) and 3-(difluoromethyl)-5-hydroxybenzonitrile, A01 (25.3 mg, 0.149 mmol) in DMF (623µL) 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 was separated and concentrated under reduced pressure. The residue was dissolved in ACN (2 mL) and TMS-I (85µL, 0.623 mmol) was added dropwise at room temperature. After addition, the resulting mixture was heated to 60°C for 2 h. The reaction was diluted with EtOAc (2 mL) and saturated NaHCO 3 Aqueous solution (1 mL) and saturated Na 2 S 2 O 3 The mixture was quenched with aqueous solution (1 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a regulator) to isolate the title compound. MS: 457.1 (M+1). 1 HNMR (600 MHz, DMSO- d 6 ) 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).

[0535] The following Examples in Table 13 were prepared in an analogous manner as described above for the synthesis of Example 35 using the appropriate Intermediate A and Intermediate BC.

[0536]

[0537] Embodiment 39

[0538]

[0539] 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

[0540] 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

[0541] A mixture of 5-fluoro-3-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-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) was heated to 80 °C overnight and then heated at 100 °C for a second night. The crude was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 501.2 (M+1).

[0542] 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

[0543] 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 (230µL) was added TMS-Cl (8.80µL, 0.069 mmol). The resulting mixture was heated to 50 °C for 4 h and then quenched with MeOH (1 mL). The crude was purified by reverse phase HPLC (ACN / water with 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 487.2 (M+1).

[0544] The following Examples in Table 14 were prepared in an analogous manner as described above for the synthesis of Example 39 using the appropriate Intermediate A and Intermediate BC.

[0545]

[0546] Embodiment 42

[0547]

[0548] 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

[0549] 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

[0550] A 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)pyrimidin-4(3H)-one, BC02 (180 mg, 0.536mmol), potassium carbonate (148 mg, 1.072 mmol) in DMF (2 mL) was stirred at 80 °C for 15 h and passed through a filter. The filter cake was washed with EtOAc (10 mL). The filtrate was partitioned between EtOAc and water. The layers were separated. The aqueous layer was further extracted with EtOAc (3×10 mL). The combined organic layers were purified by anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 499.1 (M+1).

[0551] 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

[0552] A 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) was heated at 100 °C for 4 nights until LCMS indicated complete conversion. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN / water containing 0.1% TFA as a modifier) ​​to isolate the title compound. MS: 481.1 (M+1). 1 H 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).

[0553] Example 43: Determination of cell killing (SMACK) activity:

[0554] PBMCs from healthy donors were cultured at approximately 2.5 x 10 in complete medium (RPMI 1640 with L-glutamine, 10% heat-inactivated fetal bovine serum, 100 U / mL penicillin-streptomycin) containing 5 µg / mL phytohemagglutinin. 6 cells / mL in 5% CO 2 , 37°C and 90% humidity for 3 days. On day 4, PHA-stimulated cells were washed and plated at approximately 20 x 10 6 10 cells / mL were resuspended with VSV-G pseudotyped HIV virus stock (VSV-G / pNLG1-P2A-∆Env - 20µg / mL p24) in complete medium containing IL-2 (10 U / mL) and incubated at 37°C, 5% CO 2 and 90% humidity for 4 hours. VSV-G / pNLG1-P2A-∆Env is a VSV-G pseudotype virus derived from pNL43, in which egfp Insert into nef The virus contains Vif that is truncated by 50 amino acids due to a single nucleotide deletion that causes a frameshift, and due to gfp The infected cells were then washed 3 times with complete medium + 10U / mL IL-2 and centrifuged at 200 x g for 3 minutes at 22°C. The cells were centrifuged at 5 x 10 6 Cells / mL were resuspended in complete medium + 10 U / mL IL-2 and incubated at 37°C, 5% CO 2 For compound treatment, infected PBMCs were diluted to 4 x 10 in RPMI 1640 containing L-glutamine, 50% normal human serum (NHS), 100 U / mL penicillin-streptomycin + IL-2 (10 U / mL). 5 cells / mL and 20,000 cells were transferred to each well of a 384-well poly-D-lysine coated compound plate containing compound with a final DMSO <0.5%. Compounds were tested using a 10-point 3-fold titration. Plates were analyzed on an Acumen ex3 imager using a BlueLaser 488 nm and the number of GFP-positive objects was collected, where loss of GFP represents death of infected cells. Titration curves and EC were calculated using a four-parameter logistic fit 50 The results are shown in Table 15.

[0555]

[0556]

[0557]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof in: R 1 is H, halogen or -C 1-3 alkyl; R 2 is CN and R 3 is H; or R 2 is H and R 3 It is CN; R 4 is -H, halogen or -C which is unsubstituted or substituted by 1-7 F 1-3 alkyl; R 5 Is -H or -C 1-3 alkyl; R 6 It is -C replaced by 1-9 -F 1-6 alkyl; R 7 Is -H or -C 1-3 alkyl; R 8 is -H or halogen; and R 9 is -H, pyrazolyl or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 It is -C replaced by 1-7 -F 1-3 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 7 It is H or -CH3.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 8 is -H or halogen.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 9 is -H, pyrazolyl or unsubstituted or substituted with -OH or -OC 1-3 Alkyl-substituted-C 1-4 alkyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, which has structural formula II or a pharmaceutically acceptable salt thereof:

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen or unsubstituted or substituted by 1-7 F -C 1-3 alkyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes -H.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 Is halogen or -C 1-3 alkyl.

10. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, which has structural formula III or a pharmaceutically acceptable salt thereof:

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 Is halogen or -C 1-3 alkyl.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 5 Is halogen or -C 1-3 alkyl.

13. The compound of 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-dihydropyrimidin-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-dihydropyrimidin-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-dihydropyrimidin-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-dihydropyrimidin-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-dihydropyrimidin-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-dihydropyrimidin-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-dihydropyrimidin-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.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 19. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, further comprising an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, and HIV maturation inhibitors.

21. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection, or treating, preventing or delaying the onset or progression of AIDS or ARC in a human subject.

22. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for selectively killing HIV-infected GAG-POL expressing cells in a human subject without concomitant cytotoxicity to HIV-naive cells.

23. The use of any one of claims 21-22, wherein the medicament is further administered in combination with one or more additional compatible HIV antiviral agents selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, 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.

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