Benzamide compounds for treatment of herpes viruses

Abstract

The present disclosure provides, in part, novel benzamide compounds, pharmaceutical compositions thereof, and methods for the treatment and prophylaxis of herpes viruses.

Description

[0001] Attorney Docket No.71180-423434 (ASP-071WO) BENZAMIDE COMPOUNDS FOR TREATMENT OF HERPES VIRUSES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 639,220, filed April 26, 2024, which is incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Human herpes viruses (Herpesviridae) are responsible for causing a wide variety of diseases in humans. Infection with herpes viruses can occur early in life and by adulthood over 95% of the population is infected by at least one herpes virus. These viruses establish a persistent life-long infection through viral latency in neuronal, lymphoid, or myeloid cells. Recurrent episodes of herpes virus disease can be triggered by numerous stimuli, including concurrent viral infections, stress, fatigue, allergies, pregnancy, sunlight, or fever. Herpes virus infection in immune competent individuals generally causes mild self-limiting disease, such as: oral (HSV- 1), and genital (HSV-2) ulcers, chicken pox (VZV), flu-like syndrome (CMV), and mononucleosis (EBV). In immunocompromised individuals however, primary infection with, or reactivation of an existing herpes virus infection is a major cause of disease and death. Key at risk immunocompromised populations include patients undergoing solid organ or stem cell transplants, individuals with HIV / AIDS, and ICU patients. Herpesviridae comprise a diverse family of double-stranded DNA viruses that are classified into three subfamilies (i.e., a, ' and y) based upon biological characteristics such as cell tropism, diseases caused, viral life-cycle, and site of viral persistence and latency. The family consists of eight members: Herpes Simplex Virus type I and 2 (HSV-1, HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and human herpes viruses 6-8 (HHV6-8). α-herpes viruses include herpes simplex virus types I and 2 (HSVI and HSV2), and varicella-zoster virus (VZV). HSVI causes orofacial lesions, commonly known as fever blisters or cold sores. Approximately 30% of the United States population suffers from recurrent episodes of HSVl. HSV2, which is less common than HSVI, causes genital lesions. Primary infection with VZV causes varicella, commonly known as chicken pox. Attorney Docket No.71180-423434 (ASP-071WO) Reactivation of latent VZV manifests as herpes zoster or shingles. Cytomegalovirus (CMV) is a prototypical herpes virus. Seroprevalance to CMV in the adult population is approximately 60%, but certain endemic areas of the world have rates closer to I00%. CMV represents the leading viral cause of morbidity and mortality in at-risk immunocompromised patients. EBV, a γ-herpes virus, causes infectious mononucleosis and is responsible for lymphoid cancers such as Burkitt' s and Hodgkin's lymphoma. Presently, there is no cure for herpes. Medicines have been developed that can prevent or shorten outbreaks, but there is a need for improved therapies for treating herpes virus infection and inhibiting viral replication. The current standard of care for immunocompromised patients at risk for herpes virus disease is pre-emptive treatment with high-dose nucleoside / nucleotide analog drugs such as acyclovir, (val)ganciclovir, and cidofovir, all of which target the viral DNA polymerase. In general, current treatments are virus specific (not broad spectrum), and in the case of (val)ganciclovir and cidofovir cannot be administered prophylactically due to dose-related toxicities including bone marrow suppression and renal toxicity. Although efficacious in many settings, the current nucleos(t)ide drugs are also limited by drug-resistant viral variants and existing cross-resistant variants which may lead to treatment failure. WO2021126902 relates to novel amido-substituted heterocycle compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein X, R1, R2, R3, and R4 are as defined therein. The invention also relates to compositions comprising at least one amido-substituted heterocycle compound, and methods of using the amido-substituted heterocycle compounds for treating or preventing a herpesvirus infection in a patient. WO2022132679 relates to novel amido-substituted heterocycle compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5are as defined therein. The invention also relates to compositions comprising at least one amido-substituted heterocycle compound, and methods of using the amido-substituted heterocycle compounds for treating or preventing a herpesvirus infection in a patient. WO2022146755 relates to novel amido-substituted heterocycle compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R7, and R8 are as defined therein. The invention also relates to compositions comprising at least one amido- Attorney Docket No.71180-423434 (ASP-071WO) substituted heterocycle compound, and methods of using the amido-substituted heterocycle compounds for treating or preventing a herpesvirus infection in a patient. There is still a need for additional antiviral compounds for the treatment and prophylaxis of viral infections, particularly herpes infections, that have an improved profile with respect to safety, potency, selectivity and / or bioavailability. SUMMARY OF THE INVENTION In one embodiment, the present disclosure provides a compound of Formula I Formula I or a variables are as described herein. In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a method of treating a herpes virus infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating a herpes virus infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION Attorney Docket No.71180-423434 (ASP-071WO) The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. I. Definitions The term “carbonyl” as used herein refers to the biradical -C(O)-. The term “cyano” as used herein refers to the radical -CN. The terms “halo” or “halogen” as used herein refer to the radicals F, Cl, Br or I. The terms “hydroxy” and “hydroxyl” as used herein refer to the -OH radical. The term “RaRbN-“ as used herein is a radical wherein Raand Rbare independently selected from the group consisting of hydrogen and C1-6alkyl; or Raand Rbtogether with the N atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group. The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon radical. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, etc. The term “alkylene” as used herein refers to a saturated straight or branched hydrocarbon biradical. The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon radical having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C2-6alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc. Attorney Docket No.71180-423434 (ASP-071WO) The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon radical having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C2-6alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl, etc. The term “alkoxy” as used herein refers to an alkyl group attached to an oxygen atom (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C1-6alkoxy and C1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy and isopropoxy, etc. The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. For example, haloC1-6alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, -CF3, CF3CH2-, CH3CF2-, CF3CCl2- and CF3CF2-. The term “haloalkylene” as used herein refers to an alkylene group substituted with one or more halo groups. The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH2O-, and CF3CF2O-. The term “halohydroxyalkyl” as used herein refers to an alkyl group substituted with one to three hydroxy groups and one or more halo groups. The term “haloalkoxyalkyl” as used herein refers to an alkyl group substituted with a haloalkoxy- group. The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with one to three hydroxy groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2- and HOCH2CH(OH)CH2-. The term “hydroxyalkylene” as used herein refers to an alkylene group substituted with one to three hydroxy groups. The term “hydroxyalkenyl” as used herein refers to an alkenyl group substituted with one to three hydroxy groups. Attorney Docket No.71180-423434 (ASP-071WO) The term “hydroxyalkynyl” as used herein refers to an alkynyl group substituted with one to three hydroxy groups. The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one to three hydroxy groups. Examples include but are not limited to HOCH2CH2O-, CH3CH(OH)CH2O- and HOCH2CH(OH)CH2O-. The term “hydroxyalkoxyalkyl” as used herein refers to an alkyl group substituted with an hydroxyalkoxy- group. The term “HOC(O)alkyl“ as used herein refers to an alkyl group substituted with a - C(O)OH group. The term “RaRbNC1-6alkyl-,” as used herein refers to an alkyl group substituted with one to three RaRbN- groups, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2- and CH3CH(NH2)CH2-. The term “RaRbNhydroxyalkyl” as used herein refers to an alkyl group substituted with one to three hydroxy groups and one to three RaRbN- groups, as defined herein. The term “RaRbNC1-6alkoxy,” as used herein refers to an alkoxy group substituted with one or two RaRbN- groups, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-. The term “monocycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as C3-7monocycloalkyl. Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. The term “coinfection” as used herein refers to simultaneous infection of a host by more than one viral pathogen. The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, Attorney Docket No.71180-423434 (ASP-071WO) and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired. The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism. The term “pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of Attorney Docket No.71180-423434 (ASP-071WO) such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect. The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease. The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(-),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred Attorney Docket No.71180-423434 (ASP-071WO) to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.” Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral- phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre- existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. All isomeric forms (especially all regio- and stereoisomeric forms, e.g. all chiral, enantiomeric, diastereomeric, racemic forms, tautomeric and all geometric isomeric forms, as Attorney Docket No.71180-423434 (ASP-071WO) well as atropisomers, (including interconverting atropisomerism) of a compound of the present description are intended within this invention, unless the specific isomer form is specifically indicated. In one embodiment, the isomer which is pharmacologically most effective and most free from side effects is preferred. The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or Attorney Docket No.71180-423434 (ASP-071WO) upon transit of the intestine, blood, or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). Compounds of the Invention In one aspect, the present disclosure provides a compound of Formula I Formula I or a L is -O- or -NH-; Ra, Rband Rcare independently selected for each occurrence from the group consisting of hydrogen and C1-6alkyl; or Raand Rbtogether with the N atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group; Rdand Reare independently selected from the group consisting of hydrogen and C1-6alkyl; or Reand Retogether with the N atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group, wherein the azetidinyl, pyrrolidinyl or piperidinyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, OH, NH2, C1-4alkyl, hydroxyC1-4alkyl, and C1-4alkoxy; R1is independently selected for each occurrence from the group consisting of halo, CN, C1-4alkyl and haloC1-4alkyl; R2is hydrogen, halo, OH, C1-4alkyloxy-, hydroxyC1-4alkyloxy-, RaRbNC1-6alkoxy-, or oxetanyl-O-, wherein the oxetanyl-O- is optionally substituted with C1-4alkyl; Attorney Docket No.71180-423434 (ASP-071WO) , halo, OH, CN, RdReN-, C1-6alkyl, C3-6monocycloalkyl-, HOC(O)alkyl, haloC1-6alkyl-, hydroxyC1-6alkyl-, RaRbNC1-6alkyl-, RaRbNhydroxyC1-6alkyl-, C1-6alkoxy-, haloC1-6alkoxy, hydroxyC1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, haloC1-6alkoxyC1-6alkyl-, hydroxyC1-6alkoxyC1-6alkyl-, C1-6alkylC(O)-, C1-6alkylS(O)q-, C1-6alkoxyC(O)-, C1-6alkylC(O)O- , C1-6alkylC(O)-C1-6alkylene-, C1-6alkylS(O)q-C1-6alkylene-, C1-6alkylC(O)O-C1-6alkylene-, C3-6monocycloalkyl-O-C1-6alkylene-, and C3-6monocycloalkyl-NRc-C1-6alkylene-; R4bis hydrogen, C1-4alkyl, haloC1-4alkyl, C3-6monocycloalkyl, or oxetanyl; n is 0, 1, 2 or 3; q is independently selected for each occurrence from the group consisting of 0, 1 and 2; v is 0, 1, 2 or 3; w is 0, 1 or 2. and u is 0 or 1. The following embodiments further describe a compound of Formula I, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention. In certain embodiments, n is 1 and R1is R1a. In certain embodiments, the compound of Formula I is of Formula Ia: Attorney Docket No.71180-423434 (ASP-071WO) Ia, or a In certain embodiments, is Cl. In certain embodiments, n is 2 and one R1is R1aand one R1is R1b. In certain embodiments, the compound of Formula I is of Formula Ib: Formula Ib or a In certain embodiments, R1ais CN and R1bis F. In certain embodiments, L is -O-. In certain embodiments, L is -NH-. In certain embodiments, R2is F. In certain embodiments, R2is OH. In certain embodiments, R2is C1-6alkoxy. Attorney Docket No.71180-423434 (ASP-071WO) In certain . In certain . Methods of Use The Compounds of the invention are useful in human and veterinary medicine for treating or preventing a viral infection in a patient. In one embodiment, the Compounds of the invention can be inhibitors of viral replication. In another embodiment, the Compounds of the invention can be inhibitors of herpesvirus replication. Accordingly, the Compounds of the invention are useful for treating viral infections, such as herpesvirus. In accordance with the invention, the Compounds of the invention can be administered to a patient in need of treatment or prevention of a viral infection. In one aspect, the invention provides methods for treating or preventing a viral infection in a patient comprising administering to the patient an effective amount of at least one Compound of the invention or a pharmaceutically acceptable salt thereof. The Compounds of the invention are useful in the inhibition of herpesvirus replication, the treatment of herpesvirus infection and / or reduction of the likelihood or severity of symptoms of herpesvirus infection and the inhibition of herpesvirus viral replication and / or herpesvirus viral production in a cell-based system. For example, the Compound of the invention are useful in treating infection by herpesvirus after suspected past exposure to herpesvirus by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery or other medical procedures. In one embodiment, the invention provides a method for treating herpesvirus infection in a patient, the method comprising administering to the patient an effective amount of at least one Compound of the invention, or a pharmaceutically acceptable salt thereof. In another embodiment, the herpesvirus being treated or prevented is of the family α- Attorney Docket No.71180-423434 (ASP-071WO) herpesviridae. Herpesviruses of the family α-herpesviridae include, but are not limited to, herpes simplex virus 1 (HSV-1 or HSV1), herpes simplex 2 (HSV-2 or HSV2), and varicella zoster virus (VZV). In another embodiment, the herpesvirus being treated or prevented is of the familyβ - herpesviridae. Herpesviruses of the family β -herpesviridae include, but are not limitedto, human cytomegalovirus (CMV), human herpesvirus 6 (HHV6), and human herpesvirus 7 (HHV7). In another embodiment, the herpesvirus being treated or prevented is of the family γ- herpesviridae. Herpesviruses of the family γ-herpesviridae include, but are not limited to, Epstein-Barr virus (EBV), human herpesvirus 4 (HHV4), and Kaposi's sarcoma-associated herpesvirus (KHSV), also known as human herpesvirus 8 (HHV8). In another embodiment, the herpesvirus being treated or prevented is HSV-1. In another embodiment, the herpesvirus being treated or prevented is HSV-2. In another embodiment, the herpesvirus being treated or prevented is VZV. In another embodiment, the herpesvirus being treated or prevented is CMV. In a further embodiment, the herpesvirus being treated or prevented is HHV4. In another embodiment, the herpesvirus being treated or prevented is HHV6. In another embodiment, the herpesvirus being treated or prevented is HHV7. In another embodiment, the herpesvirus being treated or prevented is EBV. In another embodiment, the herpesvirus being treated or prevented is KSHV. In another embodiment, the amount administered is effective to treat or prevent infection by herpesvirus in the patient. In another embodiment, the amount administered is effective to inhibit herpesvirus viral replication and / or viral production in the patient. The compositions and combinations of the present invention can be useful for treating a patient suffering from infection related to any herpesvirus infection. Herpesvirus types may differ in their antigenicity, level of viremia, severity of disease produced, and response to therapy. See Poole et al., Clinical Therapeutics, 40:8 (2018), 1282-1298. Combination Therapy In another aspect, the present methods for treating or preventing herpesvirus Attorney Docket No.71180-423434 (ASP-071WO) infection can further comprise the administration of one or more additional therapeutic agents which are not Compounds of the invention. In one embodiment, the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an anti-herpes agent. Anti-herpes agents useful in the present compositions and methods include, but are not limited to, nucleoside polymerase inhibitors, such as acyclovir, valaciclovir, famciclovir, penciclovir, cidofovir, brincidofovir (CMX-001), valmanciclovir, ganciclovir, valganciclovir, and N-methanocarbathymidine (N-MCT); pyrophosphate polymerase inhibitors, such as foscarnet; CMV terminase inhibitors, such as letermovir; viral kinase inhibitors, such as maribavir; and helicase-primase inhibitors, such as pritelivir (AIC-316), and amenamevir (ASP- 2151). In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent. Immunosuppressant agents useful in the present compositions and methods include, but are not limited to, cytotoxic agents, such as cyclophosphamide and cyclosporin A; corticosteroids, such as hydrocortisone and dexamethasone, and non-steroidal anti-inflammatory agents (NSAID). In another aspect, the present invention provides methods for treating a herpesvirus infection in a patient, the method comprising administering to the patient: (i) at least one Compound of the invention, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than Compound of the invention, wherein the amounts administered are together effective to treat or prevent the herpesvirus infection. When administering a combination therapy of the invention to a patient, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a Compound of the invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like). In one embodiment, the at least one Compound of the invention is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic Attorney Docket No.71180-423434 (ASP-071WO) effect, or vice versa. In another embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection. In another embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection. In another embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection. In one embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, this composition is suitable for parenteral administration. The at least one Compound of the invention and the additional therapeuticagent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy. In one embodiment, the administration of at least one Compound of the invention and the additional therapeutic agent(s) may inhibit the resistance of a herpesvirus infection to these agents. The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of herpesvirus infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Compound(s) of the invention, and the other agent(s) can be administered Attorney Docket No.71180-423434 (ASP-071WO) simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the preferred pharmaceutical compositions are different, e.g., one is a tablet, and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous. In one embodiment, one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an immunomodulator, an anti- herpes agent, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating any type of herpesvirus infection. Compositions and Administration Due to their activity, the Compounds of the invention are useful in veterinary and human medicine. As described above, the Compounds of the invention are useful for treating or preventing herpesvirus infection in a patient in need thereof. In another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present invention provides pharmaceutical compositions comprising (i) an effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (ii) one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents and immunomodulators. When administered to a patient, the Compounds of the invention can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present invention provides pharmaceutical compositions comprising an effective amount of at least one Compound of the invention and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier Attorney Docket No.71180-423434 (ASP-071WO) materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms), and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral or intravenous injection. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions. For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and Attorney Docket No.71180-423434 (ASP-071WO) the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. In one embodiment, the one or more Compounds of the invention are administered orally. In another embodiment, the one or more Compounds of the invention are administered intravenously. In another embodiment, the one or more Compounds of the invention are administered sublingually. In another embodiment, a pharmaceutical preparation comprising at least one Compound of the invention is in unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components. Compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1%, to about 99% of the Compound(s) of the invention by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1%, to about 70% or from about 5%, to about 60% of the Compound(s) of the invention by weight or volume. The amount and frequency of administration of the Compounds of the invention will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Generally, a total daily dosage of the at least one Compound(s) of the invention alone, or when administered as combination therapy, can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration. In one embodiment, the dosage is from about 10 to about 1000 mg / day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg / day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg / day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg / day, administered in a single dose or in 2-4 Attorney Docket No.71180-423434 (ASP-071WO) divided doses. In another embodiment, the dosage is from about 500 to about 1500 mg / day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg / day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg / day, administered in a single dose or in 2-4 divided doses. The compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one Compound of the invention or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Compound of the invention; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat herpesvirus infection. In one embodiment, the present invention provides compositions comprising a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the present invention provides compositions comprising a Compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a second therapeutic agent selected from the group consisting of anti- herpes agents and immunomodulators. In another embodiment, the present invention provides compositions comprising a Compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and two additional therapeutic agents, each of which are independently selected from the group consisting of anti-herpes agents and immunomodulators. Examples The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the Attorney Docket No.71180-423434 (ASP-071WO) functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Preparation of Intermediates: Synthesis of (7R,8aS)-7-hydroxytetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-1) acid (1-2). To a stirred solution of (S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (1- 1) (5 g, 20.5 mmol) in anhydrous THF (40 mL) was added L-Selectride (1M in THF, 45 mL, 45 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h. The reaction mixture was acidified with 1N HCl to pH - 5 and extracted with DCM (40 mL x 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dried in vacuo to give (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid (1-2) (10 g, >99%) as a brown oil, which was used for the next step without further purification. MS (ESI): calcd. for C11H19NO5: 245.1; Found: 146.2 [M - 100 + 1]+. Step 2. Synthesis of (2S,4R)-tert-butyl-4-hydroxy-2-(hydroxymethyl)piperidine-1- carboxylate (1-3). To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypiperidine- 2-carboxylic acid (1-2) (10 g, 20.5 mmol) in dry THF (40 mL) was added borane-dimethyl sulfide (1M in THF, 45 mL, 45 mmol) dropwise at 0 °C. The reaction mixture was stirred at 70 °C for 4 h. The reaction mixture was quenched with methanol. The reaction mixture was stirred for 15 mins at room temperature and concentrated. The resulting residue was partitioned between water (25 mL) and EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4, Attorney Docket No.71180-423434 (ASP-071WO) filtered, concentrated. The residue was dried in vacuo to give (2S,4R)-tert-butyl-4-hydroxy-2- (hydroxymethyl)piperidine-1-carboxylate (1-3) (8 g, >99%) as a gray oil, which was used for next step without further purification. MS (ESI): calcd. for C11H21NO4: 231.2; Found: 176.2 [M - 55]+. Step 3. Synthesis of (7R,8aS)-7-hydroxytetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-1). To a suspension of (2S,4R)-tert-butyl-4-hydroxy-2-(hydroxymethyl)piperidine-1- carboxylate (1-3) (8 g, 20.5 mmol) in ethanol (50 mL) was added K2CO3(5.7 g, 41 mmol). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of Celite®545. The Celite®545 cake was washed with ethanol. The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography to give (7R,8aS)-7-hydroxytetrahydro-1H- oxazolo[3,4-a]pyridin-3(5H)-one (INT-1) (1 g, 31% for 3 steps) as a white solid. MS (ESI): calcd. for C7H11NO3: 157.1; Found: 158.3 [M + 1]+. Synthesis of (7S,8aS)-7-aminotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-2) Step 1. methylbenzenesulfonate (2-1). To a stirred solution of (7R,8aS)-7-hydroxyhexahydro-3H- oxazolo[3,4-a]pyridin-3-one (INT-1) (3 g, 19.1 mmol) in DCM (20 mL) was added DMAP (240 mg, 1.96 mmol), TEA (2.2 g, 21.7 mmol), and TsCl (7.28 g, 38.2 mmol). The reaction mixture was stirred at 20 °C overnight. The resulting mixture was quenched with H2O (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting with 70% EtOAc in petroleum ether to give (7R,8aS)-3- oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl-4-methylbenzenesulfonate (2-1) (3.6 g, 61%) as a yellow oil. MS (ESI): calcd. for C14H17NO5S: 311.08; Found: 329.2 [M + 18]+. Attorney Docket No.71180-423434 (ASP-071WO) Step 2. Synthesis of (7S,8aS)-7-azidotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-2). To a stirred solution of (7R,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl-4- methylbenzenesulfonate (2-1) (3.58 g, 11.5 mmol) in DMF (20 mL) was added NaN3 (1.5 g, 23.1 mmol). The reaction mixture was stirred at 80 °C overnight. The resulting mixture was quenched with H2O (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was dried in vacuo to give (7S,8aS)-7- azidotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-2) (2.6 g, >99%) as a yellow oil. MS (ESI): calcd. for C7H10N4O2: 182.08; Found: 183.2 [M + 1]+. Step 3. Synthesis of (7S,8aS)-7-aminotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT- 2). A mixture of (7S,8aS)-7-azidotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-2) (2.6 g, 11.5 mmol) and 10% Pd / C (w / w) (260 mg) in CH3OH (20 mL) was hydrogenated at 15 °C overnight. The reaction mixture was filtered through a pad of Celite®545 and washed with CH3OH (20 mL). The filtrate was concentrated under reduced pressure and the residue was dried in vacuo to give (7S,8aS)-7-aminotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-2) (2.2 g, >99%) as a colorless oil, which was used for the next step without further purification. MS (ESI): calcd. for C7H12N2O2: 156.1; Found: 157.3 [M + 1]+. Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (INT-3) Step 1. Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (INT-3). To a stirred solution of 4-bromo-1H-imidazole (1 g, 6.8 mmol) in acetone (10 mL) was added K2CO3(2.8 g, 20.4 mmol) and SEMCl (1.4 g, 8.2 mmol) at 15 °C. The reaction mixture was stirred at 15 °C overnight, quenched with H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dried in vacuo to give 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (INT-3) (0.96 g, 52%) as a colorless oil. MS (ESI): calcd. for C9H17BrN2OSi: 277.2; Found: 278.1 [M + 1]+. Attorney Docket No.71180-423434 (ASP-071WO) Preparation of Representative Compounds of the Invention: N-(4-chlorobenzyl)-2-fluoro-4-(oxazol-5-yl)-5-(((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4- a]pyridin-7-yl)oxy)benzamide (Example 1) of 2- fluoro-5-hydroxybenzoic acid (1-1) (1.5 g, 9.6 mmol) in CHCl3(15 mL) was added bromine (1.5 mL, 28.8 mmol) in AcOH (15 mL) slowly at 0 ℃. The reaction mixture was stirred at room temperature overnight then quenched with aqueous Na2SO3 (200 mL). The resulting mixture was acidified to pH - 2 with 12N HCl and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dried in vacuo to give 4-bromo-2-fluoro-5-hydroxybenzoic acid (1-2) (1.8 g) as a white solid, which was used for the next step without further purification. Step 2. Synthesis of 4-bromo-N-(4-chlorobenzyl)-2-fluoro-5-hydroxybenzamide (1-3). To a stirred solution of 4-bromo-2-fluoro-5-hydroxybenzoic acid (1-2) (1.1 g, 4.6 mmol) in THF (10 mL) was added (4-chlorophenyl)methanamine (0.98 g, 6.9 mmol), DIEA (2.4 mL, 13.8 mmol), and HATU (2.1 g, 5.5 mmol). The reaction mixture was stirred at 20 ℃ overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography, eluting with 0- 40% EtOAc in petroleum ether, to give 4-bromo-N-(4-chlorobenzyl)-2-fluoro-5- hydroxybenzamide (1-3) (0.66 g, 39%) as a white solid. MS (ESI): calcd. for C14H10BrClFNO2: 356.96; Found: 357.7 [M + 1]+. Attorney Docket No.71180-423434 (ASP-071WO) Step 3. Synthesis of 4-bromo-N-(4-chlorobenzyl)-2-fluoro-5-(((7S,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yl)oxy)benzamide (1-4). To a stirred solution of 4-bromo-N-(4- chlorobenzyl)-2-fluoro-5-hydroxybenzamide (1-3) (0.66 g, 1.85 mmol) in toluene (5 mL) was added (7R,8aS)-7-hydroxyhexahydro-3H-oxazolo[3,4-a]pyridin-3-one (INT-1) (0.377 g, 2.40 mmol), PPh3 (0.873 g, 3.33 mmol), and DIAD (0.71 g, 3.51 mmol) at 0 ℃. The reaction mixture was stirred at 20 ℃ overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to give 4-bromo-N-(4-chlorobenzyl)-2-fluoro- 5-(((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl)oxy)benzamide (1-4) (0.55 g, 60%) as a white solid. MS (ESI): calcd. for C21H19BrClFN2O4: 496.0; Found: 496.7 [M + 1]+. Step 4. Synthesis of N-(4-chlorobenzyl)-2-fluoro-4-(oxazol-5-yl)-5-(((7S,8aS)-3- oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl)oxy)benzamide (Example 1). To a stirred solution of 4-bromo-N-(4-chlorobenzyl)-2-fluoro-5-(((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4- a]pyridin-7-yl)oxy)benzamide (1-4) (0.1 g, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (0.084 g, 0.24 mmol), and K2CO3(0.069 g, 0.5 mmol) in 1,4-dioxane / H2O (4 mL / 1 mL) was added Pd(dppf)Cl2 (0.015 g, 0.02 mmol). The mixture was stirred at 100 ℃ overnight. The mixture was quenched with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC to give N-(4-chlorobenzyl)-2-fluoro-4-(oxazol-5-yl)-5-(((7S,8aS)-3-oxohexahydro- 1H-oxazolo[3,4-a]pyridin-7-yl)oxy)benzamide (Example 1) (0.074 g, 76%) as a white solid. MS (ESI): calcd. for C24H21ClFN3O5: 485.1; Found: 486.3 [M + 1]+;1H NMR (400 MHz, CD3OD): δ 8.34 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 11.2 Hz, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.37 ‒ 7.32 (m, 4H), 4.57 (s, 2H), 4.46 (t, J = 8.4 Hz, 1H), 4.14 ‒ 4.07 (m, 1H), 3.99 ‒ 3.96 (m, 1H), 3.79 ‒ 3.74 (m, 1H), 3.27 ‒ 3.22 (m, 2H), 2.37 ‒ 2.33 (m, 1H), 2.16 ‒ 2.12 (m, 1H), 1.93 ‒ 1.76 (m, 2H) ppm. Synthesis of N-(4-chlorobenzyl)-2-fluoro-4-(1H-imidazol-4-yl)-5-((7S,8aS)-3-oxohexahydro- 1H-oxazolo[3,4-a]pyridin-7-yloxy)benzamide (Example 2) Attorney Docket No.71180-423434 (ASP-071WO) oxazolo[3,4-a]pyridin-7-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2-1). To a stirred solution of 4-bromo-N-(4-chlorobenzyl)-2-fluoro-5-(((7S,8aS)-3- oxohexahydro-3H-oxazolo[3,4-a]pyridin-7-yl)oxy)benzamide (1-4) (130 mg, 0.26 mmol) in dioxane (1.5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (264 mg, 1 mmol), KOAc (128 mg, 1.3 mmol), and Pd(dppf)Cl2 (38 mg, 0.05 mmol). The reaction mixture was stirred at 80 ℃ overnight. The reaction mixture was concentrated under reduced pressure to give N-(4-chlorobenzyl)-2-fluoro-5-(((7S,8aS)-3-oxohexahydro-3H-oxazolo[3,4-a]pyridin-7- yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2-1) (140 mg) as a red solid, which was used for the next step without further purification. MS (ESI): calcd. for C27H31BClFN2O6: 544.2; Found: 545.2 [M + 1]+. Step 2. Synthesis of N-(4-chlorobenzyl)-2-fluoro-5-((7S,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yloxy)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)benzamide (2-2). To a stirred solution of N-(4-chlorobenzyl)-2-fluoro-5-(((7S,8aS)-3- oxohexahydro-3H-oxazolo[3,4-a]pyridin-7-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (2-1) (140 mg, 0.26 mmol) in dioxane / H2O (1 mL / 0.25 mL) was added 4-bromo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (INT-4) (86 mg, 0.3 mmol), K2CO3 (72 mg, 0.52 mmol) and Pd(dppf)Cl2(38 mg, 0.05 mmol). The reaction mixture was stirred at 100 ℃ for 3 h. The resulting mixture was diluted with H2O (2 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated Attorney Docket No.71180-423434 (ASP-071WO) under reduced pressure. The resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 100 / 1-10 / 1 (v / v)) to afford N-(4-chlorobenzyl)-2-fluoro-5-((7S,8aS)- 3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yloxy)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)benzamide (2-2) (65 mg, 41%) as a yellow oil. MS (ESI): calcd. for C30H36ClFN4O5Si: 614.2; Found: 615.1 [M + 1]+. Step 3. Synthesis of N-(4-chlorobenzyl)-2-fluoro-4-(1H-imidazol-4-yl)-5-((7S,8aS)-3- oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yloxy)benzamide (Example 3). To a stirred solution of N-(4-chlorobenzyl)-2-fluoro-5-((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin- 7-yloxy)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzamide (2-2) (65 mg, 0.1 mmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was basified with 1N aq. NaOH solution and extracted with DCM (2 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by prep-HPLC to afford N-(4-chlorobenzyl)-2-fluoro-4-(1H-imidazol-4-yl)-5-((7S,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yloxy)benzamide (Example 2) (15 mg, 31%) as a red oil. MS (ESI): calcd. for C24H22ClFN4O4: 484.1; Found:485.1 [M+ 1]+;1H NMR (400 MHz, DMSO-d6): δ 12.24 (s, 1 H), 8.79 ‒ 8.77 (m, 1H), 7.88 ‒ 7.86 (m, 1H), 7.79 (s, 1H), 7.67 (s, 1 H), 7.42 ‒ 7.33 (m, 5H), 5.07 (s, 1H), 4.46 (d, J = 6 Hz,, 2 H), 4.36 (t, J = 8 Hz, 1 H), 3.98 ‒ 3.88 (m, 2H), 3.63 ‒ 3.59 (m, 1H), 3.18 ‒ 3.10 (m, 1H), 2.23 ‒ 2.19 (m, 1H), 2.01 ‒ 1.98 (m, 1H), 1.17 ‒ 1.67 (m, 2H) ppm. Synthesis of N-(4-chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)-5-((7S,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yloxy)benzamide (Example 3)

[0002] Attorney Docket No.71180-423434 (ASP-071WO) dihydroxybenzene (3-1) (5.74 g, 28.3 mmol) and K2CO3(25.4 g, 184 mmol) in dry acetone (420 mL) was stirred at room temperature for 30 min. To the mixture was added TsCl (5.40 g, 28.3 mmol). The resulting mixture was refluxed for 23 h followed by addition of iodomethane (10.9 g, 76.8 mmol). The mixture was refluxed for 28 h. After cooling, the resulting precipitate was filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with hexanes / ethyl acetate (30 / 1 (v / v)), to give methyl 2-methoxy-5- (tosyloxy)benzoate (3-2) (8.86 g, 84%) as a solid. MS (ESI): calcd. for C16H16O6S: 336.1; Found: 337.1 [M + 1]+. Step 2. Synthesis of 5-hydroxy-2-methoxybenzoic acid (3-3). Tosylate (3-2) (8.85 g, 23.8 mmol) was boiled with KOH (3.00 g) in a mixture of ethanol (150 mL) and water (150 mL) for 16 h. After the ethanol was evaporated, the aqueous solution was acidified with acetic acid. The resulting mixture was extracted with diethyl ether (30 mL x 2). The combined organic layers were washed with 1M aq. NaHCO3 solution and 5% aqueous KOH solution. The aqueous layer was acidified with 6M aq. HCl solution and extracted with diethyl ether (30 mL x 2). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting Attorney Docket No.71180-423434 (ASP-071WO) with hexanes / ethyl acetate (4 / 1 (v / v)), to give 5-hydroxy-2-methoxybenzoic acid (3-3) (4.88 g, 94%) as a white solid, MS (ESI): calcd. for C8H8O4: 168.0; Found: 169.3 [M + 1]+. Step 3. Synthesis of 4-bromo-5-hydroxy-2-methoxybenzoic acid (3-4). 5-hydroxy-2- methoxybenzoic acid (3-3) (1.24 g, 7.40 mmol) was dissolved in acetic acid (30 mL) by heating to 60 ℃. After cooling to room temperature, bromine (0.38 ml, 7.4 mmol) was added dropwise. The reaction mixture was stirred for 3 h and then evaporated under reduced pressure. The resulting residue was purification by column chromatography (AcOH / toluene = 1 / 10 (v / v)) to give 4-bromo-5-hydroxy-2-methoxybenzoic acid (3-4) (1.5 g, 82%). MS (ESI): calcd. for C8H7BrO4: 246.0; Found: 247.1 [M + 1]+. Step 4. Synthesis of 4-bromo-N-(4-chlorobenzyl)-5-hydroxy-2-methoxybenzamide (3-5). To a mixture of 4-bromo-5-hydroxy-2-methoxybenzoic acid (3-4) (600 mg, 2.45 mmol) and DIEA (948 mg, 7.35 mmol) in DMF (10 mL) was added (4-chlorophenyl)methanamine (414 mg, 2.94 mmol) and HATU (1120 mg, 2.94 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with 50-100% EtOAc in hexanes (v / v), to give 4-bromo-N-(4- chlorobenzyl)-5-hydroxy-2-methoxybenzamide (3-5) (600 mg, 67%) as a white solid. MS (ESI): calcd. for C15H13BrClNO3: 369.0; Found: 370.0 [M + 1]+. Step 5. Synthesis of 4-bromo-N-(4-chlorobenzyl)-2-methoxy-5-((7S,8aS)-3-oxohexahydro- 1H-oxazolo[3,4-a]pyridin-7-yloxy)benzamide (3-6). To a stirred mixture of bromo-N-(4- chlorobenzyl)-5-hydroxy-2-methoxybenzamide (3-5) (200 mg, 0.54 mmol) and (7R,8aS)-7- hydroxytetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-1) (114 mg, 0.652 mmol) in dry toluene (5 mL) was added PPh3(283 mg, 1.08 mmol) and DIAD (327 mg, 1.62 mmol). The reaction mixture was allowed to stir at 35 ℃ for 3 h, then diluted with water, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with 0-95% EtOAc in hexanes (v / v), to give 4-bromo-N-(4- chlorobenzyl)-2-methoxy-5-((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7- Attorney Docket No.71180-423434 (ASP-071WO) yloxy)benzamide (3-6) (260 mg, 95%) as a yellow solid. MS (ESI): calcd. for C22H22BrClN2O5: 508.0; Found: 509.0 [M + 1]+. Step 6. Synthesis of N-(4-chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)-5-((7S,8aS)-3- oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yloxy)benzamide (Example 4). To a stirred solution of 4-bromo-N-(4-chlorobenzyl)-2-methoxy-5-((7S,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yloxy)benzamide (3-6) (100 mg, 0.2 mmol) and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (83 mg, 0.236 mmol) in 1,4-dioxane / H2O (2.4 mL / 0.6 mL) was added K2CO3 (54 mg, 0.39 mmol) and Pd(dppf)Cl2 (28 mg, 0.04 mmol). The reaction mixture was stirred at 100 °C overnight. The mixture was quenched with EtOAc (25 mL) and filtered through Celite®545. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with 0 - 6% of MeOH in DCM (v / v), to give N-(4-chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)-5-((7S,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yloxy)benzamide (Example 3) (20 mg, 20%) as a white solid. MS (ESI): calcd. for C25H24ClN3O6: 497.1; Found: 498.1 [M + 1]+;1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.56 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.41 (dd, J = 18.4, 9.2 Hz, 5H), 5.05 (s, 1H), 4.50 (d, J = 5.6 Hz, 2H), 4.40 (t, J = 8.0 Hz, 1H), 3.94 ‒ 3.88 (m, 5H), 3.61 (dd, J = 12.4, 4.8 Hz, 1H), 3.11 (t, J = 12.0 Hz, 1H), 2.20 (d, J = 14.0 Hz, 1H), 1.98 (d, J = 14.4 Hz, 1H), 1.74 ‒ 1.68 (m, 2H) ppm. Synthesis of N-(4-chlorobenzyl)-2-fluoro-4-(oxazol-5-yl)-5-(((7S,8aS)-3-oxohexahydro-3H- oxazolo[3,4-a]pyridin-7-yl)amino)benzamide (Example 4)

[0003] Attorney Docket No.71180-423434 (ASP-071WO) Step 1. Synthesis of N-(4-chlorobenzyl)-2-fluoro-5-hydroxy-4-(oxazol-5-yl)benzamide (4-1). To a stirred mixture of 4-bromo-N-(4-chlorobenzyl)-2-fluoro-5-hydroxybenzamide (1-3) (300 mg, 0.84 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (442 mg, 1.26 mmol) and K2CO3(290 mg, 2.10 mmol) in 1,4-dioxane / H2O (4 mL / 1 mL) was added Pd(dppf)Cl2 (61 mg, 0.08 mmol). The reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (EtOAc / petroleum ether = 0 - 60% (v / v)) to give N-(4-chlorobenzyl)-2-fluoro-5-hydroxy-4-(oxazol-5-yl)benzamide (5-1) (172 mg, 62%) as a white solid. MS (ESI): calcd. for C17H12ClFN2O3: 346.1; Found: 347.0 [M + 1]+. Step 2. Synthesis of 5-((4-chlorobenzyl)carbamoyl)-4-fluoro-2-(oxazol-5- yl)phenyltrifluoromethanesulfonate (4-2). To a stirred solution of N-(4-chlorobenzyl)-2- fluoro-5-hydroxy-4-(oxazol-5-yl)benzamide (4-1) (172 mg, 0.5 mmol), TEA (152 mg, 1.5 mmol) and DMAP (6 mg, 0.05 mmol) in DMF (3 mL) was added Tf2NPh (266 mg, 0.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with EtOAc / petroleum ether = 0 - 40% (v / v), to give 5-((4-chlorobenzyl)carbamoyl)-4-fluoro-2-(oxazol-5-yl)phenyltrifluoromethanesulfonate (4- 2) (100 mg, 42%) as a white solid. MS (ESI): calcd. for C18H11ClF4N2O5S: 478.0; Found: 479.0 [M + 1]+. Step 3. Synthesis of N-(4-chlorobenzyl)-2-fluoro-4-(oxazol-5-yl)-5-(((7S,8aS)-3- oxohexahydro-3H-oxazolo[3,4-a]pyridin-7-yl)amino)benzamide (Example 5). A mixture of 5-((4-chlorobenzyl)carbamoyl)-4-fluoro-2-(oxazol-5-yl)phenyltrifluoromethanesulfonate (4-2) (100 mg, 0.2 mmol), (7S,8aS)-7-aminohexahydro-3H-oxazolo[3,4-a]pyridin-3-one (INT-2) (65 mg, 0.4 mmol), Cs2CO3(170 mg, 0.5 mmol), Pd2(dba)3(10.8 mg, 0.012 mmol), and Xantphos (12.1 mg, 0.02 mmol) in toluene (3 mL) was stirred at 110 ℃ overnight. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by prep-HPLC to give N-(4-chlorobenzyl)-2-fluoro-4-(oxazol-5-yl)-5- Attorney Docket No.71180-423434 (ASP-071WO) (((7S,8aS)-3-oxohexahydro-3H-oxazolo[3,4-a]pyridin-7-yl)amino)benzamide (Example 4) (30 mg, 31%) as a white solid. MS (ESI): calcd. for C24H22ClFN4O4: 484.1; Found: 484.8 [M + 1]+;1H NMR (400 MHz, DMSO-d6): δ 8.87 (t, J = 2.4 Hz, 1H), 8.55 (s, 1H), 7.74 (s, 1H), 7.46 (d, J = 11.2 Hz, 1H), 7.42 ‒ 7.34 (m, 4H), 7.02 (d, J = 6.4 Hz, 1H), 5.14 (d, J = 4.4 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.37 (t, J = 8.4 Hz, 1H), 4.04 ‒ 4.02 (m, 1H), 3.93 ‒ 3.86 (m, 2H), 3.54 (dd, J = 14.0 Hz, 4.4 Hz, 1H), 3.17 (td, J = 13.2 Hz, 3.2 Hz, 1H), 2.11 ‒ 2.08 (m, 1H), 1.90 (d, J = 14.0 Hz, 1H), 1.68 ‒ 1.56 (m, 2H) ppm. Table 1 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art. Table 1: Representative Examples of the Invention. Example Structure MS1H NMR + ), m, , , , , , , Attorney Docket No.71180-423434 (ASP-071WO) 7.47 (d, J = 3.0 Hz, 1H), 7.38-7.32 (m, 4H), 5.07 6 m, 6 2 9 Attorney Docket No.71180-423434 (ASP-071WO) 2H), 7.38 – 7.34 (m, 2H), 7.31 (d, J = 6.4 Hz, 1H), , , - ),

[0004] Attorney Docket No.71180-423434 (ASP-071WO) 499.01H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 2 m, , J .8 Attorney Docket No.71180-423434 (ASP-071WO) 7.59 (s, 1H), 7.53 (d, J = 12.4 Hz, 1H), 7.31 (t, J = z, , , , Attorney Docket No.71180-423434 (ASP-071WO) 495.01H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), m, m, ), s, , Attorney Docket No.71180-423434 (ASP-071WO) 3H), 7.45 (d, J = 6.0 Hz, 1H), 7.37-7.32 (m, 4H), , 1 ), H) m, m, , , Attorney Docket No.71180-423434 (ASP-071WO) 7.49 (d, J = 4.0 Hz, 1H), 7.38-7.33 (m, 4H), 5.10 m, = z, , 9 - Attorney Docket No.71180-423434 (ASP-071WO) 7.35 (m, 5H), 5.10 (s, 1H), 4.46 (d, J = 2.8 Hz, 2H), = J m, 6 = Attorney Docket No.71180-423434 (ASP-071WO) (m, 1H), 8.11 (d, J = 10.4 Hz, 1H), 7.55 (d, J = 5.6 m, = (t, - , , Attorney Docket No.71180-423434 (ASP-071WO) 6.31 (d, J = 14.8 Hz, 1H), 4.87 (brs, 1H), 4.61-4.58 4 ), 1 2 s, Attorney Docket No.71180-423434 (ASP-071WO) 7.63 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.36-7.31 (m, s, Attorney Docket No.71180-423434 (ASP-071WO) 5.6 Hz, 2H), 4.42 (t, J = 8.0 Hz, 1H), 4.15-4.12 (m, 6 s, , , , , z, , = = = z, Attorney Docket No.71180-423434 (ASP-071WO) 5.32 (s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 4.40 (t, J = , = , m, m, Attorney Docket No.71180-423434 (ASP-071WO) 7.48 (m, 2H), 7.44-7.37 (m, 4H), 5.32 (brs, 1H), 6 = , 6 - 6 Attorney Docket No.71180-423434 (ASP-071WO) (d, J = 6.0Hz, 2H), 4.39 (t, J = 8.4, 8.0Hz, 1H), 4.02- , m, ), , s, Attorney Docket No.71180-423434 (ASP-071WO) 3.90 (m, 1H), 3.49-3.53 (m, 1H), 3.22-3.29 (m, ), , = m, 6 = = 2 Attorney Docket No.71180-423434 (ASP-071WO) 3.94-3.90 (m, 1H), 3.67- 3.62 (m, 1H), 3.34-3.31 = m, , ), , = , , s, ), Attorney Docket No.71180-423434 (ASP-071WO) 3.92-3.85 (m, 5H), 3.57- 3.51 (m, 1H), 3.08-3.00 = , - ), ), Attorney Docket No.71180-423434 (ASP-071WO) 3.22 (m, 1H), 2.49 (s, 3H), 2.21-2.15 (m, 1H), 1.99- m, , ), - ), , , Attorney Docket No.71180-423434 (ASP-071WO) (m, 1H), 1.86-1.73 (m, 2H) ppm. , m, , J ), s, , , ), ), z, .2 Attorney Docket No.71180-423434 (ASP-071WO) 1.90 (m, 1H), 1.78-1.67 (m, 2H) ppm , , t, s, t, 2 Attorney Docket No.71180-423434 (ASP-071WO) 564.21H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H), , t, ), m, ), ), Attorney Docket No.71180-423434 (ASP-071WO) 5021H NMR (400 MHz, DMSO-d6): δ 8.55 (t, J = m, , ), 7 9- m, Attorney Docket No.71180-423434 (ASP-071WO) 5361H NMR (400 MHz, DMSO-d6): δ 9.02-8.99 5 6- ), m, , 6, m, = Attorney Docket No.71180-423434 (ASP-071WO) 3.6 Hz, 1H), 8.59 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = = ), , , J ), Attorney Docket No.71180-423434 (ASP-071WO) 1H), 7.78 (d, J = 10.4 Hz, 1H), 7.58 (t, J = 6.4 Hz, t, , = , ), ), 3 , , Attorney Docket No.71180-423434 (ASP-071WO) 556.11H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), = ), ), , z, , , .3 Attorney Docket No.71180-423434 (ASP-071WO) 484.21H NMR (600 MHz, [M-1]- DMSO-d6) δ 8.95 – 8.85 6 , J J z, = ), , , 5 8 5 Attorney Docket No.71180-423434 (ASP-071WO) 492.31H NMR (300 MHz , , , ), , , , 5 4 Attorney Docket No.71180-423434 (ASP-071WO) 488.11H NMR (300 MHz, N CD3OD) δ 8.36 (s, 1H), = 9 – ), 7 7 z, s, , , Attorney Docket No.71180-423434 (ASP-071WO) 590.21H NMR (300 MHz, DMSO-d6) δ 8.89 (t, J = , , 7 – , , , , 9 – , Attorney Docket No.71180-423434 (ASP-071WO) 4891H NMR (400 MHz, DMSO-d6): δ 8.99 – 8.90 5 ), 3 ), Attorney Docket No.71180-423434 (ASP-071WO) 534.21H NMR (400 MHz, CD3OD): δ 8.63 (m, 1H), 0 , , J , z, 3 7 Attorney Docket No.71180-423434 (ASP-071WO) 5071H NMR (400 MHz, DMSO-d6): δ 9.06 (m, , , J = , 1 0 4 , , J 0 7 Attorney Docket No.71180-423434 (ASP-071WO) 5431H NMR (400 MHz, DMSO-d6): δ 9.05 (m, ), , ), , = , 4 6 Attorney Docket No.71180-423434 (ASP-071WO) 1H), 8.78 (d, J = 7.6 z, 1H), 8.78 (t, J = 2.4 Hz, , , , z, .2 1 4 , , Attorney Docket No.71180-423434 (ASP-071WO) 518.21H NMR (400 MHz, DMSO-d6): δ 9.18 (t, J = , ), 6 4 , , J .8 4 Attorney Docket No.71180-423434 (ASP-071WO) 1.74 (m, 1H), 1.72 (s, 6H) ppm , m, 8 m, , = d, = Attorney Docket No.71180-423434 (ASP-071WO) 476.31H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), , , , , , , s, z, , , , Attorney Docket No.71180-423434 (ASP-071WO) 1.73 (m, 1H), 1.69 (d, J = 6.4 Hz, 3H) ppm , , ), d, , , ), Attorney Docket No.71180-423434 (ASP-071WO) (td, J = 13.2, 2.8 Hz, 1H), 2.22 (m, 1H), 2.00 (m, , ), ), 3 8 d, , ), Attorney Docket No.71180-423434 (ASP-071WO) 578.11H NMR (400 MHz, DMSO-d6): δ 9.97 (m, d, , J 7 , s, , ), 4 4 Attorney Docket No.71180-423434 (ASP-071WO) 5551H NMR (400 MHz, DMSO-d6): δ 9.56 (t, J = , , 1 (t, = , , , 1 (t, , Attorney Docket No.71180-423434 (ASP-071WO) 1H), 1.97 (d, J = 13.6 Hz, 1H), 1.80 – 1.70 (m, 2H), , = ), , , = ), , , t, Attorney Docket No.71180-423434 (ASP-071WO) (m, 1H), 1.76 – 1.69 (m, 2H) ppm = ), , ), , , 2 9 Attorney Docket No.71180-423434 (ASP-071WO) 5301H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 8 , z, = = , , ), = = = Attorney Docket No.71180-423434 (ASP-071WO) 540.31H NMR (400 MHz, DMSO-d6): δ 8.76 (t, J = , , , ), ), 6 5 , 7 – ), , m, Attorney Docket No.71180-423434 (ASP-071WO) 5681H NMR (400 MHz, DMSO-d6): δ 8.91 (t, J = , , J J ) s, , , Attorney Docket No.71180-423434 (ASP-071WO) 5011H NMR (400 MHz, CDCl3): δ 7.89 (d, J = = ), – = – z, , Attorney Docket No.71180-423434 (ASP-071WO) 545.21H NMR (400 MHz, DMSO-d6): δ 8.89 (s, , ), , , , ), 0 , , Attorney Docket No.71180-423434 (ASP-071WO) 531.21H NMR (400 MHz, CD3OD): δ 7.77 (d, J = = ), , , ), , 8 0 Attorney Docket No.71180-423434 (ASP-071WO) 522.21H NMR (400 MHz, DMSO-d6): δ 8.85 (m, , = , , ), ), , , Attorney Docket No.71180-423434 (ASP-071WO) 5221H NMR (400 MHz, DMSO-d6): δ 9.14 (t, J = ), = , = , , , = = , , Attorney Docket No.71180-423434 (ASP-071WO) 1.54 (d, J = 6.8 Hz, 3H) ppm = 5 = = , , 9 ), Attorney Docket No.71180-423434 (ASP-071WO) 544.31H NMR (400 MHz, DMSO-d6): δ 9.05 (m, , , 9 ), 2 , = Attorney Docket No.71180-423434 (ASP-071WO) 5231H NMR (400 MHz, DMSO-d6): δ 8.94 (m, , ), ), = , , Attorney Docket No.71180-423434 (ASP-071WO) 570.91H NMR (400 MHz, DMSO-d6): δ 9.07 (m, , , 7 – , , m, Attorney Docket No.71180-423434 (ASP-071WO) 586.41H NMR (400 MHz, DMSO-d6): δ 9.05 (m, , , ), 1 , , , Attorney Docket No.71180-423434 (ASP-071WO) 529.31H NMR (400 MHz, DMSO-d6): δ 8.93 (m, ), m, = ), , 5 , d, Attorney Docket No.71180-423434 (ASP-071WO) 2H), 4.36 (t, J = 8.0 Hz, 1H), 3.99 (m, 1H), 3.97 (s, , , , d, , ), 4

[0005] Attorney Docket No.71180-423434 (ASP-071WO) 536.2 H NMR (400 MHz, DMSO-d6): δ 8.98 (d, J = , , = = = , J 6 z, , Attorney Docket No.71180-423434 (ASP-071WO) 3.22 (s, 2H), 2.28 (d, J = 13.6 Hz, 1H), 2.11 (d, J = 5 7 4 9 , , z, , , Attorney Docket No.71180-423434 (ASP-071WO) 1.91 (d, J = 14.4 Hz, 1H), 1.72 – 1.61 (m, 2H) ppm , m , , 5 Attorney Docket No.71180-423434 (ASP-071WO) 588.01H NMR (400 MHz, CDCl3): δ 8.03 (m, 1H), , = ), ), , s, ) Attorney Docket No.71180-423434 (ASP-071WO) 5171H NMR (400 MHz, DMSO-d6): δ 8.32 (q, J = 2 , ), , , , 1 2 Attorney Docket No.71180-423434 (ASP-071WO) = 13.2, 5.2 Hz, 1H), 3.12 (td, J = 13.2, 3.2 Hz, 1H), 1 2 , ), , , , Attorney Docket No.71180-423434 (ASP-071WO) 138 5571H NMR (400 MHz, DMSO-d6): δ 8.90 (t, J = , z, d, , – ), 6 2 Biological Data Cell culture MRC-5 fibroblast cells were cultured in Eagle’s Minimum Essential Medium (MEM) supplemented with 1.5 g / L sodium bicarbonate, non-essential amino acids, 292 mg / L L- glutamine, 110 mg / L sodium pyruvate,10% fetal bovine serum and 100 units / mL penicillin and streptomycin. The cells are incubated at 37°C and 5% CO2 and passaged 2-3 times per week to maintain sub-confluent densities. Assay AD-169 HCMV antiviral assay MRC-5 cells were seeded into transparent 96-well plates at a density of 5.0 × 103cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (MEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 4-fold serial dilution format. The DMSO concentration was Attorney Docket No.71180-423434 (ASP-071WO) normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing a 1:200 dilution of an HCMV stock (1.6 x 107TCID50 / mL) was added to the cells for a final dilution of 1:400 and incubated at 37⁰C for 7 days. After the incubation, 10 uL of WST-1 was added to each well and incubated for 4 hours at 37°C. The absorbance was then measured at a wavelength of 450 nm using a Tecan Infinite M1000 Pro plate reader and the cytopathic effect (CPE) was then quantified relative to the full inhibition achieved with 0.5 uM of Letermovir. Cell culture Vero cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and 100 units / mL penicillin and streptomycin. The cells were passaged 2-3 times per week to maintain sub-confluent densities. Assays HSV-1 antiviral assay Vero cells were seeded into 96-well plates at a density of 2.5 × 103cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing 80 TCID50HSV-1 was added to the cells and incubated at 37⁰C for 4 days. After the incubation, the plates were equilibrated to room temperature, the media was removed, and 60 of a 1:1 dilution of Cell titer glow and phosphate buffered saline was added to the cells. Following a 5-minute incubation, cell viability was quantified by measuring luminance using a Tecan Infinite M1000 Pro plate reader. HSV-2 antiviral assay Vero cells were seeded into 96-well plates at a density of 1.0 × 104cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds Attorney Docket No.71180-423434 (ASP-071WO) to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing 160 TCID50 HSV-2 G strain was added to the cells and incubated at 37⁰C for 5 days. After the incubation, 10 µL / well of WST-8 chromogenic reagent was added and the plates incubated at 37⁰C for 3 hours. Following the incubation, cell viability was quantified by measuring the absorbance at 460 nm and 620 nm using a Tecan Infinite M1000 Pro plate reader. Table 2 provides antiviral activity for exemplified compounds of the invention grouped in the following ranges: A indicates EC50 < 100 nM; B indicates 100 ≤ EC50 < 500 nM; C indicates EC50 ≥ 500 nM. Table 2: Biological assay data for representative Compounds of the invention Example CMV (mM) HSV-2 (mM) Attorney Docket No.71180-423434 (ASP-071WO) A C A A Attorney Docket No.71180-423434 (ASP-071WO) A B A B Attorney Docket No.71180-423434 (ASP-071WO) 109 A C 110 A C EQUIVALENTS While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. Attorney Docket No.71180-423434 (ASP-071WO) Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

Attorney Docket No.71180-423434 (ASP-071WO) CLAIMS:

1. A compound of Formula I Formula I or aL is -O- or -NH-; Ra, Rband Rcare independently selected for each occurrence from the group consisting of hydrogen and C1-6alkyl; or Raand Rbtogether with the N atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group; Rdand Reare independently selected from the group consisting of hydrogen and C1-6alkyl; or Reand Retogether with the N atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group, wherein the azetidinyl, pyrrolidinyl or piperidinyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, OH, NH2, C1-4alkyl, hydroxyC1-4alkyl, and C1-4alkoxy; R1is independently selected for each occurrence from the group consisting of halo, CN, C1-4alkyl and haloC1-4alkyl; R2is hydrogen, halo, OH, C1-4alkyloxy-, hydroxyC1-4alkyloxy-, RaRbNC1-6alkoxy-, or oxetanyl-O-, wherein the oxetanyl-O- is optionally substituted with C1-4alkyl;Attorney Docket No.71180-423434 (ASP-071WO) ,halo, OH, CN, RdReN-, C1-6alkyl, C3-6monocycloalkyl-, HOC(O)alkyl, haloC1-6alkyl-, hydroxyC1-6alkyl-, RaRbNC1-6alkyl-, RaRbNhydroxyC1-6alkyl-, C1-6alkoxy-, haloC1-6alkoxy, hydroxyC1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, haloC1-6alkoxyC1-6alkyl-, hydroxyC1-6alkoxyC1-6alkyl-, C1-6alkylC(O)-, C1-6alkylS(O)q-, C1-6alkoxyC(O)-, C1-6alkylC(O)O- , C1-6alkylC(O)-C1-6alkylene-, C1-6alkylS(O)q-C1-6alkylene-, C1-6alkylC(O)O-C1-6alkylene-, C3-6monocycloalkyl-O-C1-6alkylene-, and C3-6monocycloalkyl-NRc-C1-6alkylene-; R4bis hydrogen, C1-4alkyl, haloC1-4alkyl, C3-6monocycloalkyl, or oxetanyl; n is 0, 1, 2 or 3; q is independently selected for each occurrence from the group consisting of 0, 1 and 2; v is 0, 1, 2 or 3; w is 0, 1 or 2. and u is 0 or 1.

2. The compound of claim 1, wherein n is 1 and R1is R1a.

3. The compound of claim 2, wherein the compound of Formula I is of Formula Ia:Attorney Docket No.71180-423434 (ASP-071WO) Formula Ia, or a4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1ais Cl.

5. The compound of claim 1, wherein n is 2 and one R1is R1aand one R1is R1b.

6. The compound of claim 5, wherein the compound of Formula I is of Formula Ib: Formula Ibor a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1ais CN and R1bis F.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L is -O-.Attorney Docket No.71180-423434 (ASP-071WO) 9. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2is F.

11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2is OH.

12. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2is C1-6alkoxy.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, .

14. The any one 1-12, or a pharmaceutically acceptablesalt thereof, .

15. A pharmaceutical composition comprising a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15, further comprising one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents, and immunomodulators.

17. A method for the treatment or prophylaxis of a herpes virus infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effectiveAttorney Docket No.71180-423434 (ASP-071WO) amount of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof.

18. A method for the treatment or prophylaxis of a herpes virus infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 16.

19. The method of claim 17 or 18, wherein infection is an HSV-1 infection.

20. The method of claim 17 or 18, wherein infection is an HSV-2 infection.

21. The method of claim 17 or 18, wherein infection is a CMV infection.

22. The compound according to any one of claims 1-14 for use as a medicament.

23. The compound according to any one of claims 1-14 for the use in therapy.

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