Bicyclic heterocycle compounds for treatment of herpes viruses

Abstract

The present disclosure provides bicyclic heterocycle compounds of formula I, pharmaceutical compositions thereof, and methods for the treatment and prophylaxis of herpes viruses.

Description

[0001] BICYCLIC HETEROCYCLE COMPOUNDS FOR TREATMENT OF HERPES

[0002] VIRUSES

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 639,269, filed April 26, 2024, which is incorporated by reference in its entirety.

[0005] BACKGROUND

[0006] 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 (EB V). 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.

[0007] 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 1 and 2 (HSV-1, HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and human herpes viruses 6-8 (HHV6-8). oc-herpes viruses include herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), and varicella- zoster virus (VZV). HSV-1 causes orofacial lesions, commonly known as fever blisters or cold sores. Approximately 30% of the United States population suffers from recurrent episodes of HSV-1. HSV-2, which is less common than HSV-1, causes genital lesions. Primary infection with VZV causes varicella, commonly known as chicken pox. 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 100%. 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.

[0008] 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.

[0009] WO2021127071 relates to novel bicyclic heterocycle compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, X, Y, Z, R1 R5, R6, and R7 are as defined therein. The invention also relates to compositions comprising at least one bicyclic heterocycle compound, and methods of using the bicyclic heterocycle compounds for treating or preventing a herpesvirus infection in a patient.

[0010] 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.

[0011] SUMMARY OF THE INVENTION

[0012] In one aspect, the present disclosure provides a compound of Formula I

[0013] Formula I or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

[0018] Figure 1 illustrates an ORTEP plot for a compound of the present disclosure, Example 54.

[0019] Figure 2 illustrates stereochemistry for a compound of the present disclosure, Example

[0020] 54, based on ORTEP plot assignment.

[0021] Figure 3 illustrates an ORTEP plot for a compound of the present disclosure, Example

[0022] 55.

[0023] Figure 4 illustrates stereochemistry for a compound of the present disclosure, Example 55, based on ORTEP plot assignment. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention is directed to bicyclic heterocycle compounds for treating herpes virus infections. W02020053654 to Novartis discloses pyridopyrazinedione compounds for treating herpes virus infections. WO2021061898 and WO2023154905 to Novartis-Gilead disclose pyrazolopyridinone compounds for treating herpes virus infections. WO2021126902 to Merck discloses amido-substituted pyridyl compounds for treating herpes virus infections.

[0025] WO2022132679 to Merck disclose amido-substituted pyridyl compounds of Formula I for treating a herpes virus infection, wherein R1is an optionally substituted -O-(5 or 6-membered monocyclic heterocycloalkyl) or -O-(9 or 10-membered bicyclic heterocycloalkyl), as defined therein.

[0026] WO2022146755 to Merck disclose amido-substituted pyridyl compounds of Formula I Formula I for treating a herpes virus infection, wherein R1is -O-(C1-C6, alkyl) or an optionally substituted 5 to 7- membered monocyclic heterocycloalkyl, -O-(5 to 7-membered monocyclic heterocycloalkyl), 6 to 10- membered bicyclic heterocycloalkyl or -O-(6 to 10-membered bicyclic heterocycloalkyls), as defined therein.

[0027] WO2021127071 to Merck discloses bicyclic heterocycle compounds of Formula I: Formula I for treating a virus infection, wherein R1is an optionally substituted 5 to 7-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, as defined therein, and the linker A is a bond or -O-. WO2022132679, WO2022146755 and WO2021127071 all disclose similar R1groups that are cither directly attached to the core or attached through an -O- linker. There is no teaching or suggestion for other possible linkers. Starting with Example 37 from WO2021127071, Applicants made and tested several analogs, according to procedures described herein, with different one-atom replacement linkers to the R1substituent. CMV EC50 and human liver microsome stability assay results are shown below in TABLE A (data was acquired using assays described herein).

[0028] TABLE A: Comparison Data for Analogs of Example 37 of W02021127071 with Different Linkers

[0029] Of the compounds tested, only Reference Compound A with a -S- linker and Reference Compound E with a -NH- linker maintained biological activity in the CMV assay. However, Reference compound A was unstable in the human liver microsome stability assay, with only 10% remaining after 45 minutes, the remainder possibly converted to the inactive -SO- and -SO2- analogs. In contrast, Reference Compound E not only matched the CMV activity of Example 37 of WO2021127071 but was more stable in the human liver microsome stability assay, while the -N(CH3)- analog was inactive. Thus, Applicants have surprisingly discovered that only -NH- offers a viable alternative to the known -O- linker.

[0030] While WO2021127071 does not exemplify any compounds with a thiazole moiety as does the present application, Applicants have observed the same trend for CMV biological activity for thiazole analogs with different linkers, as shown in TABLE B.

[0031] TABLE B: Comparison Data for Analogs of a Compound of the Invention with Different Linkers

[0032] While investigating the structure activity relationships for the presently claimed genus, Applicants further discovered that potential clinical compounds preferably demonstrate not only substantial biological activity in a herpes virus assay (e.g., a CMV assay) but are also chemically and metabolically stable with minimal hERG liability. TABLE C shows comparison data for three compounds from WO2021127071, all having an -O- linker, versus Example 55 of the presentation invention having a -NH-linker.

[0033]

[0034] Example 51 Example 16 Example 82 of WO2021127071 of WO2021127071 of WO2021127071

[0035] TABLE B: Comparison Data for Three Compounds of W02021127071 versus Example 55 of the Present Invention

[0036] Given the data provided above in TABLE A and TABLE B, it is surprising that Example 55 of the present invention, with its -NH- linker, has comparable biological activity in the CMV assay with these three compounds from W02021127071, all having an -O- linker. More surprisingly, compared to these three compounds, Example 55 of the present invention has significantly less hERG liability and is significantly more metabolically stable in liver microsomes across the species tested.

[0037] 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.

[0038] I. Definitions

[0039] The term “carbonyl” as used herein refers to the biradical -C(O)-. The term “cyano” as used herein refers to the radical -CN.

[0040] The terms “halo” or “halogen” as used herein refer to the radicals F, Cl, Br or I.

[0041] The terms “hydroxy” and “hydroxyl” as used herein refer to the -OH radical.

[0042] 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.

[0043] 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 C1-6alkyl and C1-4alkyl, 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.

[0044] The term “alkylene” as used herein refers to a saturated straight or branched hydrocarbon biradical.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] The term “cyanoalkyl” as used herein refers to an alkyl group substituted with one to three CN groups.

[0049] The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halo groups. For example, halo C1-6alkyl 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, -CHCI2, -CHF2, -CF3, CF3CH2-, CH3CF2-, CF3CC12- and CF3CF2-.

[0050] The term “haloalkylene” as used herein refers to an alkylene group substituted with one or more halo groups.

[0051] The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halo groups. Examples include, but are not limited to, CC13O-, CF3O-, CHF2O-CF3CH2O-, and CF3CF2O-.

[0052] The term “haloalkoxyalkyl” as used herein refers to an alkyl group substituted with a haloalkoxy group.

[0053] The term “halohydroxy alkyl” as used herein refers to an alkyl group substituted with one to three hydroxy groups and one or more halo groups.

[0054] The term “hydroxy alkyl” 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-.

[0055] The term “hydroxy alkylene” as used herein refers to an alkylene group substituted with one to three hydroxy groups.

[0056] The term “hydroxy alkenyl” as used herein refers to an alkenyl group substituted with one to three hydroxy groups.

[0057] The term “hydroxyalkynyl” as used herein refers to an alkynyl group substituted with one to three hydroxy groups.

[0058] 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 “RaRbN C1-6alkyl-,” as used herein refers to an alkyl group substituted with one to three RaRbN- groups, as defined herein. Examples include but arc not limited to NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2- and CH3CH(NH2)CH2-.

[0059] 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.

[0060] The term “RaRbNC1-6alkoxy,” as used herein refers to an alkoxy group substituted with one to three RaRbN- groups, as defined herein. Examples include but are not limited to NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0061] The term “cycloalkyl” 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.

[0062] The term “coinfection” as used herein refers to simultaneous infection of a host by more than one viral pathogen.

[0063] 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, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.

[0064] The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0065] The term “pharmaceutically acceptable” includes 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 Biologies 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.

[0066] 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.

[0067] 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--- 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 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.

[0068] 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 arc 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.

[0069] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating a viral infection that results in the improvement of the disease.

[0070] 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.

[0071] 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 arc 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 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.

[0072] 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 depicting 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 arc designated “cis / trans.”

[0073] 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 example, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0074] All isomeric forms (especially all regio- and stereoisomeric forms, e.g. all chiral, enantiomeric, diastereomeric, racemic forms, tautomeric and all geometric isomeric forms, as 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.

[0075] 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 arc 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,18P, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0076] 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.

[0077] 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 upon transit of the intestine, blood, or liver). Prodrugs are well known in the ait (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).

[0078] Bicyclic Heterocycle Compounds

[0079] In one aspect, the present invention provides a compound of Formula I:

[0080] Formula I of a pharmaceutically acceptable salt thereof, wherein:

[0081] L is -C1-4alkylene- or a bond;

[0082] X1is independently selected for each occurrence from the group consisting of O and S;

[0083] 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;

[0084] Rdand Reare independently selected for each occurrence from the group consisting of hydrogen, C1-6alkyl, and C1-6alkoxyC1-6alkyl-; or Rdand Retogether with the N atom to which they are attached form an azetidinyl, pyrrolidiyl, piperidinyl or dioxazinanyl 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, and C1-4alkyl; or Rdis Rcand Reis R5;

[0085] Rxis independently selected for each occurrence from the group consisting of hydrogen, OH, C1-4alkyl and C1-4alkoxy-;

[0086] R1is independently selected for each occurrence from the group consisting of halo, CN, C1-4alkyl and haloC1-4alkyl;

[0087] R2is hydrogen, OH, RaRbN-, C1-6alkyl, C3-6monocycloalkyl-, cyanoC1-6alkyl-, hydroxyC1-6alkyl-, RaRbN C1-6alkyl-, C1-6alkyloxy-, C1-6alkoxyC1-6alkyl-, RaRbNhydroxyC1- ealkyl-, RaRbNC(O)-C1-6alkyene-, C1-6alkylC(O)-C1-6alkylene-, C1-6alkylS(O)q-C1-6alkylene-, or C1-6alkylC(O)O-C1-6alkylcnc- ;

[0088]

[0089] R4and R4aare independently selected for each occurrence from the group consisting of halo, OH, CN, RaRbN-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6monocycloalkyl-, cyanoC1-6alkyl, haloC1-6alkyl-, hydroxyC1-6alkyl-, hydroxyC2-6alkenyl-, hydroxyC2-6alkynyl-, halohydroxyC1-6alkyl-, RaRbNC1-6alkyl-, RaRbNhydroxyC1-6alkyl-, RdRbNC1-6alkyl-NRc-, C1-6alkoxy-, haloC1- 6 alkoxy. hydroxyC1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, haloC1-6alkoxy-C1-6alkyl-, hydroxyC1-6alkoxy-C1-6alkylene-, HC(O)-, RdReNC(O)-, RdReNS(O)q-, C1-6alkylC(O)-, C1-6alkylS(O)q-, RaRbNC(O)-C1-6alkylene-, RaRbNC(O)-haloC1-6alkylene-, C1-6alkoxyC(O)-, C1-6alkylC(O)O-, C1-6alkylS(O)q-NRc-, C1-6alkylC(O)-C1-6alkylene-, C1-6alkylS(O)q-C1-6alkylene-, C1-6alkylC(O)O-C1-6alkylene-, C1-6alkylC(=NRx)-, RaRbNC(=NRx)-, C1-6alkoxyC(O)NRc-, C1-6alkoxyC(O)NRc-C1-6alkylene-, C1-6alkoxyC(O)NRc-hydroxyC1-6alkylene- and -L-R6;

[0090] R4bis hydrogen or C1-4alkyl; R5and R6are independently selected for each occurrence from the group consisting of:

[0091]

[0092] R7is independently selected for each occurrence from the group consisting of halo, CN, OH and RaRbN-;

[0093] R7ais independently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl; n is 0, 1, 2 or 3; q is independently selected for each occurrence from the group consisting of 0, 1 and 2; t is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3; v is 0, 1, 2 or 3; w is 0, 1 or 2. and u is 0 or 1.

[0094] 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.

[0095] In certain embodiments, n is 1 and R1is R1a.

[0096] In certain embodiments, the compound of Formula I is of Formula la:

[0097] Formula la, or a pharmaceutically acceptable salt thereof.

[0098] In certain embodiments, R1ais Cl.

[0099] In certain embodiments, R1ais CN.

[0100] In certain embodiments, n is 2 and one R1is R1aand one R1is R1b.

[0101] In certain embodiments, the compound of Formula I is of Formula lb: Formula lb or a pharmaceutically acceptable salt thereof.

[0102] In certain embodiments, R1ais CN and R1bis F.

[0103] In certain embodiments, R2is hydrogen. In certain embodiments, R2is C1-4alkyl.

[0104] In certain embodiments, R2is methyl.

[0105] In certain embodiments, R3is

[0106] In certain embodiments, R3is Methods of Use

[0107] 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.

[0108] 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.

[0109] 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 Compounds 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.

[0110] 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.

[0111] In another embodiment, the herpesvirus being treated or prevented is of the family a- herpesviridae. Herpesviruses of the family a-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).

[0112] In another embodiment, the herpesvirus being treated or prevented is of the family P - herpesviridae. Herpesviruses of the family P -herpesviridae include, but are not limited to, 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 y- herpesviridae. Herpesviruses of the family y-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).

[0113] In another embodiment, the herpesvirus being treated or prevented is HSV-1.

[0114] In another embodiment, the herpesvirus being treated or prevented is HSV-2.

[0115] In another embodiment, the herpesvirus being treated or prevented is VZV.

[0116] In another embodiment, the herpesvirus being treated or prevented is CMV.

[0117] In another embodiment, the herpesvirus being treated or prevented is HHV4.

[0118] In another embodiment, the herpesvirus being treated or prevented is HHV6.

[0119] In another embodiment, the herpesvirus being treated or prevented is HHV7.

[0120] In another embodiment, the herpesvirus being treated or prevented is EBV.

[0121] In another embodiment, the herpesvirus being treated or prevented is KSHV.

[0122] In another embodiment, the amount administered is effective to treat or prevent infection by herpesvirus in the patient.

[0123] In another embodiment, the amount administered is effective to inhibit herpesvirus viral replication and / or viral production in the patient.

[0124] 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.

[0125] Combination Therapy

[0126] In another aspect, the present methods for treating or preventing herpesvirus infection can further comprise the administration of one or more additional therapeutic agents which are not Compounds of the invention.

[0127] In one embodiment, the additional therapeutic agent is an antiviral agent.

[0128] In another embodiment, the additional therapeutic agent is an anti-herpes agent.

[0129] 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 foscarnct; CMV tcrminasc inhibitors, such as Ictcrmovir; viral kinase inhibitors, such as maribavir; and helicase-primase inhibitors, such as pritelivir (AIC-316), and amenamevir (ASP- 2151).

[0130] 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).

[0131] 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.

[0132] 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).

[0133] 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 effect, or vice versa.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] In another 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.

[0138] The at least one Compound of the invention and the additional therapeutic agent(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.

[0139] In one embodiment, the administration of at least one Compound of the invention and the additional therapeutic agcnt(s) may inhibit the resistance of a herpesvirus infection to these agents.

[0140] 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 simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This is 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. Tn 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.

[0141] Compositions and Administration

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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 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.

[0146] 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.

[0147] Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral or intravenous injection.

[0148] 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.

[0149] 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.

[0150] 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 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.

[0151] In one embodiment, the one or more Compounds of the invention are administered orally. Tn another embodiment, the one or more Compounds of the invention are administered intravenously.

[0152] In another embodiment, the one or more Compounds of the invention are administered sublingually.

[0153] 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.

[0154] 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.

[0155] 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 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] Examples

[0161] 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 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.

[0162] At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure.

[0163] Abbreviations:

[0164] AcOH Acetic acid ACN Acetonitrile BMS Borane dimethyl sulfide Boc2O Di-tert-butyl dicarbonate DCM Dichloromethane DIEA Diisopropyl ethylamine DMF N,N-Dimethylformamide DMAP 4-Dimethylaminopyridine DMSO Dimethyl sulfoxide Dppf 1 , 1 '-Ferrocenediyl-bis(diphenylphosphine) EA, EtOAc Ethyl acetate Et3N Triethylamine HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium h, hr Hour(s) HPLC High performance liquid chromatography LiHMDS Lithium bis(trimethylsilyl)amide LCMS Liquid chromatography-mass spectrometry MCPBA meta-Chloroperoxybenzoic acid MeOH Methanol NMP N-Methyl-2-pyrrolidone PE Petroleum ether rt, r.t. Room temperature SEMC1 2-(Trimethylsilyl)ethoxymethyl chloride SFC Supercritical Fluid Chromatography TBAF Tetrabutylammonium fluoride TEA Triethylamine TMSC1 Trimethylsilyl chloride TFA Trifluoroacetic acid

[0165] THF Tetrahydrofuran

[0166] TLC Thin-layer chromatography

[0167] TsCI p-Toluenesulfonyl chloride

[0168] Preparation of Intermediates:

[0169] Synthesis of (7R,8aS)-7-hydroxytetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-1)

[0170] Step 1. Synthesis of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic 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 (IM 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 then acidified with IN aq. HC1 solution to pH - 5 and extracted with DCM (40 mL x 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (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]+.

[0171] 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 BMS (IM 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, filtered, concentrated in vacuo to afford (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): ealed. for C11H21NO4: 231.2; Found: 176.2 [M- 55]+.

[0172] Step 3. Synthesis of (7R,8aS)-7-hydroxytetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (1- 4). 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 column chromatography to afford (7R,8aS)-7-hydroxytetrahydro-1H-oxazolo[3,4-a]pyridin- 3(5H)-one (1-4) (1 g, 31% for 3 steps) as a white solid. MS (ESI): ealed. for C7H11NO3: 157.1; Found: 158.3 [M + 1]+.

[0173] Step 4. Synthesis of (7R,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl-4- methylbenzenesulfonate (1-5). To a stirred solution of (7R,8aS)-7-hydroxyhexahydro-3H- oxazolo[3,4-a]pyridin-3-one (1-4) (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, concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting with 70% EA in PE to afford (7R,8aS)-3-oxohexahydro-1H- oxazolo[3,4-a]pyridin-7-yl-4-methylbenzenesulfonate (1-5) (3.6 g, 61%) as a yellow oil. MS (ESI): ealed. for C14H17NO5S: 311.08; Found: 329.2 [M + 18]+.

[0174] Step 5. Synthesis of (7S,8aS)-7-azidotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (1-6).

[0175] To a stirred solution of (7R,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl-4- methylbenzenesulfonate (1-5) (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 EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo to afford (7S,8aS)-7-azidotetrahydro-1H- oxazolo[3,4-a]pyridin-3(5H)-one (1-6) (2.6 g, >99%) as a yellow oil. MS (ESI): ealed. for C7H10N4O2: 182.08; Found: 183.2 [M + 1]+.

[0176] Step 6. Synthesis of (7S,8aS)-7-aminotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT- 1). A mixture of (7S,8aS)-7-azidotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (1-6) (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. The Celite®545 cake was washed with CH3OH (20 mL). The filtrate was concentrated under reduced pressure to afford (7S,8aS)-7-aminotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-1) (2.2 g, >99%) as a colorless oil, which was used for next step without further purification. MS (ESI): ealed. for C7H12N2O2: 156.1; Found: 157.3 [M+ 1]+.

[0177] Synthesis of (7S,8aS)-7-mercaptohexahydro-3H-oxazolo[3,4-a]pyridin-3-one (INT-2)

[0178] Step 1. Synthesis of S-(7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl- ethanethioate (2-1). To a stirred solution of (7R,8aS)-3-oxohexahydro-1H-oxazolo[3,4- aJpyridin-7-yl 4-methylbenzenesulfonate (1-5) (0.8 mg, 2.57 mmol) in DMF (10 mL) was added potassium ethanethioate (0.88 g, 7.7 mmol). The reaction mixture was stirred at 60 °C overnight, quenched with water, and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting with 40% EA in PE to afford S-(7S,8aS)-3- oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl-ethanethioate (2-1) (0.5 g, 90%) as a brown solid. MS (ESI): calcd. for C9H13NO3S: 215.1 ; Found: 216.2 [M+ 1]+.

[0179] Step 2. Synthesis of (7S,8aS)-7-mercaptotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one

[0180] (INT-2). To a stirred solution of S-(7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl ethanethioate (2-1) (125 mg, 0.58 mmol) in methanol (10 mL) was added NaBH4(110 mg, 2.9 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O (40 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting with 40% EA in PE to afford (7S,8aS)- 7-mercaptotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-2) (80 mg, 79%) as a brown oil. MS (ESI): calcd. for C7H11NO2S: 173.1; Found: 174.2 [M + 1]+.

[0181] Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (INT-3)

[0182] Step 1. Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (INT-3). To a stirred solution of 4-bromo-1H-imidazole (3-1) (1 g, 6.8 mmol) in acetone (10 mL) was added K2CO3(2.8 g, 20.4 mmol) and SEMCI (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 EA (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dried in vacuo to afford 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]+.

[0183] Preparation of Representative Compounds of the Invention:

[0184] Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-(trifluoromethyl)thiazol-2- yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 1)

[0185]

[0186] Step 1. Synthesis of 4-bromo-N-[(4-chlorophenyl)methyl]-5-fluoro-2-nitrobenzamide (1-2).

[0187] To a solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (1-1) (10.0 g, 38.0 mmol) in DMF (60 mL) at 0 °C was added (4-chlorophenyl)methanamine (5.9 g, 41.8 mmol), DIEA (9.82 g, 76.1 mmol) and HATU (14.7 g, 45.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (400 mL). The formed precipitate was filtered off, washed with water, and dried to afford 4-bromo-N-(4-chlorobenzyl)-5-fluoro-2- nitrobenzamide (1-2) (11 g, 75%). MS (ESI): calcd. for C14H9BrClFN2O3: 386.0, Found: 386.8 [M + 1]+.

[0188] Step 2. Synthesis of 5-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino- 4-bromo-N-[(4-chlorophenyl)methyl]-2-nitrobenzamide (1-3). To a solution of 4-bromo-N- [(4-chlorophenyl)methyl]-5-fluoro-2-nitrobenzamide (1-2) (5.4 g, 134.0 mmol) in NMP (25 mL) at O °C was added (7S,8aS)-7-amino-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-3-one (INT-1) (2.4 g, 15.4 mmol) and DIEA (3.6 g, 27.9 mmol). The reaction mixture was stirred at 110 °C overnight. The reaction mixture was then cooled and poured into ice-water (250 mL). The formed precipitate was filtered off, washed with water, and dried to afford 5-[(7S,8aS)-3-oxo- hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-4-bromo-N-[(4-chlorophenyl)methyl]-2- nitrobenzamide (1-3) (6.2 g, 84%). MS (ESI): calcd. for C21H20BrClN4O5: 522.0, Found: 523.0 [M + 1]+.

[0189] Step 3. Synthesis of 5-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-

[0190] 2-amino-4-bromo-N-[(4-chlorophenyl)methyl]benzamide (1-4). To a solution of 5-[(7S,8aS)-

[0191] 3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-4-bromo-N-[(4- chlorophenyl)methyl]-2-nitrobenzamide (1-3) (6.2 g, 11.8 mmol) in ethanol (240 mL) was added NH4CI (624.4 mg, 11.8 mmol) in water (40 mL) and concentrated hydrochloric acid (0.3 mL). The resulting mixture was heated to 82 °C and iron powder (16.5 g, 294.5 mmol) was added in portions. The reaction mixture was stimed at reflux for 3 h. After completion of the reaction, NaHCO3(0.5 g) was added. The mixture was filtered and washed with hot methanol (200 mL). The filter was concentrated. The residue was taken into CH2CI2(150 mL) and poured into water (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford 5-[(7S,8aS)-3-oxo-hexahydro-1H-[1,3]oxazolo[3,4-a]pyridin-7-yl]amino-

[0192] 2-amino-4-bromo-N-[(4-chlorophenyl)methyl]benzamide (1-4) (5.1 g, 87%). MS (ESI): calcd. for C21H22BrCIN4O3: 492.1, Found: 493.0 [M + 1]+.

[0193] Step 4. Synthesis of 6-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino- 7-bromo-3-[(4-chlorophenyl)methyl]-2-methyl-3,4-dihydroquinazolin-4-one (1-5). To a stirred mixture of 5-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-2- amino-4-bromo-N-[(4-chlorophenyl)methyl]benzamide (1-4) (850.0 mg, 1.7 mmol) in ethanol (7 mL) and acetic acid (7 mL) was added 1,1,1 -triethoxyethane (836.92 mg, 5.16 mmol). The reaction mixture was stirred at 100 °C for 14 h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography to afford 6-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-7-bromo-3- [(4-chlorophenyl)methyl]-2-methyl-3,4-dihydroquinazolin-4-one (1-5) (580 mg, 65%). MS (ESI): calcd. for C23H22BrClN4O3: 516.1, Found: 517.0 [M + 1]+.

[0194] Step 5. Synthesis of 6-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-

[0195] 3-[(4-chlorophenyl)methyl]-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroquinazolin-4-one (1-6). A suspension of 6-[(7S,8aS)-3-oxo-hexahydro-1H- [l ,3]oxazolo[3,4-a]pyridin-7-yl]amino-7-bromo-3-[(4-chlorophenyl)methyl]-2-methyl-3,4- dihydroquinazolin-4-onc (1-5) (580.0 mg, 1.1 mmol), bis(pinacolato)diboron (2.0 g, 7.8 mmol), potassium acetate (329.4 mg, 3.4 mmol), [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane complex (130.1 mg, 159.8 pmol) in a degassed dioxane (10 mL) was stirred under argon at 100 °C for 2 h. The mixture was then concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with CH2CI2 (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 6-[(7S,8aS)-3- oxo-hexahydro- 1 H- [ 1 ,3]oxazolo[3,4-a]pyridin-7 -yl] amino-3- [(4-chlorophenyl)methyl] -2- methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-4-one (1-6) (300 mg, 47%). ^NMR (400 MHz, DMSO-d6): δ 7.75 (s, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.11 (s, 1H), 6.42 (d, J - 52.2 Hz, 1H), 5.33 (s, 2H), 4.42 (s, 1H), 4.1 - 4.02 (m, 1H), 3.94 - 3.82 (m, 2H), 3.68 (d, J= 15.1 Hz, 1H), 3.07 (d, J= 10.7 Hz, 1H), 2.42 (s, 3H), 2.08 (d, J= 14.6 Hz, 1H), 1.88 - 1.6 (m, 3H), 1.36 (s, 12H) ppm.

[0196] Step 6. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5- (trifluoromethyl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H- oxazolo[3,4-a]pyridin-3-one (Example 1). A mixture of 6-[(7S,8aS)-3-oxo-hexahydro-1H- [1,3]oxazolo[3,4-a]pyridin-7-yl]amino-3-[(4-chlorophenyl)methyl]-2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-4-one (1-6) (1.1 g, 2 mmol), 2- bromo-5-(trifluoromethyl)thiazole (700 mg, 3.0 mmol), K2CO3(3.3 g, 24.0 mmol) and Pd(dppf)Ch (73 mg, 0.1 mmol) in dioxane / H2O (15 mL, 4 / 1) was stirred at 100 °C for 12 h. The reaction mixture was filtered through a celite. The celite cake was washed with EtOAc (10 mL x 2). The filter was concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with 60% EA in PE. The combined fractions were concentrated in vacuo. The resulting residue was recrystallized from acctonitrilc / H2O (7 / 14 mL) to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-(trifluoromethyl)thiazol-2-yl)-3,4- dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 1) as an orange solid (515 mg, 97%). MS (ESI): calcd. for C27H23CIF3N5O3S: 589.1; Found: 590.0 [M + 1]+;1H NMR (400 MHz, CD3OD): 5 8.82 (d, J = 7.2 Hz, 1H), 8.74 (d, J = 1.2 Hz, 1H), 8.07 (s, 1H), 7.41 (m, 3H), 7.23 (m, 2H), 5.35 (s, 2H), 4.37 (m, 1H), 4.23 (m, 1H), 3.95 (m, 2H), 3.67 (dd, J = 14.0, 4.8 Hz, 1H), 3.14 (m, 1H), 2.45 (s, 3H), 2.11 (m, 1H), 1.90 - 1.81 (m, 2H), 1.75 - 1.68 (m, 1H) ppm.

[0197] Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-(2-hydroxyethyl)-4-oxo-7-(5- (ti'ifluoromethyl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4- a]pyridin-3(5H)-one (Example 2)

[0198] Step 1. Synthesis of ethyl 3-((5-bromo-2-((4-chlorobenzyl)carbamoyl)-4-(((7S,8aS)-3- oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl)amino)phenyl)amino)-3-oxopropanoate (2-1).

[0199] A solution of 5-[(7S,8aS)-3-oxo-hexahydro-1H-[l,3]oxazolo[3,4-a]pyridin-7-yl]amino-2-amino- 4-bromo-N-[(4-chlorophenyl)methyl]benzamide (1-4) (2 g, 4.1 mmol) and triethylamine (821 mg, 8.1 mmol) in DCM (35 mL) was added ethyl 3-chloro-3-oxopropanoate (921 mg, 6.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O (30 mL). The aqueous layer was extracted with DCM (30 mL x 2). The combined organic layers were dried over anhydrous Na^SCL, filtered, and concentrated. The resulting residue was purified by column chromatography, eluting with 10% MeOH in DCM to afford ethyl 3-((5- bromo-2-((4-chlorobenzyl)carbamoyl)-4-(((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin- 7-yl)amino)phcnyl)amino)-3-oxopropanoatc (2-1) (1.9 g. 78%) as a white solid. MS (ESI): ealed. for C26H28BrClN4O6: 606.1; Found: 607.0 [M + 1]+.

[0200] Step 2. Synthesis of 4-bromo-N-(4-chlorobenzyl)-2-(3-hydroxypropanamido)-5-(((7S,8aS)- 3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl)amino)benzamide (2-2). A solution of ethyl 3-((5-bromo-2-((4-chlorobenzyl)carbamoyl)-4-(((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4- a]pyridin-7-yl)amino)phenyl)amino)-3-oxopropanoate (2-1) (1.9 g, 3.2 mmol) in MeOH (30 mL) was added NaBH4(1.7 g, 44.8 mmol) slowly at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then quenched with H2O (30 mL). The reaction mixture was extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography, eluting with 5% MeOH in DCM to afford 4-bromo-N-(4-chlorobenzyl)-2-(3-hydroxypropanamido)-5- (((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7-yl)amino)benzamide (2-2) (1.2 g. 66%) as a white solid. MS (ESI): ealed. for C24H26BrClN4O5: 564.1; Found: 565.0 [M + 1]+.

[0201] Step 3. Synthesis of (7S,8aS)-7-((7-bromo-3-(4-chlorobenzyl)-4-oxo-2-(2- ((trimethylsilyl)oxy)ethyl)-3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4- a]pyridin-3(5H)-one (2-3). A solution of 4-bromo-N-(4-chlorobenzyl)-2-(3- hydroxypropanamido)-5-(((7S,8aS)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-7- yl)amino)benzamide (2-2) (1.2 g, 2.1 mmol) in NMP ( 20 mL) was added ZnCl2(8.6 mL, 8.6 mmol) and HMDS (2.08 g, 12.9 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was then cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 3), dried over anhydrous Na2SO4, and concentrated to afford (7S,8aS)-7-((7-bromo-3-(4- chlorobenzyl)-4-oxo-2-(2-((trimethylsilyl)oxy)ethyl)-3,4-dihydroquinazolin-6- yl)amino)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-3) (1.2 g) as a yellow oil, which was used for next step without further purification. MS (ESI): ealed. for C27H32BrClN4O4Si: 618.1; Found: 619.0 [M + 1]+. Step 4. Synthesis of (7S,8aS)-7-((7-bromo-3-(4-chlorobenzyl)-2-(2-hydroxyethyl)-4-oxo-3,4- dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-4). A solution of (7S,8aS)-7-((7-bromo-3-(4-chlorobenzyl)-4-oxo-2-(2-((trimethylsilyl)oxy)ethyl)-3,4- dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-3) (1.2 g, 1.9 mmol) in THF (10 mL) was added TBAF in THF solution (7.5 mL, 7.5 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with aqueous NH4CI (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography, eluting with 10% MeOH in DCM to afford (7S,8aS)-7-((7-bromo-3-(4- chlorobenzyl)-2-(2-hydroxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H- oxazolo[3,4-a]pyridin-3(5H)-one (2-4) (864 mg, 84 %) as a white solid. MS (ESI): calcd. for C24H24BrClN4O4: 546.1; Found: 547.0 [M + 1]+.

[0202] Step 5. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-(2-hydroxyethyl)-4-oxo-7-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H- oxazolo[3,4-a]pyridin-3(5H)-one (2-5). A mixture of (7S,8aS)-7-((7-bromo-3-(4-chlorobenzyl)- 2-(2-hydroxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4- a]pyridin-3(5H)-one (2-4) (864 mg, 1.6 mmol), 4,4,4’,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (402 mg, 15.8 mmol), KO Ac (2.17 g, 22.2 mmol), and Pd(dppf)Cl2(230 mg, 0.3 mmol) in 1,4-dioxane (35 mL) was stirred at 100 °C for 2 h. The reaction mixture was then filtered. The filtrate was concentrated to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2-(2- hydroxyethyl)-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-6- yl)amino)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-5), which was used for next step without further purification. MS (ESI): calcd. for C30H36BCIN4O6: 594.2; Found: 595.2 [M + 1]+.

[0203] Step 6. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-(2-hydroxyethyl)-4-oxo-7-(5- (trifluoromethyl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H- oxazolo[3,4-a]pyridin-3(5H)-one (Example 2). A mixture of (7S,8aS)-7-((3-(4-chlorobenzyl)- 2-(2-hydroxyethyl)-4-oxo-7-(4,4,5 ,5-tetramethyL 1 ,3 ,2-dioxaborolan-2-yl)-3 ,4- dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (2-5) (950 mg, 1.6 mmol), 2-bromo-5-(trifluoromethyl)thiazole (733 mg, 3.2 mmol), K2CO3(654 mg, 4.7 mmol), and Pd(dppf)Ch (230 mg, 0.3 mmol) in 1 ,4-dioxane / H2O (25 mL / 2.5 mL) was stirred at 100 °C overnight. The reaction mixture was filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography, eluting with 10% MeOH in DCM to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2-(2-hydroxyethyl)-4-oxo-7-(5-(trifluoromethyl)thiazol-2-yl)- 3,4-dihydroquinazolin-6-yl)amino)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (Example 2). (400 mg. 41%) as a yellow solid. MS (ESI): ealed. for C28H25CIF3N5O4S: 619.1; Found: 620.0 [M + 1]+;1H NMR (400 MHz, DMSO-d6): δ 8.84 (d, J= 7.2 Hz, 1H), 8.73 (s, 1H), 8.09 (s, 1H), 7.43 - 7.39 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 5.39 (s, 2H), 4.76 (t, J = 5.6 Hz, 1H), 4.40 - 4.36 (m, 1H), 4.24 (s, 1H), 3.97 - 3.91 (m, 2H), 3.83 (q, 7= 6.4 Hz, 2H), 3.67 (dd, J= 13.6, 4.8 Hz, 1H), 3.14 (td, 7 = 13.2, 3.2 Hz, 1H), 2.85 (t, 7= 6.4 Hz, 2H), 2.11 (d, 7= 13.2 Hz, 1H), 1.90 -

[0204] 1.68 (m, 3H) ppm.

[0205] Preparation of Comparison Compounds to Example 37 of WO2021127071:

[0206] Example 37 was prepared according to the procedures published on (Cooke, Andrew John et al., Bicyclic Heterocycle Compounds Methods of Use Thereof for the Treatment of Herpesviruses; International Publication W02021 / 127071 (PCT / US2020 / 065453)). Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6- yl)thio)hcxahydro-3H-oxazolo[3,4-a]pyridin-3-onc (Reference Compound A), (7S,8aS)-7-((3-(4- chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)hexahydro-3H- oxazolo[3,4-a]pyridin-3-one (Reference Compound B) and (7S,8aS)-7-((3-(4-chlorobenzyl)-7- (oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound C) Step 1. Synthesis of 4-bromo-5-methoxy-2-nitrobenzoic acid (3-2). A mixture of 4-bromo-5- fluoro-2-nitrobenzoic acid (3-1) (500 mg, 1.89 mmol) and NaOMe (307 mg, 5.68 mmol) in MeOH (10 mL) was stirred at 60 °C overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-5- methoxy-2-nitrobenzoic acid (3-2) (519 mg, 99%) as a white solid.

[0207] Step 2. Synthesis of 4-bromo-N-(4-chlorobenzyl)-5-methoxy-2-nitrobenzamide (3-3). To a stirred solution of 4-bromo-5-methoxy-2-nitrobenzoic acid (3-2) (519 mg, 1.89 mmol) in THF (10 mL) was added (4-chlorophenyl)methanamine (401 mg, 2.84 mmol), DIEA (731 mg, 5.67 mmol) and HATU (862 mg, 2.27 mmol). The reaction mixture was stirred at 20 °C overnight. The reaction mixture was quenched with water (50 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 EA in PE (0 - 35%) to afford 4-bromo-N-(4-chlorobenzyl)-5-methoxy-2-nitrobenzamide (3-3) (400 mg, 53%) as a white solid. MS (ESI): ealed. for C1 5H12BrClN2O4: 398.0; Found: 398.7 [M + 1]+.

[0208] Step 3. Synthesis of 2-amino-4-bromo-N-(4-chlorobenzyl)-5-methoxybenzamide (3-4). A mixture of 4-bromo-N-(4-chlorobenzyl)-5-methoxy-2-nitrobenzamide (3-3) (400 mg, 1.0 mmol), Fe powder (280 mg, 5.0 mmol), and NH4CI (538 mg, 10.0 mmol) in EtOH / H2O (10 mL / 2 mL) was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 2-amino-4-bromo-N-(4-chlorobenzyl)-5-methoxybenzamide (3-4) (340 mg, 92%) as a white solid. MS (ESI): ealed. for C1 5H14BrClN2O2: 368.0; Found: 368.7 [M + 1]+.

[0209] Step 4. Synthesis of 7-bromo-3-(4-chlorobenzyl)-6-methoxyquinazolin-4(3H)-one (3-5). A solution of 2-amino-4-bromo-N-(4-chlorobenzyl)-5-methoxybenzamide (3-4) (340 mg, 0.92 mmol) in trimethoxymethane (3mL) was stirred at 105 °C overnight. The reaction 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 column chromatography, eluting with MeOH in DCM (0 - 5%) to afford 7-bromo-3-(4-chlorobenzyl)-6-methoxyquinazolin-4(3H)-one (3-5) (330 mg, 94%) as a white solid. MS (ESI): ealed. for C1 6H12BrClN2O2: 378.0; Found: 378.7 [M + 1]+.

[0210] Step 5. Synthesis of 3-(4-chlorobenzyl)-6-methoxy-7-(oxazol-5-yl)quinazoIin-4(3H)-one (3- 6). A mixture of 7-bromo-3-(4-chlorobenzyl)-6-methoxyquinazolin-4(3H)-one (3-5) (311 mg, 0.82 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (INT- 3) (433 mg, 1.23 mmol), K2CO3(284 mg, 2.06 mmol), and Pd(dppf)Ch (58 mg, 0.08 mmol) in 1 ,4-dioxane in H2O (12 mL / 3 mL) was stirred at 100 °C overnight. The reaction mixture was quenched with water (30 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 MeOH in DCM (0 - 5%) to afford 3-(4-chlorobenzyl)-6-methoxy-7-(oxazol-5-yl)quinazolin-4(3H)-one (3-6) (240 mg, 80%) as a yellow solid. MS (ESI): ealed. for C1 6H12BrCIN2O2: 367.1; Found: 368.1 [M + 1]+.

[0211] Step 6. Synthesis of 3-(4-chlorobenzyl)-6-hydroxy-7-(oxazol-5-yl)quinazolin-4(3H)-one (3- 7). A mixture of 3-(4-chlorobenzyl)-6-methoxy-7-(oxazol-5-yl)quinazolin-4(3H)-one (3-6) (240 mg, 0.65 mmol) and NaSMe (458 mg, 6.5 mmol) in DMF (5 mL) was stirred at 90 °C overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 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 MeOH in DCM (0 - 8%) to afford 3-(4-chlorobenzyl)-6-hydroxy-7-(oxazol-5- yl)quinazolin-4(3H)-one (3-7) (180 mg, 78%) as a yellow solid. MS (ESI): ealed. for C18H12CIN3O3: 353.06; Found: 354.1 [M + 1]+.

[0212] Step 7. Synthesis of 3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6-yl trifluoromethanesulfonate (3-8). 3-(4-chlorobenzyl)-6-hydroxy-7-(oxazol-5-yl)quinazolin- 4(3H)-one (3-7) (180 mg, 0.42 mmol), TEA (129 mg, 1.27 mmol), and DMAP (5 mg, 0.04 mmol) were dissolved in DMF (5 mL). Then Tf2NPh (225 mg, 0.63 mmol) was added into the reaction mixture at 0 °C. The resulting reaction mixture was stirred at 15 °C overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 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 EA in PE (0 - 80%) to afford 3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin- 6-yl trifluoromethanesulfonate (3-8) (190 mg, 93%) as a white solid. MS (ESI): ealed. for C19H11CIF3N3O5S: 485.0; Found: 486.2 [M + 1]+.

[0213] Step 8. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound A). To a stirred solution of 3-(4-chlorobenzyl)-7-(oxazoL5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl trifluoromcthancsulfonatc (3-8) (200 mg, 0.41 mmol) in dioxane (12 mL) was added (7S,8aS)-7-mercaptotetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (INT-2) (80 mg, 0.48 mmol), Pd2(dba)3(36.6 mg, 0.04 mmol), xantphos (40.0 mg, 0.08 mmol), and DIEA (105.0 mg, 0.82 mmol). The reaction mixture was refluxed for 4 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography to afford (7S,8aS)-7-(3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6- ylthio)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (Reference Compound A) (200 mg, 96%) as a white solid. MS (ESI): ealed. for C25H21CIN4O4S: 508.1; Found: 509.1 [M + 1]+;1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.37 - 7.31 (m, 4H), 5.16 (s, 2H), 4.42 (t, J = 8.0 Hz, 1H), 4.15 - 4.13 (m, 1H), 3.95 (brs, 1H), 3.90 - 3.87 (m, 1H), 3.79 (dd, J = 13.6, 4.4 Hz, 1H), 3.34 - 3.27 (m, 1H), 2.05 - 1.81 (m, 4H) ppm.

[0214] Step 9. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound B) and (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound B): A mixture of (7S,8aS)-7-(3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-ylthio)tetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (Reference Compound A) (100 mg, 0.2 mmol) and MCPBA (60 mg, 0.3 mmol) in DCM (3 mL) was stirred at room temperature for 1 h. The reaction mixture was then quenched with aqueous Na2SO3solution and extracted with DCM (10 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 (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound B) (50 mg, 48%) as a white solid and (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo- 3,4-dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound C) (30 mg, 28%) as a white solid. Reference Compound B: MS (ESI): ealed. for C25H21CIN4O5S: 524.1; Found: 525.1 [M + 1]+;1H NMR (400 MHz, CDCl3): δ 9.05 (d, J = 10.0 Hz, 1H), 8.22 (s, 1H), 8.08 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.37 (m, 4H), 5.30 - 5.13 (m, 2H), 4.54 - 4.42 (m, 2H), 3.89 - 3.79 (m, 1H), 3.75 - 3.36 (m, 1H), 3.01 - 2.94 (m, 1H), 2.28 (d, J = 14.8 Hz, 1H), 2.09 - 1 .97 (m, 2H), 1 .70 (m, 1H) ppm. Reference Compound C: MS (ESI): calcd. for C25H21CIN4O6S: 540.1; Found: 540.9 [M+ 1]+;1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.28 (s, 1H), 8.09 (s, 2H), 7.86 (s, 1H), 7.36 (m, 4H), 5.20 (s, 2H), 4.44 (m, 2H), 3.87 (m, 1H), 3.79 (dd, J = 13.6, 4.8 Hz, 1H), 3.65 (m, 1H), 3.58 (m, 1H), 2.37 (m, 1H), 2.09 (m, 1H), 1.91 - 1.70 (m, 2H) ppm.

[0215] Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6- yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound E) and (7S,8aS)-7-

[0216] ((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6- yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound D)

[0217] Step 1. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound E). A mixture of 3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin- 6-yl trifluoromethanesulfonate (3-8) (190 mg, 0.39 mmol), (7S,8aS)-7-aminohexahydro-3H- oxazolo[3,4-a]pyridin-3-one (INT-1) (122 mg, 0.78 mmol), CS2CO3(318 mg, 0.98 mmol), Pd2(dba)3(202 mg, 0.2 mmol), and Xantphos (226 mg, 0.39 mmol) in toluene (8 mL) was stirred at 1 10 °C overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 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-HPLC to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6- yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound E) (40 mg, 21%) as a white solid. MS (ESI): calcd. for C25H22CIN5O4: 491.1; Found: 492.0 [M + 1]+;1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.43 - 7.38 (m, 4H), 7.31 (s, 1H), 5.17 (s, 2H), 4.36 (t, J= 8.0 Hz, 1H), 4.04 - 4.00 (m, 2H), 3.90 - 3.87 (m, 1H), 3.58 - 3.16 (m, 2H), 2.16 (d, J= 12.0 Hz, 1H), 1.96 (d, J = 12.4 Hz, 1H), 1.76 - 1.61 (m, 2H) ppm. Step 2. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound D). A mixture of (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4- oxo-3, 4-dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound E) (100 mg, 0.2 mmol), CH3I (34 mg, 0.24 mmol) and NaH (60% in mineral oil, 16.0 mg, 0.4 mmol) in DMF (3 mL) was stirred at room temperature for 4 h. The reaction mixture was then quenched with water and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column and prep-HPLC to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-7-(oxazol-5-yl)-4-oxo-3,4-dihydroquinazolin-6- yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound D) (55 mg, 55%) as a white solid. MS (ESI): calcd. for C26H25CIN5O4: 505.2; Found: 505.9 [M+ 1]+;1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.41 (d, J= 8.0 Hz, 4H), 5.18 (s, 2H), 4.27 (t, J= 8.0 Hz, 1H), 3.87 (d, J= 4.4 Hz, 1H), 3.77 (m, 2H), 3.353 (m, 1H), 2.94 (t, 7= 8.0 Hz, 1H), 2.60 (s, 3H), 2.06 (d, 7 = 12.8 Hz, 1H), 1.82 (d, 7 = 13.2 Hz, 1H), 1.54 (m, 2H) ppm.

[0218] Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4- a]pyridin-3-one (Example 54) and (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)- 1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 55)

[0219]

[0220] Step 1. Synthesis of 2-(2-bromothiazol-5-yl)-1,1,1-trilfluoropropan-2-ol (4-2). A solution of diisopropylamine (11.2 mL, 79.25 mmol, note: diisopropylamine was dried by molecular sieves for 24 h prior to use) and butyllithium (2.5M in hexanes, 31.7 mL, 79.3 mmol) in THF (100 mL) was stirred at -20 °C for 15 min. A solution of 2-bromothiazole (4-1) (10.0 g, 60.96 mmol) in dry THF (60 mL) was added dropwise to the above LDA solution at -78 °C. The resulting mixture was stirred at -78 °C for 30 min. l,l-Trifluoropropan-2-one (10.24 g, 91.44 mmol) was then added dropwise over 20 min, and the reaction mixture was stirred at -78 °C for an additional 1 h. The reaction mixture was quenched with saturated aq. NH4CI solution (60 mL). The separated aqueous layer was extracted with EtOAc (150 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with 20% EA in PE to afford 2-(2- bromothiazol-5-yl)-1,1,1-trifluoropropan-2-ol (4-2) (9.5 g, 59%) as a white solid. MS (ESI): calcd. for C6H5BrF3NOS: 274.9; Found: 275.9 [M + 1]+; NMR (400 MHz, CDCl3): δ 7.53 (s, 1H); 3.65 (s, 1H); 1.81 (s, 3H) ppm.

[0221] Step 2. Synthesis of (S)-2-(2-bromothiazol-5-yl)-1,1,1-trilluoropropan-2-ol (4-3a) and (R)-2- (2-bromothiazol-5-yl)-1,1,1-trifluoropropan-2-ol (4-3b). 2-(2-bromothiazol-5-yl)- 1,1,1- trifluoropropan-2-ol (4-2) (470 g) was dissolved in IPA (1.65 L) and purified by Prep-SFC using the following conditions: column: XA-CHIRALPAK IH (5 x 25cm; 5 μm ); mobile phase A: CO2, mobile phase B: IPA; flow rate: 170 mL / min; gradient: isocratic 15% B; column temperature (°C): 35; back pressure (bar): 100; wave length: 220 nm; sample solvent: IPA; injection volume: 2.0 mL. The combined fractions were concentrated in vacuo to afford (S)-2-(2- bromothiazol-5-yl)-1,1,1-trifluoropropan-2-ol (4-3a) (RT = 3.09 min, 197 g, 42%, 99% purity) as a white solid and (R)-2-(2-bromothiazol-5-yl)-1,1,1-trifluoropropan-2-ol (4-3b) (RT = 3.67 min, 194 g, 41%, 99% purity) as a white solid. MS (ESI): calcd. for C6H5BrF3NOS: 274.9; Found: 275.9 [M + 1]+.

[0222] Step 3. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H- oxazolo[3,4-a]pyridin-3-one (Example 55). A mixture of 6-{ [(7S,8aS)-3-oxo-hexahydro- [l,3]oxazolo[3,4-a]pyridin-7-yl]amino}-3-[(4-chlorophenyl)methyl]-2-methyl-7-(4,4,5,5- tetramethyl- 1, 3, 2-dioxaborolan-2-yl)quinazolin-4-one (1-6) (330 g, 584.2 mmol) and (S)-2-(2- bromothiazol-5-yl)-1,1,1-trifluoropropan-2-ol (4-3a) (160.9 g, 584.2 mmol), Pd(dppf)C12 (21.4 g, 29.2 mmol), K2CO3(242.2 g, 1752.6 mmol) in EtOH (3.0 L) and water (300 mL) was stirred at 100 °C for 16 h. The reaction mixture was allowed to cool down to room temperature and diluted with H2O (6.0 L). The precipitated solid was collected by filtration and washed with H2O (1.0 L). The residue was purified by silica gel column chromatography, eluting with EA to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2- yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 55) (205 g, 55%) as a yellow solid. MS (ESI): calcd. for C29H27CIF3N5O4S: 633.1; Found: 634.3 [M + 1]+;1H NMR (400 MHz, DMSO-d6): 6 9.15 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.46 (s, 1H), 7.40 (d, J - 8.4 Hz, 2H), 7.32 (s, 1H), 7.21 (d, J - 8.4 Hz, 2H), 5.33 (s, 2H), 4.42 - 4.35 (m, lH), 4.19 (s, 1H), 4.O1 - 3.85 (m, 2H), 3.72 - 3.59 (m, 1H), 3.18 - 3.05 (m, 1H), 2.42 (s, 3H), 2.10 (d, J = 13.2 Hz, 1H), 1.95 - 1.60 (m, 6H) ppm.

[0223] Step 4. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((R)-1,1,1- trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro- 3H-oxazolo[3,4-a]pyridin-3-one (Example 54). A mixture of (7S,8aS)-7-((3-(4-chlorobenzyl)- 2-methyl-4-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-6- yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (1-6) (330 g, 584.21 mmol) and (R)-2-(2- bromothiazol-5-yl)-1,1,1-trifluoropropan-2-ol (4-3b) (160.9 g, 584.2 mmol), Pd(dppf)Ch (21.4 g, 29.2 mmol), K2CO3(242.2 g, 1752.6 mmol) in EtOH (3.0 L) and water (300 mL) was stirred at 100 °C for 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (6.0 L). The precipitated solid was collected by filtration and washed with H2O (1.0 L). The residue was purified by silica gel column chromatography, eluting with EA to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4- a]pyridin-3-one (Example 54) (207 g, 55 %) as a yellow solid. MS (ESI): calcd. for C29H27CIF3N5O4S: 633.1; Found: 634.3 [M + 1]+;1H NMR (400 MHz, DMSO-d6): δ 9.14 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.46 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 5.33 (s, 2H), 4.42 - 4.35 (m, 1H), 4.19 (s, 1H), 4.01 - 3.85 (m, 2H), 3.72 - 3.59 (m, 1H), 3.18 - 3.05 (m, 1H), 2.42 (s, 3H), 2.10 (d, J = 13.2 Hz, 1H), 1.95 - 1.60 (m, 6H) ppm.

[0224] Preparation of Comparison Compounds of Example 55:

[0225]

[0226] Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4- a]pyridin-3-one (Reference Compound F), (7S,8aS)-7-((S)-(3-(4-chlorobenzyl)-2-methyl-4-oxo- 7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)sulfinyl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound G), and (7S,8aS)- 7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2- yl)-3,4-dihydroquinazolin-6-yl)sulfonyl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound H)

[0227]

[0228] Step 1. Synthesis of 4-bromo-N-(4-chlorobenzyl)-2-nitro-5-(((7S,8aS)-3-oxohexahydro-3H- oxazolo[3,4-a]pyridin-7-yl)thio)benzamide (5-1). A mixture of 4-bromo-N-(4-chlorobenzyl)-5- fluoro-2-nitrobenzamide (1-2) (2.0 g, 5.2 mmol), (7S,8aS)-7-mercaptohexahydro-3H- oxazolo[3,4-a]pyridin-3-one (INT-2) (900 mg, 5.0 mmol) and DIEA (1.3 g, 10.0 mmol) in DMF (15 mL) was stirred at 100 °C for 2 h. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The formed solids were filtered, washed with water and PE, and dried in vacuo to afford 4-bromo-N-(4-chlorobenzyl)-2-nitro-5-(((7S,8aS)-3-oxohexahydro- 3H-oxazolo[3,4-a]pyridin-7-yl)thio)benzamide (5-1) (1.5 g, 56%) as a brown solid, which was used for the next step without further purification. MS (ESI): calcd. for C21H19BrCIN3O5S: 539.0; Found: 540.0 [M + 1 ]+. Step 2. Synthesis of 2-amino-4-bromo-N-(4-chlorobenzyl)-5-(((7S,8aS)-3-oxohexahydro-3H- oxazolo[3,4-a]pyridin-7-yl)thio)benzamide (5-2). A mixture of 4-bromo-N-(4-chlorobcnzyl)-2- nitro-5-(((7S,8aS)-3-oxohexahydro-3H-oxazolo[3,4-a]pyridin-7-yl)thio)benzamide (5-1) (1.5 g, 2.8 mmol), Fe powder (388 mg, 6.95 mmol) and NH4CI (610 mg, 11.2 mmol) in EtOH / H2O (20 mL, v / v = 4:1 (v / v)) was stirred at 90 °C for 4 h. The reaction mixture was then filtered through a pad of Celite®545. The Celite®545 cake was washed with EtOH. The filtrate was concentrated under reduced pressure to afford 2-amino-4-bromo-N-(4-chlorobenzyl)-5-(((7S,8aS)-3- oxohexahydro-3H-oxazolo[3,4-a]pyridin-7-yl)thio)benzamide (5-2) (2 g, 100%) as a brown solid, which was used for next step without further purification. MS (ESI): ealed. for C21H21BrClN3O3S: 509.0; Found: 510.2 [M + 1]+.

[0229] Step 3. Synthesis of (7S,8aS)-7-((7-bromo-3-(4-chIorobenzyl)-2-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (5-3). A mixture of 2-amino-4-bromo-N-(4-chlorobenzyl)-5-(((7S,8aS)-3-oxohexahydro-3H-oxazolo[3,4-a]pyridin- 7-yl)thio)benzamide (5-2) (2 g, 2.8 mmol), TFA (5 mL), and 1,1,1 -triethoxyethane (40 mL) was stirred at 120 °C for 2 days. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column, eluting with 70% EA in PE to afford (7S,8aS)-7-((7-bromo-3-(4-chlorobenzyl)-2-methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (5-3) (400 mg, 27% for 3 steps) as a brown solid. MS (ESI): ealed. for C23H21BrClN3O3S: 533.0; Found: 534.0 [M + 1]+.

[0230] Step 4. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yI)thio)hexahydro-3H- oxazolo[3,4-a]pyridin-3-one (Reference Compound F). A mixture of (7S,8aS)-7-((7-bromo-3- (4-chlorobenzyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4- a]pyridin-3-one (5-3) (400 mg, 0.75 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (1.9 g, 7.5 mmol), KOAc (220 mg, 2.25 mmol) and Pd(dppf)Cl2(80 mg, 0.11 mmol) in dioxane (20 mL) was stirred at 100 °C for 2 h. (S)-2-(2-bromothiazol-5-yl)-1,1,1- trifluoropropan-2-ol (412 mg, 1.5 mmol), Pd(dppf)Cl2(80.0 mg, 0.11 mmol), K2CO3(310.0 mg, 2.25 mmol) and H2O (4 mL) was then added. The reaction mixture was stirred at 100 °C for additional 4 h. The reaction mixture was concentrated. The resulting residue was purified by silica gel column, eluting with 100% EA, and prcp-HPLC to afford (7S,8aS)-7-((3-(4-chlorobcnzyl)-2- methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4- dihydroquinazolin-6-yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound F) (200 mg, 41%) as an off-white solid. MS (ESI): ealed. for C29H26CIF3N4O4S2: 650.1; Found: 650.8 [M + 1]+;1H NMR (400 MHz, CD3OD): δ 8.45 (d, J = 1.6 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.25 (d, J - 8.8 Hz, 2H), 5.43 (s, 2H), 4.42 (t, J- 8.4 Hz, 1H), 4.12 (m, 1H), 3.91 (dd, J = 8.8, 6.0 Hz, 1H), 3.79 (brs, 1H), 3.65 (m, 1H), 3.24 (m, 1H), 2.57 (s, 3H), 2.02 (m, 1H), 1.92 - 1.79 (m, 6H) ppm.

[0231] Step 5. Synthesis of (7S,8aS)-7-((S)-(3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1- trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)sulfinyl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound G) and (7S,8aS)-7-((3-(4-chIorobenzyI)-2-methyI-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-

[0232] 2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)sulfonyl)hexahydro-3H-oxazolo[3,4-a]pyridin-

[0233] 3-one (Reference Compound H). A mixture of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo- 7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)thio)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound F) (180 mg, 0.3 mmol) and MCPBA (84 mg, 0.3 mmol) in DCM (12 mL) was stirred at room temperature for 1 h. The reaction mixture was then quenched with aqueous Na2SO3solution and extracted with DCM (10 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 (7S,8aS)-7-((S)- (3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2- yl)-3,4-dihydroquinazolin-6-yl)sulfinyl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound G) (40 mg, 21%) as a white solid and (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4- oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)sulfonyl)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound H) (20 mg, 11%) as a white solid. Reference Compound G: MS (ESI): ealed. for C29H26CIF3N4O5S2: 666.1; Found: 666.7 [M + 1]+; 'H NMR (400 MHz, CD3OD): δ 8.96 (d, J= 22.0 Hz, 1H), 8.07 (dd, 7= 19.2, 1.2 Hz, 2H), 7.35 (m, 2H), 7.27 (m, 2H), 5.50 - 5.39 (m, 2H), 4.64 - 4.54 (m, 1H), 4.47 - 4.41 (m, 1H), 4.05 - 3.69 (m, 2H), 3.64 - 3.52 (m, 2H), 2.80 - 2.62 (m, 1H), 2.61 (s, 3H), 2.30 - 2.07 (m, 2H), 1.86 (s, 3H), 1.78 - 1.59 (m, 1H) ppm. Reference Compound H: MS (ESI): calcd. for C29H26CIF3N4O6S2: 682.1; MS Found: 682.7 [M + 1]+;1H NMR (400 MHz, CD3OD): δ 8.98 (s, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.37 (m, 2H), 7.29 (d, J= 8.8 Hz, 2H), 5.46 (s, 2H), 4.83 (m, 1H), 4.49 (t, J= 8.4 Hz, 1H), 4.40 (m, 1H), 3.95 (dd, J = 8.8, 5.2 Hz, 1H), 3.72 (dd, J = 13.2, 4.4 Hz, 1H), 3.54 (m, 1H), 2.63 (s, 3H), 2.44 (d, J = 15.2 Hz, 1H), 2.22 (d, J = 14.4 Hz, 1H), 2.03 - 1.88

[0234] (m, 2H), 1.86 (s, 3H) ppm.

[0235] Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)(methyl)amino)hexahydro-3H- oxazolo[3,4-a]pyridin-3-one (Reference Compound I)

[0236] Reference Compound I

[0237] Step 1. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro- 2-((2-(trimethylsilyl)ethoxy)methoxy)propan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (6-1). A mixture of ((7S,8aS)-7-((3-(4- chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4- dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 55) (200 mg, 0.3 mmol), NaH (60% in mineral oil, 25 mg, 0.6 mmol), and SEMCl (78 mg, 0.5 mmol) in DMF (12 mL) was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column, eluting with 75% EA in PE to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2- methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)propan-2- yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (6-1) (160 mg, 67%) as a yellow solid. MS (ESI): calcd. for C35H41ClF3N5O5SSi: 763.2; Found: 764.2 [M + 1]+. Step 2. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro- 2-((2-(trimethylsilyl)ethoxy)methoxy)propan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (6-2). A mixture of (7S,8aS)- 7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-((2- (trimethylsilyl)ethoxy)methoxy)propan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (6-1) (160 mg, 0.2 mmol), NaH (60% in mineral oil, 16.0 mg, 0.4 mmol), and CH3I (34 mg, 0.2 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. The reaction mixture was quenched with water, extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column, eluting with 80% EA in PE to afford (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2- ((2-(trimethylsilyl)ethoxy)methoxy)propan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (6-2) (110 mg, 68%) as a brown oil. MS (ESI): calcd. for C36H43ClF3N5O5SSi: 777.2; Found: 778.2 [M + 1]+. Synthesis of (7S,8aS)-7-((3-(4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6-yl)(methyl)amino)hexahydro- 3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound I). A mixture of (7S,8aS)-7-((3-(4- chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-((2- (trimethylsilyl)ethoxy)methoxy)propan-2-yl)thiazol-2-yl)-3,4-dihydroquinazolin-6- yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (6-2) (110 mg, 0.14 mmol) and TFA (2 mL) in DCM (8 mL) stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by prcp-HPLC to afford (7S,8aS)-7-((3- (4-chlorobenzyl)-2-methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)- 3,4-dihydroquinazolin-6-yl)(methyl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Reference Compound I) (32 mg, 35%) as a yellow solid. MS (ESI): ealed. for C30H29CIF3N5O4S: 647.1; Found: 647.8 [M + 1]+; 'H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.36 (d, J= 8.8 Hz, 2H), 7.24 (d, 7 = 8.4 Hz, 2H), 5.43 (s, 2H), 4.34 (t, J = 8.4 Hz, 1H), 4.18 (m, 1H), 3.86 (m, 2H), 3.50 (m, 1H), 3.21 - 3.13 (m, 1H), 2.74 (s, 3H), 2.57 (s, 3H), 2.22 (m, 1H), 2.03 - 1.95 (m, 1H), 1.86 (s, 3H), 1.74 - 1.60 (m, 2H) ppm.

[0238] 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 present invention 6 (d, J ), 5.44 8 (t, J (m, 3.55 H), 2.14 H), O-d6): , 8.35 – 7.38 H), m,m, 2H), (m, 1H), O-d6): ), 8.36 – NH 7.12 (m, 6H), 5.17 (s, 2H), 4.34 O (m, 1H), 4.24 (m, 1H), 3.93 (m, N 2H), 3.67-3.63 (m, 1H), 3.15 (m, O O 1H), 2.09 (m, 1H), 1.84 – 1.68 (m, 3H) ppm 56

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[0280] Attorney Docket No.71180-423314 (ASP-072WO) 2 Hz, 2.66 Hz, 76 – 6.8 Hz, 3H) ppm Biological Data Cell culture MRC-5 fibroblast cells were cultured in Eagle’s Minimum Essential Medium (MEM) 5 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% CO2and passaged 2-3 times per week to maintain sub-confluent densities. 10 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 15 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 normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing a 1:200 dilution of a 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 20 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 188 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 TCID50 HSV-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 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. VZV antiviral assays were conducted through a Contract Research Organization. In brief, MRC-5 cells were cultured, infected with VZV Ellen strain and treated with test compounds as described for the CMV assay, with the exception that a 3-fold serial dilution format was employed. Following incubation at 37⁰C for 3 days, nucleic acids were extracted from cells, and VZV infection was quantified by quantitative PCR analysis, with quantification relative to the full inhibition achieved with 100 uM of acyclovir. EBV antiviral assay EBV antiviral assays were conducted through a Contract Research Organization. In brief, B95-8 cells were treated with phorbol 12-myristate-13-acetate for one day to activate EBV expression. B95-8 cells were subsequently plated and treated with test compounds as described for the CMV assay, with the exception that a 3-fold serial dilution format was employed. Following incubation at 37⁰C for 5 days, nucleic acids were extracted from cells, and EBV infection was quantified by quantitative PCR analysis, with quantification relative to the full inhibition achieved with 100 uM of acyclovir. hERG Cardiotoxicity Conventional patch clamp was used to determine the drug blocking effects on hERG channels. Cell culture and cell preparation for manual patch: A CHO cell line stably transfected with hERG cDNA and expressing hERG channels of P21 was used for the study. Cells were cultured in medium (from Invitrogen) containing: • Ham’s F12 • 10 % (v / v) FBS • 100 μg / ml Hygromycin B • 100 μg / ml Geneticin Flasks or dishes of CHO hERG cells were maintained in the above medium and incubated at 37 °C in a humidified incubator with 5% CO2.24 to 48 hours prior to electrophysiological recordings, the cells were plated on glass cover slips placed in culture dishes and maintained under the same incubation and media conditions. The number of cells being plated on the cover slip should reach a confluence rate at which majority of the cells are single. Solutions: For the electrophysiological recordings the following solutions were used. Table 1. Composition of internal and external solutions used in hERG patch clamp studies Reagent External Solution (mM) Internal Solution (mM) CaCl22 5.374 MgCl2 1 1.75 KCl 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 Na-ATP - 4 pH 7.4 (adjusted with NaOH), 7.25 (adjusted with KOH), &Osmolarity Osmolarity ~305 mOsm Osmolarity ~280 mOsm Table 2. Chemicals and reagents information Chemicals and reagents Catalog No. MW Supplier NaCl S1679-1KG 58.44 Sigma KCl 31248-100G 74.55 Sigma CaCl2 (1M solution) 21114-1L 110.98 Sigma MgCl2·6H2O M7304-100G 203.30 Sigma HEPES H3375-1KG 238.30 Sigma Glucose G8270-1KG 180.16 Sigma EGTA 03777-50G 380.15 Sigma Na2-ATP A-7699-5G 551.14 Sigma NaOH (2M solution) 35254-1L 40.00SigmaKOH 232041-50G 149.91 Sigma DMSO D2650-100ML 78.13 Sigma Manual whole cell patch and recording procedures: HEKA EPC 10 USB patch clamp amplifier (from HEKA Elektronik, Germany) was used in the whole cell recording. A cover slip with plenty of single CHO hERG cells on the surface was removed and placed into a continuously perfused (approximately 1 ml / minute) recording chamber mounted on an inverted microscope. HERG channel currents were recorded from single cells using standard whole cell recording techniques. The cells were voltage clamped at a holding potential of -80 mV. The hERG current was activated by depolarizing at +20 mV for 5 sec, after which the current was taken back to -50 mV for 5 sec to remove the inactivation and observe the deactivating tail current. The K+ tail current through HERG channels observed during this step was allowed to stabilize under continuous bath perfusion. Cells were then superfused with drug until steady state block was achieved. Steady state was considered reached when three consecutive super-imposable current records were collected. At this point, cells were once again superfused with extracellular solution until the current amplitude returned to values close to those measured before application of drug. One or more compounds or concentrations of drugs were tested on each cell with washout in between each drug application. Cisapride was used in the experiments to ensure the normal response and good quality of the hERG cells. Compound handling and dilutions: Single dose (10 µM) was chosen to evaluate compound effect on hERG channel. Before manual patch clamp test, compounds were made into 10 mM DMSO stock, diluted in extracellular solution (with 2% FBS) to the final test concentration.5-10 min of sonication and vortex were routinely applied to the solutions to assist the complete dissolution of compound. Final DMSO concentration was 0.1%. Data Analysis: Data were analyzed using Assay Software provided by Patchmaster and Graphpad Prism 10.0. Quality Control: Data included in the report originated from experiments which satisfied all of the following criteria: Recording parameters: • membrane resistance Rm > 500 MΩ • access resistance (Ra) < 10 MΩ • tail current amplitude > 200 pA • rundown < 2 % per minute • leak current < 200 pA or 10% of the tail current amplitude in 90% of the recording time References: ➢ Mitcheson JS, et al (2000) A structural basis for drug-induced long QT syndrome. Proceedings of the National Academy of Science; 97 (22): 12329-12333. ➢ Netzer R, et al (2001) Screening compounds for QT interval prolongation. Drug Discovery Today; 6 (2): 78-84. ➢ Zhou Z, et al (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophysical Journal; 74: 230-241. ➢ Tsujimae K, et al (2004) Comparison of kinetic properties of quinidine and dofetilide block of HERG channel. European Journal of Pharmacology; 493: 29-40. Microsomal Stability Protocol: Study details: Test concentration 1 µM Reference compound Ketanserin Test systems Human liver microsomes (Corning or Xenotech) with final liver microsomal protein concentration of 0.5 mg / mL Incubation condition 0, 5, 15, 30, 45 min at 37°C Sample size Duplicates (n=2) Bioanalytical method LC-MS / MS Experimental procedure: 1. Prepare 0.1 M Potassium Phosphate Buffer, pH 7.4 (K-buffer): Buffer A: 1.0 L of 0.1 M Monobasic Potassium Phosphate buffer containing 1.0 mM EDTA. Buffer B: 1.0 L of 0.1 M Dibasic Potassium Phosphate buffer containing 1.0 mM EDTA. K-buffer (Buffer C): add 150 mL Buffer A into 500 mL of Buffer B (pH was adjusted to 7.4 with Buffer A or Buffer B). 2. Prepare reference compound (Ketanserin) and test compounds spiking solution: - 500 µM spiking solution: add 10 µL of 10 mM reference compound or test compound stock solution into 190 µL CAN. - 1.5 µM spiking solution in microsomes (0.75 mg / mL): add 1.5 µL of 500 µM spiking solution and 18.75 µL of 20 mg / mL liver microsomes into 479.75 µL of K-buffer (stored on ice). 3. Prepare NADPH stock solution (6 mM) by dissolving NADPH into K-buffer. 4. Dispense 30 µL of 1.5 µM spiking solution containing 0.75 mg / mL microsomes solution to the assay plates designated for different time points (0, 5, 15, 30, 45 min) on ice. 5. For 0 min, add 135 µL of ACN containing IS to the wells of 0 min plate and then add 15 µL of NADPH stock solution (6 mM). 6. Pre-incubate all other plates at 37°C for 10 min. 7. Add 15 µL of NADPH stock solution (6 mM) to the plates to start the reaction. 8. At 5 min, 15 min, 30 min, and 45 min, add 135 µL of ACN containing IS to the wells of corresponding plates to stop the reaction, respectively. 9. After quenching, shake the plates at the vibrator (IKA, MTS 2 / 4) for 10 min (600 rpm) and then centrifuge at 5,594 g for 15 min (Thermo Multifuge × 3R). 10. Transfer 30 μL of the supernatant from each well into a 96-well sample plate containing 150 μL of purified water for LC-MS / MS analysis. Data analysis: All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro T1 / 2) was determined from the slope value. Conversion of the in vitro T1 / 2(min) into the in vitro intrinsic clearance (in vitro CLint,in μL / min / mg protein) was done using the following equation (mean of duplicate determinations): The in vitro half-life (in vitro T1 / 2) was determined from the slope value: Conversion of the in vitro T1 / 2 (min) into the in vitro intrinsic clearance (in vitro CLint, in μL / min / mg protein) was done using the following equation (mean of duplicate determinations): CLint = (0.693 / T1 / 2) × (1 / (microsomal protein concentration (0.5 mg / mL))) × Scaling Factors CLhep = (QH × CLint × fub) / (QH + CLint × fub), where CLhep = (QH × CLint × fub) / (QH + CLint × fub) Scaling Factors for Intrinsic Clearance Prediction in Liver Microsomes: Table 2 provides antiviral activity for exemplified compounds of the invention grouped in the following ranges: A indicates EC50< 100 nM; and B indicates 100 ≤ EC50<500 nM. Table 2: Biological assay data for representative Compounds of the invention Stereochemistry of Examples A crystal with size of 0.17 x 0.17 x 0.05 mm of (7S,8aS)-7-((3-(4-chlorobenzyl)-2- methyl-4-oxo-7-(5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4- dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 54) was obtained from MeOH / H2O (5 / 1 (v / v)) after 10 days of volatilization and was used for X-ray diffraction data collection. The data were collected on a Bruker D8 Venture diffractometer at 174.00 K using GaKα (λ = 1.34139) radiation. 101249 reflections were collected, of which 19956 reflections were unique (R(int) = 0.0817, R(sigma) = 0.0577). The crystal belongs to monoclinic crystal system, with a space group P21(no.4). The unit cell parameters were as follows: a= 15.1396(4) Å，b= 9.9383(2) Å，c= 38.7511(10) Å， α=γ=90.0°，β= 100.3820(10)°, V= 5735.1(2) Å3, Z=8. The structure was solved by direct methods and all of the non-H atoms were refined against F2 by full-matrix least-squares methods using the SHELXT structure solution program. Using the intrinsic phase method and using the SHELXL refinement package minimized by the least squares method for refinement. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7508 and 0.5120, respectively. The final R, wR2, GOF are 0.0635 (I > 2σ(I)), 0.1901 and 1.023, respectively. There are four C29H27ClF3N5O4S molecules in the asymmetric unit. The ORTEP plot for Example 54 is presented in Fig. 1. The stereochemistry of Example 54 is shown in Fig.2. A crystal with size of 0.17 x 0.17 x 0.05 mm of (7S,8aS)-7-((3-(4-chlorobenzyl)-2- methyl-4-oxo-7-(5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)thiazol-2-yl)-3,4- dihydroquinazolin-6-yl)amino)hexahydro-3H-oxazolo[3,4-a]pyridin-3-one (Example 55) was obtained from MeOH / H2O (5 / 1 (v / v)) after 14 days of volatilization and was used for X-ray diffraction data collection. The data were collected on a Bruker D8 Venture diffractometer at 170.00 K using GaKα (λ = 1.34139) radiation. 56742 reflections were collected, of which 20886 reflections were unique (R(int) = 0.1036, R(sigma) = 0.1049). The crystal belongs to monoclinic crystal system, with a space group P21(no.4). The unit cell parameters were as follows: a= 9.7134(2) Å，b= 38.1699(8) Å，c= 15.1712(3) Å， α=γ=90.0°，β= 90.100(5)°, V= 5624.9(2) Å3, Z=8. The structure was solved by direct methods and all of the non-H atoms were refined against F2 by full-matrix least-squares methods using the SHELXT structure solution program. Using the intrinsic phase method and using the SHELXL refinement package minimized by the least squares method for refinement. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7508 and 0.4674, respectively. The final R, wR2, GOF are 0.0660 (I > 2σ(I)), 0.1659 and 1.031, respectively. There are four C29H27ClF3N5O4S molecules in the asymmetric unit. The ORTEP plot for Example 55 is presented in Fig. 3. The stereochemistry of Example 55 is shown in Fig.4. 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. 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

CLAIMS:

1. A compound of Formula I: Formula I of a pharmaceutically acceptable salt thereof, wherein: L is -C1-4alkylene- or a bond; X1is independently selected for each occurrence from the group consisting of O and S; 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 for each occurrence from the group consisting of hydrogen, C1-6alkyl, and C1-6alkoxyC1-6alkyl-; or Rdand Retogether with the N atom to which they are attached form an azetidinyl, pyrrolidiyl, piperidinyl or dioxazinanyl 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, and C1-4alkyl; or Rdis Rcand Reis R5; Rxis independently selected for each occurrence from the group consisting or hydrogen, OH, C1-4alkyl and C1-4alkoxy-; R1is independently selected for each occurrence from the group consisting of halo, CN, C1-4alkyl and haloC1-4alkyl; R2is hydrogen, OH, RaRbN-, C1-6alkyl, C3-6monocycloalkyl-, cyanoC1-6alkyl-, hydroxyC1-6alkyl-, RaRbNC1-6alkyl-, C1-6alkyloxy-, C1-6alkoxyC1-6alkyl-, RaRbNhydroxyC1-6alkyl-, RaRbNC(O)-C1-6alkyene-, C1-6alkylC(O)-C1-6alkylene-, C1-6alkylS(O)q-C1-6alkylene-, or C1-6alkylC(O)O-C1-6alkylene-;R4and R4aare independently selected for each occurrence from the group consisting of halo, OH, CN, RaRbN-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6monocycloalkyl-, cyanoC1-6alkyl, haloC1-6alkyl-, hydroxyC1-6alkyl-, hydroxyC2-6alkenyl-, hydroxyC2-6alkynyl-, halohydroxyC1- 6alkyl-, RaRbNC1-6alkyl-, RaRbNhydroxyC1-6alkyl-, RdRbNC1-6alkyl-NRc-, C1-6alkoxy-, haloC1-6alkoxy, hydroxyC1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, haloC1-6alkoxy-C1-6alkyl-, hydroxyC1-6alkoxy-C1-6alkylene-, HC(O)-, RdReNC(O)-, RdReNS(O)q-, C1-6alkylC(O)-, C1- 6alkylS(O)q-, RaRbNC(O)-C1-6alkylene-, RaRbNC(O)-haloC1-6alkylene-, C1-6alkoxyC(O)-, C1-6alkylC(O)O-, C1-6alkylS(O)q-NRc-, C1-6alkylC(O)-C1-6alkylene-, C1-6alkylS(O)q-C1-6alkylene-, C1-6alkylC(O)O-C1-6alkylene-, C1-6alkylC(=NRx)-, RaRbNC(=NRx)-, C1-6alkoxyC(O)NRc-, C1- 6alkoxyC(O)NRc-C1-6alkylene-, C1-6alkoxyC(O)NRc-hydroxyC1-6alkylene- and -L-R6; R4bis hydrogen or C1-4alkyl; R5and R6are independently selected for each occurrence from the group consisting ofR7is independently selected for each occurrence from the group consisting of halo, CN, OH and RaRbN-; R7aindependently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl; n is 0, 1, 2 or 3; q is independently selected for each occurrence from the group consisting of 0, 1 and 2; t is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3; 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: Formula Ia, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1ais Cl.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1ais CN.

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

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

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

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

10. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2is C1-4alkyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

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

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R3is14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3is15. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein:

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

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

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 compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof.

19. 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.

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

21. The method of claim 18 or 19, wherein infection is an HSV-2 infection.

22. The method of claim 18 or 19, wherein infection is a CMV infection.

23. The compound according to any one of claims 1-15 for use as a medicament.

24. The compound according to any one of claims 1-15 for the use in therapy.

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