Tricyclic heteroaryl compounds useful for enhancing innate immune responses

Abstract

The present disclosure provides pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine compounds, pharmaceutical compositions thereof, and methods of using them to treat and / or prevent viral infections by enhancing one or more innate immune responses within a subject.

Description

Attorney Docket No. 71180-431269 (ASP-078-WO) TRICYCLIC HETEROARYL COMPOUNDS USEFUL FOR ENHANCING INNATE IMMUNE RESPONSES CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 707,150, filed October 14, 2024, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] Provided are pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine compounds, pharmaceutical compositions, methods for their preparation, and methods for their use in treating and / or preventing viral infections, and in particular, to certain compounds that can enhance one or more innate immune responses within a subject. BACKGROUND

[0003] Antiviral drugs can work by interacting with the virus to reduce its pathogenicity or by targeting the host to improve the host's defense against the virus. Most antiviral drugs on the market (e.g., zanamivir for treating influenza, zidovudine for treating HIV, acyclovir for treating HSV, and entecavir for treating HBV) interact directly with the virus to reduce pathogenicity. However, viruses can mutate and, thereby, develop resistance to these types of antiviral drugs. Consequently, antiviral drugs aimed at directly targeting a virus are prone to decreased efficacy over time.

[0004] As a result, there is an unmet need for an antiviral drug that targets the host rather than the virus directly. Therapeutic agents that bolster existing host immune mechanisms of viral defense, specifically the host innate immune response to infection, hold potential for treatment of multiple infections with a single agent.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0005] Interferon (IFN) is one of the cytokines secreted by immune cells, which activates immune cells and acts on various points in the virus life cycle to suppress the growth of viruses. Currently, injectable pegylated interferon (Peg-IFN) is available for general clinical use. A significant number of patients with Peg-IFN have a therapeutic effect regardless of whether they are HBe antigen positive or negative, and various side effects have been reported.

[0006] WO2013 / 059559 to Glaxo SmithKline, LLC discloses non-nucleic acid, low- molecular-weight, antiviral therapeutics suitable for oral administration. For example, imidazonaphthyridine compound RO8191 and related compounds are reported as IFN mimetic drugs using HCV replicon cells.

[0007] WO2018043747 to Kyoto University discloses imidazonaphthyridine compounds for treatment of HBV.

[0008] WO2023025312 to Assembly Biosciences discloses 2-(imidazo[l,2-a]l,8-naphthyridin- 8- yl)-l,3,4-oxadiazole derivatives of formula (I) as enhancers of innate immune response for the treatment of viral infections.

[0009] There is still a long-felt and unmet need for new non-nucleic acid, low-molecular- weight, antiviral therapeutics, that are not only suitable for oral administration, but also have increased efficacy, safety, and pharmacokinetic profiles. SUMMARY

[0010] The present disclosure provides, in part, pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine compounds and pharmaceutical compositions thereof, useful for treating viral infections by enhancing one or more innate immune responses within a subject.

[0011] In one aspect, the disclosure provides a compound of Formula I:Attorney Docket No. 71180-431269 (ASP-078-WO)or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description.

[0012] 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.

[0013] In another aspect, the disclosure provides a method of treating a viral 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.

[0014] In another aspect, the disclosure provides a method of treating a viral infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION

[0015] 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,Attorney Docket No. 71180-431269 (ASP-078-WO) examples and appended claims are collected here. These definitions should be read in view of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. I. Definitions

[0016] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. 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.

[0017] The term “alkylene” as used herein refers to a biradical alkyl group.

[0018] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon 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, propene, butenyl, and pentenyl, etc.

[0019] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon 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.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0020] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (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.

[0021] The term “cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-7 carbons, referred to herein as monoC3-7cycloalkyl, or bicyclic hydrocarbon ring structure of, for example, 5-12 carbons, referred to herein as biC5-12cycloalkyl. For bicyclic cycloalkyl groups, the two rings may be attached through the same or different carbons. Exemplary monocycloalkyl groups include, but are not limited to, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. Exemplary bicycloalkyl groups include, but are not limited to, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, decahydronaphthalene, octahydro-1H-indene, bicyclo[4.2.0]octanyl, bicyclo[4.1.0]heptanyl, octahydropentalenyl, bicyclo[3.2.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, and bicyclo[1.1.1]pentanyl.

[0022] The term “halo” or “halogen” as used herein refers to F, Cl, Br or I.

[0023] The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. For example, haloC1-6alkyl refers to a straight or branched alkyl group of 1- 6 carbon atoms substituted with one halogen atom up to 2n+1, where n is number of carbon atoms in the haloalkyl group. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, - CF3, CF3CH2-, CH3CF2-, CF3CCl2- and CF3CF2-.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0024] The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2- and HOCH2CH(OH)CH2-.

[0025] The terms “Individual,” “patient,” and “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.

[0026] 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 Biologics standards.

[0027] 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.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0028] 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.

[0029] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of 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.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0030] The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0031] The term “treating” as used herein includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease.

[0032] 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.

[0033] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E”Attorney Docket No. 71180-431269 (ASP-078-WO) 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.

[0034] 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 are designated “cis / trans.”

[0035] 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 asAttorney Docket No. 71180-431269 (ASP-078-WO) chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0036] 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.

[0037] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0038] 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.Attorney Docket No. 71180-431269 (ASP-078-WO) 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. II. Compounds of the Invention

[0039] In another embodiment, the present disclosure provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof, wherein:

[0040] R1is halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, monoC3-7cycloalkyl or phenyl, wherein the monoC3-7cycloalkyl or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, cyano, C1-6alkyl and haloC1-6alkyl;

[0041] R2is halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, monoC3-7cycloalkyl, phenyl, pyridyl or pyrazole, wherein the monoC3-7cycloalkyl, phenyl, pyridyl or pyrazole is optionally substituted 1-3 substituents independently selected from the groupAttorney Docket No. 71180-431269 (ASP-078-WO) consisting of halo, cyano, nitro, hydroxyl, RaRbN, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy and R4-OC(O)-C1-6alkylene-;

[0042] R3is hydrogen, halo, cyano, nitro, C1-6alkyl or haloC1-6alkyl;

[0043] R4is C1-4alkyl or phenyl; and

[0044] Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl. III. Methods of Use

[0045] Without being bound by any theory, since the compounds of the present disclosure behave as interferon mimicking agents (IFN mimetic agents), it is believed that may exhibit their antiviral activity through a variety of mechanisms. One such mechanism involves modulating the expression of interferon-stimulated genes (ISGs) through the janus kinase / signal transducer and activator (JAK / STAT) pathway, a common target for attack by a variety of viruses (Fleming, 2016, herein incorporated by reference with regard to such background teaching). Like other antiviral agents – the compounds of the present disclosure may also function as protease or polymerase inhibitors, disrupt the viral replication machinery or have general anti-viral activity against viral components. The presence of these mechanisms in a broad group of viruses suggests the compounds disclosed herein may provide therapeutic anti-viral activity against a diverse group of viruses.

[0046] Thus, one aspect described herein is a method of treating a hepatitis B infection (HBV) in a patient in need thereof is provided, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administeringAttorney Docket No. 71180-431269 (ASP-078-WO) to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0047] With regard to HBV / hepatitis D (HDV) coinfection or superinfection, HDV encodes HDAg, the HDV protein responsible for HDV RNA replication. HDV infection is facilitated by the interaction of HDAg with HBV viral envelope protein HBsAg, for both entry into the hepatocytes and assembly and release of the HDV virions (Negro, 2014). Thus, because HDV infection is dependent on the presence of an existing HBV infection, strategies for treating HBV / HDV coinfection may focus on targeting HBV alone, HDV alone or both viruses together.

[0048] Thus, the present disclosure also contemplates a method of treating an HBV or HDV infection, or HBV / HDV coinfection, in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating an HBV or HDV infection or HBV / HDV coinfection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0049] In some aspects, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsidAttorney Docket No. 71180-431269 (ASP-078-WO) formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV capsid assembly promoter therapeutic. Other combinations contemplated herein include administering a first compound selected from any one of the disclosed compounds, in combination with any available HBV treatment, including not limited to, entecavir, tenofovir, Baraclude, Viread, lamivudine, Vemlidy, Hepsera, Epivir-HBV, adefovir, epivir, tenofovir alafenamide, and other suitable HBV drugs.

[0050] In some aspects, the disclosure further provides a method of treating HBV or HDV infection or HBV / HDV coinfection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other additional antivirals, the one or more additional antivirals include HDV therapies, such as lonafarnib, and one or more of HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBV viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating an HBV or HDV infection or HBV / HDV coinfection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV therapeutic or an HDV therapeutic.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0051] Another IFN mimetic, RO 8191 has demonstrated antiviral activity against hepatitis C virus (HCV) (Wang et al., 2015), Corona viruses (WO2022 / 049521), and Zika virus (ZIKV) (Fernandes et al., 2021). Given that the compounds of the instant disclosure are also IFN mimicking agents anti-viral activity against HCV, Corona virus and Zika virus is also contemplated herein.

[0052] Thus, another aspect described herein is a method of treating a hepatitis C virus (HCV) infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating an HCV infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0053] In some aspects, the disclosure provides a method of treating a hepatitis C infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for HCV including, but not limited to, lbasvir / Grazoprevir (Zepatier), Glecaprevir / Pibrentasvir (Mavyret), Sofosbuvir / Ledipasvir (Harvoni), Sofosbuvir / Velpatasvir (Epclusa), second line hepatitis C medications such as Sofosbuvir / Velpatasvir / Voxelaprevir (Vosevi), and other suitable HCV drugs.

[0054] Coronaviruses are another possible viral target for the compounds of the present disclosure (See, for example, WO2022 / 049521). Thus, another aspect of the present disclosure provides methods for treating viral infection, wherein said viral infection comprises one or moreAttorney Docket No. 71180-431269 (ASP-078-WO) viruses from the Coronaviridae family including human coronavirus, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS- CoV) and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV- 2). The diseases caused by these viruses are SARS (SARS-CoV), MERS (MERS-CoV) and COVID-19 (SARS- CoV-2). Another aspect described herein, are methods for treating viral infections, and the disease caused by such viral infection, wherein said viral infection is SARS-CoV, and the resulting disease is SARS, MERS-CoV, and the resulting disease is MERS, or SARS-CoV-2, and the disease is COVID-19.

[0055] In some aspects, the disclosure provides a method of treating any Coronaviridae viral infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for Coronavirus infection including, but not limited to, nirmatrelvir, ritonavir, Lagevrio (molnupiravir), baricitinib, and the various coronavirus vaccines and other suitable Coronavirus drugs.

[0056] Another aspect described herein, is a method of treating a Zika virus (ZIKV) viral infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a ZIKV infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0057] In some aspects, the disclosure provides a method of treating a Zika virus infection in a patient in need thereof, comprising administering a first compound selected from any one of theAttorney Docket No. 71180-431269 (ASP-078-WO) disclosed compounds, in combination with suitable treatments for ZIKV infection. Although there are no medications to treat ZIKV, because treatment includes over the counter use of pain, anti-inflammatory drugs, suitable drugs for combining administration of the compounds of the instant disclosure include acetaminophen, ibuprofen, non-steroidal anti-inflammatory drugs and hydration therapies.

[0058] Human papillomavirus (HPV) is another common sexually transmitted virus with more than 100 known varieties. Interferons have been successfully used to treat HPV infections, making this virus an ideal candidate for treatment by the compounds of the present disclosure. Thus, another aspect described herein, is a method of treating HPV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a HPV infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0059] Combination therapy with the compounds disclosed herein, and known HPV drugs are also contemplated herein. In some aspects, the disclosure provides a method of treating any HPV viral infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, in combination with suitable treatments for HPV infection including, but not limited to, condylax (podofilox), trichloroacetic acid, aldara (imiquimod), zyclara, keratoyltic agents, immune response modifiers, and various commonly used HPV vaccines.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0060] Prion infection results in fatal brain diseases and encephalopathies in both humans and animals. Recombinant and IFN mimicking interferon therapy have both been found to possibly protect neurons from prion infections (Ishibashi, 2019). Thus, one aspect described herein is a method of treating prion infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a prion infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds, and a pharmaceutically acceptable excipient.

[0061] Chikungunya virus (CHIKV) and Dengue virus are both related mosquito-borne viruses with no approved therapies. Studies have demonstrated that CHIKV replication has been found to be inhibited by an agonist of Liver X receptor (LXR-623) by activation of the interferon signaling pathway (Hwang et al., 2019), and halofuginone has been found to work synergistically with another IFN mimicking agent. Thus, both CHIKV and Dengue virus represent yet another group of viruses ideally suited for therapy with the compounds described herein. Without being bound by any theory, it is possible the compounds of the present disclosure could demonstrate a synergistic effect with LXR-623 agonists for the treatment of CHIKV and / or with halofuginone for the treatment of both CHIV and Dengue virus. Thus, another embodiment described herein is a method of treating CHIKV by administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In one aspect, a method of treatment would include administering any of the disclosed compounds in combination with LXR-623. In another aspectAttorney Docket No. 71180-431269 (ASP-078-WO) described herein is a method of treating CHIKV virus comprising administering to a subject in need thereof, a combination of the compounds disclosed herein and LXR-623 or halofuginone. In yet another aspect, is a method of treating Dengue virus comprising administering to a subject in need thereof, a combination of the compounds disclosed herein and halofuginone.

[0062] Without being bound by any theory, it is further understood that the compounds of the present disclosure may be useful for the treatment of human norovirus (HNV) and encephalomyocarditis virus (EMCV) – both of which have been found to be respond to interferon-mediated antiviral therapy (de Graff et al., 2016; Campillay-Veliz et al., 2020)). Thus, another aspect described herein is a method of treating HNV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s). In another embodiment, a method for treating a EMCV infection in a patient in need thereof, comprising administering to a subject or patient an effective amount of a disclosed compound, and / or administering a first disclosed compound and optionally, an additional, different disclosed compound(s).

[0063] Further contemplated herein is a method for treating any of the viral infections described herein, in a subject that has been diagnosed with said viral infection or is at risk of developing said viral infection comprising administering to said subject, any one of the compounds described herein.

[0064] Another aspect described herein, is a method for enhancing the immune response to a viral infection from any of the viruses described herein, in a subject that is immunocompromised or is at risk of developing an immunocompromised immune system, comprising administering to said subject, any of the compound as described herein.Attorney Docket No. 71180-431269 (ASP-078-WO) IV. Administration and Formulations

[0065] In further embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease.

[0066] The compounds of the present invention can also be supplied in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.

[0067] Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.

[0068] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,Attorney Docket No. 71180-431269 (ASP-078-WO) isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0069] Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Lists of suitable salts are found in Remington's Pharmaceutical Sciences.Attorney Docket No. 71180-431269 (ASP-078-WO) 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts.

[0070] In general, the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the chemical entity, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors. The drug can be administered more than once a day, such as once or twice or three times a day.

[0071] Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01-100 mg / kg / day, for example, from about 0.1 to 50 mg / kg / day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.

[0072] In addition, the amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the at least one chemical entity described herein is present at a level of about 1-80 wt%.

[0073] In certain embodiments, the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), sublingually, subcutaneously, topically, intrapulmonarilly, vaginally, rectally, or intraocularly, or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. In other embodiments, oral administration with a convenient daily dosage regimen that can beAttorney Docket No. 71180-431269 (ASP-078-WO) adjusted according to the degree of disorder or disease may be used. The choice of administration route and / or formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.

[0074] In one embodiment, the compounds of the present invention may be administered topically to the diseased area on the skin or mucous membranes of a subject. In another embodiment, the compounds of the present invention may be administered topically to the diseased area on the skin or mucous membranes of a subject so that the topical administration allows for the compound to penetrate into the subject's skin layer keratinocyte cells.

[0075] In some embodiments, the compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of at least one chemical entity described herein. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate,

[0076] glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0077] Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The chemical entities can also be administered in sustained orAttorney Docket No. 71180-431269 (ASP-078-WO) controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and / or timed, pulsed administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0078] The chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0079] In certain embodiments, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0080] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution.

[0081] In one embodiment, the compounds of the present invention can be formulated into dermatological topical delivery formulations. Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For treatments of external tissues, such as skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[0082] In addition to the compounds of the present invention, the compositions herein may additionally include an organic solvent, an adhesive, plasticizer, and a water swellable polymer. The organic solvent may be one or more of dimethylsulfoxide (DMSO), N,N'-dimethylacetamide (DMA), N',N'-dimethylformamide (DMF), dioxane, tetraglycol, or the like.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0083] Appropriate adhesives for use in the invention include, but are not limited to, polyvinyl alcohol, polyethylene oxides, polyethylene glycols of molecular weight 3350 and higher, hydroxypropylcellulose, and povidone. Polyvinyl alcohol is preferred. The adhesive is typically present in an amount from about 10 to 75% by weight, preferably about 45-55% by weight, and most preferably about 50% by weight of the composition.

[0084] The compositions herein may optionally also include a plasticizer. Suitable plasticizers are typically high-boiling, water-soluble organic compounds containing hydroxyl, amide, or amino groups. Such plasticizers include, but are not limited to, soy, egg or synthetic lecithin, ethylene glycol, tetraethylene, hexamethylene, nonaethylene glycol, formamide, ethanolamine salts, water, glycerin, or combinations thereof. Such plasticizers are well known in the art. A plasticizer is therefore preferably included in the formulation to provide these benefits. The plasticizer is typically present in the composition in an amount ranging from about 0.4-2.0% by weight, with about 1-2% by weight being preferred, and about 0.9% by weight being most preferred.

[0085] The composition may also include a water swellable polymer which acts as an extender and serves to thicken the composition. Such water swellable polymers are well known in the art and include, but are not limited to, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, methyl ethyl cellulose, sodium carboxymethylcellulose, gums, carboxyvinyl polymer, hydroxyethyl cellulose, cornstarch, casein, urea, dextrin, and fume silica. The filler is typically present in an amount from about 1- 10% by weight, preferably about 3-6% by weight, with about 4.67% by weight being most preferred.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0086] The present invention is further directed to a method of treating warts by applying the pharmaceutical composition(s) topically to the location on the skin where the warts are present. The method of the invention comprises topically applying to a wart on an individual a therapeutically effective amount of the compositions of the invention. The composition may be applied using an applicator, for example, a swab, sponge, finger cot or a toothpick. While some compositions of this invention can be adhesive in and of themselves, in another embodiment of the invention, the method further comprises occluding the wart with an occluding agent to aid the composition's absorption into the wart, protect the composition from rubbing off, and also further keratolytic activity. Many occluding agents are known to those skilled in the art. These include, but are not limited to, bandages, plastic wrap, and adhesive tape, for example, duct tape.

[0087] The compositions of the invention may further include a variety of substances, including suitable stabilizers, buffers, thickeners, lubricants, wetting, and dissolving agents as well as colorings, moisturizers, preservatives, and fragrances. These minors are added in small amounts and are conventionally known in pharmaceutical formulation work to enhance elegance. Such minors typically comprise less than about 1% of the overall composition.

[0088] In still other embodiments, the compounds of the present invention can be formulated into dermatological delivery formulations, such as a stick-gel, which can be used to target the delivery of the compound directly onto the site of action. For example, if the compounds of the present invention are intended to be used as a treatment for papillomavirus induced warts, then the compound(s) may be formulated into a stick-gel that can apply the compounds in a formulation directly to the surface of the wart. In still other embodiments, the stick-gel application formulation can be based on a PSAs (Pressure Sensitive Adhesives) concept. PSAs, unlike structural adhesives or sealants, differ in that the adhesive-substrate interface does notAttorney Docket No. 71180-431269 (ASP-078-WO) resist separation when the adhesive is peeled off. In other words, PSAs are intended to show adhesive failure, especially when skin is the substrate, whereas this would be a major fatal flaw for cement and glue. Developing a suitable PSA-GeI for a targeted adherend to treat a skin common wart, takes the following two critical adhesive attributes into consideration: surface activity and visco-elastic properties.

[0089] As such, these attributes are associated to the three steps of adhesion process. The first step involves contact between the adhesive and the surface. This dynamic step is known as "bonding or sticking" and is dependent on wetting behavior and quick spreadability of the adhesive composition. The second step "adhering" relies on the capacity of the adhesive to remain in contact with surface. This is important for treating warts where the active should be adherent to the warts long enough to exert its intended action. Flowability and creep resistance are the physical characteristics that contribute to maintain the established bond and stick. During this more static phase, the adhesion will build up if the adhesive-to-surface interactions increase (e.g., interpenetration). The third step "debonding" is also dynamic. It consists in separating the adhesive-stick from the surface by means of a peel release process. The peel adhesion property of the adhesive composition will direct the force required to break the bond in an adhesive failure mode.

[0090] The formulation composition to achieve all these attributes can comprise suitable hydrophilic polymers incorporated into a gel matrix containing the active drug in solution. Large organic macromolecules that are either natural or synthetic hydrophilic polymers (e.g., hydroxy propyl methyl cellulose, ethyl cellulose, etc.) on the other hand, exist as randomly coiled chains that entangle with each other to form the gel structure. The nature of the solvent determines whether the gel is a hydrogel (water based) or an organogel (nonaqueous solvent). For example,Attorney Docket No. 71180-431269 (ASP-078-WO) gels prepared with hydroxyethyl cellulose containing water are hydrogels, whereas gels prepared with polyethylene-containing mineral oil (PIastibase) are organogels. Another class of gels, called thermally sensitive gels, are prepared from poloxamers. In addition to hydrophilic polymers, silicones are versatile materials permitting the design of various transdermal and topical drug delivery forms. The substantivity to skin can be adjusted from hours to one week in duration. Moreover, the hydrophobic, highly open, and mobile dimethylsiloxane network allows for the preparation of semi-occlusive matrices, permeable to many molecules including the compound(s) of the present invention.

[0091] In other embodiments of the present invention, there is provided sustained release of certain compounds described herein from silicone pressure sensitive adhesive matrices. This capability can also be expanded to other types of silicone matrices including fillerless or reinforced elastomers. As such, modulation of the release of certain compounds of the present invention could enhance drug targeting and therapeutic effectiveness. The silicone formulations could include a loosely cross-linked fillerless elastomer dispersion (Dow Corning® 9040 Silicone Elastomer Blend), a fully cross-linked fillerless elastomer (Dow Corning® 7-9800 A&B Soft Skin Adhesive), a rubber film-forming dispersion (Dow Corning® 7-5300 Film-In-Place Coating), and / or a visco-elastic system (Dow Corning® PSA 7-4502 and 7-4602 pressure sensitive adhesive. In certain embodiments, the compound(s) of the present invention could be formulated in the different silicone and polymer matrices along with the following excipients: surfactants, citric-sodium bicarbonates, and / or carbomer 974.

[0092] Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such aAttorney Docket No. 71180-431269 (ASP-078-WO) case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.

[0093] For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free-flowing powder that can be dispersed in the patient's inspiratory air stream during breathing by the device. To achieve a free-flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation. Likewise, compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0094] Recently, pharmaceutical compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No.Attorney Docket No. 71180-431269 (ASP-078-WO) 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. V. Examples

[0095] The compounds described herein can be prepared in a number of 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.

[0096] At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations: AcOH Acetic acid ACN Acetonitrile Boc2O Di-tert-butyl dicarbonate DAST Diethylaminosulfur trifluorideAttorney Docket No. 71180-431269 (ASP-078-WO) DCM Dichloromethane DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1’-Bis(diphenylphosphino)ferrocene EA, EtOAc Ethyl acetate EtOH Ethanol h, hr Hour(s) HPLC High performance liquid chromatography LCMS Liquid chromatography–mass spectrometry m-CPBA meta-Chloroperoxybenzoic acid MeOH Methanol Mn(Dpm)3Tris(dipivaloylmethanato)manganese PE Petroleum ether PPA Polyphosphoric acid TsOH p-Toluenesulfonic acid rt Room temperature TEA Triethylamine TFA Trifluoroacetic acid THF TetrahydrofuranAttorney Docket No. 71180-431269 (ASP-078-WO) Example 1. 2-(2,4-Bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4- oxadiazole

[0097] . A solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate (1-1) (10.00 g, 45.61 mmol) and TEA (6.92 g, 68.42 mmol) in DCM (100 mL) was stirred at room temperature. The mixture was cooled down to 0 °C and MsCl (6.27 g, 54.74 mmol) was added. The reaction was gradually warmed to room temperature and stirred for 2 h. After completion of the reaction (monitored by LCMS), the resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, elutedAttorney Docket No. 71180-431269 (ASP-078-WO) with PE / EA (4:1 (v / v)) to afford 1-2 (6.00 g, 65.37%) as a colorless oil. MS (ESI, m / z): calcd. for C9H15O4: 201.1; Found: 102.2 [M – 100 + 1]+.1H NMR (300 MHz, CDCl3): δ 7.03 (s, 1H), 6.18 (s, 1H), 5.75 (d, J = 1.6 Hz, 1H), 3.85 (s, 3H), 1.51 (s, 9H) ppm.

[0098] Step 2. Synthesis of methyl 2-[bis(tert-butoxycarbonyl)amino]prop-2-enoate (1-3). A solution of methyl 2-[(tert-butoxycarbonyl)amino]prop-2-enoate (1-2) (6.00 g, 29.82 mmol) Boc2O (6.51 g, 29.82 mmol) and DMAP (0.73 g, 5.96 mmol) in ACN (60 mL) was stirred for 12 h at 80 °C under a hydrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v / v)) to afford 1-3 (6 g, 66.78%) as a colorless oil. MS (ESI, m / z): calcd. for C14H23NO6: 301.2; Found: 302.2 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 6.36 (s, 1H), 5.66 (s, 1H), 3.81 (s, 3H), 1.48 (s, 18H) ppm.

[0099] Step 3. Synthesis of methyl 2-[bis(tert-butoxycarbonyl)amino]-3-(2-formylpyrrol- 1-yl)propanoate (1-4). A solution of methyl 2-[bis(tert-butoxycarbonyl)amino]prop-2-enoate (1- 3) (6.00 g, 19.91 mmol), 1H-pyrrole-2-carbaldehyde (2.27 g, 23.89 mmol) and K2CO3(5.54 g, 39.82 mmol) in ACN (100 mL) was stirred for 2 h at 80 °C under a nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. TheAttorney Docket No. 71180-431269 (ASP-078-WO) residue was purified by silica gel column chromatography, eluted with PE / EA (4:1 (v / v)) to afford 1-4 (7.00 g, 88.68%) as a colorless oil. MS (ESI, m / z): calcd. for C19H28N2O7: 396.2; Found: 397.1 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 9.55 (d, J = 1.1 Hz, 1H), 6.94 (dd, J = 3.9, 1.8 Hz, 1H), 6.83J = 1.2 Hz, 1H), 6.22 (dd, J = 3.9, 2.4 Hz, 1H), 5.49 (dd, J = 10.2, 4.5 Hz, 1H), 5.26 (dd, J = 13.8, 4.5 Hz, 1H), 4.56 (dd, J = 13.8, 10.2 Hz, 1H), 3.79 (s, 3H), 1.42 (s, 18H) ppm.

[0100] Step 4. Synthesis of methyl 3,4-dihydropyrrolo[1,2-a]pyrazine-3-carboxylate (1-5). A mixture of methyl 2-[bis(tert-butoxycarbonyl)amino]-3-(2-formylpyrrol-1-yl)propanoate (1-4) (45.00 g, 113.51 mmol) in TFA was stirred for 1 h at room temperature. After completion of the reaction (monitored by LCMS), the mixture was basified to pH 7 with saturated NaHCO3(aq.). The resulting mixture was extracted with CH2Cl2 (300 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (15:1 (v / v)) to afford 1-5 (14.00 g, 69.22%) as a brown oil. MS (ESI, m / z): calcd. for C9H10N2O2: 178.1; Found: 179.1 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 8.27 (d, J = 2.7 Hz, 1H), 6.82 (t, J = 2.1 Hz, 1H), 6.54 (dd, J = 3.9, 1.5 Hz, 1H), 6.27 (dd, J = 3.9, 2.4 Hz, 1H), 4.61 – 4.56 (m, 1H), 4.31 (dd, J = 12.9, 5.7 Hz, 1H), 4.17 – 4.08 (m, 1H), 3.87 (s, 3H) ppm.

[0101] Step 5. Synthesis of methyl pyrrolo[1,2-a]pyrazine-3-carboxylate (1-6). A solution of methyl 3,4-dihydropyrrolo[1,2-a]pyrazine-3-carboxylate (1-5) (14.00 g, 78.56 mmol) and manganese dioxide (68.30 g, 785.67 mmol) in CH2Cl2 was stirred for 4 h at 40°C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to roomAttorney Docket No. 71180-431269 (ASP-078-WO) temperature, the resulting mixture was filtered, the filter cake was washed with CH2Cl2(100 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1 (v / v)) to afford 1-6 (11.00 g, 79.47%) as a brown oil. MS (ESI, m / z): calcd. for C9H8N2O2: 176.1; Found: 177.1 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 8.88 (s, 1H), 8.81 (t, J = 1.2 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.04 (dd, J = 4.2, 2.7 Hz, 1H), 6.94 (d, J = 4.2 Hz, 1H), 4.03 (s, 3H) ppm.

[0102] Step 6. Synthesis of methyl 6-nitropyrrolo[1,2-a]pyrazine-3-carboxylate (1-7). A solution of methyl pyrrolo[1,2-a]pyrazine-3-carboxylate (1-6) (11.00 g, 62.44 mmol) in Ac2O (300 mL) was treated with Cu(NO3)2 (35.13 g, 187.31) for 3 h at room temperature. After completion of the reaction (monitored by LCMS), the resulting mixture was extracted with CH2Cl2 (300 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2 (v / v)) to afford 1-7 (3.00 g, 21.72%) as a yellow solid. MS (ESI, m / z): calcd. for C9H7N3O4: 221.0; Found: 222.1 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 10.05 (t, J = 1.2 Hz, 1H), 9.15 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.03 (dd, J = 4.8, 0.9 Hz, 1H), 4.07 (s, 3H) ppm.

[0103] Step 7. Synthesis of methyl 6-aminopyrrolo[1,2-a]pyrazine-3-carboxylate (1-8). A mixture of methyl 6-nitropyrrolo[1,2-a]pyrazine-3-carboxylate (1-7) (3.00 g, 13.56 mmol), NH4Cl (2.18 g, 40.69 mmol) and iron (3.79 g, 67.82 mmol) in methanol / H2O (30 / 30 mL) was stirred for 5 h at 65 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The resulting mixture was filtered, the filter cake was washed with CH2Cl2(30 mL x 3). The filtrate was concentrated under reduced pressure. TheAttorney Docket No. 71180-431269 (ASP-078-WO) resulting mixture was extracted with CH2Cl2(60 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 1-8 was directly used in the next step without further purification. MS (ESI, m / z): calcd. for C9H9N3O2: 191.1; Found: 192.1 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 8.69 (d, J = 1.2 Hz, 1H), 8.59 (t, J = 1.2 Hz, 1H), 6.81 (d, J = 4.2 Hz, 1H), 6.45 (d, J = 4.2 Hz, 1H), 4.02 (s, 3H) ppm.

[0104] Step 8. Synthesis of methyl 2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (1-9). A mixture of methyl 6-aminopyrrolo[1,2-a]pyrazine-3- carboxylate (1-8) (400.00 mg, 2.09 mmol) and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (2.18g, 10.46 mmol) in PPA (20 mL) was stirred for 16 h at 120 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The mixture was basified to pH 7 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1 (v / v)) to afford 1-9 (200.00 mg, 26.32%) as a yellow solid. MS (ESI, m / z): calcd. for C14H7 F6N3O2: 363.0; Found: 364.0 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 9.58 (s, 1H), 9.34 (s, 1H), 8.16 (s, 1H), 7.42 (s, 1H), 4.12 (s, 3H) ppm.

[0105] Step 9. Synthesis of 2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (1-10). A mixture of methyl 2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (1-9) (200.00 mg, 0.55 mmol) and hydrazine (176.46 mg, 5.51 mmol) in ethanol was stirred for 4 h at 70 °C. AfterAttorney Docket No. 71180-431269 (ASP-078-WO) completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The precipitated solids were collected by filtration and washed with ethanol (10 mL x 3) to afford 1-10 (200 mg, quantitative) as a yellow solid. MS (ESI, m / z): calcd. for C13H7F6N5O: 363.1; Found: 364.0 [M + 1]+.

[0106] Step 10. Synthesis of 2-(2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin- 8-yl)-1,3,4-oxadiazole (Example 1). A mixture of 2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (1-10) (200.00 mg, 0.55 mmol) and p-toluene sulfonate (47.41 mg, 0.28 mmol) in trimethyl orthoformate (5 mL) was stirred for 4 h at 70 °C. After completion of the reaction (monitored by LCMS), the resulting solution was cooled to room temperature. The crude product was purified by Prep-HPLC, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.5% NH3·H2O) and ACN (5% ACN up to 95% in 3 min) to afford Example 1 (60.00 mg, 29.20%) as a yellow solid.Attorney Docket No. 71180-431269 (ASP-078-WO) Example 2. 2-(2-(Perfluoroethyl)-4-(prop-1-en-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazole(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (2-1). Into a 40 mL vial were added methyl 6-aminopyrrolo[1,2-a]pyrazine-3-carboxylate (1-8) (700 mg, 3.66 mmol), PPA (14 g) and ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (12.86 g, 54.92 mmol) at room temperature. The resulting mixture was stirred for 5 h at 100 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.5% FA), 20% to 70% gradient in 10 min; detector, UV 254 nm, to afford 2-1 (350 mg, 26.46%) as a yellow solid. MS (ESI, m / z): calcd. for C14H8F5N3O3: 361.0; Found: 362.0 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0108] Step 2. Synthesis of methyl 2-(perfluoroethyl)-4- (((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (2-2). Into a 8 mL vial were added methyl 4-hydroxy-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (2-1) (200 mg, 0.55 mmol), DMF (4 mL), N- bis(trifluoromethanesulfonyl)aniline (296.49 mg, 0.83 mmol) and TEA (168.08 mg, 1.66 mmol) at room temperature. The resulting mixture was stirred for 4 h at room temperature then diluted with water (20 mL). The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford 2-2 (100 mg, 36.61%) as a yellow solid. MS (ESI, m / z): calcd. for C15H7F8N3O5S: 493.0; Found: 494.0 [M + 1]+.

[0109] Step 3. Synthesis of methyl 2-(perfluoroethyl)-4-(prop-1-en-2- yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (2-3). To a solution of methyl 2- (perfluoroethyl)-4-(((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (2-2) (100 mg, 0.20 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (62.45 mg, 0.41 mmol) in dioxane (2 mL) and H2O (0.4 mL) were added K2CO3(84.05 mg, 0.61 mmol) and Pd(dppf)Cl2·CH2Cl2 (16.51 mg, 0.020 mmol). After stirring for 3 h at 80 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford 2-3 (60 mg, 76.82%) as a yellow solid. MS (ESI, m / z): calcd. for C17H12F5N3O2: 385.1; Found: 386.1 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0110] Step 4. Synthesis of 2-(perfluoroethyl)-4-(prop-1-en-2- yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (2-4). Into a 8 mL vial were added methyl 2-(perfluoroethyl)-4-(prop-1-en-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (2-3) (60 mg, 0.16 mmol), EtOH (3 mL) and NH2NH2·H2O (91.71 mg, 1.56 mmol, 85%) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The precipitated solids were collected by filtration and washed with hexane (10 mL x 2) to give 2-4 (40 mg, 66.67%) as a yellow solid. MS (ESI, m / z): calcd. for C16H12F5N5O: 385.1; Found: 386.1 [M + 1]+.

[0111] Step 5. Synthesis of 2-(2-(perfluoroethyl)-4-(prop-1-en-2- yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 2). Into a 8 mL vial were added 2-(perfluoroethyl)-4-(prop-1-en-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carbohydrazide (2-4) (40 mg, 0.10 mmol), CH(OCH3)3(2 mL) and TsOH (8.94 mg, 0.052 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under a N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep-HPLC with the following conditions: Column, X-Bridge Shield RP18 OBD Column, 5um, 19x150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm to afford Example 2 (7 mg, 17.06%) as a yellow solid.Attorney Docket No. 71180-431269 (ASP-078-WO) Example 3. 2-(4-Bromo-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4- oxadiazole

[0112] Step(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (3-1). A solution of methyl 2-(perfluoroethyl)-4-(((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (2-2) (650 mg, 1.32 mmol) in 30% HBr / AcOH (13 mL) was stirred for 3 h at 80 °C under a N2 atmosphere. The mixture was allowed to cool down to room temperature and diluted with H2O (26 mL). The precipitated solids were collected by filtration and washed with hexane (25 mL x 2) to give 3-1 (400 mg, 60.84%) as a yellow solid. MS (ESI, m / z): calcd. for C14H7BrF5N3O2: 423.0; Found: 424.0 [M + 1]+.

[0113] Step 2. Synthesis of 4-bromo-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (3-2). Into a 8 mL vial were added methyl 4-bromo-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (3-1) (100 mg, 0.24 mmol), EtOH (3 mL) and NH2NH2·H2O (138.86 mg, 2.36 mmol, 85%) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The precipitated solids were collectedAttorney Docket No. 71180-431269 (ASP-078-WO) by filtration and washed with hexane (10 mL x 2) to give 3-2 (48 mg, 48.00%) as a yellow solid. MS (ESI, m / z): calcd. for C13H7BrF5N5O: 423.0; Found: 424.0 [M + 1]+.

[0114] Step 3. Synthesis of 2-(4-bromo-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 3). Into a 8 mL vial were added 4-bromo-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (3-2) (48 mg, 0.11 mmol), CH(OCH3)3(3 mL) and TsOH (9.74 mg, 0.057 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under a N2 atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, X-Bridge Shield RP18 OBD Column, 5um, 19x150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm to afford Example 3 (9 mg, 18.32%) as a yellow solid. Example 4. 2-(2,4-Bis(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4- oxadiazole

[0115] Step 1. Synthesis of methyl 2,4-bis(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (4-1). To a solution of methyl 4-bromo-2-Attorney Docket No. 71180-431269 (ASP-078-WO) (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (3-1) (300 mg, 0.71 mmol) and CF3CF2CO2Na (394.72 mg, 2.12 mmol) in DMF (6 mL) were added CuI (134.71 mg, 0.71 mmol). After stirring for 2 h at 130 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was added water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3 (v / v)) to afford 4-1 (65 mg, 19.84%) as a yellow solid. MS (ESI, m / z): calcd. for C16H7F10N3O2: 463.0; Found: 464.0 [M + 1]+.

[0116] Step 2. Synthesis of 2,4-bis(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine- 8-carbohydrazide (4-2). Into a 8 mL vial were added methyl 2,4- bis(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (4-1) (65 mg, 0.14 mmol), EtOH (3 mL) and NH2NH2·H2O (82.64 mg, 1.40 mmol, 85%) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The precipitated solids were collected by filtration and washed with hexane (10 mL x2) to give 4-2 (40 mg, 59.11%) as a yellow solid. MS (ESI, m / z): calcd. for C15H7F10N5O: 463.0; Found: 464.0 [M + 1]+.

[0117] Step 3. Synthesis of 2-(2,4-bis(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 4). Into a 8 mL vial were added 2,4- bis(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (4-2) (40 mg, 0.083 mmol), CH(OCH3)3(4 mL) and TsOH (7.14 mg, 0.042 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure.Attorney Docket No. 71180-431269 (ASP-078-WO) The crude product was purified by Prep-HPLC with the following conditions: Column, X-Bridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm. to afford Example 4 (10 mg, 25.48%) as a yellow solid. Example 5. 2-(5-Chloro-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazole

[0118] Step 1. Synthesis of methyl 5-chloro-2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (5-1). A mixture of methyl 2,4-bis(trifluoromethyl)pyrido[3’,2’:4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (1-9) (150 mg, 0.41 mmol) and N-chlorosuccinimide (82.12 mg, 0.62 mmol) in DMF (3 mL) was stirred for 12 h at room temperature. The mixture was poured into water (80 mL) and was extracted with EA (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE and THFAttorney Docket No. 71180-431269 (ASP-078-WO) (1: 4 (v / v)) to afford 5-1 (120 mg, 73.07%) as a yellow solid. MS (ESI, m / z): calcd. for C14H6ClF6N3O2: 397.0; Found: 397.9 [M + 1]+.

[0119] Step 2. Synthesis of 5-chloro-2,4-bis(trifluoromethyl)pyrido[3’,2’:4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (5-2). A mixture of methyl 5-chloro-2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (5-1) (80 mg, 0.20 mmol) and NH2NH2·H2O (118.48 mg, 2.01 mmol) in EtOH (2 mL) was stirred for 2 h at room temperature. The mixture was filtered, and the filter cake was washed with ice EtOH 3 times. The filter cake was dried to give the crude product 5-2 (70 mg, 87.50%) as a brown solid, which was used into the next step reaction directly. MS (ESI, m / z): calcd. for C13H6ClF6N5O: 397.0; Found: 398.0 [M + 1]+.

[0120] Step 3. Synthesis of 2-(5-chloro-2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 5). A mixture of 5-chloro-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carbohydrazide (5-2) (23 mg, 0.06 mmol) and TsOH (4.98 mg, 0.03 mmol) in CH(OMe)3(1 mL) was stirred for 4 h at 70°C. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep-HPLC to afford Example 5 (8 mg, 33.90%) as a yellow solid.Attorney Docket No. 71180-431269 (ASP-078-WO) Example 6. 2-(5-Methyl-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazole

[0121] Stepbis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (6-2). A solution of methyl 5-bromo-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (6-1) (200 mg, 0.45 mmol) in dioxane (5 mL) and water (1 mL) was treated with trimethyl- 1,3,5,2,4,6-trioxatriborinane (567.87 mg, 4.52 mmol), Na2CO3(389.31 mg, 1.35 mmol) and Pd(dppf)Cl2 (98.72 mg, 0.14 mmol) for 4 h at 90°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and then poured into water (100 mL). The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (80 mL) and dried over anhydrous NaSO4 (5 g). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE and THF (1: 4 (v / v)) to afford 6-2 (100 mg, 58.60%) as a light brown solid. MS (ESI, m / z): calcd. for C15H9F6N3O2: 377.1; Found: 378.0 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0122] Step 2. Synthesis of 5-methyl-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (6-3). A mixture of methyl 5-methyl-2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (6-2) (100 mg, 0.27 mmol) and NH2NH2·H2O (159.60 mg, 2.71 mmol) in EtOH (2 mL) was stirred for 3 h at room temperature. The mixture was filtered and the filter cake was washed with ice EtOH for 3 times. The filter cake was dried to give the crude product 6-3 (90 mg, 90.00%) as a brown solid, which was used into the next step reaction directly. MS (ESI, m / z): calcd. for C14H9F6N5O: 377.1; Found: 378.0 [M + 1]+.

[0123] Step 3. Synthesis of 2-(5-methyl-2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 6). A mixture of 5-methyl-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carbohydrazide (14-3) (90 mg, 0.24 mmol) and TsOH (20.54 mg, 0.12 mmol) in CH(OMe)3(1 mL) was stirred for 4 h at 70°C. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC to afford Example 6 (12 mg, 13.00%) as a yellow solid.Attorney Docket No. 71180-431269 (ASP-078-WO) Example 7. 2-(2-(Perfluoroethyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazole

[0124] Step 1.(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (7-1). A mixture of methyl 4-bromo-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (3-1) (200 mg, 0.47 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (634.14 mg, 3.30 mmol) and CuI (718.47 mg, 3.78 mmol) in DMF (2 mL) was stirred for 6 h at 100°C under nitrogen atmosphere. The mixture was then allowed to cool down to room temperature. The reaction was diluted with H2O (20 mL), and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA: PE (2:1) to afford 7-1 (50 mg, 25.66%) as a yellow solid. MS (ESI, m / z): calcd. for C15H7F8N3O2: 413.0; Found: 414.1 [M + 1]+.

[0125] Step 2. Synthesis of 2-(perfluoroethyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (7-2). A solutionAttorney Docket No. 71180-431269 (ASP-078-WO) of methyl 2-(perfluoroethyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (7-1) (50 mg, 0.12 mmol) and NH2NH2·H2O (0.1 mL) in EtOH (1.0 mL) was stirred for 6 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to give 7-2 (40 mg, 80.00%) as a yellow solid. MS (ESI, m / z): calcd. for C14H7F8N5O: 413.1; Found: 414.2 [M + 1]+.

[0126] Step 3. Synthesis of 2-(2-(perfluoroethyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 7). A solution of 2-(perfluoroethyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carbohydrazide (7-2) (40 mg, 0.097 mmol) and TsOH (8.33 mg, 0.049 mmol) in CH(OMe)3(1 mL) was stirred for 4 h at 70°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions: XSelect C18 Column, 5 um, 19 * 150 mm; mobile phase, water (0.1% NH3·H2O) and MeCN (45% Phase B to 90% in 7 min); Detector, UV 254 nm, to give Example 7 (2.1 mg, 5.13%) as a yellow solid.Attorney Docket No. 71180-431269 (ASP-078-WO) Example 8. 2-(4-(2-Fluoropropan-2-yl)-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin- 8-yl)-1,3,4-oxadiazole

[0127] Step 1. Synthesis of methyl 4-(2-hydroxypropan-2-yl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (8-1). A solution of methyl 2-(perfluoroethyl)-4-(prop-1-en-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (2-3) (270 mg, 0.70 mmol) in i-PrOH (5 mL) was treated with Mn(Dpm)3 (119.91 mg, 0.21 mmol) at room temperature under oxygen atmosphere followed by the addition of PhSiH3 (151.20 mg, 1.40 mmol) dropwise at -10°C. The final reaction mixture was stirred for 2 h at -10°C. After completion of the reaction (monitored by LCMS), the mixture was allowed to warm to room temperature and then poured into water (80 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:4 (v / v)) to afford 8-1 (100 mg, 35.38%) as a yellow solid. MS (ESI, m / z): calcd. for C17H14F5N3O3: 403.1; Found: 404.1 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0128] Step 2. Synthesis of methyl 4-(2-fluoropropan-2-yl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (8-2). To a solution of methyl 4-(2-hydroxypropan-2-yl)-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (8-1) (100 mg, 0.25 mmol) in DCM (3 mL) was added DAST (155.25 mg, 0.75 mmol) dropwise at -78°C. The final reaction mixture was stirred for 4 h at -78°C. After completion of the reaction (monitored by LCMS), the mixture was poured into cooled saturated NaHCO3(aq.) (50 mL). The resulting mixture was extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:3 (v / v)) to afford 8-2 (80 mg, 79.61%) as a yellow solid. MS (ESI, m / z): calcd. for C17H13F6N3O2: 405.1; Found: 406.1 [M + 1]+.1H NMR (300 MHz, CDCl3): δ 9.55 (s, 1H), 9.19 (s, 1H), 7.81 (s, 1H), 7.34 – 7.24 (m, 1H), 4.09 (s, 3H), 2.00 (s, 3H), 1.92 (s, 3H) ppm.

[0129] Step 3. Synthesis of 4-(2-fluoropropan-2-yl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (8-3). A solution methyl 4-(2-fluoropropan-2-yl)-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (8-2) (80 mg, 0.20 mmol) and NH2NH2·H2O (0.2 mL) in EtOH (2 mL) was refluxed for 4 h. The resulting mixture was concentrated under reduced pressure to offer the crude product 8-3 (60 mg, 75.00 %) as brown solid. MS (ESI, m / z): calcd. for C16H13F6N5O: 405.1; Found: 406.1 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0130] Step 4. Synthesis of 2-(4-(2-fluoropropan-2-yl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 8). A mixture of 4-(2-fluoropropan-2-yl)-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine- 8-carbohydrazide (8-3) (60 mg, 0.15mmol) and TsOH (12.75 mg, 0.07 mmol) in CH(OMe)3 (1 mL) was stirred for 4 h at 70°C. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC, XSelect CSH Prep C18 OBD Column, 19*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 30 mL / min; Gradient: 45% B to 67% B in 8 min; Wavelength: 220 nm, 254nm; RT1(min): 6.80; to afford Example 8 (2.90 mg, 4.72 %) as a yellow solid. Example 9. 2-(2-(Prop-1-en-2-yl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8- yl)-1,3,4-oxadiazole

[0131] Step 1. Synthesis of 6-chloro-3,5-diiodo-4-(trifluoromethyl)pyridin-2-amine (9-2). To a solution of 6-chloro-4-(trifluoromethyl)pyridin-2-amine (9-1) (15 g, 76.31 mmol) in DMFAttorney Docket No. 71180-431269 (ASP-078-WO) (300 mL) and TFA (30 mL) was added NIS (51.51 g, 228.94 mmol). After stirring for 6 h at 80 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (450 mL). The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford 9-2 (20 g, 58.45%) as a brown solid. MS (ESI, m / z): calcd. for C6H2ClF3I2N2: 447.8; Found: 448.8 [M + 1]+.

[0132] Step 2. Synthesis of 6-chloro-3-iodo-4-(trifluoromethyl)pyridin-2-amine (9-3). To a solution of 6-chloro-3,5-diiodo-4-(trifluoromethyl)pyridin-2-amine (9-2) (20 g, 44.61 mmol) in THF (400 mL) was added dropwise n-BuLi solution (2.5 M in THF / hexane, 21.41 mL, 53.53 mmol) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 2 h. The reaction was quenched with sat. NH4Cl (600 mL), and then the mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford 9-3 (9.5 g, 66.05%) as a yellow solid. MS (ESI, m / z): calcd. for C6H3ClF3IN2: 321.9; Found: 322.9 [M + 1]+.

[0133] Step 3. Synthesis of 6-chloro-3-(3,3-diethoxyprop-1-yn-1-yl)-4- (trifluoromethyl)pyridin-2-amine (9-4). To a solution of 6-chloro-3-iodo-4- (trifluoromethyl)pyridin-2-amine (9-3) (4 g, 12.41 mmol) and 3,3-diethoxyprop-1-yne (4.77 g, 37.22 mmol) in DMF (80 mL) were added TEA (7.53 g, 74.43 mmol), Pd(Ph3P)2Cl2 (870.71 mg, 1.24 mmol) and CuI (236.25 mg, 1.24 mmol). After stirring for 10 h at 60 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (120 mL). The resulting mixture was extracted with EtOAc (80 mL x 3).Attorney Docket No. 71180-431269 (ASP-078-WO) The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford 9-4 (1.6 g, 39.97%) as a brown solid. MS (ESI, m / z): calcd. for C13H14ClF3N2O2: 322.1; Found: 323.0 [M + 1]+.

[0134] Step 4. Synthesis of 6-chloro-2-(diethoxymethyl)-4-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridine (9-5). To a solution of 6-chloro-3-(3,3-diethoxyprop-1-yn-1-yl)-4- (trifluoromethyl)pyridin-2-amine (9-4) (1.6 g, 4.96 mmol) in NMP (32 mL) was added t-BuOK (1.11 g, 9.92 mmol). After stirring for 10 h at 50 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The resulting mixture was diluted with 0.5 M HCl (64 mL). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford 9-5 (1.1 g, 68.75%) as a yellow solid. MS (ESI, m / z): calcd. for C13H14ClF3N2O2: 322.1; Found: 322.9 [M + 1]+.

[0135] Step 5. Synthesis of methyl 2-[bis(tert-butoxycarbonyl)amino]-3-[6-chloro-2- (diethoxymethyl)-4-(trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]propanoate (9-6). To a solution of 6-chloro-2-(diethoxymethyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (9-5) (1.1 g, 3.41 mmol) in MeCN (33 mL) were added methyl 2-[bis(tert-butoxycarbonyl)amino]prop-2- enoate (1.03 g, 3.41 mmol) and K2CO3 (1.42 g, 10.23 mmol). After stirring for 24 h at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (30 mL x 3). The filtrate was concentrated under reduced pressure. The residueAttorney Docket No. 71180-431269 (ASP-078-WO) was purified by silica gel column chromatography, eluted with EA / PE (1:10) to afford 9-6 (2.1 g, 98.72%) as a yellow solid. MS (ESI, m / z): calcd. for C27H37ClF3N3O8: 623.2; Found: 646.2 [M + 23]+.

[0136] Step 6. Synthesis of methyl 2-chloro-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-7). A solution of methyl 2-[bis(tert-butoxycarbonyl)amino]-3-[6-chloro-2-(diethoxymethyl)-4- (trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]propanoate (9-6) (1.8 g, 2.88 mmol) in FA (36 mL) was stirred for 30 min at room temperature. To the above mixture was added SeO2 (0.64 g, 5.77 mmol) and the resulting mixture was stirred for another 16 h. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford 9-7 (700 mg, 73.62%) as an orange solid. MS (ESI, m / z): calcd. for C13H7ClF3N3O2: 329.0; Found: 330.0 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 9.21 (s, 1H), 8.18 (s, 1H), 7.40 (s, 1H),3H) ppm.

[0137] Step 7. Synthesis of methyl 2-(prop-1-en-2-yl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (9-8). To a solution of methyl 2-chloro-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate 9-7) (320 mg, 0.97 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (489.35 mg, 2.91 mmol) in dioxane (6.4 mL) and H2O (0.6 mL) were added K2CO3 (402.47 mg, 2.91 mmol) and Pd(dppp)Cl2 (57.25 mg, 0.097 mmol). After stirring for 6 h at 100 °C under a nitrogen atmosphere, the mixture was allowed to cool down to room temperature. The resultingAttorney Docket No. 71180-431269 (ASP-078-WO) mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford 9-8 (210 mg, 64.52%) as a yellow solid. MS (ESI, m / z): calcd. for C16H12F3N3O2: 335.1; Found: 336.1 [M + 1]+.

[0138] Step 8. Synthesis of 2-(prop-1-en-2-yl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (9-9). Into a 8 mL vial were added methyl 2-(prop-1-en-2-yl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (9-8) (90 mg, 0.27 mmol), EtOH (4 mL) and NH2NH2•H2O (134.38 mg, 2.68 mmol) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The precipitated solids were collected by filtration and washed with hexane (10 mL x 2), which provided 9-9 (50 mg, 55.55%) as a yellow solid. MS (ESI, m / z): calcd. for C15H12F3N5O: 335.1; Found: 336.1 [M + 1]+.

[0139] Step 9. Synthesis of 2-(2-(prop-1-en-2-yl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 9). Into a vial were added 2-(prop-1-en-2-yl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (9-9) (50 mg, 0.15 mmol), CH(OCH3)3 (3 mL) and TsOH (12.84 mg, 0.074 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions(Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm) to afford Example 9 (19 mg, 36.90%) as a yellow solid.Attorney Docket No. 71180-431269 (ASP-078-WO) Example 10. 2-(2-Isopropyl-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazole(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (10-1). To a solution of methyl 2-(prop-1-en-2-yl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (9-8) (120 mg, 0.36 mmol) in EA (5 mL) was added Pd / C (38.09 mg, 0.036 mmol, 10%) under nitrogen atmosphere in a 50-mL round-bottom flask. The mixture was hydrogenated at room temperature for 3 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford 10-1 (80 mg, 66.27%) as a yellow solid. MS (ESI, m / z): calcd. for C16H14F3N3O2: 337.1; Found: 338.1 [M + 1]+.

[0141] Step 2. Synthesis of 2-isopropyl-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (10-2). Into a 8 mL vial were added methyl 2-isopropyl-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (10-1) (80 mg, 0.24 mmol), EtOH (5 mL) and NH2NH2•H2O (118.73 mg, 2.37 mmol) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The precipitated solids were collected by filtration and washed with hexane (10 mL x 2). This resulted in 10-2 (60 mg, 75.00%) as a yellow solid. MS (ESI, m / z): calcd. for C15H14F3N5O: 337.1; Found: 338.1 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0142] Step 3. Synthesis of 2-(2-isopropyl-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 10). Into a vial were added 2-isopropyl-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (10-2) (60 mg, 0.18 mmol), CH(OMe)3(3 mL) and TsOH (15.32 mg, 0.089 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm. to afford Example 10 (22 mg, 35.61%) as a yellow solid. Example 11. 2-(4-(1-Methylcyclopropyl)-2-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole

[0143] Step 1. Synthesis of methyl 4-(prop-1-en-2-yl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (11-2). To a solution of methyl 2-(trifluoromethyl)-4-(((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (11-1) (300 mg, 0.68 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2- yl)-1,3,2-dioxaborolane (136.50 mg, 0.81 mmol) in dioxane (6 mL) were added K2CO3 (280.60Attorney Docket No. 71180-431269 (ASP-078-WO) mg, 2.03 mmol) and Pd(dppf)Cl2(49.52 mg, 0.068 mmol). After stirring for 1 h at 80 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford 11-2 (210 mg, 92.55%) as a yellow solid. MS (ESI, m / z): calcd. for C16H12F3N3O2: 355.1; Found: 336.1 [M+1]+.

[0144] Step 2. Synthesis of methyl 4-(1-methylcyclopropyl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (11-3). To a solution of Et2Zn (209.96 mg, 1.70 mmol) in DCM (5 mL) at 10 °C was added dropwise a solution of TFA (193.84 mg, 1.70 mmol) in DCM (2 mL). The resulting solution was stirred for 20 min. Then CH2I2 (455.33 mg, 1.70 mmol) was added dropwise. After 45 min, of stirring a white precipitate was formed and a solution of methyl 4-(prop-1-en-2-yl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (11-2) (190 mg, 0.57 mmol) in DCM (2 mL) was slowly added. The resulting mixture was allowed to warm to room temperature overnight. The reaction was quenched with 10% aqueous HCl (10 mL). The mixture was extracted with DCM (10 mL x 3), the combined organic layers were washed with saturated aqueous NaHCO3(10 mL x 3), brine (10 mL). The solution was dried over Na2SO4and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford 11-3 (50 mg, 25.26%) as a yellow solid. MS (ESI, m / z): calcd. for C17H14F3N3O2: 349.1; Found: 350.1 [M+1]+.

[0145] Step 3. Synthesis of 4-(1-methylcyclopropyl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (11-4). Into a 8 mL vial were added methyl 4-(1-methylcyclopropyl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (11-3) (50 mg, 0.14 mmol), EtOH (3 mL) and NH2NH2•H2O (71.66 mg, 1.43 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 11-4 (35 mg, 70.00%) as a yellow solid. MS (ESI, m / z): calcd. for C16H14F3N5O: 349.1; Found: 350.1 [M+1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0146] Step 4. Synthesis of 2-(4-(1-methylcyclopropyl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 11). Into a vial were added 4-(1-methylcyclopropyl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (11-4) (35 mg, 0.10 mmol), CH(OMe)3(3 mL) and TsOH (8.63 mg, 0.050 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm. to afford Example 11 (12 mg, 33.33%) as a yellow solid. Example 12. 2-(2-(1-Fluorocyclopropyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazoleAttorney Docket No. 71180-431269 (ASP-078-WO)

[0147] Step 1. Synthesis methyl 2-(1-ethoxyvinyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-1). Into a 40 mL vial were added methyl 2-chloro-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (9-7) (950 mg, 2.88 mmol), dioxane (19 mL), tributyl(1-ethoxyvinyl)stannane (3.12 g, 8.65 mmol) and Pd(PPh3)2Cl2 (202.27 mg, 0.29 mmol) at room temperature. The resulting mixture was stirred for 3 h at 110 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 12-1 (800 mg, 75.99%) as a yellow oil. MS (ESI, m / z): calcd. for C17H14F3N3O3: 365.1; Found: 366.1 [M + 1]+.

[0148] Step 2. Synthesis of methyl 2-acetyl-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-2). To a solution of methyl 2-(1-ethoxyvinyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (12-1) (800 mg, 2.19 mmol) in THF (24 mL) was added HCl / dioxane (6 M) (8 mL) at 0°C and the reaction was stirred for 3 h at room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH2Cl2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with hexane (30 mL). The precipitated solids were collected by filtration and washed with hexane (2 x 10 mL). This resulted in 12-2 (650 mg, 88.01%) as a yellow solid. MS (ESI, m / z): calcd. for C15H10F3N3O3: 337.1; Found: 338.1 [M+1]+.

[0149] Step 3. Synthesis of methyl 2-(1-((tert-butyldimethylsilyl)oxy)vinyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-3). Into a 40 mLAttorney Docket No. 71180-431269 (ASP-078-WO) vial were added methyl 2-acetyl-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (12-2) (650 mg, 1.93 mmol), ACN (13 mL), tert-Butyldimethylsilyl chloride (435.73 mg, 2.89 mmol), NaI (433.34 mg, 2.89 mmol) and TEA (390.06 mg, 3.854 mmol) at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 12-3 (600 mg, 68.95%) as a yellow solid. MS (ESI, m / z): calcd. for C21H24F3N3O3Si: 451.2; Found: 452.4 [M+1]+.

[0150] Step 4. Synthesis of methyl 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-4). Into a 40 mL vial were added CH2I2 (1.78 g, 6.65 mmol), DCM (12 mL) and Et2Zn (820.77 mg, 6.65 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. Then the methyl 2-(1-((tert-butyldimethylsilyl)oxy)vinyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-3) (600 mg, 1.33 mmol) was added. The resulting mixture was stirred overnight at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CH2Cl2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 12-4 (430 mg, 69.51%) as a yellow solid. MS (ESI, m / z): calcd. for C22H26F3N3O3Si: 465.2; Found: 466.1 [M+1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0151] Step 5. Synthesis of methyl 2-(1-hydroxycyclopropyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-5). Into a 40 mL vial were added methyl 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-4) (430 mg, 0.92 mmol) and HCl (6M in dioxane, 9 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 12-5 (165 mg, 50.85%) as a yellow solid. MS (ESI, m / z): calcd. for C16H12F3N3O3: 351.1; Found: 352.0 [M+1]+.

[0152] Step 6. Synthesis of methyl 2-(1-fluorocyclopropyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (12-6). To a solution of methyl 2-(1-hydroxyethyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (12-5) (165 mg, 0.49 mmol) in DCM (4 mL) was added DAST (90.19 mg, 2.43 mmol) dropwise at -78 °C. The reaction was then warmed to room temperature and stirred for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.5% formic acid aqueous solution in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 12-6 (30 mg, 17.46%) as a yellow solid. MS (ESI, m / z): calcd. for C16H11F4N3O2: 353.1; Found: 354.1 [M + 1]+.1H NMR (400 MHz, DMSO-d6): δ 9.31 (dd, J = 16, 1.6 Hz, 2H), 8.07 (s, 1H), 7.37 (s, 1H), 3.93 (s, 3H), 1.78 – 1.68 (m, 4H) ppm.

[0153] Step 7. Synthesis of 2-(1-fluorocyclopropyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (12-7). AAttorney Docket No. 71180-431269 (ASP-078-WO) mixture of methyl 2-(1-fluorocyclopropyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (12-6) (30 mg, 0.085 mmol) and NH2NH2•H2O (1.1 mL) in EtOH (11 mL) was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product 12-7 which was used for next reaction. MS (ESI, m / z): calcd. for C15H11F4N5O: 353.1; Found: 354.1 [M + 1]+.

[0154] Step 8. Synthesis of 2-(2-(1-fluorocyclopropyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 12). A mixture of 2-(1-fluorocyclopropyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (12-7) (23 mg, 0.065 mmol) and TsOH (25 mg, 0.13 mmol) in CH(OMe)3(11 mL) was stirred for 4 h at 70°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 60% B in 8 min, 60% B; Wavelength: 254 nm, to afford Example 12 (3.7 mg, 10.19%) as a yellow solid. Example 13. 2-(5-Nitro-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazoleAttorney Docket No. 71180-431269 (ASP-078-WO)

[0155] Step 1, 5-nitro-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylic acid (13-2). To the suspension of 2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylic acid (13-1) (500.0 mg, 1.43 mmol) in conc. H2SO4 (5 mL) was added dropwise conc. HNO3 (5 mL). The reaction mixture was stirred at 40 °C. After completion (HPLC control) the mixture was poured onto ice water and filtered to give pure 13-2 (400 mg, 70% yield) as a yellow powder. MS (ESI, m / z): calcd. for C13H4F6N4O4: 394.0, MS Found: 395.0 [M + 1]+.

[0156] Step 2, 2-(5-nitro-2,4-bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8- yl)-1,3,4-oxadiazole (Example 13). To the suspension of 5-nitro-2,4- bis(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylic acid (13-2) (60.0 mg, 152.28 µmol) in DCM (5 mL) was added N-isocyaniminotriphenylphosphorane (69.02 mg, 0.23 mmol). After completion (HPLC control) the solution was concentrated in vacuo and purified by prep-HPLC to give pure Example 13 (10 mg, 15.8% yield). Example 14. 2-(2-Methyl-4-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4- oxadiazoleAttorney Docket No. 71180-431269 (ASP-078-WO)

[0157] Step 1. Synthesis of (E)-methyl 6-((5,5,6,6,6-pentafluoro-4-oxohex-2-en-2- yl)amino)pyrrolo[1,2-a]pyrazine-3-carboxylate (14-1). To the solution of methyl 6- aminopyrrolo[1,2-a]pyrazine-3-carboxylate hydrochloride (1-8 HCl) (300.0 mg, 1.32 mmol) in MeOH (10 mL) (4E)-1,1,1,2,2-pentafluoro-5-methoxyhex-4-en-3-one (575.63 mg, 2.64 mmol), and triethylamine (266.96 mg, 2.64 mmol) were added at rt. The obtained solution was stirred at RT for 2 h, then heated to 60°C and stirred overnight. After completion reaction the mixture was concentrated in vacuo. The residue was suspended in water and filtered, dried on air overnight to give pure 14-1 (420 mg, 84% yield) as a yellow solid. MS (ESI, m / z): calcd. for C15H12F5N3O3: 377.1, MS Found: 377.9 [M + 1]+.

[0158] Step 2. Synthesis of methyl 2-methyl-4- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (14-2). To the freshly prepared PPA (4 g), methyl (E)-6-((5,5,6,6,6-pentafluoro-4-oxohex-2-en-2- yl)amino)pyrrolo[1,2-a]pyrazine-3-carboxylate (14-1) (420.0 mg, 1.11 mmol) was added at 80°C. The obtained solution was stirred at 120°C for 3 d. Then it was poured onto crushed ice. The product was extracted with EtOAc. The combined extracts were evaporated in vacuo toAttorney Docket No. 71180-431269 (ASP-078-WO) afford the crude residue mixture of 14-2 and 14-3. The mixture was dissolved in MeOH and conc H2SO4 (0.5 mL) was added, and this solution was refluxed overnight. After concentration, the residue was partitioned between sat. aq. NaHCO3and EtOAc, extracted with EtOAc, and evaporated. The crude product was purified by flash chromatography to give pure 14-2 (100 mg, 25% yield) as a yellow solid. MS (ESI, m / z): calcd. for C15H10F5N3O2: 359.1, MS Found: 360.0 [M + 1]+

[0159] Step 3. Synthesis of 2-methyl-4-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylic acid (14-3). To a stirred solution of Methyl 2-methyl-4- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (14-2) (100.0 mg, 278.5 µmol) in a mixture of dioxane and water (8 mL, 4:1), LiOH hydrate (23.4 mg, 556.74 µmol) was added and the reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was acidified with diluted HCl (1.5 N, to pH = 2) and diluted with water (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic solution was washed with brine (10 mL), dried over Na2SO4 and evaporated in vacuo to give acid 14-3 (90 mg, 94% yield). MS (ESI, m / z): calcd. for C14H8F5N3O2: 345.1, MS Found: 346.0 [M + 1]+.

[0160] Step 4. Synthesis of 2-(2-methyl-4-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 14). To the suspension of 2-Methyl-4- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylic acid (14-3) (90.0 mg, 260.83 µmol) in DCM (10 mL) N-isocyaniminotriphenylphosphorane (118.18 mg, 391.2 µmol) was added. After completion (HPLC control) the solution was concentrated in vacuo and purified by prep-HPLC to give pure Example 14 (13.3 mg, 13.8% yield).Attorney Docket No. 71180-431269 (ASP-078-WO) Example 15. 2-(2-(Perfluoroethyl)-4-phenylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4- oxadiazole

[0161] Step 1. Synthesis of methyl 2-(perfluoroethyl)-4- phenylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (15-1). A solution of methyl 2- (perfluoroethyl)-4-(((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (2-2) (200.00 mg, 0.41 mmol) dioxane (10 mL) was treated with phenylboronic acid (98.87 mg, 0.81 mmol), K2CO3(170.00 mg, 1.23 mmol) and Pd(dppf)Cl2(30.00 mg, 0.04 mmol) for 2 h at 80°C under nitrogen atmosphere. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature and then poured into water (40 mL). The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with eluted with PE / EA (1:2) to afford 15-1 (160 mg, 93.66 %) as a yellow solid. MS (ESI, m / z): calcd. for C20H12F5N3O2:421.1; Found: 422.0[M + 1]+.

[0162] Step 2. Synthesis of 2-(perfluoroethyl)-4-phenylpyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (15-2). A solution of methyl 2-(perfluoroethyl)-4- phenylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (15-1) (160 mg, 0.38 mmol) andAttorney Docket No. 71180-431269 (ASP-078-WO) NH2NH2•H2O (1.5 mL) in EtOH (15 mL) was stirred for 2 h at 70℃. After completion of the reaction (monitored by LCMS), the mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with cool EtOH (2 mL x 3). This resulted in crude 15-2 (110 mg, 68.75 %) as yellow solid. MS (ESI, m / z): calcd. for C19H12F5N5O: 421.1; Found: 422.1 [M + 1]+

[0163] Step 3. Synthesis of 2-(2-(perfluoroethyl)-4-phenylpyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 15). A mixture of 2-(perfluoroethyl)-4- phenylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (15-2) (110 mg, 0.26 mmol) and TsOH (80.92 mg, 0.47 mmol) in CH(OMe)3 (3 mL) was stirred for 4 h at 70°C. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC Column, Xselect CSH Fluoro-Phenyl , 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN(0.1%FA); Flow rate: 20 mL / min; Gradient: 45% B to 53% B in 8 min,53% B to 53%B in 3mim; Wave Length: 254 / 220 nm to afford Example 15 (49.00 mg, 43.51 %) as a yellow solid. Example 16. 2-(2-(p-Tolyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4- oxadiazole

[0164] Step 1. Synthesis of methyl 2-(p-tolyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (16-1). To a stirredAttorney Docket No. 71180-431269 (ASP-078-WO) mixture of methyl 2-chloro-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (9-7) (135 mg, 0.41 mmol) and p-tolylboronic acid (105.53 mg, 1.23 mmol) in dioxane / H2O (10 / 1, 11 mL) were added Pd(dppf)Cl2(29.96 mg, 0.041 mmol) and K2CO3(169.79 mg, 1.23 mmol) for 6 h at 100 °C under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford 16-1 (90.0 mg, 56.97%) as a yellow solid. MS (ESI, m / z): calcd. for C20H14F3N3O2: 385.1; Found: 386.1 [M + 1]+.1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.27 (d, J = 1.2 Hz, 1H), 8.51 (s, 1H), 8.35= 6 Hz, 2H), 7.42 (d, J = 5.7 Hz, 2H), 7.34 (s, 1H), 3.95 (s, 3H), 2.94 (s, 3H) ppm.

[0165] Step 2. Synthesis of 2-(p-tolyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (16-2). A mixture of 2-(p-tolyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (16-1) (90 mg, 0.46 mmol) and NH2NH2.H2O (1.1 mL) in EtOH (2 mL) was stirred for 6 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 16-2 (65 mg, crude) as a yellow oil. MS (ESI, m / z): calcd. for C19H14F3N5O: 385.1; Found: 386.1 [M + 1]+.

[0166] Step 3. Synthesis of 2-(2-(p-tolyl)-4-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 16). A mixture of 2-(p-tolyl)-4- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (16-2) (65 mg, 0.17Attorney Docket No. 71180-431269 (ASP-078-WO) mmol) and TsOH (64.0 mg, 0.34 mmol) in CH(OMe)3(2 mL) was stirred for 4 h at 70°C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 30 mL / min; Gradient: 50% B to 80% B in 8 min, 80% B; Wave Length: 254nm. This resulted in Example 16 (19.6 mg, 18.19%) as a yellow solid. Example 17. 2-(4-(4-Chlorophenyl)-2-cyclopentylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)- 1,3,4-oxadiazoleAttorney Docket No. 71180-431269 (ASP-078-WO)

[0167] Step 1. Synthesis of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (17-2). To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (17-1) (25 g, 126.88 mmol) in DCM (1.5 L) was added m-CPBA (32.84 g, 190.32 mmol) at 0°C and the reaction mixture was stirred overnight at room temperature. The resulting mixture was diluted with diethyl ether (3 L). The precipitated solids were collected by filtration and washed with diethyl ether (500 mL x 3). This resulted in 17-2 (26 g, 96.19%) as a brown solid. MS (ESI, m / z): calcd. for C7H5BrN2O: 212.0; Found: 213.0 [M+1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0168] Step 2. Synthesis of 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (17-3). A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (17-2) (26 g, 122.046 mmol) and MsCl (34.95 g, 305.12 mmol) in DMF (520 mL) was stirred for 5 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 17-3 (12 g, 42.48%) as a white solid. MS (ESI, m / z): calcd. for C7H4BrClN2: 229.9; Found: 273.9 [M+23+41]+.

[0169] Step 3. Synthesis of 4-bromo-6-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (17-4). To a solution of 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (17-3) (12 g, 51.84 mmol) in THF (240 mL) was added NaH (4.15 g, 103.68 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred for 15 min and TsCl (14.82 g, 77.76 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was quenched by ice water (300 mL). The resulting mixture was extracted with EtOAc (240 mL x 3). The combined organic layers were washed with brine (240 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 17-4 (12 g, 60.02%) as a white solid. MS (ESI, m / z): calcd. for C14H10BrClN2O2S: 383.9; Found: 384.9 [M+1]+.

[0170] Step 4. Synthesis of 4-bromo-6-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2- carbaldehyde (17-5). In a 500-mL round bottom flask, to a solution of 4-bromo-6-chloro-1- tosyl-1H-pyrrolo[2,3-b]pyridine (17-4) (12 g, 31.12 mmol) in THF (240 mL) was added dropwise LDA (2 M in THF) (20.23 mL, 40.45 mmol) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then a solution of DMF (11.37 g, 155.55Attorney Docket No. 71180-431269 (ASP-078-WO) mmol) in 20 mL THF was added dropwise and the mixture was stirred for another 5.5 h. The reaction was quenched with sat. NH4Cl (300 mL), and then the mixture was extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 17-5 (8.2 g, 63.71%) as a white solid. MS (ESI, m / z): calcd. for C15H10BrClN2O3S: 411.9; Found: 412.9 [M+1]+.

[0171] Step 5. Synthesis of 4-bromo-6-chloro-2-(dimethoxymethyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridine (17-6). A solution of 4-bromo-6-chloro-1-tosyl-1H-pyrrolo[2,3- b]pyridine-2-carbaldehyde (17-5) (8.2 g, 19.82 mmol) and TsOH (0.34 g, 1.98 mmol) in CH3OH (82 mL) was stirred overnight at 65 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (160 mL). The mixture was basified to pH = 8 with sat. NaHCO3(aq.). The resulting mixture was extracted with CH2Cl2(80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 17-6 (7.5 g, 82.30%) as a white semi-solid. MS (ESI, m / z): calcd. for C17H16BrClN2O4S: 458.0; Found: 459.0 [M+1]+.

[0172] Step 6. Synthesis of 4-bromo-6-chloro-2-(dimethoxymethyl)-1H-pyrrolo[2,3- b]pyridine (17-7). A solution of 4-bromo-6-chloro-2-(dimethoxymethyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridine (17-6) (7.5 g, 16.31 mmol) and t-BuOK (3.66 g, 32.63 mmol) in DMSO (150 mL) was stirred for 6 h at 65°C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150Attorney Docket No. 71180-431269 (ASP-078-WO) mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 17-7 (4.3 g, 86.26%) as a light yellow solid. MS (ESI, m / z): calcd. for C10H10BrClN2O2: 304.0; Found: 305.0 [M+1]+.

[0173] Step 7. Synthesis of methyl 2-[bis(tert-butoxycarbonyl)amino]-3-[4-bromo-6- chloro-2-(dimethoxymethyl)pyrrolo[2,3-b]pyridin-1-yl]propanoate (17-8). A solution of 4- bromo-6-chloro-2-(dimethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (17-7) (1.4 g, 4.58 mmol), methyl 2-[bis(tert-butoxycarbonyl)amino]prop-2-enoate (1.66 g, 5.50 mmol) and K2CO3 (1.28 g, 9.16 mmol) in ACN (21 mL) was stirred for 4 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with CH2Cl2(42 mL). The resulting mixture was filtered, and the filter cake was washed with CH2Cl2 (20 mL x 3). The filtrate was concentrated under reduced pressure. This resulted in 17-8 (2.1 g, 75.52%) as a light brown oil. MS (ESI, m / z): calcd. for C24H33BrClN3O8: 605.1; Found: 606.0 [M+1]+.

[0174] Step 8. Synthesis of methyl 4-bromo-2-chloropyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (17-9). To a solution of methyl 2-[bis(tert-butoxycarbonyl)amino]-3- [4-bromo-6-chloro-2-(dimethoxymethyl)pyrrolo[2,3-b]pyridin-1-yl]propanoate (17-8) (2.1 g, 3.46 mmol) in TFA (21 mL) was stirred 30 min at room temperature. Then, SeO2(1.92 g, 17.30 mmol) was added and the mixture was stirred overnight. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gelAttorney Docket No. 71180-431269 (ASP-078-WO) column chromatography, eluted with EA / PE (1:3) to afford 17-9 (910 mg, 77.22%) as an orange solid. MS (ESI, m / z): calcd. for C12H7BrClN3O2: 338.9; Found: 339.9 [M+1]+.

[0175] Step 9. Synthesis of methyl 2-chloro-4-(4- chlorophenyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-10). To a solution of methyl 4-bromo-2-chloropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-9) (200 mg, 0.59 mmol) and (4-chlorophenyl)boronic acid (101.01 mg, 0.65 mmol) in dioxane (4 mL) and water (1 mL) were added Na2CO3(186.73 mg, 1.76 mmol) and Pd(PPh3)2Cl2(41.22 mg, 0.059 mmol). After stirring for 3 h at 100°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 17-10 (110 mg, 50.32%) as a yellow solid. MS (ESI, m / z): calcd. for C18H11Cl2N3O2: 371.0; Found: 372.1 [M+1]+.

[0176] Step 10. Synthesis of methyl 4-(4-chlorophenyl)-2-(cyclopent-1-en-1- yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-11). To a solution of methyl 2- chloro-4-(4-chlorophenyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-10) (110 mg, 0.30 mmol) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86.04 mg, 0.44 mmol) in dioxane (2 mL) were added Na2CO3(93.97 mg, 0.89 mmol) and Pd(PPh3)2Cl2(20.74 mg, 0.030 mmol). After stirring for 3 h at 110°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (10 mL x 3). The combinedAttorney Docket No. 71180-431269 (ASP-078-WO) organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 17-11 (60 mg, 50.27%) as a yellow solid. MS (ESI, m / z): calcd. for C23H18ClN3O2: 403.1; Found: 404.1 [M+1]+.

[0177] Step 11. Synthesis of methyl 4-(4-chlorophenyl)-2-cyclopentyl-8,9- dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-12). To a solution of methyl 4-(4-chlorophenyl)-2-(cyclopent-1-en-1-yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carboxylate (17-11) (60 mg, 0.15 mmol) in EA (5 mL) was added Pd / C (60 mg) in a pressure tank. The mixture was hydrogenated at 0°C under 30 psi of hydrogen pressure for 30 min, filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This resulted in 17-12 (60 mg, 99.01%) as a white solid. MS (ESI, m / z): calcd. for C23H22ClN3O2: 407.1; Found: 408.1 [M+1]+.

[0178] Step 12. Synthesis of methyl 4-(4-chlorophenyl)-2- cyclopentylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-13). Into a 8 mL vial were added methyl 4-(4-chlorophenyl)-2-cyclopentyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (17-12) (60 mg, 0.15 mmol), DCM (3 mL) and manganese dioxide (63.94 mg, 0.74 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was filtered, and the filter cake was washed with CH2Cl2(15 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 17-13 (30 mg, 50.25%) as a yellow solid. MS (ESI, m / z): calcd. for C23H20ClN3O2: 405.1; Found: 406.0 [M+1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0179] Step 13. Synthesis of 4-(4-chlorophenyl)-2-cyclopentylpyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (17-14). Into a 8 mL vial were added methyl 4-(4-chlorophenyl)- 2-cyclopentylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-13) (30 mg, 0.074 mmol), EtOH (6 mL) and NH2NH2•H2O (18.50 mg, 0.37 mmol) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 17-14 (30 mg, crude) as a yellow solid. MS (ESI, m / z): calcd. for C22H20ClN5O: 405.1; Found: 406.0 [M-1]+.

[0180] Step 14. Synthesis of 2-(4-(4-chlorophenyl)-2- cyclopentylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 17). Into a vial were added 4-(4-chlorophenyl)-2-cyclopentylpyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8- carbohydrazide (17-14) (30 mg, 0.074 mmol), CH(OCH3)3 (2 mL) and TsOH (6.36 mg, 0.037 mmol) at room temperature. The resulting mixture was stirred for 4 h at 70 °C under N2atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep- HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and ACN (45% Phase B up to 75% in 7 min); Detector, UV 254 nm. to afford Example 17 (4 mg, 13.01%) as a yellow solid. Example 18. 2-(4-(4-Chlorophenyl)-2-(1-fluorocyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-8-yl)-1,3,4-oxadiazoleAttorney Docket No. 71180-431269 (ASP-078-WO)

[0181] hydroxycyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (18-1). To a stirred solution of methyl 4-(4-chlorophenyl)-2-(cyclopent-1-en-1- yl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (17-11) (170.00 mg, 0.42 mmol) and Mn(Dpm)3 (76.37 mg, 0.12 mmol) in i-PrOH (100 mL) were added PhSiH3 (455.51 mg, 4.21 mmol) dropwise at -10 °C under O2atmosphere. The resulting mixture was slowly warmed to room temperature and stirred for 2 h. After completion of the reaction, the mixture was quenched by the addition of sat. Na2S2O3 (aq.) (50 mL) at 0 °C. The resulting mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 100% gradient in 20 min; detector, UV 254 nm afford 18-1 (75.00 mg, 42.23%) as an off- white solid. MS (ESI, m / z): calcd. for C23H20ClN3O3: 421.1; Found: 422.2 [M+1]+.1H NMRAttorney Docket No. 71180-431269 (ASP-078-WO) (300 MHz, Chloroform-d): δ 9.53 (s, 1H), 9.12 (s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.22 (s, 1H), 4.09 (s, 3H), 2.41 – 1.87 (m, 9H) ppm.

[0182] Step 2. Synthesis of methyl 4-(4-chlorophenyl)-2-(1- fluorocyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (18-2). To a stirred solution of methyl 4-(4-chlorophenyl)-2-(1-hydroxycyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (18-1) (75.00 mg, 0.18 mmol) in DCM (19 mL) were added DAST (19.78 mg, 0.53 mmol) dropwise at -78 °C under nitrogen atmosphere. After completion of the reaction, the resulting mixture was slowly warmed to room temperature and stirred for 4 h. The reaction was quenched with sat. NaHCO3 (aq.) (20 mL) at 0 °C. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 100% gradient in 50 min; detector, UV 254 nm to afford 18-2 (50.00 mg, 66.35%) as a light yellow solid. MS (ESI, m / z): calcd. for C23H19ClFN3O2: 423.1; Found: 424.2 [M+1]+.1H NMR (300 MHz, Chloroform-d): δ 9.51 (s, 1H), 9.12 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.25 (s, 1H), 4.10 (s, 3H), 2.67 – 2.08 (m, 8H) ppm.

[0183] Step 3. Synthesis of 4-(4-chlorophenyl)-2-(1- fluorocyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (18-3). A mixture of methyl 4-(4-chlorophenyl)-2-(1-fluorocyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (18-2) (50.00 mg, 0.12 mmol) and NH2NH2·H2O (118.10 mg, 2.36 mmol) in EtOH (2.5 mL) was stirred for 6 h at room temperature under nitrogen atmosphere.Attorney Docket No. 71180-431269 (ASP-078-WO) After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product 18-3 was used in the next step directly without further purification. MS (ESI, m / z): calcd. for C22H19ClFN5O: 423.1; Found: 424.2 [M+1]+.

[0184] Step 4. Synthesis of 2-(4-(4-chlorophenyl)-2-(1- fluorocyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (Example 18). A mixture of 4-(4-chlorophenyl)-2-(1-fluorocyclopentyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (18-3) (50.00 mg, 0.12 mmol) and TsOH (10.16 mg, 0.06 mmol) in CH(OMe)3 (2.5 mL) was stirred for 4 h at 70 °C under nitrogen atmosphere. After completion of the reaction, the mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (50.00 mg) was purified by Pre-HPLC Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.5% FA) and ACN (20% ACN up to 95% in 5 min) to afford Example 18 (5.00 mg, 9.77%) as a yellow solid. Example 19. (4-(8-(1,3,4-Oxadiazol-2-yl)-2-(perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-4-yl)phenyl)methanolAttorney Docket No. 71180-431269 (ASP-078-WO)

[0185] Step 1. Synthesis of methyl 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (19-1). A solution of methyl 2-(perfluoroethyl)-4-(((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (2-2) (180 mg, 0.36 mmol) and (4-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)boronic acid (194.29 mg, 0.73 mmol), K2CO3 (152.40 mg, 1.10 mmol), Pd(dppf)Cl2(13.35 mg, 0.018 mmol) in dioxane (2 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE (1:2) to afford 19- 1 (150 mg, 72.68%) as a yellow solid. MS (ESI, m / z): calcd. for C27H28F5N3O3Si: 565.2; Found: 566.2 [M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0186] Step 2. Synthesis of 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (19-2). A solution of methyl 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (19-1) (150 mg, 0.27 mmol) and NH2NH2•H2O (0.2 mL) in EtOH (3 mL) was stirred for 6 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 19-2 (120 mg, 80.00%) as a yellow solid. MS (ESI, m / z): calcd. for C26H28F5N5O2Si: 565.2; Found: 566.1[M + 1]+.

[0187] Step 3. Synthesis of 2-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (19-3). A solution of 4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (19-2) (120 mg, 0.21 mmol) and TsOH (18.27 mg, 0.11 mmol) in CH(OMe)3 (2 mL) was stirred for 4 h at 70°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE (1:2) to afford 19-3 (80 mg, 65.51%) as a yellow solid. MS (ESI, m / z): calcd. for C27H26F5N5O2Si: 575.2; Found:576.1[M + 1]+.Attorney Docket No. 71180-431269 (ASP-078-WO)

[0188] Step 4. Synthesis of (4-(8-(1,3,4-oxadiazol-2-yl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-4-yl)phenyl)methanol (Example 19). A solution of 2-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (perfluoroethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-8-yl)-1,3,4-oxadiazole (19-3) (80 mg, 0.14 mmol) and TBAF (158.47 mg, 1.39 mmol) in DCM (1 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with H2O (10 mL). The aqueous layer was extracted with DCM (3x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions: XSelect C18 Column, 5um, 19 * 150 mm; mobile phase, water (0.1% NH3•H2O) and MeCN (20% Phase B to 70% in 9 min); detector, UV 254 nm. This resulted in Example 19 (13.8 mg, 21.52%) as a yellow solid. Example 20. (4-(8-(1,3,4-Oxadiazol-2-yl)-2-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-4-yl)phenyl)methanol- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carboxylate (20-1). A solution of methyl 2-(trifluoromethyl)-4-(((trifluoromethyl)sulfonyl)oxy)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (11-1) (210 mg, 0.47 mmol), [4-(4,4,5,5-tetramethyl-1,3,2-Attorney Docket No. 71180-431269 (ASP-078-WO) dioxaborolan-2-yl)phenyl]methanol (554.51 mg, 2.37 mmol), Pd(dppf)Cl2(34.66 mg, 0.05 mmol) and Na2CO3 (150.63 mg, 1.42 mmol) in dioxane (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1:4) to afford 20-1 (170 mg, 89.41%) as a yellow solid. MS (ESI, m / z): calcd. for C20H14F3N3O3: 401.1; Found: 402.1 [M + 1]+.

[0190] Step 2. Synthesis of 4-(4-(hydroxymethyl)phenyl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazine-8-carbohydrazide (20-2). A solution of methyl 4-(4-(hydroxymethyl)phenyl)-2-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carboxylate (20-1) (170 mg, 0.42 mmol) and NH2NH2•H2O (1 mL, 20.58 mmol) in EtOH (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 20-2 (150 mg, 88.23%) as a brown solid. MS (ESI, m / z): calcd. for C19H14F3N5O2: 401.1; Found: 402.2 [M + 1]+.

[0191] Step 3. Synthesis of (4-(8-(1,3,4-oxadiazol-2-yl)-2- (trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-4-yl)phenyl)methanol (Example 20). A solution of 4-(4-(hydroxymethyl)phenyl)-2-(trifluoromethyl)pyrido[3',2':4,5]pyrrolo[1,2- a]pyrazine-8-carbohydrazide (20-2) (150 mg, 0.37 mmol) and TsOH (32.18 mg, 0.19 mmol) in CH(OCH3)3 (5 mL) was stirred for 4 h at 70 °C. The mixture was allowed to cool down to room temperature. The mixture was basified to pH = 8 with saturated NaHCO3(aq.). The resultingAttorney Docket No. 71180-431269 (ASP-078-WO) mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (15 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, Water (0.5% FA) and ACN (25% ACN up to 90% in 7 min); Detector, UV254 nm) to afford Example 20 (10 mg, 6.50%) as a yellow solid. 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: Analytical data of representative compounds. MS Example Structure1H NMR δ ), 6 m, 1Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR (300 MHz, CDCl3): δ 9.58 J 7 ), δ ), H) 4Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR (300 MHz, Acetonitrile-d3): s, z, 8 6 , ): 0Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR (300 MHz, Methanol-d4): δ δAttorney Docket No. 71180-431269 (ASP-078-WO) 1 δ 5 ): J ,Attorney Docket No. 71180-431269 (ASP-078-WO) 1 , δ ), H) δ = H)Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR (300 MHz, DMSO-d6): δ ), ), .4 4 6 ), m, 6 ), 2 6 δ ), J 1, H)Attorney Docket No. 71180-431269 (ASP-078-WO) 1 δ ), δ ), H) δ 7- z, ): s, z, s,Attorney Docket No.71180-431269 (ASP-078-WO) 1H NMR MH A t itil3): z, 3 2 m δ ), J z, δ 9 0 0Attorney Docket No. 71180-431269 (ASP-078-WO) δ 6 s, δ = ), ), ), H) δ ), 3 6, 2, ),Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR (500 MHz, DMSO-d6): δ .7 ), δ = = ), = δ .7 ), 6 m δ ), = 6 mAttorney Docket No. 71180-431269 (ASP-078-WO) 1 δ = ), ), ), δ = = ), δ ), s, δ ), ), 0Attorney Docket No. 71180-431269 (ASP-078-WO) (dd, J = 8.2, 1.5 Hz, 1H), 7.23 – 7.14 (m, 2H), 3.80 (s, 3H) ppm δ .3 ), ), = δ ), J .3 δ ), 7Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR MH DM δ .4 m, z, ): J s, = δ ), ), ), ), ), 7Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR MH DM δ ), ), = = δ 0 s, δ 5 m, ),Attorney Docket No. 71180-431269 (ASP-078-WO) 1H NMR (300 MHz, DMSO-d6): δ 15 ), 48 .8VI Biological Data IFNα pathway induction

[0192] HEK293 cells expressing the firefly luciferase gene under the control of ISRE stably integrated into HEK293 cells were obtained from BPS Bioscience. ISRE reporter was used to measure IFNα pathway induction. Upon IFNα stimulation, pospho-STAT1 and phosphor-STAT2 form a complex with IRF9, named as ISGF3, which translocates to the nucleus and activates the transcription of interferon inducible genes (ISGs) through binding to ISRE in the promoter region of ISGs.

[0193] The cells were culture in MEM medium (Corning) supplemented with 10% FBS, 1% non-essential amino acids, 1 mM sodium pyruvate, 1% Penicillin / Streptomycin plus 400 µg / ml of Geneticin. Sub-confluent culture is passaged and split twice a week, not exceeding 30 passages. Cells are detached using 0.05% Trypsin / 0.53mM EDTA solution (Corning).

[0194] For testing the compound effect on IFNα pathway, HEK293 ISRE reporter cells were seeded in 96-well plate at density of 50,000 cells / well 24 hours before treatment in a black clear bottom plate (Corning). Next day, the cells were treated with compounds in a three-fold serial dilution. The final DMSO concentration in each well is normalized to 0.5%. After 24-hour incubation, the activity of ISRE induction was measured using One-Glo luciferase substrateAttorney Docket No. 71180-431269 (ASP-078-WO) (Promega) on a Tecan Infinite M1000 Pro plate reader. The fold of induction was calculated by the activity of compound treated cells relative to DMSO treated cells. Cell-based HCV replicon assay

[0195] HCV 1b replicon (NanoLuc luciferase) cell line was generated in Huh7-Lunet cells. HCV replicon cells were cultured in DMEM medium (Cytiva) supplemented with 10% FBS, 1% Penicillin / Streptomycin plus 250 µg / ml of Geneticin. Sub-confluent culture of HCV replicon is passaged and split twice a week, not exceeding 40 passages. Cells are detached using 0.25% Trypsin / 2.21 mM EDTA solution (Corning).

[0196] For testing the antiviral activity of compounds, HCV 1b replicon cells were seeded in DMEM medium supplemented with 5% FBS and 1% % Penicillin / Streptomycin at a density of 5,000 cells / well in a black clear bottom half-well 96-well plate (Corning), following by the addition of compounds in a three-fold serial dilution. The final DMSO concentration in each well is normalized to 1%. After 48-hour incubation, the luciferase activity was measured using Nano- Glo luciferase substrate (Promega) on a Tecan Infinite M1000 Pro plate reader. The antiviral activity of compound was calculated from the percentage of luciferase signals relative to DMSO treated cells.

[0197] Table 2 provides assay data for exemplified compounds of the invention. The antiviral activity of the exemplified compounds at 20 uM is grouped in the following ranges: A indicates < 25%; B indicates 25% to 50%; C indicates > 50%. The ISRE induction of the exemplified compounds at 20 uM is grouped in the following ranges: A indicates greater than 2 folds; B indicates 0.5-2 fold(s).Attorney Docket No. 71180-431269 (ASP-078-WO) Table 2. Assay data for exemplified compounds of the invention. Example Antiviral Activity ISRE InductionAttorney Docket No. 71180-431269 (ASP-078-WO) 21 A AAttorney Docket No. 71180-431269 (ASP-078-WO) 43 B BEQUIVALENTS

[0198] 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.

[0199] 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, theAttorney Docket No. 71180-431269 (ASP-078-WO) numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

Attorney Docket No. 71180-431269 (ASP-078-WO) CLAIMS:

1. A compound of Formula 1, or a pharmaceutically acceptable salt thereof, wherein: R1is halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, monoC3-7cycloalkyl or phenyl, wherein the monoC3-7cycloalkyl or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, cyano, C1-6alkyl and haloC1-6alkyl; R2is halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl haloC1-6alkyl, monoC3-7cycloalkyl, phenyl, pyridyl or pyrazole, wherein the monoC3-7cycloalkyl, phenyl, pyridyl or pyrazole is optionally substituted 1-3 substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, RaRbN, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy and R4- OC(O)-C1-6alkylene-; R3is hydrogen, halo, cyano, nitro, C1-6alkyl or haloC1-6alkyl; R4is C1-6alkyl or phenyl; and Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-4alkyl.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.Attorney Docket No. 71180-431269 (ASP-078-WO) 3. A method of treating a viral infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. A method of treating a viral infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 2.

5. The method of claim 3 or 4, wherein the viral infection is an HBV infection.

6. The method of claim 3 or 4, wherein the viral infection is an HDV infection.

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