WO2023069544A1 - 5-membered heteroaryl carboxamide compounds for treatment of hbv - Google Patents

Abstract

The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds, and pharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating Hepatitis B (HBV) infection.

Description

5-MEMBERED HETEROARYL CARBOXAMIDE COMPOUNDS FOR TREATMENT OF HBV CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 62/257,736, filed October 20, 2021, the contents of which are hereby incorporated by reference. BACKGROUND Hepatitis B (HBV) causes viral hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths. HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children born to HBV-positive mothers may also be infected, unless vaccinated at birth. The hepatitis virus particle is composed of a lipid envelope studded with surface protein (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core. At present, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g., entecavir) that suppress the virus while the patient remains on treatment, but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleos(t)ide analogs, most must continue taking them or risk the possibility of a life-threatening immune response due to viral rebound. Further, nucleotide therapy may lead to the emergence of antiviral drug resistance. The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon α or pegylated interferon α. Unfortunately, the adverse event incidence and profile of interferon α can result in poor tolerability, and many patients are unable to complete therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients is likely to have a sustained clinical response to a course of interferon therapy. As a result, interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment. Thus, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon α has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections. SUMMARY The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds and pharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating HBV infections. In one aspect, the disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, where the variables are described in the detailed description. In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating an HBV 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. BRIEF DESCRIPTION OF DRAWINGS FIGURE 1 illustrates the ORTEP plot for compound CP-AIA-227-2. FIGURE 2 illustrates the relative stereochemistry scheme of compound CP-AIA-227-2. DETAILED DESCRIPTION The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. I. Definitions The term “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, butenyl, and pentenyl, etc. 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 C_1-6alkoxy and C1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc. The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH₃CH₂OCH₂-, CH₃OCH₂CH₂- and CH₃OCH₂-, etc. 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 C_1-6 alkyl and C1-4 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2- methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, etc. The term “alkylene” as used herein refers to a biradical alkyl group. 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. The term “carbonyl” as used herein refers to the biradical -C(O)-. The term “cyano” as used herein refers to the radical -CN. The terms “halo” or “halogen” as used herein refer to F, Cl, Br or I. The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. For example, haloC_1-6alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, CH₂F-, CHCl2-, -CHF2, CF3-, CF3CH₂-, CH₃CF2, CF3CCl2- and CF3CF2-. The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH₂O-, and CF3CF2O-. The term “heteroaryl” as used herein refers to a 5-6 membered monocyclic aromatic ring system containing one to four independently selected heteroatoms, such as nitrogen, oxygen and sulfur. Where possible, the heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of 5-6 membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also referred to as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H- 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also referred to as pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and tetrazolyl. The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH. 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-. The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one or more hydroxy groups. Examples include but are not limited to HOCH₂O-, HOCH₂CH₂O-, CH₃CH(OH)CH₂O- and HOCH₂CH(OH)CH₂O-. The term “R^aR^bN C_1-6 alkyl-,” as used herein refers to an alkyl group substituted with a R^aR^bN- group, as defined herein. Examples include but are not limited to NH₂CH₂-, NH(CH₃)CH₂-, N(CH₃)2CH₂CH₂- and CH₃CH(NH₂)CH₂-. The term “R^aR^bNC_1-6alkoxy,” as used herein refers to an alkoxy group substituted with a R^aR^bN- groups, as defined herein. Examples include but are not limited to NH₂CH₂-, NH(CH₃)CH₂O-, N(CH₃)₂CH₂CH₂O-, and CH₃CH(NH₂)CH₂O-. The term “oxo” as used herein refers to the radical =O. As used herein, when a bicyclic ring is shown with a floating point of attachment and/or floating substituents, for example as in

it signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R³³ group(s)) can be independently attached to either or both rings. The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired. The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism. The term “pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, via disruption of HBV core protein assembly, that results in the improvement of the disease. “Disruption” includes inhibition of HBV viral assembly and infection. The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(- ),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures 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.” Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). II. 5-Membered Heteroaryl Carboxamide Compounds In one aspect, the present disclosure provides a compound of Formula I

, or a pharmaceutically acceptable salt thereof, wherein: L¹ and L² are independently selected from the group consisting of a bond, C1- 4alkylene, C1-4alkenylene, C1-4alkynylene, haloC1-4alkylene, hydroxyC1-4alkylene, O, NR^c, C(O), C(O)O, C(O)NR^c, S(O)t, S(O)tNR^c, C1-4alkyleneS(O)t and haloC1-4alkyleneS(O)t; L³ is C_1-6alkylene, C2-6alkenylene or C2-6alkynylene, wherein the C_1-6alkylene, C2- 6alkenylene, C2-6alkynylene is optionally substituted with 1-10 substituents independently selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)t-, R^aR^bNC(O)-, C1- 6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, R^aR^bN-C_1-6alkoxy, and haloC_1-6alkylNR^c-; X¹ is NR^x1, O or S; X⁴ is O or S; X⁵ is O, S or NR^6a; R^a, R^b and R^c are independently selected for each occurrence from the group consisting of hydrogen, C_1-6 alkyl, and haloC_1-6 alkyl; R^d is hydrogen, OH, C_1-6 alkyl or C_1-6 alkoxy; R^x1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, haloC1-4 alkyl, or C3-6 monocycloalkyl; R^0a is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, R^aR^bN-, C1-4alkyl and haloC1-4 alkyl; R^6a is hydrogen, C1-4 alkyl, haloC1-4 alkyl or C3-4cycloalkyl; R^6b is C_1-6alkyl, C2-6alkenyl or C2-6alkynyl, wherein the C_1-6alkyl, C2-6alkenyl, C2- 6alkynyl is optionally substituted with 1-10 substituents independently selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)t-, R^aR^bNC(O)-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, R^aR^bN-C_1-6alkoxy, and haloC_1-6alkylNR^c-; R⁰, R⁶ and R¹¹ are independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)t-, R^aR^bNC(O)-, R^6b, R^6bC(O)-, R^6bC(O)O-, R^6bC(O)NR^c-, R^6bS(O)tNR^c-, R^6bS(O)t-, R^6bO-, R^6bNR^c-, R^6bC(O)-L³-, and R^6bC(O)O-L³-, R^6bC(O)NR^c-L³-, R^6bS(O)tNR^c-L³-, R^6bS(O)q-L³-, R^6bO-L³-, and R^6bNR^c-L³-; R¹ is a phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with one, two, or three independently selected R¹¹ groups; R², R⁷ and R⁸ are independently selected from the group consisting of hydrogen, halo, CN, OH, R^aR^bN, C1-4alkyl, haloC1-4alkyl, C3-5monocycloalkyl, C1-4alkoxy, and haloC1- 4alkoxy; R³ is

R⁴ is R^5a-L¹-, R^5b-L¹-, R^5c-L¹-, R^5d-L¹-, R^5e-L¹- or R⁶;

R^5d and R¹⁰ are independently selected from the group consisting of:

; R^5e is

p is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3; r is independently selected for each occurrence from the group consisting of 0, 1 and 2; t is independently selected for each occurrence from the group consisting of 0, 1 and 2; v is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3; and w is independently selected for each occurrence from the group consisting of 0, 1 and 2. The following embodiments further describe a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, X¹ is S. In certain embodiments, X¹ is NR^x1. In certain embodiments, X¹ is NR^x1 and R^x1 is hydrogen of methyl. In certain embodiments, X¹ is NR^x1 and R^x1 is methyl. In certain embodiments, L¹ is a bond. In certain embodiments, L¹ is C1-4alkylene. In certain embodiments, p is 0. In certain embodiments, R⁰ is selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN- , R^aR^bNS(O)t-, R^aR^bNC(O)-, C_1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC_1-6alkyl, hydroxyC1- 6alkyl-, R^aR^bNC_1-6alkyl-, HOC(O)C_1-6alkyl-, C_1-6alkylC(O)-, C_1-6alkylC(O)O-, C1- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC1- 6alkoxy-, R^aR^bNC_1-6alkoxy-, R^aR^bNC_1-6alkylNR^c-, C_1-6alkylNR^aC_1-6alkyleneNR^c-, C1- 6alkoxyC_1-6alkylene-, haloC_1-6alkoxyC_1-6alkylene-, C_1-6alkoxyC(O)-, C_1-6alkylS(O)tC1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, C_1-6alkylC(O)OC1- 6alkylene- and R⁹, wherein: R⁹ is R¹²S(O)t-C_1-6alkylene-, R¹²S(O)tNH-C_1-6alkylene-, R¹²C(O)NH-C_1-6alkylene-, R¹²S(O)t-haloC_1-6alkylene-, R¹²S(O)tNH-haloC_1-6alkylene-, or R¹²C(O)NH-haloC_1-6alkylene-; and R¹² is R^aR^bN-, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, or C_1-6haloalkoxy. In certain embodiments, R⁰ is selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN- , R^aR^bNS(O)t-, R^aR^bNC(O)-, C_1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC_1-6alkyl, hydroxyC1- 6alkyl-, R^aR^bNC_1-6alkyl-, HOC(O)C_1-6alkyl-, C_1-6alkylC(O)-, C_1-6alkylC(O)O-, C1- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC1- 6alkoxy-, R^aR^bNC_1-6alkoxy-, R^aR^bNC_1-6alkylNR^c-, C_1-6alkylNR^aC_1-6alkyleneNR^c-, C1- 6alkoxyC_1-6alkylene-, haloC_1-6alkoxyC_1-6alkylene-, C_1-6alkoxyC(O)-, C_1-6alkylS(O)tC1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, and C1- 6alkylC(O)OC_1-6alkylene-. In certain embodiments, R⁰ is R⁹; wherein: R⁹ is R¹²S(O)t-C_1-6alkylene-, R¹²S(O)tNH-C_1-6alkylene-, R¹²C(O)NH-C_1-6alkylene-, R¹²S(O)t-haloC_1-6alkylene-, R¹²S(O)tNH-haloC_1-6alkylene-, or R¹²C(O)NH-haloC_1-6alkylene-; and R¹² is R^aR^bN-, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, or C_1-6haloalkoxy. In certain embodiments, R¹ is

; R¹¹ is independently selected for each occurrence from the group consisting of halogen, CN, C_1-6alkyl and haloC_1-6alkyl; and z1 is 0, 1, 2 or 3. In certain embodiments, R¹¹ is independently selected for each occurrence from the group consisting of halogen and CN. In certain embodiments, R¹¹ is independently selected for each occurrence from the group consisting of F, Cl, Br and I. In certain embodiments, R¹ is selected from the group consisting of:

In certain embodiments, R¹ is In certain embodiments, R¹ is

In certain embodiments, X¹ is NR^x1, R^x1 is hydrogen or methyl, and R¹ is

In certain embodiments, R² is hydrogen. In certain embodiments, X¹ is NR^x1, R^x1 is hydrogen or methyl, R¹ is

, and R² is hydrogen. In certain embodiments, R³ is In certain embodiments, R³ is

In certain embodiments, R³ is In certain embodiments, R³ is

In certain embodiments, R⁴ is R^5a-L¹-, R^5b-L¹-, R^5d-L¹-, R^5e-L¹- or R⁶. In certain embodiments, R⁴ is R^5a-L¹-, R^5d-L¹-, R^5e-L¹- or R⁶. In certain embodiments, R⁴ is R^5a-L¹-, R^5d-L¹- or R^5e-L¹-. In certain embodiments, L¹ is a bond, C_1-4alkylene, haloC_1-4alkylene or hydroxyC_{1- 4}alkylene. In certain embodiments, L¹ is a bond. In certain embodiments, R⁴ is R⁶. In certain embodiments, R⁴ is R^5a-L¹-. In certain embodiments, R⁴ is R^5d-L¹-. In certain embodiments, R⁴ is R^5e-L¹-_. In certain embodiments, R⁴ is R^5a. In certain embodiments, R⁴ is R^5d. In certain embodiments, R⁴ is R^5e _. In certain embodiments, R⁴ is In certain embodiments, R⁴ is

In certain embodiments, L² is a bond, C_1-4alkyl, haloC_1-4alkyl. In certain embodiments, L² is a bond. In certain embodiments, R⁶ is selected from the group consisting of hydrogen, halogen, OH, CN, NO₂, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN- , R^aR^bNS(O)_t-, R^aR^bNC(O)-, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6alkyl, hydroxyC_{1- 6}alkyl-, R^aR^bNC_1-6alkyl-, HOC(O)C_1-6alkyl-, C_1-6alkylC(O)-, C_1-6alkylC(O)O-, C_{1- 6}alkylC(O)NR^c-, C_1-6alkylS(O)_t-, C_1-6alkylS(O)_tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_{1- 6}alkoxy-, R^aR^bNC_1-6alkoxy-, R^aR^bNC_1-6alkylNR^c-, C_1-6alkylNR^aC_1-6alkyleneNR^c-, C_1- 6alkoxyC_1-6alkylene-, haloC_1-6alkoxyC_1-6alkylene-, C_1-6alkoxyC(O)-, C_1-6alkylS(O)tC1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, C_1-6alkylC(O)OC1- 6alkylene- and R⁹, wherein: R⁹ is R¹²S(O)t-C_1-6alkylene-, R¹²S(O)tNH-C_1-6alkylene-, R¹²C(O)NH-C_1-6alkylene-, R¹²S(O)t-haloC_1-6alkylene-, R¹²S(O)tNH-haloC_1-6alkylene-, or R¹²C(O)NH-haloC_1-6alkylene-; and R¹² is R^aR^bN-, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, or C_1-6haloalkoxy. In certain embodiments, R⁶ is selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN- , R^aR^bNS(O)t-, R^aR^bNC(O)-, C_1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC_1-6alkyl, hydroxyC1- 6alkyl-, R^aR^bNC_1-6alkyl-, HOC(O)C_1-6alkyl-, C_1-6alkylC(O)-, C_1-6alkylC(O)O-, C1- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC1- 6alkoxy-, R^aR^bNC_1-6alkoxy-, R^aR^bNC_1-6alkylNR^c-, C_1-6alkylNR^aC_1-6alkyleneNR^c-, C1- 6alkoxyC_1-6alkylene-, haloC_1-6alkoxyC_1-6alkylene-, C_1-6alkoxyC(O)-, C_1-6alkylS(O)tC1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, and C1- 6alkylC(O)OC_1-6alkylene-. In certain embodiments, R⁶ is R⁹, wherein: R⁹ is R¹²S(O)t-C_1-6alkylene-, R¹²S(O)tNH-C_1-6alkylene-, R¹²C(O)NH-C_1-6alkylene-, R¹²S(O)t-haloC_1-6alkylene-, R¹²S(O)tNH-haloC_1-6alkylene-, or R¹²C(O)NH-haloC_1-6alkylene-; and R¹² is R^aR^bN-, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, or C_1-6haloalkoxy. In certain embodiments, R⁷ is hydrogen, halogen, methyl, methoxy or OH. In certain embodiments, R⁷ is hydrogen or OH. In certain embodiments, R⁷ is OH. In certain embodiments, R⁸ is hydrogen, halogen, methyl, methoxy or OH. In certain embodiments, R⁸ is hydrogen or OH. In certain embodiments, R⁸ is OH. In certain embodiments, X¹ is NR^x1; R^x1 is hydrogen or methyl; R¹ is

R² is H; R³ is ; and R⁸ is hydrogen, OH or C_1-6alkoxy.

In certain embodiments, X¹ is NR^x1; R^x1 is hydrogen or methyl; R¹ is

R² is H; R³ is

; and R⁸ is OH. It will be appreciated that all chemically allowable combinations of the aforementioned embodiments are also contemplated as embodiments of the invention. III. Pharmaceutical Compositions and Kits In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration. In another aspect, the disclosure provides a pharmaceutical composition comprises a compound according to any combination of the Examples described herein, or a pharmaceutically acceptable salt and/or stereoisomer thereof. Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non- toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent. Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams, and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure. Advantageously, the disclosure also provides kits for use by e.g., a consumer in need of HBV infection treatment. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form tomediate, reduce or prevent HBV infection. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, .. . etc.... Second Week, Monday, Tuesday, ...” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. IV. Methods In a further aspect, a method for treating a hepatitis B infection 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 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. For use in accordance with this aspect, the appropriate dosage is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 μg/kg body weight. In some cases, the administration dose of the compound may be less than 400 μg/kg body weight. In other cases, the administration dose may be less than 200 μg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 μg/kg body weight. The dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form. A compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g., in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally). For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate. Preparations for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan. A disclosed compound may also be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents. Alternatively, the compound may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Also contemplated herein are methods and compositions that include a second active agent or administering a second active agent. For example, in addition to being infected with HBV, a subject or patient can further have HBV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV. Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these HBV-infection- related conditions. In some cases, a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals. Example antivirals include nucleoside analogs, interferon α, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl- 2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). For example, provided herein is a method of treating a patient suffering from hepatitis B infection comprising administering to the patient a first amount of a disclosed compound and a second amount of an antiviral, or other anti HBV agent, for example a second amount of a second compound selected from the group consisting of: an HBV capsid assembly promoter (for example, GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below),

; NVR 3-778, NVR1221 (by code); and N890 (as depicted below):

other capsid inhibitors such as those disclosed in the following patent applications hereby incorporated by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167, and WO2014033170; Nucleos(t)ide analogs interfering with viral polymerase, such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g. AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir) and:

viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below:

; and BM601 as depicted below:

disruptors of nucleocapsid formation or integrity such as NZ-4/W28F:

; cccDNA formation inhibitors such as BSBI-25, CCC-0346, CCC-0975 (as depicted below):

HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cp183-V124W and related mutations as described in WO/2013/010069, WO2014/074906, each incorporated by reference); inhibitors of HBx- interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA;, e.g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS- HBV), or nucleic acid based polymer: (REP 2139-Ca); immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda 1a and PEG IFN lambda 1a, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); Non-Interferon Immune enhancers such as Thymosin alpha-1 (Zadaxin) and Interleukin-7 (CYT107); TLR-7/9 agonists such as GS- 9620, CYT003, Resiquimod; Cyclophilin inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, Core antigen vaccine; SMAC mimetics such as birinapant and other IAP-antagonists; Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING Agonists; Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins. In some embodiments, 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, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF 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 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. In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be co- administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy. In another embodiment, a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of a disclosed compound), with a detection moiety, for e.g., a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation). Contemplated fluorophores include AlexaFluor^® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection moiety may be used in e.g., a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity. V. Examples 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. At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations: AcOH Acetic acid ACN Acetonitrile AIBN Azobisisobutyronitrile Boc2O Di-tert-butyl dicarbonate nBuLi n-Butyllithium Cu(OAc)2 Copper diacetate CuI Copper iodide DCC N,N′-Dicyclohexylcarbodiimide DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropyl ethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1’-Bis(diphenylphosphino)ferrocene EA, EtOAc Ethyl acetate Et3N Triethylamine HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium h, hr Hour(s) HPLC High performance liquid chromatography LCMS Liquid chromatography–mass spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide LiTMP Lithium tetramethylpiperidide MeOH Methanol NBS N-Bromosuccinimide Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium (II) dichloride Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) PE Petroleum ether iPrOH Isopropanol rt, r.t. Room temperature SFC Supercritical Fluid Chromatography TBAF Tetra-n-butylammonium fluoride TBSCl tert-Butyldimethylsilyl chloride TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

LCMS methods used for the analysis of final compounds: Method A: X-Bridge BEH C-18 (3x50 mmx2.5μm); Mobile phase: A; 0.025% formic acid in H₂O; B; CH₃CN; Injection volume: 2 μL; Flow rate:1.2 mL/min, column temperature: 50 ^oC; Gradient program: 2% B to 98% B in 2.2 min, hold until 3 min, at 3.2 min B conc. is 2 % till up to 4 min. Method B: X-select CSH 18 (3x50 mmx2.5μm); Mobile phase: A; 0.025% formic acid in H₂O; B; CH₃CN; Injection volume: 2 μL; Flow rate:1.2 mL/min, column temperature: 50 ^oC; Gradient program: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % till up to 4 min. Method C: X-select CSH 18 (3x50 mmx2.5μm); Mobile phase: A; 0.05% formic acid in H₂O:CH₃CN (95:5); B; 0.05% formic acid in CH₃CN; Injection volume: 2 μL; Flow rate: 1.2 mL/min, column temperature: 50 ^oC; Gradient program: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % till up to 4 min. Method D: X-select CSH C18 (3x50 mmx2.5µm); Mobile phase: A; 2 mM in Ammonium Bicarbonate; B; CH₃CN; Injection volume: 2 µL; Flow rate: 1.2 mL/min, column temperature: 50 ^oC; Gradient program: 0% B to 98% B in 2 min, hold till 3 min, at 3.2 min B conc. is 0 % until up to 4 min. Method E: X-select CSH 18 (3x50 mmx2.5μm); Mobile phase: A; 0.05% formic acid in H₂O; B; CH₃CN; Injection volume: 2 μL; Flow rate:1.5 mL/min, column temperature: 50 oC; Gradient program: 0% B to 100% B in 1.5 min, hold till 2.2 min, at 2.6 min B conc. is 0 % until up to 3 min. General Procedure for Amidation: Method A (amide coupling using EDC^.HCl): To a stirred solution of carboxylic acid (1 eq.) in 1,4-dioxane (5.84 mL/mmol) were added EDC^.HCl (1.1 eq.), HOBt (1.1 eq.) and corresponding amine (1 eq.) at 0 ^oC and stirred for 5 min. To this solution, DIPEA (3 eq.) was added, and the resulting reaction mixture was stirred at 90 °C for overnight. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with sat. NaHCO3 solution, water, dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound which was purified by silica gel column chromatography/prep. HPLC to afford the desired compound. Method B (amide coupling using HATU): To a stirred solution of acid compound (1.1-1.2 eq.) in DMF/DCM (1.01 mL/mmol) at 0 ^oC, DIPEA (2-3 eq.) and HATU (1.5-2.5 eq.) were added and stirred for 5 min. To this solution, corresponding amine (1 eq.) was added. The resulting reaction mixture was stirred at room temperature for 12-16 hr. After completion, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a crude compound. The crude compound was purified by either prep-HPLC or CombiFlash^® column chromatography to afford the desired compound. Method C (AlMe3 mediated amidation): To a stirred solution of corresponding anilines (1.1 eq.) in DCM/Toluene (3 mL/mmol) at 0 °C under Argon atmosphere, AlMe3 (2M in toluene, 2.5 eq.) was added and the reaction mixture was stirred at 0 °C for 10 min and continued stirring at room temperature for 1h. To this solution, corresponding ester compound (1 eq.) was added at 0 °C under Argon atmosphere and the resulting reaction mixture was refluxed at 100 °C for 16 hr. After completion, the reaction mixture was cooled to 0 °C; quenched with aqueous 1N HCl solution slowly and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude compound was purified by washing with methanol to afford the desired compound. Method D (amide coupling using acid chloride/derivatives): To a stirred solution of amine compound (1 eq.) in DCM (1.01 mL/mmol) was added TEA (1.5-3 eq.) at 0 ^oC and stirred for 5 min. To this solution, corresponding acid chloride/carbamic chloride/chloroformate (1.1-1.5 eq.) was added slowly at 0 ^oC and the reaction mixture was allowed to stir at room temperature until completion. After completion, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate/DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a crude compound. The crude compound was purified by either prep-HPLC or CombiFlash^® column chromatography to afford the desired compound. General procedure for Nucleophilic Addition of a Substituted Alkynyl Anion to a Carbonyl-bearing Substrate: Method A (n-BuLi, LiHMDS, LDA, LTMP method at low temperature): To a stirred solution of a substituted alkyne (5 eq.) in anhydrous THF (0.2 M) in an inert atmosphere was added n-BuLi, LiHMDS, LDA or LTMP (5 eq.) slowly via glass syringe at - 78 ^oC. After stirring at -78 ^oC for 30 min, a solution of a carbonyl-bearing substrate (1 eq.) in anhydrous THF (0.2 M) was added. The reaction mixture was slowly warmed to rt and stirred for another 4 h. Subsequently, the reaction was quenched by adding sat. aq. NH4Cl and concentrated to removed organic solvent. The residue was extracted with EtOAc several times, and the organic combined organic layers washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by CombiFlash^® column chromatography or prep-HPLC to afford the desired compound. Method B (NaH, EtMgBr, iPrMgBr method at 0 ^oC or rt): To a stirred solution of a substituted alkyne (5 eq.) in anhydrous THF (0.2 M) in an inert atmosphere was added NaH, EtMgBr or iPrMgBr (5 eq.) slowly at 0 ^oC. After stirring at 0 ^oC for 30 min, a solution of a carbonyl-bearing substrate (1 eq.) in anhydrous THF (0.2 M) was added. The reaction mixture was warmed to rt and stirred for another 4 h. Subsequently, the reaction was quenched by adding sat. aq. NH4Cl and concentrated to removed organic solvent. The residue was extracted with EtOAc several times, and the organic combined organic layers washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by CombiFlash^® column chromatography or prep-HPLC to afford the desired compound. General Method for Sonogashira Coupling: Method A: A mixture of a halo compound (1 eq.), a substituted alkyne (1 eq.), CuI (0.05 eq.) Pd(dppf)Cl2 (0.025 eq.), and DIEA (1.5 eq.) in DMF (0.2 M) was stirred at rt or an elevated temperature under an inert atmosphere for 2 to 48 h. After completion of the reaction, the reaction mixture was filtered through Celite^®545, and the filtered cake was washed with EtOAc. The filtrate was evaporated to dryness. The residue was taken in ethyl acetate, washed with water, followed by brine, dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by either CombiFlash^® column chromatography or prep-HPLC to afford the desired compound.

5-Oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate. To a solution of 1,3,3a,4,6,6a-hexahydropentalene-2,5-dione (40.0g, 289.5 mmol) and pyridine (24.0 g, 304.0 mmol) in DCM (600 ml) was added Tf₂O (89.8 g, 318.5 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 3 h. Brine (300 mL) was added, and the aqueous layer extracted with DCM (200 mL x 3). The organic layer was separated, dried over Na₂SO₄ and concentrated to give the crude product which was purified by silica gel column chromatography using 8:1 (v/v) petroleum ether/ethyl acetate to afford Intermediate 1 as a yellow oil.¹H NMR (400 MHz, CDCl3): δ 5.63 (q, J = 1.92 Hz, 1 H), 3.57 - 3.50 (m, 1 H), 3.14 - 3.00 (m, 2 H), 2.67 - 2.58 (m, 1 H), 2.56 -2.40 (m, 2 H), 2.34 - 2.26 (m, 1 H), 2.17 (ddd, J = 19.14, 7.34, 1.63 Hz, 1 H) ppm.

5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen- 2(1H)-one. A mixture of Intermediate 1 (110.0 g, 407.0 mmol), 4,4,5,5-tetramethyl-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (108.5 g, 427.4 mmol), Pd(dppf)Cl2 (8.9 g, 12.2 mmol) and potassium acetate (119.7 g, 1221.0 mmol)^in dioxane (1000 ml) was stirred at 80 °C under an N2 atmosphere for 2 h. The reaction mixture was filtered through a pad of Celite^® and the filter cake was washed with EtOAc (250 mL x 3). The filtrate was concentrated under vacuo and the residue was purified by silica gel column chromatography using 8:1 petroleum ether/ethyl acetate to afford Intermediate 2 as a yellow oil.¹H NMR (400 MHz, CDCl3): δ 6.37 (q, J = 2.08 Hz, 1 H), 3.54 - 3.41 (m, 1 H), 3.05 - 2.93 (m, 1 H), 2.79 (ddt, J = 16.48, 7.58, 2.64, 2.64 Hz, 1 H), 2.55 - 2.24 (m, 4 H), 2.07 - 1.95 (m, 1 H), 1.28 (s, 13 H) ppm.

Methyl 2,4-dibromo-1-methyl-1H-imidazole-5-carboxylate. To a solution of methyl 1-methyl-1H-imidazole-5-carboxylate (16.6 g, 118.5 mmol) in CHCl₃ (200 mL) was added NBS (78.3 g, 414.8 mmol) and AIBN (1.95 g, 11.9 mmol). The reaction mixture was stirred at 60 ^oC for 24 h. The mixture was concentrated and purified by column chromatography (Rf = 0.4, PE/EA = 5/1 (v/v)) to give Intermediate 3 (22.2 g, 63%) as a yellow solid.

N-(3-Chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 1-methyl-1H-imidazole-5-carboxylic acid (10 g, 83 mmol), 3-chloro-4- fluoroaniline (18 g, 124 mmol) and Et3N (16 g, 160 mmol) in DMF (100 mL) was added HATU (63 g, 160 mmol) at room temperature. The reaction mixture was stirred at 25 °C overnight then poured into water (200 mL). Yellow solid was formed from the solution which was filtered and dried to provide Intermediate 4 as a pale white solid. TLC: Rf = 0.3 (EtOAc/PE = 1/1 (v/v)). MS (ESI): calcd. for C11H9ClFN3O: 253; Found: 254 [M+1]⁺.

2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5- carboxamide. To a solution of Intermediate 4 (4 g, 15 mmol) in CHCl₃ (100 mL) was added NBS (10 g, 60 mmol) and AIBN (0.25 g, 1.5 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 18 h. The mixture was evaporated under vacuo to give a yellow residue. The residue was purified by silica gel chromatography to give Intermediate 5 as a yellow solid. TLC: R_f = 0.3 (EtOAc/PE = 2/3 (v/v)). MS (ESI): calcd. for C₁₁H₇Br₂ClFN₃O: 409; Found; 411 [M+2]⁺. Alternative synthesis of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H- imidazole-5-carboxamide. To a solution of 2,4-dibromo-1-methyl-1H-imidazole-5- carboxylic acid (9.94 g, 35.0 mmol) in DMF (50 mL) was added HATU (13.3 g, 35.0 mmol) and DIPEA (9.69 g, 175 mmol) at 0 ^oC, the reaction mixture was stirred at 0 ^oC for 1 h. Then 3-chloro-4-fluoroaniline (6.1 g, 42.0 mmol) was added and the reaction mixture stirred at room temperature overnight. The mixture was added dropwise to water (600 mL) and the resulting precipitate filtered to provide Intermediate 5 (12.5 g, 87%) as a yellow solid.

4-Bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5- carboxamide (1.1 g, 2.0 mmol) in THF (50 mL) was added CH₃MgI (2 mL, 4.0 mmol) slowly at room temperature. The reaction mixture was stirred at 50 °C for 4 h then poured into water (50 ml) and extracted with ethyl acetate (20 mL x 3). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography to give Intermediate 6 as a yellow solid. TLC: R_f = 0.3 (EtOAc/PE = 1/1 (v/v)). MS (ESI): calcd. for C₁₁H₈BrClFN₃O: 331; Found: 332 [M+1]⁺. Alternative procedure for the synthesis of 4-bromo-N-(3-chloro-4-fluorophenyl)- 1-methyl-1H-imidazole-5-carboxamide. The titled compound was synthesized following the general procedure described above for amidation (Method C) to afford Intermediate 6 as a brown solid. TLC: R_f = 0.45 (EtOAc/hexanes = 3/7 (v/v)); ¹H NMR (DMSO-d_6, 400 MHz): δ 10.41 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.85 (s, 1H), 7.63-7.60 (m, 1H), 7.43 (t, J = 9.6 Hz, 1H), 3.75 (s, 3H); MS (ESI): calcd. for C₁₁H₈BrClFN₃O: 331; Found: 332 [M+1]⁺.

N-(3-Chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a- hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide. To a solution of Intermediate 6 (13.3 g, 40.0 mmol) in 1,4-dioxane/H₂O (v/v=7:1, 120 mL) were added Intermediate 2 (12.2 g, 48.0 mmol), Pd(dppf)Cl2 (2.9 g, 4.0 mmol) and Na2CO3 (10.6 g, 100.0 mmol), respectively, and the mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite. The solid was washed with EA and the filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel with 5% of methanol in DCM (120 g silica gel column, 60 mL/min) to afford Intermediate 7 (12.8 g, 85.6%) as a brown solid. TLC: Rf: 0.5 (Methanol/DCM = 7/93 (v/v)); MS (ESI): calcd. for C₁₉H₁₇ClFN₃O₂: 373; Found: 374 [M+1]⁺.

N-(3-Chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H- imidazole-5-carboxamide. To a solution of Intermediate 7 (12.8 g, 34.2 mmol) in THF (200 mL) was added Pd/C (6.4 g, 10%) under H₂ and the mixture stirred at room temperature for 4 hours. The mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel with 5% of methanol in DCM (80 g silica gel column, 50 mL/min) to afford Intermediate 8 as a gray solid and as a single diastereomer (12.0 g, 93.3%). TLC: Rf = 0.5 (methanol/DCM = 7/93 (v/v)). MS (ESI): calcd. for C19H19ClFN3O2: 375; Found: 376 [M+1]⁺. Example 1. N-(3-chloro-4-fluorophenyl)-4-(5-((3,3-difluoro-1- hydroxycyclobutyl)ethynyl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole- 5-carboxamide.

Step 1. Synthesis of 3,3-difluorocyclobutanone (1-2): To a solution of 1-1 (12.6 g, 0.12 mmol) in DCM (300 mL) were added SiO2 (5.0 g, 100 - 200 mesh) and PCC (42 g, 0.19 mmol) at rt. After stirring at rt for 22 hrs at 28 °C, the reaction mixture was filtered through Celite^®545, and the filtered cake was washed with DCM (60 mL). The filtrate was dried over anhydrous molecular sieve (5g). The solution was used for next step without further purification. GC-MS: calcd. for C4H4F2O: 106; found 107 [M+1]⁺. Step 2. Synthesis of 1-ethynyl-3,3-difluorocyclobutanol (1-3): A solution of 1-2 (12.6 g, 0.12 mol) in DCM (360 mL) was added to EtMgBr (950 mL, 0.5 M, 0.47 mol) in THF 0 °C~5 °C under argon. The reaction was stirred at the same temperature for 4 hrs. The reaction mass was poured onto sat. aq. NH₄Cl (600 mL) below 10 °C and the resulting mixture was extracted with MTBE (500 mL x 2). The organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solvent was removed and the residue which was purified by silica gel column chromatography using EtOAc/PE = 1/5 (v/v) as eluent to afford 1-3 (5.5 g, 36% in two steps) as a yellow oil. GC-MS: calcd. for C6H6F2O: 132; found 133 [M+1]⁺. Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-((3,3-difluoro-1- hydroxycyclobutyl)ethynyl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole- 5-carboxamide (Example 1): To a solution of 1-3 (9.7 g, 73.6 mmol) in THF (240 mL) was added iPrMgCl (147 mL, 1.0 M, 147 mmol) slowly at 0 °C~3 °C in 40 min under argon, the mixture was stirred for 50 min. Then a solution of Intermediate 8 (4.6 g, 12 mmol) in THF (120 mL) was added drop wise at 0 °C~3 °C for 20 min. The reaction was stirred for 16~48 hrs at 25°C and then quenched with sat. NH₄Claq. at 0 °C. The resulting mixture was concentrated to remove most of the organic solvents and the residue was extracted with DCM (200 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by silica gel column chromatography using DCM and MeOH/DCM = 1/99 to 1/9 (v/v) as eluents to give Example 1 (2.1 g, 34%) as a white solid. MS (ESI): calcd. for C25H₂5ClF3N3O3: 507; Found: 508 [M +1]⁺.¹H NMR (CD3OD, 400 MHz): δ 7.87 (dd, J = 6.8, 2.8 Hz, 1H), 7.64 (s, 1H), 7.53 ‒ 7.47 (m, 1H), 7.24 (t, J = 8.8 Hz, 1H), 3.76 (s, 3H), 3.36 ‒ 3.28 (m, 1H), 2.98 ‒ 2.89 (m, 2H), 2.83 ‒ 2.62 (m, 4H), 2.30 ‒ 2.18 (m, 4H), 1.82 ‒ 1.72 (m, 4H) ppm. Examples 2, 2a and 2b. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(4,4,4-trifluoro-3- hydroxybut-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 2), N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((S)-4,4,4-trifluoro-3- hydroxybut-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 2a) and N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((R)-4,4,4-trifluoro-3- hydroxybut-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 2b).

Step 1. Synthesis of 1,1,1-trifluoro-4-(trimethylsilyl)but-3-yn-2-ol (2-2): A solution of trimethylsilylacetylene (22.5 g, 230 mmol) in anhydrous Et2O (500 mL) was added n-BuLi (2.5 M in hexanes, 100 mL) at -78 ℃. After stirring at -78 ℃ for 30 min, R-1 (50 g, 352 mmol) was added dropwise, and the resulting mixture was stirred at -78 ℃ for another 4 h. Subsequently, the reaction was quenched with water (10 mL) and diluted with THF (500 mL), followed by NaBH4 (9.6 g, 253 mmol) in one portion. After stirred at rt overnight, the reaction mixture was poured into sat. NH4Cl (aq.) (2 L) and stirred for 2-3 hr. The mixture was concentrated to remove most of the organic solvent. The residue was extracted with DCM (500 mL x 3) and the combined organic layer was dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by silica gel column chromatography using EtOAc/PE = 1/19 (v/v) as eluent to give 2-2 as a colorless oil (20 g, 44 % yield). Step 2. Synthesis of tert-butyldimethyl(1,1,1-trifluoro-4-(trimethylsilyl)but-3-yn- 2-yloxy)silane (2-3): A solution of 2-2 (20 g, 102 mmol) in DCM (200 mL) was added imidazole (8.16 g, 120 mmol) and TBSCl (22.5 g, 150 mmol) at 0 ^oC. The reaction was stirred at rt for 2 h and quenched with sat. NH4Cl (aq.) (200 mL). The mixture was extracted with DCM (200 mL x 3), and the combined organic extracts were dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified silica gel column chromatography using EtOAc/PE = 1/19 (v/v) as eluent to give 2-3 as a colorless oil (30 g, 94 % yield). Step 3. Synthesis of tert-butyldimethyl(1,1,1-trifluorobut-3-yn-2-yloxy)silane (2- 4): A solution of 2-3 (30 g, 96.7 mmol) in MeOH (50 mL) was added K2CO3 (13.3 g, 96.7 mmol). After stirring at rt for 1 h, the reaction mixture was diluted with H₂O (300 mL). The mixture was extracted with DCM (200 mL x 3), and the combined organic extracts were dried over Na2SO4. The solvent was removed, and the residue was purified by flash column chromatography (PE = 100%) to afford 2-4 as a colorless oil (22 g, 95 % yield). Step 4.4-(5-(3-((tert-butyldimethylsilyl)oxy)-4,4,4-trifluorobut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5- carboxamide (2-5): A solution of 2-4 (21.5 g, 90 mmol) in THF (100 mL) was added n-BuLi (2.5 M in hexanes, 30 mL) at -78℃ (5 min). After addition, the reaction was stirred at - 78 ℃ for another 15 min and a solution of Intermediate 8 (2.25 g, 6 mmol) in THF (10 mL) was added in one portion. The reaction was stirred at -78^oC for another 1 h and quenched with sat. NH4Cl (aq.) (100 mL). The reaction was concentrated to remove most of the organic solvent, and the residue was extracted with DCM (200 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified reverse phase column chromatography (90% to 95% (v/v) MeCN in H₂O) to afford 2-5 as a yellow solid (1.8 g, ~ 70 % purity, 34 %). MS (ESI): calcd. for C29H₃6ClF4N3O3Si: 613; found 614 [M+1]⁺. Step 5. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(4,4,4-trifluoro- 3-hydroxybut-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 2): A solution of 2-5 (1.8 g, ~ 70 % purity, 2.1 mmol) in THF (2 mL) was added TBAF (1.0 M in THF, 3 mL) and stirred at rt for 1 h. After consuming the starting material, the reaction mixture was diluted with H₂O (30 mL) and extracted with DCM (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase column chromatograph (42% to 46% (v/v) MeCN in H₂O) to give Example 2 (880 mg, 85%). MS (ESI): calcd. for C23H₂2ClF4N3O3: 499; found 498 [M-1]-.¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.52 (ddd, J = 9.1, 4.3, 2.7 Hz, 1H), 7.25 (t, J = 8.9 Hz, 1H), 4.78 (q, J = 6.3 Hz, 1H), 3.77 (s, 3H), 3.38 (dd, J = 12.1, 6.1 Hz, 1H), 2.68 (d, J = 6.1 Hz, 2H), 2.24 (dt, J = 7.7, 3.8 Hz, 4H), 1.88 – 1.63 (m, 4H) ppm. Step 6. SFC separation of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(4,4,4- trifluoro-3-hydroxybut-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide. Example 2 was separated by SFC to give two diastereomerically pure isomers Example 2a as white solid (340 mg, 33 %) and Example 2b as white solid (340 mg, 33 %). The stereochemistry was arbitrarily assigned. Prep-SFC Condition: Sample solution: Crude 180mg in 20 mL MeOH/ACN filtered by 0.45 um filter; Instrument: SFC-80 (Waters); Column: CHIRALPAK AD (30*250 mm 5 μm) (Daicel); Column temperature: 35 ℃; Mobile phase: liquid CO2/MeOH = 80/20 (v/v); Flow Rate: 45 ml/min; Back Pressure: 100 bar; UV Detection Wavelength: 215 nm; Cycle time: 6.75 min; Injection volume: 4.8 mL; and Run Time: 15 min. MS (ESI): calcd. for C23H₂2ClF4N3O3: 499; found 500 [M + 1]⁺. Example 2a: tR = 10.9 min; ¹H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.64 (s, 1H), 7.59 - 7.55 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 5.47 (s, 1H), 4.99 - 4.92 (m, 1H), 3.67 (s, 3H), 3.29 - 3.19 (m, 1H), 2.59 - 2.52 (m, 2H), 2.08 - 1.99 (m, 4H), 1.76 - 1.68 (m, 4H) ppm. Example 2b: tR = 7.3 min; ¹H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.8 Hz, 1H), 7.64 (s, 1H), 7.58 - 7.54 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 6.86 (d, J = 6.8 Hz, 1H), 5.47 (s, 1H), 4.98 - 4.92 (m, 1H), 3.67 (s, 3H), 3.27 - 3.21 (m, 1H), 2.57 - 2.53 (m, 2H), 2.11 -2.01 (m, 4H), 1.79 - 1.68 (m, 4H) ppm. Example 3. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(prop-1-yn-1-yl)octahydro- pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of diisopropylamine (0.57 mL, 4.0 mmol) in anhydrous THF (15 mL) was added dropwise n-butyllithium (2.5M in hexane, 4.0 mmol, 1.6 mL, 30.0 equiv.) at -20 °C. The resulting mixture was stirred for 10 min and warmed to 0 °C over 10 min. Then it was cooled to -78 °C, and a solution of 1,2-dibromopropane (268.93 mg, 1.33 mmol, 10.0 eq.) in THF (2 mL) was added. The reaction mixture was stirred at -70 °C for 10 min, warmed to 0 °C for 20 min, and then cooled to -78 °C. Then a solution of Intermediate 8 (50.06 mg, 133.21 µmol) in THF (1.5 mL) was added dropwise to reaction. The resulting mixture was stirred at -70 °C for 30 min and left to warm gradually to rt. After 12 h the mixture was poured into saturated NH4Cl solution and extracted with EtOAc (20 mL x 3). The combined organic solution was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 3 (24 mg, 43%) as an off-white solid. MS (ESI): calcd. for C22H₂3ClFN3O2: 415; Found: 416 [M + 1]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 8.02 – 7.90 (m, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.41 (t, J = 9.0 Hz, 1H), 5.14 (s, 1H), 3.66 (s, 3H), 3.27 – 3.14 (m, 1H), 2.54 (s, 2H), 2.12 – 1.90 (m, 4H), 1.76 (s, 5H), 1.68 – 1.51 (m, 2H) ppm. Example 4. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(prop-1-yn-1-yl-d3)octahydro- pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of diisopropylamine (0.45 mL, 3.19 mmol, 24.0 eq.) in anhydrous THF (15 mL) was added dropwise n-butyllithium (2.5 M in hexane, 3.19 mmol, 1.28 mL, 24.0 eq.) at -20 °C. The resulting mixture was stirred for 10 min and warmed to 0 °C over 10 min. Then it was cooled to -78 °C, and a solution of dibromo(²H6)propane (221.17 mg, 1.06 mmol, 8.0 equiv) in THF (2 mL) was added dropwise to reaction solution. The obtained mixture was stirred at -70 °C for 10 min, warmed to 0 °C for 40 min, and then recooled to -78 °C and a solution of Intermediate 8 (50.0 mg, 133.04 µmol) in THF (1.5 mL) was added dropwise to reaction. The resulting mixture was stirred at -70 °C for 30 min and left to warm gradually to RT. After 12 h the mixture was poured into saturated NH4Cl solution, extracted with EtOAc (3 × 20 mL). The combined organic solution was dried over Na2SO4 and evaporated in vacuo to give 60 mg of the crude product, purified with prep-HPLC to give Example 4 (25 mg, 44%) as an off-white solid. MS (ESI): calcd. for C22H₂0D3ClFN3O2: 418; Found: 419 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.90 (dd, J = 6.7, 2.7 Hz, 1H), 7.65 (s, 1H), 7.52 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.25 (t, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.36 (s, 2H), 2.66 (d, J = 7.6 Hz, 2H), 2.20 (ddd, J = 20.3, 13.1, 7.5 Hz, 4H), 1.89 – 1.55 (m, 4H) ppm. Example 5. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(perfluorobut-1-yn-1- yl)octahydro-pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of diisopropylamine (0.59 mL, 4.2 mmol, 21.0 equiv.) in anhydrous THF (15 mL) was added dropwise n-butyllithium (2.5 M in hexane, 4.2 mmol, 1.68 mL, 21.0 equiv.) at -25 °C. The resulting mixture was stirred for 10 min and warmed to -10 °C over 10 min. Then it was cooled to -78 °C, and a solution of 3,3,4,4,4-pentafluorobutan-2-one (648.4 mg, 4.0 mmol, 20.0 eq.) in THF (4 mL) was added to solution. To the reaction mixture, which was stirred at -78 °C for 1 h, was added dropwise a solution of diethyl chlorophosphate (759.4 mg, 4.4 mmol) in THF (1.5 mL). The mixture was stirred at -78 °C for 30 min, and warmed to rt for 20 min. Then the reaction mixture was added dropwise to a freshly prepared LDA (9 mmol, 2.25 eq.) in THF (25 mL) at -78 °C and stirred at the same temperature for 1 h. Then a solution of Intermediate 8 (75.0 mg, 199.56 µmol) in THF (2 mL) was added dropwise to reaction. The resulting mixture was stirred at -70 °C for 30 min and left to warm gradually to rt. After 4 h the mixture was poured into saturated NH4Cl solution, extracted with EtOAc (50 mL x 3). The combined organic solution was dried over Na2SO4 and evaporated in vacuo to give 0.5 g of the crude product, which was purified by flash chromatography on SiO2 (CH₂Cl2/MeOH = 9/1 (v/v)) as eluent, followed by prep-HPLC to give Example 5 (24 mg, 23%). MS (ESI): calcd. for C23H₂0ClF6N3O2: 519; Found: 520 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.90 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.52 (ddd, J = 9.1, 4.2, 2.6 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 3.77 (s, 3H), 3.40 – 3.35 (m, 1H), 2.79 – 2.63 (m, 2H), 2.25 (dt, J = 13.5, 6.9 Hz, 4H), 1.98 – 1.72 (m, 4H) ppm. Example 6. N-(3-chloro-4-fluorophenyl)-4-(5-((3,3-difluorocyclobutyl)ethynyl)-5- hydroxy-octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of 3-ethynyl-1,1-difluorocyclobutane (61 mg, 0.5 mmol) in THF (50 mL) was added n-BuLi (0.8 mL, 2.5 M, 2 mmol) at -78 °C under an argon atmosphere, the mixture was stirred at -20 °C for 1 h. Then a solution of Intermediate 8 (100 mg, 0.27 mmol) in THF (2 mL) was added to reaction at -78 °C by a syringe. The resulting mixture was allowed to warm to rt slowly and stirred overnight. Then the reaction mixture was quenched with water and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give a crude compound, which was purified by Prep-HPLC to give Example 6 (69 mg, 52%) as an off-white solid. MS (ESI): calcd. for C25H₂5ClF3N3O2: 491; Found: 492 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 7.95 (dd, J = 7.0, 2.5 Hz, 1H), 7.63 (s, 1H), 7.57 (dt, J = 7.4, 3.4 Hz, 1H), 7.40 (t, J = 9.1 Hz, 1H), 5.24 (s, 1H), 3.67 (s, 3H), 3.28 (s, 1H), 3.27 – 3.19 (m, 1H), 3.11 – 2.55 (m, 4H), 2.42 (s, 2H), 2.10 – 1.91 (m, 4H), 1.87 – 1.45 (m, 4H) ppm. Example 7. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-methyloxetan-3-yl)ethynyl)- octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of 3-ethynyl-3-methyloxetane (191.87 mg, 2.0 mmol) in anhydrous THF (10 mL) was added dropwise n-butyllithium (110.81 mg, 1.73 mmol, 690 µL) at -78 °C. The resulting mixture was warmed for 45 min to -10 °C. Then a solution of Intermediate 8 (50.01 mg, 133.06 µmol) in THF (1 mL) was added dropwise to reaction at -78 °C by a syringe. The resulting mixture was stirred at -78 °C for 15 min, and left to warm gradually to rt. After 12 h the mixture was poured into saturated NH4OH solution, extracted with EtOAc (20 mL x 3). The combined organic solution was dried over Na₂SO₄ and concentrated to give the crude compound, which was purified by Prep-HPLC to afford Example 7 (16.7 mg, 27%) as an off-white solid. MS (ESI): calcd. for C25H₂7ClFN3O3: 471; Found: 470 [M - 1]-; ¹H NMR (400 MHz, CD₃CN): δ 8.31 (s, 1H), 7.89 (dd, J = 6.8, 2.6 Hz, 1H), 7.54 (dq, J = 6.8, 2.8 Hz, 1H), 7.48 (s, 1H), 7.27 (t, J = 9.0 Hz, 1H), 4.68 (d, J = 5.3 Hz, 2H), 4.40 (d, J = 5.3 Hz, 2H), 3.74 (s, 3H), 3.34 (dq, J = 11.9, 5.9 Hz, 2H), 2.69 (s, 2H), 2.16 – 2.11 (m, 2H), 1.94 – 1.69 (m, 5H), 1.57 (s, 3H) ppm. Example 8. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3-methyl- cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1: Synthesis of 3-ethynylcyclobutanone (8-2). To a flask with 3-ethynyl-1,1- dimethoxycyclobutane (8-1) (3.0 g, 21.4 mmol) was added trifluoroacetic acid (10 mL). The resulting mixture was stirred at rt for 2 h. Then the reaction mixture was concentrated, suspended in ether, washed with saturated sodium bicarbonate, dried over Na₂SO₄, filtered, and concentrated in vacuo to give the crude compound, which was purified by column chromatography (MTBE/Hex = 1/5 (v/v)) to give 8-2 (1.2 g, 60%) as a brown oil. Step 2: Synthesis of 3-ethynyl-1-methylcyclobutan-1-ol (8-3). A 2.27 M solution of methyl magnesium chloride in THF (7 mL, 3 eq.) was added dropwise to a stirred solution of 8-2 (0.5 g, 5.3 mmol) in THF (20 mL) at 0-10 °C. The mixture was stirred at 0-10 °C for 3 h, then the mixture was added to an ice cooled solution of saturated NH₄CI (30 mL) and stirred for 10 min then extracted three times with MTBE. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The afforded crude product was purified by silica gel chromatography (hexane / MTBE) to give 8-3 (0.4 g, 69%). Step 3: Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3- methyl-cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 8). To a solution of 8-3 (204.68 mg, 1.86 mmol) in THF (20 mL) was added n-BuLi (238.04 mg, 3.72 mmol, 1.52 mL, 14.0 eq.) at -78 °C under an argon atmosphere, the mixture was stirred at -10 °C for 10 min. Then a solution of Intermediate 8 (100.0 mg, 266.08 µmol, 100.0 mL, 1.0 eq.) in THF (2 mL) was added at -78 °C by a syringe. The resulting mixture was allowed to warm to rt slowly and stirred overnight. Then the reaction was quenched with water and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude compound, which was purified by Prep-HPLC to give Example 8 (21 mg, 11%). MS (ESI): calcd. for C26H₂9ClFN3O3: 485; Found: 484 [M - 1]-; ¹H NMR (400 MHz, CD3OD): δ 7.96 – 7.86 (m, 1H), 7.65 (s, 1H), 7.51 (s, 1H), 7.26 (t, J = 9.0 Hz, 1H), 3.77 (s, 3H), 3.36 (s, 1H), 2.66 (s, 2H), 2.57 (t, J = 9.1 Hz, 1H), 2.31 (t, J = 9.9 Hz, 2H), 2.27 – 2.02 (m, 6H), 1.86 – 1.67 (m, 4H), 1.29 (s, 3H) ppm. Example 9. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-3-methylbut-1-yn- 1-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of 2-methylbut-3-yn-2-ol (133.87 mg, 1.59 mmol) in THF (10 mL) was added n-butyllithium (3.18 mmol, 1.27 mL, 2.5 M in hexane, 12.0 eq.) at -80 °C. The reaction mixture was warm up to -40 °C and stirred for 1 h. Then reaction mixture was cooled to -78 °C and THF solution of Intermediate 8 (100.0 mg, 266.08 µmol) was added at this temperature. The reaction mixture was stirred at the same temperature for 30 min, then warm up to RT and stirred overnight. Then 5 mL of water and 10 mL of ethyl acetate were added to reaction mixture. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep- HPLC to give Example 9 (29 mg, 24%). MS (ESI): calcd. for C24H₂7ClFN3O3: 459; Found: 460 [M + 1]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 5.10 (s, 1H), 5.04 (s, 1H), 3.67 (s, 3H), 2.19 – 1.90 (m, 5H), 1.74 (d, J = 9.3 Hz, 2H), 1.66 (d, J = 12.0 Hz, 2H), 1.34 (s, 6H) ppm. Example 10. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-methyl-3-(4- (trifluoromethyl)-1H-pyrazol-1-yl)but-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide

Step 1. Synthesis of 1-(2-methylbut-3-yn-2-yl)-4-(trifluoromethyl)-1H-pyrazole. To a solution of 10-1 (2 g, 14.7 mmol) in THF (50 mL) at 0 °C was added in success Et3N (2.86 mL, 20.6 mmol), 3-chloro-3-methylbut-1-yne (1.96 g, 19.1 mmol) and CuCl (150 mg, 1.47 mmol). The resulting mixture was slowly warmed to rt and stirred overnight. Subsequently, water was added to the reaction mixture and the mixture was extracted with MTBE (100 mL x 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was distilled to give 10-2 (280 mg, 10%) as an oil. MS (ESI): calcd. for C9H9F3N2: 202; Found: 203 [M + 1]⁺. Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-methyl-3-(4- (trifluoromethyl)-1H-pyrazol-1-yl)but-1-yn-1-yl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide. A solution of 10-2 (280 mg, 1.39 mmol) in THF (7 mL) was added n-BuLi (0.55 mL, 2.5 M, 1.39 mmol) at -78 °C under argon, the mixture was stirred at -50 °C for 1 h. Then a solution of Intermediate 8 (87 mg, 0.23 mmol) in THF (2 mL) was added at -78 °C. The resulting mixture was allowed to warm to rt slowly and stirred for 1 h. Then the reaction was quenched with water and extracted with EtOAc (130 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give Example 10 (28 mg, 21 %) as an off-white solid. MS (ESI): calcd. for C28H₂8ClF4N5O2: 577; MS Found: 576 [M - 1]-; ¹H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.50 (s, 1H), 7.95 (d, J = 6.5 Hz, 2H), 7.64 (s, 1H), 7.57 (ddt, J = 9.0, 4.4, 2.2 Hz, 1H), 7.40 (t, J = 9.1 Hz, 1H), 5.49 (s, 1H), 3.67 (s, 3H), 3.24 (dq, J = 12.0, 6.0 Hz, 1H), 2.54 (s, 2H), 2.07 (dd, J = 12.2, 7.6 Hz, 4H), 1.77 (s, 6H), 1.75 – 1.65 (m, 3H) ppm. Example 11.4-(5-((2-aminopyridin-4-yl)ethynyl)-5-hydroxyoctahydropentalen-2-yl)-N- (3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of 4-ethynylpyridin-2-amine (94.28 mg, 798.04 µmol, 6.0 eq.) in anhydrous THF (10 mL) was added dropwise n-butyllithium (2.5M in n-hexane, 1.6 mmol, 0.64 mL, 12.0 eq. at -78 °C. The resulting mixture was stirred for 30 min and warmed to -20 °C over 30 min. Then it was cooled to -78 °C, and a solution of Intermediate 8 (50.0 mg, 133.04 µmol) in THF (2 mL) was added dropwise to reaction. The reaction mixture was stirred at -78 °C for 1 h, and left to warm gradually to rt. After 12 h the mixture was poured into saturated aq. NH4Cl solution, extracted with EtOAc (10 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 11 (18 mg, 27%) as an off-white solid. MS (ESI): calcd. for C26H₂5ClFN5O2: 493; Found: 492 [M - 1]-; ¹H NMR (400 MHz, CD3CN): δ 7.96 (d, J = 5.2 Hz, 1H), 7.90 (dd, J = 6.6, 2.7 Hz, 1H), 7.49 (s, 1H), 7.28 (t, J = 9.0 Hz, 1H), 6.64 – 6.54 (m, 1H), 6.50 (s, 1H), 4.95 (s, 2H), 3.75 (s, 3H), 3.32 (s, 2H), 2.75 (s, 2H), 2.24 (d, J = 7.3 Hz, 5H) ppm. Example 12. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((6-methylpyridin-3- yl)ethynyl)-octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

A suspension of N-(3-chloro-4-fluorophenyl)-4-(5-ethynyl-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (70.0 mg, 174.19 µmol), which was readily prepared by reacting Intermediate 8 with ethynylmagnesium bromide, 5-bromo-2-methylpyridine (89.92 mg, 522.75 µmol, 3.0 eq.), triethylamine (176.32 mg, 1.74 mmol, 240.0 µl, 10.0 eq.), copper(I) iodide (3.32 mg, 17.43 µmol, 0.1 eq.) and Pd(dppf)Cl₂ DCM complex (14.23 mg, 17.42 µmol, 0.1 eq.) in degassed THF was stirred under Argon atmosphere at 65 °C overnight. After cooling to rt, the mixture was evaporated in vacuo, diluted with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic extracts were dried over Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 12 (19 mg, 22%). MS (ESI): calcd. for C27H₂6ClFN4O2: 492; Found 493 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 8.42 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 6.7, 2.6 Hz, 1H), 7.72 (dd, J = 8.0, 2.2 Hz, 1H), 7.66 (s, 1H), 7.52 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.36 – 7.18 (m, 2H), 3.78 (s, 3H), 3.38 (dd, J = 12.1, 6.0 Hz, 1H), 2.71 (d, J = 34.5 Hz, 2H), 2.53 (s, 3H), 2.29 (ddd, J = 35.3, 16.6, 10.7 Hz, 4H), 1.97 – 1.69 (m, 4H) ppm. Example 13. N-(3-chloro-4-fluorophenyl)-4-(5-(3,3-difluorobut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of (Z)-1-bromo-2,3,3-trifluorobut-1-ene (13-2). To a solution of 1-bromo-2,2,3,3-tetrafluorobutane (13-1) (1.28 g, 6.12 mmol) in DMSO (2.5 mL) was added a solution of KOH (721.37 mg, 12.86 mmol) in water (1.2 mL) at rt. After stirring of the reaction mixture for 24 h, it was heated at 80 ~ 100 °C for distillation. The collected distillate was washed with water, dried over anhydrous Na2SO4, then filtered to give 13-2 (900.0 mg, 78%) as a light-yellow oil. Step 2: Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(3,3-difluorobut-1-yn-1-yl)- 5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 13-2 (241.42 mg, 1.28 mmol) in anhydrous THF (15 mL) was added dropwise n- butyllithium (2.5M in n-hexane, 2.56 mmol, 1.02 mL, 16.0 eq.) at -78 °C. The resulting mixture was stirred for 1 h at -65 °- 78 °C. Then a solution of Intermediate 8 (60.0 mg, 0.16 mmol) in THF (2 mL) was added dropwise to the reaction mixture. The resulting mixture was stirred at -78 °C for 40 min, and left to warm gradually to rt. After 12 h the mixture was poured into saturated aq. NH4Cl solution, extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to give Example 13 (75 mg, 51%). MS (ESI): calcd. for C23H₂3ClF3N3O2: 465; Found: 466 [M + 1]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.96 (dd, J = 6.9, 2.6 Hz, 1H), 7.64 (s, 1H), 7.61 – 7.53 (m, 1H), 7.40 (t, J = 9.1 Hz, 1H), 5.68 (s, 1H), 3.67 (s, 3H), 3.24 (dt, J = 12.0, 6.0 Hz, 1H), 2.54 (s, 2H), 2.14 – 1.96 (m, 4H), 1.87 (t, J = 17.9 Hz, 3H), 1.81 – 1.62 (m, 4H) ppm. Example 14. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3-(1-methyl-1H- imidazol-4-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide

Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-((3,3-dimethoxycyclobutyl)- ethynyl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (14- 1). To a solution of 8-1 (1.4 g, 10 mmol) in anhydrous THF (50 mL) was added n-BuLi (6.25 mL, 1.6 M in THF, 10 mmol) dropwise at -78 ^oC under an atmosphere of Ar. After stirring at -40 ^oC for 30 min, the solution was cooled to -78 ^oC, followed by adding a solution of Intermediate 8 (720 mg, 2 mmol) in THF (10 mL) dropwise over 30 min. The resulting mixture was stirred at -78 ^oC for 30 min then gradually warmed to rt. After stirring rt overnight, the reaction mixture was added sat. aq. NH4Cl (10 mL) at 0 ^oC. The resulting mixture was concentrated to remove most of the organic solvent, and the residue was diluted with water and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by silica gel column Chromatography using EtOAc/Hexanes = 1/4 (v/v) as eluent to give 14-1 (600 mg, 58%) as an off-white solid. MS (ESI): calcd. for C27H₃1ClFN3O4: 515; Found: 514 [M - 1]-. Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3- oxocyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (14-2). A mixture of 14-1 (600 mg, 1.17 mmol) in Acetone/H₂O (12 mL, 10/1 (v/v)) was added TsOH (201 mg, 1.17 mmol). The resulting mixture was stirred at 40 ^oC and monitored by LC-MS. After stirring at 40 ^oC overnight, the reaction mixture was concentrated, and the residue was diluted with sat. aq. NaHCO3 (20 mL). The mixture was extracted with EtOAc (25 mL x 3), and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by silica gel column chromatography using EtOAc/Hexanes = 1/4 (v/v) as eluent to give 14-2 (360 mg, 65%) as an off-white solid. MS (ESI): calcd. for C25H₂5ClFN3O3: 469; Found: 468 [M - 1]-. Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3- (1-methyl-1H-imidazol-4-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide (Example 14). To a solution of 4-iodo-1-methyl-1H-imidazole (440.84 mg, 2.12 mmol) in anhydrous THF (10 mL) n-butyllithium (122.18 mg, 1.91 mmol, 910.0 µl, 9.0 eq.) was added dropwise at -78 °C. The resulting mixture was warmed for 45 min to -10 °C. Then a solution of 14-2 (100.0 mg, 212.8 µmol) in THF (1 mL) was added dropwise at -78 °C by a syringe. The reaction mixture was stirred at -78 °C for 15 min, and left to warm gradually to rt. After 12 h, the mixture was poured into saturated NH4OH solution, extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give Example 14 (15 mg, 13%) as an off-white solid. MS (ESI): calcd. for C29H₃1ClFN5O3: 551; Found: 550 [M - 1]-; ¹H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 7.96 (dd, J = 6.9, 2.6 Hz, 1H), 7.63 (s, 1H), 7.60 – 7.53 (m, 1H), 7.46 (s, 1H), 7.40 (t, J = 9.1 Hz, 1H), 6.93 (s, 1H), 5.34 (s, 1H), 5.14 (s, 1H), 3.81 – 3.42 (m, 7H), 3.23 (d, J = 5.7 Hz, 1H), 2.67 (dq, J = 47.5, 11.3, 9.7 Hz, 4H), 2.22 (t, J = 10.0 Hz, 2H), 2.15 – 1.90 (m, 4H), 1.75 (t, J = 10.4 Hz, 2H), 1.65 (d, J = 9.1 Hz, 2H) ppm. Example 15. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3- (trifluoromethyl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide

Step 1: Synthesis of 3-ethynyl-1-(trifluoromethyl)cyclobutan-1-ol (15-1). To the solution of 8-2 (0.5 g, 5.3 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (1.57 mL, 10.6 mmol) and tetrabutylammonium fluoride (1.0M solution in THF, 10.6 mL, 10.6 mmol) at 0 °C, the resulting mixture was stirred at rt for 2 h. A saturated aq. NH₄Cl solution (10 mL) was added to the reaction liquid and stirred for 10 minutes, then concentrated under reduced pressure. Distilled water (10 mL) was added to the residue thus obtained, followed by extraction with MTBE (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentration. The residue was purified by column chromatography to give 15-1 (0.65 g, 74%) as a yellow oil. Step 2: Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3- (trifluoromethyl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 15). A solution of 15-1 (438 mg, 2.67 mmol, 10 eq.) in THF (20 mL) was added n-BuLi (5.34 mmol, 2.1 mL, 20.0 eq.) at -78 °C under an argon atmosphere, the mixture was stirred at -10 °C for 10 min. Then a solution of Intermediate 8 (100.0 mg, 266.08 µmol, 1.0 eq.) in THF (2 mL) was added at -78 °C by a syringe to reaction. The resulting mixture was allowed to warm to rt slowly and stirred overnight. Then the reaction was quenched with water and extracted with EtOAc (30 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give Example 15 (25 mg, 17%). MS (ESI): calcd. for C26H₂6ClF4N3O3: 539; Found: 540 [M + 1]⁺; Found: 538 [M - 1]-; ¹H NMR (400 MHz, CD3OD): δ 7.94 – 7.87 (m, 1H), 7.65 (s, 1H), 7.52 (d, J = 9.9 Hz, 1H), 7.26 (t, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.37 (d, J = 17.3 Hz, 1H), 2.80 (d, J = 8.0 Hz, 3H), 2.67 (s, 2H), 2.21 (dd, J = 19.1, 11.2 Hz, 6H), 1.84 – 1.68 (m, 4H) ppm. Example 16, 16a and 16b. N-(3-chloro-4-fluorophenyl)-4-(5-(4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (16), N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (16a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (16b)

Step 1. Synthesis of 1,1-difluoro-2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (16-2). To a solution of trimethylsilylacetylene (5.7 g, 58 mmol) in THF (100 mL) was added n-BuLi (24 mL, 2.5 M, 61 mmol) at -78 °C under an argon atmosphere, the mixture was stirred at -30 °C for 1 h. Then the resulting mixture was cooled to -78 °C and 16-1 (5 g, 53 mmol) was added, keeping the reaction temperature under -30 °C. The resulting mixture was allowed to rt overnight. Then the reaction mixture was poured on 10% water solution of NH₄Cl and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give a crude 16-2 (3.0 g, 30%), which was carried onto the next step without further purification. Step 2. Synthesis of 1,1-difluoro-2-methyl-but-3-yn-2-ol (16-3). To a solution of 16-2 (3.0 g, 16 mmol) in MeOH (150mL) was added K2CO3 (2 eq., 32 mmol, 4.4 g). The mixture stirred vigorously for 16 h at room temperature. After reaction completed, the mixture was filtered. MeOH was concentrated under reduced pressure and the residue was distilled to give 16-3 (100 mg, 5%). Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 16). To a solution of 16-3 (100 mg, 0.8 mmol) in THF (8 mL) was added n-BuLi (2.6 mL, 2.5 M, 1 mmol) at -78 °C under an argon atmosphere, the mixture was stirred at -20 °C for 1 h. Then a solution of Intermediate 8 (150 mg, 0.4 mmol) in THF (2 mL) was added at -78 °C by a syringe to reaction. The resulting mixture was allowed to warm to rt slowly and stirred overnight. Then the reaction was quenched with water and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give Example 16 (16 mg, 8%). MS (ESI): calcd. for C24H₂5ClF3N3O3: 495; Found: 496 [M + 1]⁺; ¹H NMR (600 MHz, CD3OD): δ 8.12 (s, 1H), 7.87 (dd, J = 6.7, 2.7 Hz, 1H), 7.68 (s, 1H), 7.50 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.24 (t, J = 9.0 Hz, 1H), 5.60 (t, J = 56.4 Hz, 1H), 3.76 (s, 3H), 3.37 – 3.32 (m, 1H), 2.67 (d, J = 18.5 Hz, 2H), 2.36 – 2.15 (m, 4H), 1.77 (h, J = 7.6 Hz, 4H), 1.49 – 1.37 (m, 3H) ppm. Step 4. N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3-hydroxy-3- methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 16a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3- hydroxy-3-methylbut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide (Example 16b). Example 16 was separated by SFC to give Example 16a and Example 16b, respectively. The stereochemistry of the chiral alcohol residue was arbitrarily assigned. SFC separation condition: Column: Chiralpak AD-H (21*250, 5 mkm); Backpressure: 100 bar; Temperature post-heater: 50 ^oC; Temperature column compartment: 40 ^oC; Eluent: liquid CO2/MeOH = 90/10 (v/v); Flow: 50 mL/min; UV detection at 215 nm. SFC analysis condition: Column: Chiralpak AD-H (4.6*250, 5 mkm); Eluent: liquid CO2/MeOH = 80/20 (v/v); Flow: 3.0 mL/min; UV detection at 215 nm. Example 16a: tR = 3.438 min; MS (ESI): calcd. for C24H₂5ClF3N3O3: 495; Found: 494 [M - 1]-; ¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.57 – 7.46 (m, 1H), 7.25 (t, J = 8.9 Hz, 1H), 5.62 (t, J = 56.4 Hz, 1H), 3.77 (s, 3H), 3.42 – 3.34 (m, 1H), 2.69 (s, 2H), 2.23 (dd, J = 12.3, 6.6 Hz, 4H), 1.80 (dd, J = 13.2, 8.2 Hz, 4H), 1.43 (t, J = 1.6 Hz, 3H) ppm. Example 16b: tR = 2.595 min; MS (ESI): calcd. for C24H₂5ClF3N3O3: 495; Found: 494 [M - 1]-; ¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.57 – 7.46 (m, 1H), 7.25 (t, J = 8.9 Hz, 1H), 5.62 (t, J = 56.4 Hz, 1H), 3.77 (s, 3H), 3.42 – 3.34 (m, 1H), 2.69 (s, 2H), 2.23 (dd, J = 12.3, 6.6 Hz, 4H), 1.80 (dd, J = 13.2, 8.2 Hz, 4H), 1.43 (t, J = 1.6 Hz, 3H) ppm. Example 17. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-methoxy- cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of 1-ethynyl-3-methoxycyclobutan-1-ol (17-2). To a stirred solution of ethynylmagnesium bromide (2.71 g, 20.97 mmol, 41.95 mL, 3.0 eq.) in dry THF was dropwise added 17-1 (700.0 mg, 6.99 mmol) at 0 °C under an Argon atmosphere. The mixture was allowed to warm to rt and stirred for 1.5 h. The reaction mixture was quenched with saturated aq. NH₄Cl and extracted with MTBE. The organic layer was washed with brine, dried over Na₂SO₄ and evaporated. The crude product was purified by flash chromatography (EtOAc/Hex = 1/4 (v/v)) to give 17-2 (500 mg, 54%). Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3- methoxy-cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 17). To a stirred solution of 17-2 (101 mg, 798 µmol) in dry THF was added dropwise n-butyllithium (94 mg, 1.46 mmol, 590 µL, 11.0 eq.) at -78 °C under an Argon atmosphere. The mixture was allowed to warm to -10 °C and then cooled to -78 °C. A solution of Intermediate 8 (50 mg, 133 µmol) in 2 mL of THF was added to reaction. The mixture was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give Example 17 (14 mg, 20%). MS (ESI): calcd. for C26H₂9ClFN3O4: 501; Found: 502 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.52 (ddd, J = 8.9, 4.3, 2.5 Hz, 1H), 7.25 (t, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.73 (q, J = 7.0 Hz, 1H), 3.37 (dt, J = 12.1, 6.3 Hz, 1H), 3.23 (s, 3H), 2.82 – 2.57 (m, 4H), 2.23 (p, J = 9.1, 7.5 Hz, 4H), 2.12 (ddt, J = 9.7, 7.5, 3.1 Hz, 2H), 1.92 – 1.60 (m, 4H) ppm. Example 18. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-(pyridin-3- yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of 1-ethynyl-3-(pyridin-3-yl)cyclobutan-1-ol (18-2). A solution of 18-1 (2 g, 13.6 mmol) in THF (7 mL) was added dropwise to a solution of ethynylmagnesium bromide (0.5M in THF, 35.4 mL, 17.7 mmol, 1.3 eq.) at -60 °C. The reaction mixture was warmed to rt and stirred overnight. Then the obtained suspension was added water, the organic layer was separated. The inorganic residue was washed several times with THF. The combined organic extracts were dried over Na2SO4 and concentrated. The residue was dissolved in MTBE and filtered through a plug of silica, concentrated and dried in vacuo to afford 18-2 (1.73 g, 74%) as a pale-yellow solid. Step 2: Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3- (pyridin-3-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 18). n-BuLi (2.5M in hexane, 1.05 mL, 14 eq.) was added dropwise to a solution of 18-2 (225 mg, 1.3 mmol, 7 eq.) in THF (5 mL) at -80 °C. The reaction mixture was warmed to -10 °C and obtained pale yellow suspension was cooled again to -80 °C. Then the solution of Intermediate 8 (70 mg, 0.186 mmol, 1 eq.) in 1 mL THF was added dropwise to the above suspension. The obtained mixture was warmed to rt and stirred overnight and treated with water. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC to afford Example 18 (21 mg, 21%) as a pale-yellow solid. MS (ESI): calcd. for C30H₃0ClFN4O3: 548; Found: 547 [M - 1]-; ¹H NMR (400 MHz, CD3OD): δ 8.44 (s, 1H), 8.39 (s, 1H), 7.90 (dd, J = 6.7, 2.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.53 (dd, J = 8.7, 3.6 Hz, 1H), 7.42 (dd, J = 7.8, 4.9 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.44 – 3.35 (m, 2H), 2.86 (td, J = 8.3, 2.8 Hz, 2H), 2.75 (s, 2H), 2.41 – 2.21 (m, 6H), 1.82 (dd, J = 12.8, 6.5 Hz, 4H) ppm. Example 19. N-(3-chloro-4-fluorophenyl)-4-(5-((6,6-difluoro-2-hydroxyspiro[3.3]heptan- 2-yl)ethynyl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of 2-ethynyl-6,6-difluorospiro[3.3]heptan-2-ol (19-2). A solution of 19-1 (0.5 g, 3.42 mmol) in THF (5 mL) was added dropwise to a stirred 0.4 M solution of ethynylmagnesium bromide in THF (25.6 mL, 3 eq.) at 0 ~ 10 °C. The mixture was stirred for 3 h at rt, then the mixture was added to an ice cooled solution of saturated aq. NH4Cl (30 mL). The mixture was stirred for 10 min then extracted three times with MTBE. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexane / MTBE) to give 19-2 (0.45 g, 76%) as a pale-yellow oil. Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-((6,6-difluoro-2- hydroxyspiro[3.3]heptan-2-yl)ethynyl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide (Example 19). To a solution of 19-2 (300 mg, 1.74 mmol, 13 eq.) in THF (20 mL) was added n-BuLi (1.3 mL, 2.5 M in hexane, 24.0 eq.) at -78 °C under an argon atmosphere, the mixture was stirred at -10 °C for 10 min. Then a solution of Intermediate 8 (50.0 mg, 133.04 µmol, 1.0 eq.) in THF (2 mL) was added at -78 °C by a syringe to reaction. The resulting mixture was allowed to warm to rt slowly and stirred overnight. Then the reaction was quenched with water and extracted with EtOAc (30 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give Example 19 (21 mg, 29%) as an off-white solid. MS (ESI): calcd. for C28H₂9ClF3N3O3: 547; Found: 548 [M + 1]⁺; ¹H NMR (400 MHz, CD3CN): δ 8.31 (s, 1H), 7.97 – 7.80 (m, 1H), 7.62 – 7.51 (m, 1H), 7.49 (s, 1H), 7.27 (t, J = 9.0 Hz, 1H), 3.74 (s, 3H), 3.34 (dt, J = 12.0, 5.9 Hz, 2H), 2.69 (dd, J = 50.4, 12.7 Hz, 6H), 2.50 (d, J = 12.1 Hz, 2H), 2.42 – 2.32 (m, 2H), 2.15 (t, J = 6.5 Hz, 3H), 1.89 (t, J = 10.4 Hz, 2H), 1.79 (dd, J = 12.6, 4.7 Hz, 2H) ppm. Example 20. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-(pyridin-2- yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of 3-(pyridin-2-yl)-1-[2-(trimethylsilyl)ethynyl]cyclobutan-1-ol (20-1). To a solution of ethynyltrimethylsilane (3.0 g, 30.57 mmol, 4.32 mL, 1.5 eq.) in THF (100 mL) was added a solution of n-butyllithium (1.96 g, 30.57 mmol, 12.23 mL, 1.5 eq.) in hexane at -78 °C. The reaction mixture was stirred at -78 °C to -20 °C for 1 h. The reaction mixture was cooled at -78 °C and added 3-(pyridin-2-yl)cyclobutan-1-one (3.0 g, 20.38 mmol). The obtained mixture was warmed to rt and stirred overnight. The saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dried in vacuo to give 20-2 (4.0 g, 76%) as a pale-yellow solid. Step 2. Synthesis of 1-ethynyl-3-(pyridin-2-yl)cyclobutan-1-ol (20-3). To a solution of 20-2 (4.0 g, 16.3 mmol) in MeOH (50 mL) and H₂O (50 mL) was added potassium carbonate (4.5 g, 32.6 mmol). The resulting solution was stirred at rt for 12 h. Then H₂O and ethyl acetate were added to reaction mixture. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was recrystallized in MeOH to give 20-3 (2.5 g, 84%) as a pale-yellow solid. Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3- (pyridin-2-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 20). To a solution of 20-3 (230.3 mg, 1.33 mmol) in THF (30 mL) was added a solution of n-butyllithium (170.0 mg, 2.65 mmol, 1.06 mL, 10.0 eq.) in hexane at -78 °C. The resulting mixture was stirred at -78 °C to -60 °C for 1 h. Then a solution of Intermediate 8 (99.94 mg, 265.92 µmol) in 5 mL THF was added at -78 °C to reaction. The obtained mixture was warmed to rt and stirred overnight. The saturated aqueous ammonium chloride solution and ethyl acetate were added to reaction mixture. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography to give Example 20 (54 mg, 37%) as an off-white solid. MS (ESI): calcd. for C30H₃0ClFN4O3: 548; Found: 549 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 8.50 – 8.41 (m, 1H), 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.66 (s, 1H), 7.56 – 7.48 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.30 – 7.19 (m, 2H), 3.77 (s, 3H), 3.52 – 3.34 (m, 2H), 2.81 (td, J = 8.3, 2.8 Hz, 2H), 2.71 (d, J = 30.7 Hz, 2H), 2.46 (td, J = 9.5, 2.8 Hz, 2H), 2.37 – 2.19 (m, 4H), 2.05 (s, 3H), 1.81 (dd, J = 12.0, 6.1 Hz, 4H) ppm. Example 21. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((6-(2-hydroxypropan-2- yl)pyridin-3-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of 2-(5-ethynylpyridin-2-yl)propan-2-ol (21-2). To a stirred solution of chloro(methyl)magnesium (2.06 g, 27.57 mmol, 12.53 mL, 4.0 eq.) in THF (2.2 M) was added dropwise a solution of 21-1 (1.0 g, 6.89 mmol) in dry THF (5 mL) under argon atmosphere, keeping the internal temperature between 0-5 °C. The resulting mixture was stirred at this temperature for additional 30 min, and then was left to warm to rt overnight. Then the reaction was quenched with sat. aq. ammonium chloride solution (50 mL) and extracted with MTBE (50 mL x 2). Organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography to give 21-2 (600 mg, 54%) as a pale-yellow solid. Step 2: Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((6-(2-hydroxypropan- 2-yl)pyridin-3-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 21). To a stirred solution of 21-2 (257.55 mg, 1.6 mmol) in dry THF (10 mL) was added dropwise a n-butyllithium (196.15 mg, 3.06 mmol, 1.46 mL, 11.5 eq.) (2.1 M solution in hexane) under argon atmosphere, keeping the internal temperature between -75 ~ 85°C (target -80 °C). The resulting mixture was allowed to warm to -10°C (about 40 min at this scale), then cooled back to -80 °C, and a solution of Intermediate 8 (100.0 mg, 266.08 µmol) in dry THF (1 mL) was added dropwise keeping the internal temperature within -75 ~ 85 °C (target -80 °C). The solution was left to warm to rt overnight. Then the reaction was quenched with sat. aq. ammonium chloride solution (10 mL) and extracted with MTBE (10 mL x 2). Organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by Prep-HPLC to give Example 21 (42 mg, 29%). MS (ESI): calcd. for C29H₃0ClFN4O3: 536; Found: 537 [M + 1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 6.8, 2.6 Hz, 1H), 7.77 (dd, J = 8.2, 2.2 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.60 – 7.54 (m, 1H), 7.40 (t, J = 9.1 Hz, 1H), 5.54 (s, 1H), 5.27 (s, 1H), 3.67 (s, 3H), 3.30 – 3.22 (m, 1H), 2.60 (s, 2H), 2.19 – 2.03 (m, 4H), 1.80 (dt, J = 13.1, 6.5 Hz, 4H), 1.41 (s, 6H) ppm. Example 22. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((5-(2-hydroxypropan-2- yl)pyridin-2-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

Step 1. Synthesis of 2-(6-ethynylpyridin-3-yl)propan-2-ol (22-2). To a solution of 22-1 (1.5 g, 10.32 mmol) in THF (100 mL) was added chloro(methyl)magnesium (1.93 g, 25.8 mmol, 8.6 mL, 2.5 eq.) in THF at -20 °C. The reaction mixture was stirred at -20 °C to 20 °C for 12 h. Saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was distilled to give 22-2 (1.5 g, 86%) as a pale-yellow oil. Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((5-(2- hydroxypropan-2-yl)pyridin-2-yl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide (Example 22). To a solution of 22-2 (214.62 mg, 1.33 mmol) in THF (30 mL) was added n-butyllithium (188.0 mg, 2.93 mmol, 1.17 mL, 11.0 eq.) in hexane at -78 °C. The reaction mixture was stirred at -78 °C to -60 °C for 1 hour then was added a solution of Intermediate 8 (100.08 mg, 266.28 µmol) in 5 mL THF at -78 °C. The reaction mixture was stirred at -78 °C to rt overnight. Saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography to give Example 22 (37 mg, 25 %) as an off-white solid. MS (ESI): calcd. for C29H₃0ClFN4O3: 536; Found: 537 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 8.62 (d, J = 2.3 Hz, 1H), 7.90 (td, J = 7.0, 6.1, 2.5 Hz, 2H), 7.66 (s, 1H), 7.52 (ddd, J = 8.9, 3.8, 2.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 3.78 (s, 3H), 3.43 – 3.35 (m, 1H), 2.78 (s, 2H), 2.36 (dd, J = 12.7, 7.4 Hz, 2H), 2.28 (dd, J = 9.2, 3.7 Hz, 2H), 1.94 – 1.75 (m, 4H), 1.55 (s, 6H) ppm. Example 23. N-(3-chloro-4-fluorophenyl)-4-(5-(4,4-difluoro-3-hydroxybut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 23), N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3-hydroxybut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 23a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3-hydroxybut-1-yn-1-yl)-5- hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Example 23b)

Step 1. Synthesis of 1,1-difluoro-4-(trimethylsilyl)but-3-yn-2-one (23-2). To a solution of trimethylsilylacetylene (11.9 g, 121 mmol) in Et2O (100 mL) was added n-BuLi (58 mL, 2.5 M, 145 mmol) at -78 °C under an argon atmosphere, the mixture was stirred at - 30 °C for 1 h. Then the resulting mixture was cooled to -78 °C, and 23-1 (15 g, 121 mmol) was added, keeping the reaction temperature under -30 °C. The resulting mixture was allowed to rt overnight and poured on a 10% aq. solution of NH4Cl. The product was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give 23-2 (21g, 90%) as a pale-yellow oil, which was used for the next step without further purification. Step 2. Synthesis of 1,1-difluoro-4-(trimethylsilyl)but-3-yn-2-ol (23-3). Compound 23-2 (21 g) was dissolved in THF, followed by NaBH4 (4.6 g, 121 mmol). The mixture stirred for 16 h at - 15 °C and then warmed to rt with stirring overnight. After the reaction was completed, the mixture was washed with water and brine. The organic layer was distilled to give the 23-3 (15 g, 50%) as a pale-yellow oil. Step 3. Synthesis of 1,1-difluorobut-3-yn-2-ol (23-4). Compound 23-3 (15 g, 84 mmol) was dissolved in THF/Et2O, followed by TBAF (168 mL, 168 mmol). The mixture was stirred for 16 h at rt overnight. After the reaction was completed, the mixture was washed with water and NaHSO4. The organic layer was distilled to give 23-4 (8 g, 62% yield) as a pale-yellow oil. Step 4. Synthesis of tert-butyl((1,1-difluorobut-3-yn-2-yl)oxy)dimethylsilane (23- 5). To a stirred mixture of 23-4 (8 g, 53 mmol) and 1H-imidazole (18 g, 265 mmol) in anhydrous CH₂Cl2 (200 mL) was added TBDMS-Cl (9.9 g, 58 mmol), and the mixture was stirred at rt for 12 h. The organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to 23-5 (3.2 g, 27 % yield) as a pale-yellow oil. Step 5. Synthesis of 4-(5-(3-((tert-butyldimethylsilyl)oxy)-4,4-difluorobut-1-yn-1- yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H- imidazole-5-carboxamide (23-6). To a solution of 23-5 (580 mg, 2.63 mmol) in THF (8 mL) was added EtMgBr (1.6 mL, 3.4 M, 5.3 mmol) at rt under an argon atmosphere, and the mixture was stirred for 1 h. Then a solution of Intermediate 8 (100 mg, 0.26 mmol) in THF (2 mL) was added. The resulting mixture was allowed to warm to 50 °C and stirred overnight. Then the reaction was quenched with a 10% aq. solution of NH4Cl and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was dried in vacuo to give crude 23-6 (200 mg, 13% yield), which was used for the next step without further purification. Step 6. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(4,4-difluoro-3- hydroxybut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 23). To a solution of crude compound 23-6 (200 mg, 0.34 mmol) in MeOH/H₂O was added KHF2 (53 mg, 0.68 mmol). The mixture stirred for 16 h. at rt overnight. After the reaction was completed, the mixture was concentrated and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The solvent was removed, and the residue was purified by pre- HPLC to give Example 23 (10 mg, 12 % yield) as an off-white solid. MS (ESI): calcd. for C23H₂3ClF3N3O3481; Found: 482 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.66 (s, 1H), 7.52 (dq, J = 9.0, 3.5, 3.0 Hz, 1H), 7.25 (t, J = 8.9 Hz, 1H), 5.71 (td, J = 55.9, 4.0 Hz, 1H), 4.48 (td, J = 10.3, 4.0 Hz, 1H), 3.77 (s, 3H), 3.40 – 3.34 (m, 1H), 2.68 (d, J = 12.0 Hz, 2H), 2.24 (dd, J = 12.2, 6.0 Hz, 4H), 1.78 (dt, J = 13.1, 7.0 Hz, 4H) ppm. Step 7: Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-((R)-4,4-difluoro-3- hydroxybut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 23a), and N-(3-chloro-4-fluorophenyl)-4-(5-((S)-4,4-difluoro-3- hydroxybut-1-yn-1-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5- carboxamide (Example 23b). Example 23 was separated by chiral HPLC to give Example 23a and Example 23b. The stereochemistry was arbitrarily assigned. Сolumn: Chiralcel OD- H (250×20 mm, 5 mkm); Mobile phase: Hexane/IPA/MeOH = 90/5/5 (v/v/v); Flow rate: 18 mL/min. Temperature: 24 °C, Wavelength: 215 nm. Example 23a, tR = 27.9 min; MS (ESI): calcd. for C23H₂3ClF3N3O3, 481; Found: 482 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.52 (ddd, J = 9.1, 4.2, 2.6 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 5.71 (td, J = 55.9, 3.9 Hz, 1H), 4.48 (td, J = 10.2, 3.9 Hz, 1H), 3.77 (s, 3H), 3.37 (dd, J = 12.2, 6.1 Hz, 1H), 2.70 (s, 2H), 2.24 (dt, J = 8.4, 5.1 Hz, 4H), 1.80 (dt, J = 12.7, 6.2 Hz, 4H) ppm. Example 23b, tR = 32.3 min. MS (ESI): calcd. for C23H₂3ClF3N3O3, 481; Found: 482 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.65 (s, 1H), 7.52 (ddd, J = 9.1, 4.2, 2.6 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 5.71 (td, J = 55.9, 3.9 Hz, 1H), 4.48 (td, J = 10.2, 3.9 Hz, 1H), 3.77 (s, 3H), 3.37 (dt, J = 12.0, 6.0 Hz, 1H), 2.70 (s, 2H), 2.24 (dt, J = 8.4, 5.1 Hz, 4H), 1.80 (dt, J = 12.7, 6.2 Hz, 4H) ppm. Example 24. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((3-hydroxy-3-(pyridin-2- yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide

To a solution of 2-bromopyridine (336.69 mg, 2.13 mmol) in anhydrous THF (10 mL), n-butyllithium (123.0 mg, 1.92 mmol, 9.0 eq.) was added dropwise at -78 °C. The resulting mixture was warmed for 45 min to -10 °C. Then a solution of N-(3-chloro-4- fluorophenyl)-4-(5-hydroxy-5-((3-oxocyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl- 1H-imidazole-5-carboxamide (14-2) (100.14 mg, 213.1 µmol) in THF (1 mL) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 15 min, and left to warm gradually to rt. After 12 h, the mixture was poured into saturated NH₄OH solution and extracted with EtOAc (20 mL x 3). The combined organic solution was dried over Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 24 (12 mg, 11%) as an off-white solid. MS (ESI): calcd. for C₃₀H₃₀ClFN₄O₃: 548; Found: 547 [M - 1]-; ¹H NMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 8.52 (d, J = 4.5 Hz, 1H), 7.96 (dd, J = 6.9, 2.6 Hz, 1H), 7.82 – 7.69 (m, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 9.1 Hz, 1H), 7.25 (dd, J = 6.9, 5.2 Hz, 1H), 5.96 (s, 1H), 5.17 (s, 1H), 3.67 (s, 3H), 3.17 (d, J = 5.5 Hz, 3H), 2.95 (q, J = 8.7 Hz, 1H), 2.84 – 2.69 (m, 2H), 2.33 (t, J = 10.2 Hz, 2H), 2.02 (d, J = 22.4 Hz, 4H), 1.72 (dt, J = 32.8, 11.2 Hz, 4H) ppm. Example 25. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3-(2- hydroxypropan-2-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide

Step 1. Synthesis of methyl 3-ethynyl-3-hydroxycyclobutane-1-carboxylate (25- 2). Potassium carbonate (3.94 g, 28.54 mmol, 4.0 eq.) was added to a solution of trans-3- ethynyl-3-hydroxycyclobutane-1-carboxylic acid (25-1) (1.0 g, 7.14 mmol) in N,N- dimethylformamide (10 mL). The mixture was stirred for 5 min, and a solution of iodomethane (4.05 g, 28.54 mmol, 4.0 eq.) in N,N-dimethylformamide (5 mL) was added. The resulting mixture was stirred at rt overnight. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL) and concentrated. The residue was purified by distillation under reduced pressure to five 25-2 (650 mg, 53%) as a pale-yellow liquid. Step 2. Synthesis of 1-ethynyl-3-(2-hydroxypropan-2-yl)cyclobutan-1-ol (25-3). To a THF solution (25 mL) of methylmagnesium chloride (8.43 mL, 3M in THF, 25.3 mmol, 6.0 equiv) at -30 °C was added dropwise a THF solution (5 mL) of 25-2 (649.82 mg, 4.22 mmol) under an Ar atmosphere. The reaction mixture was stirred overnight, then cooled to 0 °C and was added water (2 mL). The mixture was filtered. The filtered plug was washed EtOAc (20 mL x 2) and the filtrate was evaporated under reduced pressure. The residue was dissolved in MTBE and dried with anhydrous sodium sulfate. The solvent was removed, and the residue was dried in vacuo to give 25-3 (700 mg, 90%) as a pale-yellow liquid, which was used in the next stage without further purification. Step 3. Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)-3- ethynylcyclobutyl)propan-2-ol (25-4). To a solution of 25-3 (700.0 mg, 4.54 mmol) in DMF (5 mL) were added tert-butyl(chloro)dimethylsilane (1.5 g, 9.98 mmol) and 1H- imidazole (1.24 g, 18.15 mmol), and the mixture was stirred at rt overnight. Then 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 25-4 (600 mg, 33%). Step 4.4-(5-((1-((tert-butyldimethylsilyl)oxy)-3-(2-hydroxypropan-2- yl)cyclobutyl)-ethynyl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)- 1-methyl-1H-imidazole-5-carboxamide (25-5). To a solution of 25-4 (400.0 mg, 1.49 mmol) in THF (10 mL) was added n-butyllithium (1.23 mL, 2.5 M in hexane, 3.08 mmol, 14.5 eq.) at -78°C. The reaction mixture was warmed up to -10 °C and stirred at this temperature for 30 min. Then the reaction mixture was cooled to -78 °C and a THF solution of Intermediate 8 (79.91 mg, 212.64 µmol) was added. The reaction mixture was allowed to warm up to rt and stirred overnight. Subsequently, water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was dried in vacuo to give 25-5 as a brown solid, which was used in the next step without further purification. MS (ESI): calcd. for C34H47ClFN3O4Si: 643; Found: 644 [M + 1]⁺. Step 5. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((1-hydroxy-3- (2-hydroxypropan-2-yl)cyclobutyl)ethynyl)octahydropentalen-2-yl)-1-methyl-1H- imidazole-5-carboxamide (Example 25). To a solution of crude 25-5 (350 mg) obtained from Step 4 in MeOH (10 mL) and H₂O (2 mL) was added potassium hydrofluoride (848.77 mg, 10.87 mmol, 20 eq.) and the resulting solution was stirred at rt for 72 h. Upon completion of the reaction (was monitored by LC-MS), the reaction mixture was extracted EtOAc (10 mL x 3), the combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to give Example 25 (35 mg, 11%). MS (ESI): calcd. for C28H₃3ClFN3O4: 529; Found: 530 [M + 1]⁺; ¹H NMR (400 MHz, CD3OD): δ 7.88 (d, J = 6.7 Hz, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 8.9 Hz, 1H), 7.11 – 7.01 (m, 2H), 3.77 (s, 3H), 3.38 (s, 1H), 3.27 (s, 2H), 2.84 (d, J = 12.9 Hz, 4H), 2.45 – 2.31 (m, 2H), 2.25 (s, 2H), 1.96 – 1.71 (m, 4H) ppm. Table 1 shows structures and analytical data for representative Examples of the invention. While the structures of the Examples shown throughout this specification are drawn without stereochemistry, unless otherwise specified they represent single isomers with stereochemistry consistent with the crystal structure shown below for reference compound AIA-227-2.

Table 1. Analytical Data of Representative Examples

11.9, 5.8 Hz, 4H) ppm

(m, 4H) ppm

VI. Biological Data Assay Measuring Activity of Test Compounds on Viral Production from HepAD38 Cells HepAD38 cells grown in a T-150 flask (Corning, cat#: 430825) with Growth Medium (DMEM/F12 (1:1) (Hyclone, cat#: SH₃0023.02), 1X Pen/Strep (Invitrogen, cat#: 15140- 122), 10% FBS (Tissue Culture Biologics, cat#: 101), 250 µg/mL G418 (Alfa Aesar, cat#: J62671), 1 µg/mL Tetracycline (Teknova, cat#: T3320)) were detached with 0.25% trypsin- EDTA (Invitrogen, cat#: 25200-056). Tetracycline-free treatment medium (15 mL DMEM/F12 (1:1), 1x Pen/step, with 2% FBS, Tet-system approved (Clontech, cat#: 631106) were then added to mix, transferred into a 50 ml conical tube (Falcon, cat#: 21008-918,) and spun at 1300 rpm for 5 min. Pelleted cells were then re-suspended/washed with 50 mL of 1X DPBS (Invitrogen, cat#: 14190-136) 2 times and 50 mL treatment medium twice. HepAD38 cells were then re-suspended with 10 mL of treatment medium, syringed, and counted. Wells of 96-well clear bottom TC plate (Corning, cat#: 3904,) were seeded at 50,000 cells/well in 180 µL of treatment medium, and 20 µL of either 10% DMSO (Sigma, cat#: D4540) as controls or a 10X solution of test compounds in 10% DMSO in treatment media was added for a final compound concentration starting at 10 µM, and plates were incubated in 5% CO2 incubator at 37°C for 5 days. Subsequently viral load production was assayed by quantitative PCR (qPCR) of the HBV core sequence. PCR reaction mixture containing forward primers HBV-f 5'- CTGTGCCTTGGGTGGCTTT-3’ (IDT DNA), Reverse primers HBV-r 5'- AAGGAAAGAAGTCAGAAGGCAAAA-3' (IDT DNA), Fluorescent TaqMan^tm Probes HBV-probe 5′-FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTC/3IABkFQ -3′ (IDT DNA), 10 µL/well of PerfeCTa^® qPCR ToughMix^® (Quanta Biosciences, Cat#: 95114- 05K), and 6 µL/well of DEPC water (Alfa Aesar, cat#: J62087) was prepared. Four µL of supernatant was added to 16 µL of the reaction mixture in a qPCR plate (Applied Biosytems, Cat#: 4309849), sealed with a film (Applied Biosystems, Cat#: 4311971), centrifuged for a few seconds, and subsequently run on an Applied Biosystems VIIA7. The PCR mixture was incubated at 45°C for 5 min, then 95 °C for 10 min, followed by 40 cycles of 10 seconds at 95 °C and 20 seconds at 60°C. Viral load was quantified against known HBV DNA standards by using ViiA™ 7 Software. Viral load in the supernatant from wells with treated cells were compared against viral load in supernatant from DMSO control wells (≥ 3 per plate). Cell viability assay was performed with CellTiter-Glo Luminescent Cell Viability Assay (Promega, cat#: G7573) with modification. Mixed appropriate amount of CellTiter-Glo (CTG) 1X DPBS in a 1:1 ratio, added 100 uL of the mixture to each well followed completely removal of all supernatants in each well without touching cell surface. Incubated the plate at room temperature for 10 min on an orbital shaker, and then read the plate with a plate reader (TECAN M1000 or Envision). EC50 or CC50 values were calculated through curve-fitting of the four-parameter nonlinear-logistic-regression model (GraphPad Prism or Dotmatics). CC₅₀ values were all >10 µM. Tables 2-5 give the viral load lowering EC50 values for exemplified compounds of the invention grouped in the following ranges: A indicates EC50 < 1 nM; B indicates EC50 ≥ 1 nM and < 10 nM; C indicates EC50 of ≥10 to <100 nM; and D indicates EC50 of ≥100 nM. Table 2. Viral Load Lowering for Examples 1-75.

Table 3. Viral Load Lowering for Examples 76-156.

Table 4. Viral Load Lowering for Examples 157-210.

Table 5. Viral Load Lowering for Examples 211-230.

VII. Stereochemistry of Examples

5-Amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5- (methylthiomethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide. To a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(hexahydro-1'H-spiro[oxirane-2,2'- pentalene]-5'-yl)-1-methyl-1H-pyrazole-4-carboxamide (200 mg, 0.495 mmol) in THF/H₂O (6 mL/2 mL) was added NaSMe (138.6 mg, 1.98 mmol). The mixture was stirred at rt overnight. The solvent was removed, and the crude product purified by silica gel column chromatography using 3:1 (v/v) petroleum ether/ethyl acetate to afford 5-amino-N-(3-chloro- 4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydropentalen-2-yl)-1-methyl-1H- pyrazole-4-carboxamide (100 mg, 44.7%) as a yellow solid. MS (m/z): calcd. for C21H₂6ClFN4O2S: 452, Found: 453 [M +1]⁺.

5-Amino-N-(3-chloro-4-fluorophenyl)-3-((2r,5r)-5-hydroxy-5- (methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-1) and 5-Amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5- (methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-2). To a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5- (methylthiomethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol) in DCM (5 mL) was added m-CPBA (114.8 mg, 0.66 mmol). The mixture was stirred at rt overnight. The solvent was removed, and the crude material purified by silica gel column chromatography using 3:1 (v/v) DCM/MeOH to afford AIA-227 (40 mg, 37.3%) as a white solid. MS (m/z): calcd.: 484, Found: 485 [M+1] ⁺. AIA-227 was separated by SFC to give AIA-227-1 (4 mg) as a white solid and AIA-227-2 (4 mg) as a white solid. AIA-227-1: ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 1H), 7.91 (dd, J = 6.8, 2.4 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (t, J = 9.2 Hz, 1H), 5.97 (s, 2H), 4.79 (s, 1H), 3.59 - 3.53 (m, 1H), 3.49 (s, 3H), 3.35 (s, 2H), 2.97 (s, 3H), 2.67 - 2.60 (m, 2H), 2.18 - 2.12 (m, 2H), 2.07 - 2.02 (m, 2H), 1.45 - 1.36 (m, 4H) ppm. AIA-227-2: ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H), 7.91 (dd, J = 2.8, 2.4 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.34 (t, J = 9.2 Hz, 1H), 5.97 (s, 2H), 4.87 (s, 1H), 3.49 (s, 3H), 3.43 - 3.35 (m, 1H), 3.25 (s, 2H), 2.97 (s, 3H), 2.49 (s, 2H), 2.15 - 2.09 (m, 2H), 2.02 - 1.97 (m, 2H), 1.73 - 1.60 (m, 4H) ppm. AIA-227-2 Alternative synthesis of 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5- hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4- carboxamide. To a solution of dimethylsulfone (77.0 g, 818.7 mmol) in THF (800 mL) was added n-BuLi (327.5 mL, 818.7 mmol, 2.5M) dropwise at -78 °C. The resulting solution was allowed to warm to -20 °C and stirred for 1 hr. The reaction was cooled to -78 °C, and a solution of AIA-002 (40.0 g, 102.3 mmol) in anhydrous tetrahydrofuran (1200 mL) was added over 2 hr. The mixture was warmed to RT and stirred for an additional 4 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (200 mL). The solvent was removed, followed by dilution with water, extraction with ethyl acetate (3 x 200 mL), drying over Na₂SO₄, filtration, and concentration to give the crude product. The crude product was purified by column chromatography using 0-5% (v/v) methanol in DCM and basic prep-HPLC to afford 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5- hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4- carboxamide (26.0 g, 52.4%) as a white solid. MS (m/z): calcd. for C₂₁H₂₆ClFN₄O₄S: 484, Found: 485 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H), 7.92 (dd, J = 6.8, 2.8 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (t, J = 8.8 Hz, 1H), 5.98 (s, 2H), 4.88 (s, 1H), 3.49 (s, 3H), 3.42 - 3.37 (m, 1H), 3.25 (s, 2H), 2.97 (s, 3H), 2.15 - 2.10 (m, 2H), 2.03 - 1.97 (m, 2H), 1.73 - 1.60 (m, 4H) ppm. A crystal with size of 0.08 x 0.10 x 0.20mm of compound AIA-227-2 was obtained from EtOH after 20 days of volatilization and was used for X-ray diffraction data collection. The data were collected on a Bruker SMART CCD area-detector diffractometer at room temperature using CuKα radiation by ω/φ scan mode.10846 reflections were collected, of which 3754 reflections were unique (Rint = 0.0507). The crystal belongs to monoclinic crystal system, with a space group P21/c. The unit cell parameters were as follows: a= 6.6143(3)，b=14.0381(8)，c=23.6870(14)Å， α=γ=90.0°，β=97.702(3) °， V= 2179.5(2)ų, Z=4. The structure was solved by direct methods and all of the non-H atoms were refined against F² by full-matrix least-squares methods using the SHELXTL program. All H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms. Multi-scans absorption correction method was used, and the maximum and minimum transmission parameters were 0.7531 and 0.6017, respectively. The final R, wR2, GOF are 0.0457, 0.1293 and 1.024, respectively. There is one C21H₂6FClN4O4S molecule in the asymmetric unit and hydrogen bonds can be found between them, which play an important role for the stable packing of the crystal structure. The ORTEP plot for compound AIA-227-2 is present in Fig.1. The relative stereochemistry scheme of compound AIA-227-2 is shown in Fig. 2. The depictions of stereochemistry in the chemical structures of related examples are based on this assignment. INCORPORATION BY REFERENCE All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

CLAIMS: 1. A compound of Formula I

, or a pharmaceutically acceptable salt thereof, wherein: L¹ and L² are independently selected from the group consisting of a bond, C1- 4alkylene, C1-4alkenylene, C1-4alkynylene, haloC1-4alkylene, hydroxyC1-4alkylene, O, NR^c, C(O), C(O)O, C(O)NR^c, S(O)t, S(O)tNR^c, C1-4alkyleneS(O)t and haloC1-4alkyleneS(O)t; L³ is C_1-6alkylene, C2-6alkenylene or C2-6alkynylene, wherein the C_1-6alkylene, C2- 6alkenylene, C2-6alkynylene is optionally substituted with 1-10 substituents independently selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)t-, R^aR^bNC(O)-, C1- 6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, R^aR^bN-C_1-6alkoxy, and haloC_1-6alkylNR^c-; X¹ is NR^x1, O or S; X⁴ is O or S; X⁵ is O, S or NR^6a; R^a, R^b and R^c are independently selected for each occurrence from the group consisting of hydrogen, C_1-6 alkyl, and haloC_1-6 alkyl; R^d is hydrogen, OH, C_1-6 alkyl or C_1-6 alkoxy; R^x1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, haloC1-4 alkyl, or C3-6 monocycloalkyl; R^0a is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, R^aR^bN-, C1-4alkyl and haloC1-4 alkyl; R^6a is hydrogen, C1-4 alkyl, haloC1-4 alkyl or C3-4cycloalkyl; R^6b is C_1-6alkyl, C2-6alkenyl or C2-6alkynyl, wherein the C_1-6alkyl, C2-6alkenyl, C2- 6alkynyl is optionally substituted with 1-10 substituents independently selected from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)t-, R^aR^bNC(O)-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, R^aR^bN-C_1-6alkoxy, and haloC_1-6alkylNR^c-; R⁰, R⁶ and R¹¹ are independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, R^dN=, hydrazino, formyl, azido, silyl, siloxy, HOC(O)-, R^aR^bN-, R^aR^bNS(O)t-, R^aR^bNC(O)-, R^6b, R^6bC(O)-, R^6bC(O)O-, R^6bC(O)NR^c-, R^6bS(O)tNR^c-, R^6bS(O)t-, R^6bO-, R^6bNR^c-, R^6bC(O)-L³-, and R^6bC(O)O-L³-, R^6bC(O)NR^c-L³-, R^6bS(O)tNR^c-L³-, R^6bS(O)q-L³-, R^6bO-L³-, and R^6bNR^c-L³-; R¹ is a phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with one, two, or three independently selected R¹¹ groups; R², R⁷ and R⁸ are independently selected from the group consisting of hydrogen, halo, CN, OH, R^aR^bN, C1-4alkyl, haloC1-4alkyl, C3-5monocycloalkyl, C1-4alkoxy, and haloC1- 4alkoxy;

R⁴ is R^5a-L¹-, R^5b-L¹-, R^5c-L¹-, R^5d-L¹-, R^5e-L¹- or R⁶;

R^5d and R¹⁰ are independently selected from the group consisting of:

p is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3; r is independently selected for each occurrence from the group consisting of 0, 1 and 2; t is independently selected for each occurrence from the group consisting of 0, 1 and 2; v is independently selected for each occurrence from the group consisting of 0, 1, 2 and 3; and w is independently selected for each occurrence from the group consisting of 0, 1 and 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹ is NR^x1 and R^x1 is hydrogen or methyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R^x1 is methyl.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein p is 0.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen.

6. The compound according to any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: R¹ is

; R¹¹ is independently selected for each occurrence from the group consisting of halogen, CN, C_1-6 alkyl and haloC_1-6 alkyl; and z1 is 0, 1, 2 or 3.

7. The compound of Claim 6, or a pharmaceutically acceptable salt thereof, wherein for each occurrence R¹¹ is independently selected from the group consisting of CN, F, Cl, Br and I.

8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein R¹ is

.

9. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein R¹ is

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R³ is

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is R⁶.

12. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is R^5a-L¹-, R^5d-L¹- or R^5e-L¹-.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein L¹ is a bond.

14. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is or R⁶.

15. The compound of claims 14, wherein R⁷ is hydrogen, OH or C1-4 alkoxy. 16. The compound of claim 14 or 15, wherein L² is a bond. 17. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen, OH or C1-4 alkoxy. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R⁸ is OH. 19. A pharmaceutical composition comprising the compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 20. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof. 21. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of pharmaceutical composition of claim 19.