WO2023069545A1 - 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. 62/257,773, 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 bom 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 vims 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 -membed heteroaryl carboxamide compounds and pharmaceutical compositions thereof, useful for disruption of HB V core protein assembly, and methods of treating HBV infections.

In one aspect, the disclosure provides a compound of Formula I:

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 shows the ORTEP plot for compound CP-AIA-227-2.

FIGURE 2 shows 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 C_2-6alkenyl. 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 C_1-4alkoxy, 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 C1-6 alkyl and CM 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-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l -pentyl,

2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3- dimethyl-1 -butyl, 2-ethyl-l -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 C_2-6alkynyl. 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-, CHCh-, -CHF₂, CF3-, CF₃CH₂-, CH₃CF₂, CF₃CC1₂- 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, CC1₃O-, 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, lH-l,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^bNC_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 =0.

As used herein, when a bicyclic ring is shown with a floating point of attachment and/or floating substituents, for example

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 Biologies standards.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

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., I , I '-methylene-/v.s-(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 Kvaemo, 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, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, 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

Formula I

, or a pharmaceutically acceptable salt thereof, wherein:

L¹ and L² are independently selected from the group consisting of a bond, C_1- 4alkylene, Ci^alkenylene, C_1-4alkynylene, haloC_1-4alkylene, hydroxyCi^alkylene, O, NR^C, C(O), C(O)O, C(O)NR^C, S(O)t, S(O)_tNR^c, Ci.₄alkyleneS(O)tandhaloCi.₄alkyleneS(O)t;

L³ is C_1-6alkylene, C_2-6alkenylene or C_2-6alkynylene, wherein the C_1-6alkylene, C2- 6alkenylene, C_2-6alkynylene 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)-, C_1- 6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, R^aR^bN-C_1-6alkoxy, and haloC_1-6alkylNR⁰-;

X¹ is NR^xl, 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, C1-6 alkyl, and haloC_1-6 alkyl;

R^d is hydrogen, OH, C1-6 alkyl or C1-6 alkoxy;

R^xl is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, haloC_1-4 alkyl, or C3-6 monocycloalkyl;

R^Oa is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, R^aR^bN-, C_1-4alkyl and haloC_1-4 alkyl; R^6a is hydrogen, C_1-4alkyl, haloC_1-4alkyl or C_3-4cycloalkyl;

R^6b is C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl, wherein the C_1-6alkyl, C_2-6alkenyl, 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_1-6alkylNR⁰-;

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, C_1-4alkyl, halo C_1-4alkyl, C_3-5monocycloalkyl, C_1-4alkoxy, and haloC_1-

4alkoxy;

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

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^xl.

In certain embodiments, X¹ is NR^xl and R^xl is hydrogen of methyl.

In certain embodiments, X¹ is NR^xl and R^xl is methyl.

In certain embodiments, L¹ is a bond.

In certain embodiments, L¹ is Ci^alkylene. In certain embodiments, p is 0.

In certain embodiments, R° 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, hydroxyC1- ₆alkyl-, R^aR^bNC_1-6alkyl-, HOC(O)C_1-6alkyl-, C_1-6alkylC(O)-, C_1-6alkylC(O)O-, C_1- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1- 6alkoxy-, 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)tC_1- 6alkylene-, C_1-6alkylS(O)_tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, C_1-6alkylC(O)OC_1- 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, R° 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- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1- 6alkoxy-, 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)tC_1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, and C_1- 6alkylC(O)OC_1-6alkylene-.

In certain embodiments, R° 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_1-6haloalkox,y C_1-6alkoxy, or C_1-ehaloalkoxy.

In certain embodiments, R¹ is

; R¹¹ is independently selected for each occurrence from the group consisting of halogen, CN, C_1-6alkyl and haloCi -6alkyl; and zl 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

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

In certain embodiments, R² is hydrogen.

In certain embodiments, X¹ is NR^xl, R^xl 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,

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, haloCi^alkylene or hydroxyC_1-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,

In certain embodiments,

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=, hydrazine, 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, hydroxy C_{1- 6}alkyl-, R^aR^bNC_1-6alkyl-, HOC(O)C_1-6alkyl-, C_1-6alkylC(O)-, C_1-6alkylC(O)O-, C_1- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1- 6alkoxy-, 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)tC_1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, C_1-6alkylC(O)OC_1- 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_1-6haloalkox,y C_1-6alkoxy, or C_1-ehaloalkoxy.

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- 6alkylC(O)NR^c-, C_1-6alkylS(O)t-, C_1-6alkylS(O)tNR^c-, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1- 6alkoxy-, 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)tC_1- 6alkylene-, C_1-6alkylS(O)tNR^aC_1-6alkylene-, C_1-6alkylC(O)C_1-6alkylene-, and C_1- 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_1-6haloalkox,y 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^xl; R^xl is hydrogen or methyl; R¹ is

R² is H; R³ is and R⁸ is hydrogen, OH or Ci salkoxy.

In certain embodiments, X¹ is NR^xl; R^xl 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 nontoxic, 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 nontoxic 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 nonirritating 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 pg/kg body weight. In some cases, the administration dose of the compound may be less than 400 pg/kg body weight. In other cases, the administration dose may be less than 200 pg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 pg/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 a, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl- 2-(pyridin-2-yl)-l,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: W02014037480, WO2014184328, W02013006394,

WO2014089296, W02014106019, WO2013102655, WO2014184350, WO2014184365,

WO2014161888, WO2014131847, WO2014033176, WO2014033167, and W02014033170;

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 Cpl83-V124W and related mutations as described in WO/2013/010069, W02014/074906, 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 la and PEG IFN lambda la, 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); TER-7/9 agonists such as GS- 9620, CYT003, Resiquimod; Cyclophilin inhibitors such as NVP018; GCB-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 biologies 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 coadministered 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)Ch [l,l'-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

TBSC1 tert-Butyldimethylsilyl chloride

TEA Triethylamine TFA Trifluoroacetic acid

THF T etrahydrofuran

TLC Thin-layer chromatography

XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

Scheme II

Scheme III

LCMS method have been used for the analysis of final compounds:

Method A: X-Bridge BEH C-18 (3x50 mmx2.5pm); Mobile phase: A; 0.025% formic acid in H2O; B; CH3CN; Injection voloume:2 pL; Flow rate: 1.2 mL/min, column temperature: 50 °C; Gradient program: 2% B to 98% B in 2.2 min, hold until 3 min, at 3.2 min B cone, is 2 % till up to 4 min.

Method B: X-select CSH 18 (3x50 mmx2.5pm); Mobile phase: A; 0.025% formic acid in H2O; B; CH3CN; Injection voloume:2 pL; Flow rate:1.2 mL/min, column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B cone, is 0 % till up to 4 min.

Method C: X-select CSH 18 (3x50 mmx2.5pm); Mobile phase: A; 0.05% formic acid in H2O:CH3CN (95:5); B; 0.05% formic acid in CH3CN; Injection volume: 2 pL; Flow rate: 1.2 mL/min, column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B cone, is 0 % till up to 4 min.

Method D: X-select CSH C18 (3x50 mmx2.5pm); Mobile phase: A; 2mM in Ammonium Bicarbonate; B; CH3CN; Injection voloume:2 pL; Flow rate: 1.2 mL/min, column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold till 3 min, at 3.2 min B cone, is 0 % until up to 4 min.

Method E: X-select CSH 18 (3x50 mmx2.5pm); Mobile phase: A; 0.05% formic acid in H2O; B; CH3CN; Injection volume: 2 pL; Flow rate:1.5 mL/min, column temperature: 50 °C; Gradient program: 0% B to 100% B in 1.5 min, hold till 2.2 min, at 2.6 min B cone, is 0 % until up to 3 min.

General procedure for amidation: Method A (amide coupling using EDC HC1): To a stirred solution of carboxylic acid (1 eq.) in 1,4-dioxane (5.84 mL/mmol) were added EDCHC1 (1.1 eq.), HOBt (1.1 eq.) and corresponding amine (1 eq.) at 0 °C 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 °C, 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 (AIMe₃ mediated amidation): To a stirred solution of corresponding anilines (1.1 eq.) in DCM/Toluene (3 mL/mmol) at 0 °C under Argon atmosphere, AIMe₃ (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 Ih. 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 IN HC1 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 °C and stirred for 5 min. To this solution, corresponding acid chloride/carbamic chloride/chloroformate (1.1-1.5 eq.) was added slowly at 0 °C 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-BuEi, EiHMDS, EDA or LTMP (5 eq.) slowly via glass syringe at -78 °C. After stirring at -78 °C 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. NH4CI 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 °C 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 °C. After stirring at 0 °C 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. NH4CI 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 CombiHash® 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)C12 (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.

General method for Suzuki coupling

Method A: To a mixture of an aromatic halide (1 eq.) and a boronic acid/boronate ester (1.2- 1.5 eq.) in 1, 4-dioxane/water (4/1 (v/v)) (0.25 M), Na2COs (2-3 eq.) was added and the mixture was purged with Argon for 15 min. To this solution, Pd(dppf)C12 (0.1 eq.) was added and the mixture was purged with Argon for another 10 min. The resulting reaction mixture was stirred at 100 °C for 12 hr to 16 hr. The progress of the reaction was monitored by TLC or LC-MS. After completion of the reaction, the reaction mixture was filtered through a Celite® 545 plug, and the filtrate was evaporated to dryness. The residue was taken in EtOAc, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by prep-HPLC or flash column chromatography to give the desired compound.

General procedure for hydrogenation

Method A: To a stirred solution of an olefinic compound (1 eq.) in EtOAc (0.25 M) under an atmosphere of nitrogen, 10% Pd/C, Pd(OH)2, or P1O2 (5% to 20% by w/w of olefinic compound) was added. The reaction mixture was stirred under an atmosphere of hydrogen (1 to 4 atm) at rt or an elevated temperature for 4 hr to 12 hr. The progress of the reaction was monitored by TLC or LC-MS. After completion, the reaction mixture was filtered through a Celite®545 plug and the filtered cake was washed with EtOAc. The filtrate was concentrated, and the residue was purified by prep-HPLC or flash column chromatography to give the desired compound.

General procedure for carbonyl reduction:

Method A: To a stirred solution of a functionalized carbonyl substrate (1 eq.) in MeOH (0.5 M) (Note: THF was added as a co-solvent for substrates that have poor solubility in alcoholic solvents.) at 0 °C under an atmosphere of Ar, NaBH4 (1-2 eq.) was added, and the resulting mixture was stirred at rt for 2 hr to 6 hr. The progress of the reaction was monitored by TLC or LCMS. After completion, the reaction mixture was added acetone, stirred for 15 min, and concentrated. The residue was diluted with water and extracted using EtOAc. The combined organic layers were collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC or flash column chromatography to give the desired compound.

General procedure for reductive amination:

Method A: To a stirred solution of a functionalized carbonyl substrate (1 eq.) in MeOH (0.25 M) (Note: THF was added as a co-solvent for substrates that have poor solubility in alcoholic solvents.) at 0 °C under an atmosphere of Ar was added an amine (1.5 eq.), followed by NaCNBtL (1.2 eq.), and the resulting mixture was stirred at rt for 2 hr to 6 hr. The progress of the reaction was monitored by TLC or LC-MS. After completion, the reaction mixture was concentrated. The residue was diluted with water and extracted using EtOAc. The combined organic layers were collected, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give the desired compound.

General procedure for nucleophilic addition

Method A: To a stirred solution of a functionalized ketone or sulfinamide (1 eq.) in dry THF (0.2 mL/mmol) in an inert atmosphere was added a nucleophile (e.g., RMgX, RLi, heteroaryl/BuLi/-78 °C, TMSCF3/TBAF, CH₃S(O)₂R/BuLi/-78 °C, or CHF2S(O)2Ar/LiHMDS/-78 °C etc.) (10 eq.) slowly via glass syringe at -78 °C. The resulting mixture was stirred for 4 hr at the same temperature, then at rt for 2 hr. The progress of the reaction was monitored by TLC or LC-MS. After completion, the reaction mixture was diluted with sat. aq. solution of NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by prep-HPLC or flash column chromatography to afford the desired compound.

Intermediate 1

5-Oxo-l,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate. To a solution of l,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 Tf20 (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. ^!H NMR (400 MHz, CDCh): 5 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, 7= 19.14, 7.34, 1.63 Hz, 1 H) ppm.

Intermediate 2

5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(lH)- one. A mixture of Intermediate 1 (110.0 g, 407.0 mmol), 4,4,5,5-tetramethyl-2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (108.5 g, 427.4 mmol), Pd(dppf)C12 (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®545 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.

NMR (400 MHz, CDCI3): 5 6.37 (q, 7 = 2.08 Hz, 1 H), 3.54 - 3.41 (m, 1 H), 3.05 - 2.93 (m, 1 H), 2.79 (ddt, 7 = 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.

Intermediate 3

Methyl 2,4-dibromo-l-methyl-lH-imidazole-5-carboxylate. To a solution of methyl 1- methyl-lH-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 °C 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.

Intermediate 4

N-(3-Chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide. To a solution of 1- methyl-lH-imidazole-5-carboxylic acid (10 g, 83 mmol), 3-chloro-4-fluoroaniline (18 g, 124 mmol) and EI3N (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 C11H9CIFN3O: 253; Found: 254 [M+l]⁺. Intermediate 5

2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-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: Rf= 0.3 (EtOAc/PE = 2/3 (v/v)). MS (ESI): calcd. for Ci 1 C₁₁Br₂C₁FN₃O: 409; Found: 411 [M+2]+.

Alternative synthesis of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-l-methyl-lH- imidazole-5-carboxamide. To a solution of 2,4-dibromo-l-methyl-lH-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 °C, the reaction mixture was stirred at 0 °C 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.

Intermediate 6

4-Bromo-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide. To a solution of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (1.1 g, 2.0 mmol) in THF (50 mL) was added CH₃Mgl (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 C₁₁H₈BrC1FN₃O: 331;

Found: 332 [M+l]⁺.

Alternative procedure for the synthesis of 4-bromo-N-(3-chloro-4-fluorophenyl)-l- methyl-lH-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));

NMR (DMSO-7₆, 400 MHz): 5 10.41 (s, 1H), 7.96 (dd, 7 = 6.8, 2.4 Hz, 1H), 7.85 (s, 1H), 7.63-7.60 (m, 1H), 7.43 (t, 7 = 9.6 Hz, 1H), 3.75 (s, 3H); MS (ESI): calcd. for C₁₁H₈BrC1FN₃O: 331; Found: 332 [M+l]⁺.

Intermediate 7

N-(3-Chloro-4-fluorophenyl)-l-methyl-4-(5-oxo-l,3a,4,5,6,6a-hexahydropentalen-2-yl)- lH-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)Ch (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: R_f: 0.5 (Methanol/DCM = 7/93 (v/v)); MS (ESI): calcd. for C19H17CIFN3O2: 373; Found: 374 [M+l]⁺.

Intermediate 8

N-(3-Chloro-4-fluorophenyl)-l-methyl-4-(5-oxooctahydropentalen-2-yl)-lH-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: R_f = 0.5 (methanol/DCM = 7/93 (v/v)). MS (ESI): calcd. for C19H19CIFN3O2: 375; Found: 376 [M+l]⁺.

Example 1. N-(3-chloro-4-fluorophenyl)-l-methyl-4-(5-(pyrimidin-2-yloxy)octahydro- pentalen-2-yl)-lH-imidazole-5-carboxamide

Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)- l-methyl-lH-imidazole-5-carboxamide (1-1). To a solution of Intermediate 8 (70 mg, 0.18 mmol) in MeOH (1 mL) was added NaBH4 (34 mg, 0.9 mmol), this mixture was stirred at rt for 3 h. Then this reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄. The solvent was removed, and the residue was dried in vacuo to give 1-1 (60 mg, 85 %) as a yellow oil, which was used for the next step without further purification. MS (ESI): calcd. for C19H21CIFN3O2: 377; found: 378 [M+l]⁺.

Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-l-methyl-4-(5-(pyrimidin-2- yloxy)octahydro-pentalen-2-yl)-lH-imidazole-5-carboxamide (Example 1). To a solution of 1-1(60 mg, 0.16 mmol) in DMSO (1 mL) was added CS2CO3 (163 mg, 0.5 mmol) and 2- cyanopyrimidine (34 mg, 0.32 mmol). The reaction mixture was stirred at 80 °C overnight, cooled to rt, and then diluted with H2O (10 mL). Subsequently, the mixture was extracted with DCM (10 mL x 3), and the combined organic extracts were dried over Na₂SO₄ and concentrated. The residue was purified by revise column (60 to 65 % of MeCN in H2O (v/v)) to give Example 1 (40 mg, 55 %) as a white solid. MS (ESI): calcd. for C23H23CIFN5O2: 455; found: 456

(400 MHz, CD3OD): 5 8.54 (d, J = 4.8 Hz, 2H), 7.89 (dd, J = 6.8, 2.4 Hz, 1H), 7.66 (s, 1H), 7.58 - 7.48 (m, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.06 (t, J = 4.8 Hz, 1H), 5.46 - 5.32 (m, 1H), 3.78 (s, 3H), 3.46 - 3.34 (m, 1H), 2.68 - 2.52 (m, 2H), 2.44 - 2.35 (m, 2H), 2.35 - 2.27 (m, 2H), 1.86 - 1.76 (m, 2H), 1.75 - 1.67 (m, 2H) ppm.

Example 2. N-(3-chloro-4-fluorophenyl)-l-methyl-4-(5-(pyrimidin-2- ylamino)octahydro-pentalen-2-yl)-lH-imidazole-5-carboxamide

To a solution of Intermediate 8 (200 mg, 0.53 mmol) in DMF (3 mL) were sequentially added TFA (228 mg, 2.0 mmol), pyrimidin-2-amine (105 mg, 1.1 mmol), and NaBH(OAc)3 (530 mg, 2.5 mmol) at rt. The mixture was stirred at 90 °C overnight. After cooling to rt, the reaction was diluted with H2O (30 mL) and extracted with DCM (20 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by reversed column (65 to 70 % of MeCN in H2O (v/v)) to afford Example 2 (30 mg, 12) as a white solid. MS (ESI): calcd. for C23H24CIFN6O: 454; found: 455 [M+l]⁺. ¹ H NMR (400 MHz, CD3OD): 5 8.24 (d, J = 4.8 Hz, 2H), 7.90 (dd, J = 6.8, 2.4 Hz, 1H), 7.70 (s, 1H), 7.56 - 7.50 (m, 1H), 7.26 (t, J = 9.2 Hz, 1H), 6.57 (t, J = 4.8 Hz, 1H), 4.34 - 4.24 (m, 1H), 3.79 (s, 3H), 3.46 - 3.37 (m, 1H), 2.62 - 2.49 (m, 2H), 2.40 - 2.32 (m, 2H), 2.32 - 2.23 (m, 2H), 1.76 - 1.65 (m, 2H), 1.42 - 1.30 (m, 4H) ppm.

Example 3. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((l-methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl)methyl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

To a solution of l,5-dimethyl-3-(trifluoromethyl)-lH-pyrazole (300 mg, 1.81 mmol) in THF (8 mL) was added n-BuLi (2.5 N in THF, 0.73 mL) at -78 °C and the resulting mixture was stirred at the same temperature for 30 min. Subsequently, a solution of Intermediate 8 (68 mg, 0.18 mmol) in anhydrous THF (0.5 mL) was added, and the reaction mixture was stirred at -78°C for 2 h. After stirring at rt overnight, the reaction was quenched with quenched saturated aqueous NH4CI. The mixture was concentrated, and the residue was extracted with EtOAc (15 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 prep-HPLC to give Example 3 (10 mg, 10%) as an off-white solid. MS (ESI): calcd. for C25H26CIF4N5O2: 539; Found: 540 [M+l] ⁺. NMR (400 MHz, DMSO-d6): 5 10.22 (s, 1H),7.96 (dd, J = 6.8, 2.8Hz, 1H), 7.64 (s, 1H), 7.59-7.55 (m, 1H),7.41 (t, J = 9.0 Hz, 1H), 6.44 (s, 1H), 4.80 (s, 1H), 4.04 (s, 2H), 3.66 (s, 3H), 3.24-3.21 (m, 1H), 2.50-2.49 (m, 2H), 2.33 (s, 3H), 2.12-2.05 (m, 2H), 1.93-1.88 (m, 2H), 1.76-1.68 (m, 2H), 1.42 (dd, J = 12.8, 4.8 Hz, 2H) ppm. Tables 1-9 show 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 enantiomers with stereochemistry consistent with the crystal structure shown below for reference compound Al A-227 -2.

Table 1. Analytical Data of Representative Examples 4-48

Example 49a and 49b. N-(3-chloro-4-fluorophenyl)-4-((4s,5's)-2,5-dioxohexahydro-l'H- spiro[imidazolidine-4,2'-pentalen]-5'-yl)-l-methyl-lH-imidazole-5-carboxamide (49a) and N-(3-chloro-4-fluorophenyl)-4-((4r,5'r)-2,5-dioxohexahydro-l'H- spiro[imidazolidine-4,2'-pentalen]-5'-yl)-l-methyl-lH-imidazole-5-carboxamide (49b)

To a solution of Intermediate 8 (100 mg, 0.27 mmol) in EtOH (8 mL) were added HCOONH4, (340 mg, 5.4 mmol), TMSCN (534 mg, 5.4 mmol), and (NH₄)CO₃ (518 mg, 5.4 mmol) at rt. After stirring at 80°C for 12 h, the reaction mixture was cooled to rt and diluted with water. The mixture was concentrated to remove organic solvent and the residue was extracted with DCM (15 mL x 3). The combined organic extracts were washed with brine and dried with anhydrous Na2SO4. The solvent was removed, and the residue was purified reversed column chromatography to give Example 49a (40 mg, 33%) as an off-white solid. MS (ESI): calcd. for C21H21CIFN5O3: 445; Found: 446 [M+l]⁺; NMR (400 MHz, DMSO- d6): 5 10.61 (s, 1H), 10.25 (s, 1H), 8.38 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.68 (s, 1H), 7.59-7.55 (m, 1H), 7.41(t, J = 9.0 Hz, 1H), 3.67 (s, 3H), 3.44-3.37 (s, 1H), 2.67-2.65 (m, 2H), 2.13-2.08 (m, 2H), 1.91-1.86 (m, 2H), 1.78-1.73 (m, 2H), 1.62-1.54 (m, 2H) ppm; and Example 49b (15 mg, 13%) as an off-white solid. MS (ESI): calcd. for C21H21CIFN5O3: 445; Found: 446 [M⁺+l]⁺; NMR (400 MHz, DMSO-d6): 5 10.46 (s, 1H), 10.22 (s, 1H), 7.97- 9.94 (m, 2H), 7.68(s, 1H), 7.58-7.55 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 3.68 (s, 3H), 3.33-3.31 (m, 1H), 2.68-2.65 (m, 1H), 2.15-2.07 (m, 4H), 1.63-1.58 (m, 4H) ppm.

Table 2. Analytical Data of Representative Examples 50-55

Example 56 and 57. tert-butyl (((5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl- lH-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)methyl)(methyl)(oxo)-16- sulfaneylidene)carbamate (56) and N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((S- methylsulfonimidoyl)-methyl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5- carboxamide (57)

Step 1. Synthesis of tert-butyl (dimethyl(oxo)-16-sulfaneylidene)carbamate (56-2).

Sodium hydride (0.31 g, 7.8 mmol) was added to a solution of S,S-dimethylsulfoximine (0.48 g, 5 mmol) in THF (15 mL) at 0 °C. After attiring at 0 °C for 30 min, BOC2O (1.46 g, 6.7 mmol) was added, and the resulting mixture was stirred at rt for 5 h. Subsequently, water (50 mL) was added and the mixture was concentrated. The residue was extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography with DCM/MEOH = 95/5 (v/v) as eluent to give 56-2 (600 mg, 60%) as a colorless oil. TLC: R_f = 0.5 (5% MeOH I DCM (v/v)); MS (ESI): calcd. for C7H15NO3S: 193; Found: 194 [M+l] ⁺.

Step 2. Synthesis of tert-butyl (((5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl- lH-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)methyl)(methyl)(oxo)-16- sulfaneylidene)carbamate (Example 56). To a solution of 56-2 (566 mg, 2.9 mmol) in THF (5 mL) was added n-BuLi (1.75 mL, 4.4 mmol) at -78 °C. The solution was stirred at -78 °C for 30 min. Then Intermediate 8 (110 mg, 0.29 mmol) was added. The reaction mixture was stirred and warmed slowly to rt for 5 h. The reaction mixture was quenched with sat. aq. NH4CI (20 mL) and concentrated. The residue was extracted with EtOAc (25 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give 56-3 (40 mg, 24%) as a white solid. TLC: Rf = 0.5 (4% MeOH/DCM (v/v)); MS (ESI): calcd. for C26H34CIFN4O5S: 568; Found: 569

NMR (400 MHz, DMSO-d6): 5 10.22(s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.65(s, 1H), 7.59-7.55(m, 1 H), 7.41 (t, J = 9.2 Hz, 1H), 5.21(s, 1H), 3.67 (s, 5H), 3.28-3.19 (m, 4H), 2.50-2.44 (m, 2H), 2.14-1.98 (m, 4H), 1.80-1.69 (m, 2H), 1.66-1.60 (m, 2H), 1.35 (s, 9H) ppm. Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((S-methyl- sulfonimidoyl)methyl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 57). A mixture of Example 56 (35 mg, 0.079 mmol) in CF3COOH I DCM (0.5 mL/1 mL) was stirred at rt for 2 h. The solvent was removed, and the residue was purified by prep-HPLC to give Example 57 (10 mg, 26%) as a white solid. MS (ESI): calcd. for C21H26CIFN4O3S: 468; Found: 469 [M+l]⁺; NMR (400 MHz, DMSO-d6 + D₂O): 5 10.22(s, 1H), 7.95 (dd, J = 6.8 Hz, 2.8 Hz, 1H), 7.65(s, 1H), 7.59-7.55(m, 1 H), 7.41 (t, J = 9.2 Hz, 1H), 3.67(s, 3H), 3.35-3.31 (m, 1H), 3.25-3.18 (m, 2H), 2.97(s, 3H), 2.46(s, 2H), 2.07-1.97 (m, 4H), 1.82-1.74 (m, 2H), 1.65-1.62 (m, 2H) ppm.

Example 58. N-(3-chloro-4-fluorophenyl)-4-(5-((dimethylphosphoryl)methyl)-5- hydroxy-octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

To a solution of trimethylphosphine oxide (100 mg, 1 mmol) in THF (2ml) was added n-BuEi (0.4 mF, 0.4 mmol) at -78 °C. After stirring at -78 °C for 30 min, Intermediate 8 (50 mg, 0.129 mmol) was added and the resulting mixture was stirred at rt overnight. Subsequently, the reaction was quenched by adding saturated aq. NH4CI and extracted with EtOAc (20 mL x 3). The combined the organic extracts were washed with brine, dried over anhydrous MgSCU, filtered, and concentrated. The residue was purified by prep-HPLC to give Example 58 (10 mg, 17%) as a white solid. MS (ESI): calcd. for C22H28CIFN3O3P: 467; Found: 468 [M+l]⁺; ¹H NMR (400 MHz, DMSO-d6): 5 10.23 (s, 1H), 7.96 (dd, J = 7.2, 2.8 Hz, 1H), 7.66 (s, 1H), 7.58-7.55 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 4.81(s, 1H), 3.67(s, 3H), 3.23-3.18 (m, 1H), 2.42-2.50 (m, 2H), 2.09-2.03 (m, 2H), 2.00-1.94 (m, 4H), 1.81-1.73 (m, 2H), 1.59-1.56 (m, 2H), 1.43-1.40 (m, 6H) ppm.

Example 59. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(l-sulfamoylcyclopropyl)- octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

Step 1. Synthesis of tert-butyl cyclopropylsulfonylcarbamate (59-2): To a solution of cyclopropanesulfonamide (2.0 g, 21.2 mmol), TEA (2.5 g, 24.8 mmol), and DMAP (0.1 g, 100 mg) in DCM (50 mL) was added (Boc)2O (4.3 g, 19.8 mmol). After stirring at rt for 16 h, the reaction mixture was adjusted to pH = 4 with 1 N aq. HC1 solution. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL), dried with anhydrous Na₂SO₄, and concentrated. The residue was dried in vacuo to give 59-2 (1.9 g, 52%) as an off-white solid. ¹ H NMR (400 MHz, CDCL): 57.27 (s, 1H), 2.94-2.85 (m, 1H), 1.52 (s, 9H), 1.40-1.34(m, 2H), 1.15-1.07 (m, 1H) ppm.

Step 2. Synthesis of tert-butyl ((l-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl- lH-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)cyclopropyl)sulfonyl)carbamate (59-3). To a solution of 59-2 (1.547 g, 7.0 mmol), TMEDA (0.812 mg, 7.0 mmol) in THF (15 mL) was added n-BuLi (6.0 mL, 15 mmol, 2.5M) dropwise at -78°C under an atmosphere of Ar. After stirring at -78 °C for 1 hr, a solution of Intermediate 8 (150.0 mg, 0.4 mmol) in anhydrous tetrahydrofuran (5 mL) was dropwise added at -78 °C, the reaction mixture was stirred at -78 °C for 2 hr in an Ar atmosphere. Subsequently, the reaction was quenched with saturated aqueous NH4CI (30 mL) and concentrated. The residue was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography using DCM/MeOH = 15/1 (v/v) as an eluent to give 59-3 (100 mg, 37%) as a brown oil, which was used for the next step without further purification. MS (ESI): calcd. for C27H34CIFN4O6S: 597; Found: 598 [M+l]⁺.

Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(l-sulfamoyl- cyclopropyl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 59). To a solution of 59-3 (90 mg, 0.15 mmol) in EA (1 mL) was added IN HC1 (1 mL, 1 mmol). The mixture was stirred at rt for 4 hr and then adjusted to pH = 8 with sat. aq. NaHCO₃ solution. The resulting mixture was extracted with EtOAc (20 mL x 3), and the combined organic layers were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to Example 59 (20 mg, 24%) as a white solid. MS (ESI): calcd. for C22H26CIFN4O4S: 497; Found: 498 [M+l]⁺. NMR (400 MHz, CD3OD): 57.87 (dd, 7 = 6.8, 2.4 Hz, 1H), 7.63 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (t, 7 = 9.2 Hz, 1H), 3.75 (s, 3H), 3.25- 3.16 (m, 1H), 2.68-2.58 (m, 2H), 2.22-2.14 (m, 2H), 2.08-1.98 (m, 2H), 1.92-1.82 (m, 2H), 1.30-1.24 (m, 2H), 1.04-0.98 (m, 2H) ppm.

Table 3. Analytical Data of Representative Examples 60-80

Examples 81, 82 and 83. Ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl- lH-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-2,2-difluoroacetate (Example 81), 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH-imidazol-4-yl)-2- hydroxyoctahydropentalen-2-yl)-2,2-difluoroacetic acid (Example 82), and 4-(5-(2- amino-l,l-difluoro-2-oxoethyl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4- fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (Example 83)

Step 1. Synthesis of ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH- imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-2,2-difluoroacetate (Example 81). To a solution of Zn (2.3 g, 34.7 mmol) in THF (30 mL), ethyl 2-bromo-2,2-difluoroacetate (7 g, 34.7 mmol) was added at 60 °C, the mixture was stirred at 60 °C for 15 min. Then a solution of Intermediate 8 (1.3 g, 3.47 mmol) in THF (10 mL) and Et2AlCl (5.3 mL, 5.3 mmol) were added at 45°C. After stirring at 45 °C for 3 h, the reaction was quenched by adding sat. aq. NH4CI (100 mL) and concentrated. The residue was added EtOAc (250 mL) and filtered. The organic layer was dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography using 1 ~ 5% EtOH/DCM (v/v) as eluent to give Example 81 (900 mg, 52%) as a yellow solid. TLC: Rf = 0.5 (5% EtOH/DCM (v/v); MS (ESI): calcd. for C23H25CIF3N3O4: 499; Found: 500 [M+l] ⁺.

NMR (DMSO-d6, 400 MHz): 5 10.22 (s, 1H), 7.96 (dd, J = 7.2, 2.4 Hz, 1H),7.63 (s, 1H), 7.57-7.55 (m, 1H), 7.41 (t, J = 9.0 Hz, 1H), 5.52 (s, 1H), 4.28-4.23 (m, 2H), 3.66 (s, 3H), 3.19-3.13 (m, 1H), 2.57-2.49 (m, 2H), 2.05-2.00 (m, 4H), 1.92-1.89 (m, 2H), 1.68 (d, J = 13.6 Hz, 2H), 1.25 (t, J = 7.0 Hz, 1H) ppm

Step 2a. Synthesis of 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH- imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-2,2-difluoroacetic acid (Example 82).

A mixture of Example 81 (100 mg, 2 mmol) and LiOH (96 mg, 4 mmol) in THF and water (3/1 (v/v), 8 mL) was stirred at rt for 4 h. Subsequently, the mixture was adjusted pH to 3 with 1 N aq. HC1 solution. The mixture was concentrated, and the residue was purified by prep-HPLC to give Example 82 (47 mg, 50%) as an off-white solid. MS (ESI): calcd. for C21H21CIF3N3O4: 471; Found: 472

NMR (DMSO-d6, 400 MHz): 10.20 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.64 (s, 1H), 7.58-7.55 (m, 1H), 7.40 (t, J = 9.0 Hz, 1H), 7.13- 7.07 (m, 2H), 3.66 (s, 3H), 3.21 -3.17 (s, 1H), 2.49~2.43 (m, 2H), 2.06- 1.95 (m, 4H), 1.88-1.75 (m, 2H), 1.46 (d, J = 12.4Hz, 2H) ppm.

Step 2b. Synthesis of 4-(5-(2-amino-l,l-difluoro-2-oxoethyl)-5-hydroxy- octahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5- carboxamide (Example 83). A solution of Example 81 (900 mg, 1.8 mmol) in NH3 in MeOH (7M, 12 mL) was sealed and stirred at 80 °C for 3 h. The excess solvent was removed in vacuo and then filtered. The solid was collected and purified by silica gel column chromatography using EtOAc/Hexanes as eluent to give Example 83 (700 mg, 82%) as a white solid. MS (ESI): calcd. for C21H22CIF3N4O3: 470; Found: 471 [M+l]⁺. NMR (400 MHz, DMSO-d6+D₂O): 5 7.95 (dd, J = 6.8, 2.8 Hz, 1H), 7.65 (s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J = 9.0 Hz, 1H), 3.67 (s, 3H), 3.20-3.15 (m, 1H), 2.50-2.49 (m, 2H), 2.12-2.06 (m, 4H), 1.91-1.83 (m, 2H), 1.64 (d, J = 14.0 Hz, 2H) ppm.

Step 3. Synthesis of 4-(5-(2-amino-l,l-difluoro-2-oxoethyl)-5-hydroxy- octahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5- carboxamide (Example 83). Example 83 was readily prepared using Example 82 as the starting material through conventional amide formation.

Examples 84 and 85. ethyl 2-(2-amino-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l- methyl-lH-imidazol-4-yl)octahydropentalen-2-yl)-2,2-difluoroacetate (Example 84) and 4-(5-amino-5-(2-amino-l,l-difluoro-2-oxoethyl)octahydropentalen-2-yl)-N-(3-chloro-4- fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (Example 85)

Step 1. Synthesis of 4-(5-((tert-butylsulfinyl)imino)octahydropentalen-2-yl)-N-(3-chloro- 4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (84-1). A solution of Intermediate 8 (600 mg, 1.6 mmol) in THF (15 mL) was added 2-methylpropane-2- sulfinamide (968 mg, 8 mmol) and Titanium tetraisopropanolate (1.36 g, 4.8 mmol) at rt. After stirring at 80 °C overnight, the reaction mixture was cooled to rt and treated with MeOH and concentrated. The residue was purified by silica gel column using EtOAc/Hexanes as eluent to give 84-1 (600 mg, 79%) as a pale-yellow solid. MS (ESI): calcd. for C23H28CIFN4O2S: 478; Found: 479 [M+l]⁺.

Step 2. Synthesis of ethyl 2-(2-((tert-butylsulfinyl)amino)-5-(5-((3-chloro-4- fluorophenyl)carbamoyl)-l-methyl-lH-imidazol-4-yl)octahydropentalen-2-yl)-2,2- difluoroacetate (84-2). A suspension of Zn powder in THF (8 mF) was added ethyl 2- bromo-2,2-difluoroacetate (594 mg, 2.9 mmol) and a catalytic amount of solid I2 under an atmosphere of Ar. After stirring at 60 °C for 15 min, the mixture was cooled to rt and 84-1 (140 mg, 0.29 mmol) was added, followed by Et2AlCl (2 N in hexanes, 1.5 mL). The resulting reaction mixture was stirred at 45 °C for 6 h and then treated with saturated aqueous NH4CI (25 mL). The mixture was concentrated, and the residue was extracted with EtOAc (15 mL x 3). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography using EtOAc/hexanes as eluent to give 84-2 (100 mg, 55%) as a pale-yellow solid. MS (ESI): calcd. for C27H34CIF3N4O4S: 602; Found: 603 [M+l]⁺.

Step 3. Synthesis of ethyl 2-(2-amino-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l- methyl-lH-imidazol-4-yl)octahydropentalen-2-yl)-2,2-difluoroacetate (Example 84). A solution of 84-2 (100 mg, 0.16 mmol) in THF (2 mL) was added 2 N HC1 aqueous solution (2 mL) and the reaction was stirred at rt for 2 h. After concentration, the residue was diluted with EtOAc (25 mL) and washed with saturated NaHCOs aqueous solution (10 mL x 3). The organic layer was dried with anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to Example 84 (70 mg, 73%) as a pale-yellow solid. MS (ESI): calcd. for C23H26CIF3N4O3: 498; Found: 499 [M+l]⁺. NMR (DMSO-d6, 400 MHz): 5 10.21 (s, 1H) ,8.43 (s, 2H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.68 (s, 1H), 7.56-7.52 (m, 1H),7.4O (t, J = 9.0 Hz, 1H), 3.68 (s, 3H), 3.39-3.36 (m, 1H), 2.50-2.49 (m, 2H), 2.33-2.24 (m, 2H), 2.13-2.07 (m, 2H), 1.75-1.65 (m, 4H) ppm

Step 4. Synthesis of 4-(5-amino-5-(2-amino-l,l-difluoro-2-oxoethyl)octahydropentalen- 2-yl)-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (Example 85).

A mixture of Example 84 (70 mg, 0.14 mmol) in MeOH (2 mL) was added aqueous NH3 solution (28% (_w/w), 2 mL) in a sealable tube. After stirring at 70°C in for 2 h, the reaction mixture was concentrated and the residue was purified prep-HPLC to give Example 85 (13 mg, 20%) as an off-white solid. MS (ESI): calcd. for C21H23CIF3N5O2: 469; Found: 470 [M+l]⁺. ¹H NMR (400 MHz, DMSO-d6+D₂O): 5 7.94 (dd, J = 2.8, 2.4 Hz, 1H), 7.65 (s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J = 9.0 Hz, 1H), 3.66 (s, 3H), 3.24-3.20 (m, 1H), 2.17-2.04 (m, 4H), 1.93-1.85 (m, 2H), 1.42 (d, J = 12.0 Hz, 2H) ppm.

Example 86. N-(3-chloro-4-fluorophenyl)-4-(5-(l,l-difluoro-2-(7-methyl-2,7- diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-5-hydroxyoctahydropentalen-2-yl)-l-methyl-lH- imidazole-5 -carboxamide

To a solution of 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH-imidazol-4-yl)- 2-hydroxyoctahydropentalen-2-yl)-2,2-difluoroacetic acid (Example 82) (30 mg, 0.06 mmol) and 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (17 mg, 0.08 mmol) in DMF (1 mL), HATU (30 mg, 0.08 mmol) and DIEA (31 mg, 0.24 mmol) were added. The mixture was stirred at rt overnight and then concentrated. The residue was purified by prep-HPLC to give Example 86 (13 mg, 37%) as a white solid. MS (ESI): calcd. for C29H35CIF3N5O3: 593; Found: 594 [M+l]⁺.

NMR (400 MHz, DMSO-d6): 5 10.20 (s, 1H), 7.93 (dd, J = 6.8, 2.4 Hz, 1H), 7.62 (s, 1H), 7.56-7.52 (m, 1H), 7.38 (t, J = 8.8 Hz, 1H), 5.38 (s, 1H), 4.02 (s, 2H), 3.63 (s, 3H), 3.59 (s, 2H), 3.15-3.12 (m, 1H), 2.51-2.48 (m, 4H), 2.11-2.09 (m, 2H), 2.08 (s, 3H), 2.05-1.97 (m, 4H), 1.94-1.88 (m, 2H), 1.64-1.58 (m, 6H) ppm.

Example 87. N-(3-chloro-4-fluorophenyl)-4-(5-(2-(4-(difluoromethyl)-4- hydroxypiperidin-l-yl)-l,l-difluoro-2-oxoethyl)-5-hydroxyoctahydropentalen-2-yl)-l- methyl-lH-imidazole-5-carboxamide

To a solution of 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH-imidazol-4-yl)- 2-hydroxyoctahydropentalen-2-yl)-2,2-difluoroacetic acid (Example 82) (25 mg, 0.05 mmol), 4-difluoromethyl-4-hydroxylpiperidine (14 mg, 0.079 mmol) and DIEA (20 mg, 0.16 mmol) in DMF (3mL), HATU (30 mg, 0.07 mmol) was added slowly. The reaction mixture was stirred at rt for 3 h and concentrated. The residue was purified by prep-HPLC to give Example 87 (7 mg, 22%) as a white solid. MS (ESI): calcd. for C27H30CIF5N4O4: 604; Found: 605 [M+l]⁺.

Table 4. Analytical Data of Representative Examples 88

Example 173. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(methyl-d3)octahydro- pentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

Magnesium (42.65 mg, 1.75 mmol) was stirred in dry diethyl ether (10 mL) in a three necked flask fitted with a thermometer and dropping funnel. Trideuterio(iodo)methane (231.27 mg, 1.6 mmol, 10.0 eq.) in diethyl ether (2 mL) was charged to the dropping funnel and a small crystal of iodine added to the magnesium suspension. The magnesium suspension was warmed briefly, and then the 1,1,1 -trideuteromethyl iodide solution added dropwise to flask. Once the addition was complete, the mixture was warmed to reflux for 30 min then cooled to -40 °C. Intermediate 8 (60.0 mg, 0.16 mmol) in THF (1.5 mL), was added dropwise to the reaction mixture, and then allowed to reach rt overnight. The mixture was partitioned between aqueous ammonium chloride (20 mL) and MTBE (50 mL) and extracted with EtOAc (15 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified with prep-HPLC to give Example 173 (15 mg, 24%) as an off-white solid. MS calcd. for C20H20D3CIFN3O2: 394; Found: 395 [M+l]⁺; ^!H NMR (400 MHz, CD3OD): 57.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.66 (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, 1H), 2.61 - 2.45 (m, 2H), 2.31 - 2.19 (m, 2H), 1.88 (dd, 7 = 12.6, 8.0 Hz, 2H), 1.73 (td, 7 = 12.3, 8.7 Hz, 2H), 1.61 (dd, 7 = 12.6, 6.7 Hz, 2H) ppm.

Example 174. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(prop-2-yn-l-yl)octahydro- pentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

Example 174

Zinc powder (520 mg, 8 mmol) was suspended in anhydrous THF (10 mL) and 3-bromoprop- 1-yne (940 mg, 8 mmol) was added in. After a catalytic amount of I₂ and TMSC1 were added, the reaction was elevated to 65 °C and stirred for 30 min and then cooled to rt.

Subsequently, Intermediate 8 (300, 0.8 mmol) was added and the reaction was stirred at rt for another 3 h. The reaction mixture was added saturated aqueous NH4CI (10 mL) and concentrated. The residue was extracted with EtOAc (15 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography using EtOAc/Hexanes as eluent to give Example 174 (150 mg,

45%) as an off-white solid. MS (ESI): calcd. for C22H23CIFN3O2: 415; Found: 416 [M+l]⁺. ¹H NMR (400 MHz, DMSO-d6): 5 10.25 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.64 (s, 1H), 7.58-7.54 (m, 1H), 7.43 (t, J =9.2 Hz, 1H), 4.53 (s, 1H), 3.66 (s, 3H), 3.20-3.18 (m, 1H), 2.73-2.71 (m, 1H), 2.44-2.38 (m, 2H), 2.29 (d, J = 2.4 Hz), 2.09-1.93 (m, 2H), 1.91-1.75 (m, 2H), 1.73-1.70 (m, 2H), 1.51-1.48 (m, 2H) ppm. Example 175. N-(3-chloro-4-fluorophenyl)-4-(5-cyclobutyl-5-hydroxyoctahydro- pentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

To a solution of HMPA (3.06 g, 17.06 mmol) was added Sml₂ (42.1 mL, 0.1 M, 4.27 mmol) drop wise at rt under an atmosphere of argon. After stirring for 40 min, a mixture of Intermediate 8 (80 mg, 0.21 mmol) and bromocyclobutane (287.9 mg, 2.13 mmol) in THF (2 mL) was added drop wise. After stirring at rt overnight, the reaction mixture was poured onto sat. aq. NH4CI (50 mL). The product was extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 175 (21 mg, 23%). MS (ESI): calcd. for C23H27CIFN3O2: 431; Found: 432 [M+l]⁺. NMR (400 MHz, CD3OD): 5 = 7.78 (dd, J = 6.8, 2.8 Hz, 1H), 7.55 (s, 1H), 7.42-7.39 (m, 1H), 7.14 (t, J = 8.8 Hz, 1H), 3.66 (s, 3H), 3.22- 3.20 (m, 1H), 2.41-2.37 (m, 3H), 2.12-2.09 (m, 2H), 1.89-1.85 (m, 2H), 1.77-1.66 (m, 7H), 1.58-1.56 (m, 1H), 1.37 (dd, J = 13.2, 5.2 Hz, 2H) ppm.

Examples 176 and 177. N-(3-chloro-4-fluorophenyl)-4-(5-(l,l-difluoro-2-oxopropyl)-5- hydroxyoctahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (176) and N-(3- chloro-4-fluorophenyl)-4-(5-(l,l-difluoro-2-hydroxy-2-methylpropyl)-5- hydroxyoctahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (177)

Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(l,l-difhioro-2-

(methoxy(methyl)amino)-2-oxoethyl)-5-hydroxyoctahydropentalen-2-yl)-l-methyl-lH- imidazole-5 -carboxamide (176-1). A solution of 2-(5-(5-((3-chloro-4- fluorophenyl)carbamoyl)-l-methyl-lH-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)- 2,2-difluoroacetic acid (Example 82) (50 mg, 0.11 mmol ), O,N-dimethylhydroxylamine hydrochloride (14.5 mg, 0. 15 mmol), DIEA (41 mg, 0. 3 mmol) in 1ml DMF (1 mL) was added HATU (60 mg, 0.15 mmol). After stirring at rt overnight, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give 176-1 (25 mg, 37 %) as a white solid. MS (ESI): calcd. for C23H26CIF3N4O4: 514; Found: 515 [M+l]⁺.

Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(l,l-difhioro-2-oxopropyl)-5- hydroxyoctahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 176). A solution of 176-1 (25 mg, 0.48 mmol) in 2 mL of THF was added CILMgBr (0.7 mL, 0.48 mmol) at 0°C . The reaction was warmed to rt and stirred for another 0.5 h. Subsequently, the reaction mixture was added sat. aq. NH4CI (10 mL) and EtOAc (25 mL). The organic layer was dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 176 (11 mg, 48 %) as a white solid. MS (ESI): calcd. for C22H23CIF3N3O3: 469; Found: 470 [M+l]⁺.

NMR (DMSO-d6, 400 MHz): 5 10.21 (s, 1H), 7.95 (dd, J = 6.8, 2.8 Hz, 1H), 7.63 (s, 1H), 7.58-7.54 (m, 1H), 7.40 (t, J = 9.0 Hz, 1H), 5.61 (s, 1H), 3.66 (s, 3H), 3.22-3.13 (m, 1H), 2.67-2.66 (m, 2H), 2.33 (s, 3H), 2.07-2.01 (m, 4H), 1.93-1.84 (m, 2H), 1.61 (d, J = 14.0 Hz, 2H) ppm.

Step 3. N-(3-chloro-4-fluorophenyl)-4-(5-(l,l-difluoro-2-hydroxy-2-methylpropyl)-5- hydroxyoctahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 177). A solution of Example 176 (80 mg, 0.17 mmol) in 3 mL of THF was added CH₃MgBr (1.5 mL, 1.7 mmol). The reaction was stirred at rt for 0.5 h and then quenched by adding sat aq. NH4CI (10 mL). The mixture was extracted with EtOAc (15 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 177 (20 mg, 24 %) as a white solid. MS (ESI): calcd. for C23H27CIF3N3O3: 486; Found: 487 [M+l]⁺. NMR (400 MHz, DMSO-d6): 5 10.21 (s, 1H), 7.96 (dd, J = 6.8, 2.8 Hz, 1H), 7.62 (s, 1H), 7.59-7.55 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 4.95 (d, J = 4.8 Hz, 2H), 3.66 (s, 3H), 3.17-3.10 (m, 1H), 2.50-2.49 (m, 2H), 2.07-1.92 (m, 6H), 1.73 (d, J = 13.6 Hz, 2H), 1.26 (s, 6H) ppm.

Example 178. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-hydroxypropan-2-yl)- octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-cyano-5-((trimethylsilyl)oxy)- octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (178-1). A solution of Intermediate 8 (526 mg, 1.4 mmol) in TMSCN (5 mL) was added ZnCl₂ (0.7 mL, 0.7mmol). After stirring at 60°C overnight, the reaction mixture was cooled to rt and treated with iPrOH (15 mL) and sat. aq. Na₂CO₃ (15 mL). The resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography using 0 to 5% of CH3OH/DCM (v/v) as eluent to give 178-1 (350 mg, 53%) as a brown solid. TLC: R/= 0.3 (5% CH3OH/DCM (v/v)); MS (ESI): calcd. for C23H₂8ClFN₄O₂Si: 474; Found: 475 [M+l]⁺.

Step 2. Synthesis of 5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH-imidazol-4- yl)-2-hydroxyoctahydropentalene-2-carboxylic acid (178-2). A mixture of 178-1 (119 mg, 0.25 mmol) in coned, aq. HC1 (5 mL) was stirred at 60 °C for 4 h. Subsequently, the mixture was cooled to rt and concentrated. The residue was purified by prep-HPLC to give 178-2 (70 mg, 66%) as a white solid. MS (ESI): calcd. for C20H21CIFN3O4: 421; Found: 422 [M+l]⁺.

Step 3. Synthesis of methyl 5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH- imidazol-4-yl)-2-hydroxyoctahydropentalene-2-carboxylate (178-3). A solution of 178-2 (72 mg, 0.17 mmol) in CH3OH (6 mL) was added SOCh (1 mL), the mixture was stirred at reflux overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography using 0 to 10% CH3OH/DCM to give 178-3 (60 mg, 81%) as a white solid. TLC: Rf = 0.2 (10% CH3OH/DCM (v/v)); MS (ESI): calcd. for C21H23CIFN3O4: 435; Found: 436 [M+l]⁺.

Step 4. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-hydroxypropan-2- yl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 178). To a solution of 178-3 (57 mg, 0.13 mmol) in THF (5 mL) was added CH3MgBr (1.3 mL, 1.3 mmol) under N2. After stirring at rt overnight, the reaction mixture was treated with sat. aq. NH4CI (10 mL) and then concentrated. The residue was extracted with EtOAc (10 mL x 3). The combined extracts were dried with anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 178 (24 mg, 42%) as a white solid. MS (ESI): calcd. for C22H27CIFN3O3: 435; Found: 436 [M+l]⁺.

NMR (400 MHz, CD3OD): 57.88 (dd, 7 = 6.4, 2.4 Hz, 1H), 7.63 (s, 1H), 7.51-7.49 (m, 1H), 7.24 (t, 7 = 9.2 Hz, 1H), 3.75 (s, 3H), 3.27-3.19 (m, 1H), 2.64-2.62 (m, 2H), 2.20-2.11 (m, 4H), 2.01-1.99 (m, 2H), 1.56 (s, 1H), 1.52 (s, 1H), 1.19 (s, 6H) ppm.

Example 179. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-hydroxy-2-methylpropyl)- octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

Step 1. Synthesis of ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-l-methyl-lH- imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)acetate (179-1). To a solution of EtoAc (290.0 mg, 3.3 mmol) in THF (10 mL) was added LDA (1.65 mL, 2.0M) at -78°C. After stirring at -78 °C for 1 hr, a solution of Intermediate 8 (250.0 mg, 0.66 mmol) in THF (1 mL) was added. The resulting mixture was warmed to rt with stirring overnight. Subsequently, the reaction mixture was added sat. aq. NH4CI (10 mL) and concentrated. The residue was extracted with EtOAc (10 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography using 0 to 5% of MeOH/DCM (v/v) as eluent to give 179-1 (180 mg, 59%) as a gray solid. TLC: Rf = 0.4 (7% of MeOH/DCM (v/v)); MS (ESI): calcd. for C23H27CIFN3O4: 436; Found: 437 [M+l]⁺.

Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-hydroxy-2- methylpropyl)-octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (example 179). To a solution of 179-1 (180 mg, 0.38 mmol) in THF (10 mL) was added CH₃Mgl (1.3 mL, 3.8 mmol) at rt. After stirring at rt for 30 min, the reaction mixture was added sat. aq. NH4CI (10 mL) and concentrated. The residue was extracted with EtOAc (10 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to give Example 179 (30 mg, 18%) as a white solid. MS (ESI): calcd. for C23H29CIFN3O3: 449; Found: 450 [M+l]⁺.

(400 MHz, DMSO-d₆): 5 10.22 (s, 1H), 7.96 (dd, 7 = 6.8, 2.4 Hz, 1H), 7.64 (s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, 7 = 9.2 Hz, 1H), 4.77 (d, 7 = 6.0 Hz, 2H), 3.67 (s, 3H), 3.22-3.16 (m, 2H), 2.42- 2.41 (m, 2H), 2.06-2.02 (m, 2H), 1.85-1.80 (m, 4H), 1.63 (s, 2H), 1.58-1.54 (m, 2H), 1.10 (s, 6H) ppm.

Table 5. Analytical Data of Representative Examples 180-204

Examples 205, 206, 207, 207a and 207b. N-(3-chloro-4-fluorophenyl)-l-methyl-4- (spiro[bicyclo[3.2.0]heptane-6,2'-[l,3]dioxolan]-3-yl)-lH-imidazole-5-carboxamide (205), N-(3-chloro-4-fluorophenyl)-l-methyl-4-(6-oxobicyclo[3.2.0]heptan-3-yl)-lH- imidazole-5 -carboxamide (206), N-(3-chloro-4-fluorophenyl)-4-(6- hydroxybicyclo[3.2.0]heptan-3-yl)-l-methyl-lH-imidazole-5-carboxamide (207), N-(3- chloro-4-fluorophenyl)-4-((lS,3S,5S,6R)-6-hydroxybicyclo[3.2.0]heptan-3-yl)-l-methyl- lH-imidazole-5-carboxamide (207a), and N-(3-chloro-4-fluorophenyl)-4-((lS,3S,5S,6R)- 6-hydroxybicyclo[3.2.0]heptan-3-yl)-l-methyl-lH-imidazole-5-carboxamide (207b).

Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-l-methyl-4- (spiro[bicyclo[3.2.0]heptane-6,2'-[l,3]dioxolan]-3-en-3-yl)-lH-imidazole-5-carboxamide (205-1). To a stirred solution of Intermediate 6 (6.5 g, 19.55 mmol) in 1, 4-dioxane/water

(4/1 (v/v), 50 mL) was added 4,4,5,5-tetramethyl-2-(spiro[bicyclo[3.2.0]heptane-6,2'- [l,3]dioxolan]-2-en-3-yl)-l,3,2-dioxaborolane (4.9 g, 17.65 mmol), which was readily prepared from commercially available 3-(benzyloxy)bicyclo[3.2.0]heptan-6-one, followed by Na2CC>3 (6.2 g, 58.65 mmol) and degassed with argon for 10 min. To the resulting solution was added Pd(dppf)C12 (1.42 g, 1.955 mmol). After stirring at 100 °C for 12 h, the reaction mixture was cooled to rt and filtered through a plug of Celte®545. The filtered cake was washed with EtOAc. The filtrate as concentrated and the residue was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The crude compound was purified by silica gel column chromatography using 0 to 3% (v/v) MeOH/DCM as eluent to give 205-1 (5.4 g, 68%) as a yellow solid. MS (ESI): calcd. for C20H19CIFN3O3, 403; Found: 404 [M+l]⁺. Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-l-methyl-4-(spiro[bicyclo[3.2.0]- heptane-6,2'-[l,3]dioxolan]-3-yl)-lH-imidazole-5-carboxamide (Example 205). An autoclave was charged with a solution of 205-1 (5.4 g, 13.40 mmol) in ethyl acetate (250 mL) and the mixture was purged with nitrogen for 5 min. 10% Palladium on carbon (1.3 g) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and then was stirred at rt for 12 h under hydrogen atmosphere at 70 psi. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite®545 and the filtered cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography using 0 to 5% (v/v) MeOH/DCM as eluent to give Example 205 (5.0 g, 92%) as an off-white solid. MS (ESI): calcd. for C20H21CIFN3O3, 405; Found: 406 [M+l]⁺. NMR (400 MHz, DMSO-d₆ ): 5 10.22 (s, 1H), 7.95 (dd, 7 = 6.4 Hz, 6.8 Hz, 1H), 7.67-7.65 (m, 1H), 7.57-7.55 (m, 1H), 7.39 (t, 7 = 9.6 Hz, 1H), 3.83-3.75 (m, 4H), 3.67 (s, 3H), 3.31-3.25 (m, 1H), 2.81-2.75 (m, 1H), 2.45-2.41 (m, 1H), 2.36-2.31 (m, 1H), 2.21-1.85 (m, 4H), 1.69-1.62 (m, 1H) ppm.

Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-l-methyl-4-(6-oxobicyclo[3.2.0]heptan- 3-yl)-lH-imidazole-5-carboxamide (Example 206). To a stirred solution of Example 205 (3.0 g, 7.407 mmol) in THF (30 mL) was added 4 N aq. HC1 solution (18.0 mL) dropwise at 0 °C. The reaction mixture was warmed to rt and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO₃ solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 0 to 5% (v/v) MeOH/DCM) as eluent to give Example 206 (2.4 g, 90%) as an off-white solid. MS (ESI): calcd. for C18H17CIFN3O2, 361; Found: 362 [M+l]⁺. ¹H NMR (400 MHz, DMSO-7₆): 5 10.20 (s, 1H), 7.95-7.94 (m, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 1H), 7.40 (t, 7 = 8.8 Hz, 1H), 3.67 (s, 3H), 3.59-3.47 (m, 1H), 3.18-3.11 (m, 1H), 2.83- 2.80 (m, 1H), 2.70-2.65 (m, 1H), 2.53-2.50 (m, 1H merged), 2.38-2.31 (m, 1H), 2.04 (t, J = 8.0 Hz, 2H), 1.79-1.71 (m, 1H) ppm.

Step 4. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(6-hydroxybicyclo[3.2.0]heptan-3-yl)- l-methyl-lH-imidazole-5-carboxamide (Example 207). To a stirred solution of Example 206 (0.15 g, 0.4 mmol) in MeOH (1.5 mL) at 0 °C, NaBH4 (18 mg, 0.48 mmol) was added and stirred at rt. After stirring at rt for 12 h, the reaction mixture as added acetone (1 mL). The resulting mixture was concentrated, and the residue was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel column chromatography using 0 to 5% (v/v) MeOH/DCM as eluent to give Example 207 (90 mg, 60%) as an off-white solid. MS (ESI): calcd. for C18H19CIFN3O2, 363; Found: 364 [M+l]⁺. ¹H NMR (400 MHz, DMSO-d6): 5 10.23 (s, 1H), 7.98-7.93 (m, 1H), 7.72 (s, 1H), 7.60-7.55 (m, 1H), 7.40 (t, J = 8.8 Hz, 1H), 5.21 (d, J = 6.8 Hz, 1H), 4.04 (t, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.50-3.38 (m, 1H), 2.86-2.75 (m, 1H), 2.48-2.30 (m, 2H), 2.20-2.08 (m, 2H), 1.86-1.76 (m, 1H), 1.65-1.48 (m, 2H) ppm.

Step 5. Synthesis of N-(3-chloro-4-fluorophenyl)-4-((lS,3S,5S,6R)-6- hydroxybicyclo[3.2.0]heptan-3-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 207a), and N-(3-chloro-4-fluorophenyl)-4-((lS,3S,5S,6R)-6- hydroxybicyclo[3.2.0]heptan-3-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 207b). Example 207 (90 mg, 0.25 mmol) was separated by prep-HPLC to give two pure enantiomers. The stereochemistry of Example 207a and Example 207b was arbitrarily assigned.

Example 207a (24 mg, 16%) as an off-white solid. MS (ESI): calcd. for C18H19CIFN3O2, 363; Found: 364 [M+l]⁺.

NMR (400 MHz, DMSO-d6): 5 10.30 (s, 1H), 7.95 (dd, J = 6.8, 2.8 Hz, 1H), 7.87 (br .s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 5.50 (br.s, 1H), 4.09-4.03 (m, 1H), 3.72 (s, 3H), 3.43-3.31 (m, 1H), 2.84-2.67 (m, 1H), 2.49-2.30 (m, 2H), 2.18-2.11 (m, 2H), 1.87-1.80 (m, 1H), 1.64-1.52 (m, 2H) ppm.

Example 207b (25 mg, 17%) as an off-white solid. MS (ESI): calcd. for C18H19CIFN3O2, 363; Found: 364 [M+l]⁺.

NMR (400 MHz, DMSO-d6): 5 10.30 (s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 1H), 7.86 (br.s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J = 8.8 Hz, 1H), 5.50 (br.s, 1H),

4.09-4.03 (m, 1H), 3.72 (s, 3H), 3.45-3.31 (m, 1H), 2.84-2.65 (m, 1H), 2.49-2.32 (m, 2H), 2.18-2.11 (m, 2H), 1.87-1.80 (m, 1H), 1.64-1.52 (m, 2H) ppm.

Table 6. Analytical Data of Representative Examples 208-222

Example 223. N-(3-chloro-4-fluorophenyl)-4-(2-hydroxyspiro[3.5]nonan-7-yl)-l-methyl- lH-imidazole-5-carboxamide

Step 1. Synthesis of 8-methylene-l,4-dioxaspiro[4.5]decane (223-2). To a suspension of MePPh₃Br (107.1 g, 300 mmol) in THF (600 mL) was added n-BuLi (117.6 mL, 294.0 mmol) drop wise below -70 °C and the reaction was stirred for 30 min. Then 1,4- dioxaspiro[4.5]decan-8-one (31.2 g, 200.0 mmol) was added drop wise below -70°C and the reaction was stirred at rt overnight. Subsequently, saturated aq. NH₄Claq was added until PH < 7 and the resulting mixture was concentrated. The residue was extracted with EtOAc (100 mL x 3). The combined 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/PE = 1/15 (v/v) as eluent to give 223-2 (22 g, 71%) as brown oil. TLC: R/= 0.4 (EtOAc/PE = 1/9 (v/v)); MS (ESI): calcd. for C9H14O2: 154; Found: 155 [M+l]⁺.

Step 2. Synthesis of l,l-dichloro-8,H-dioxadispiro[3.2.47.24]tridecan-2-one (223-3):

To a suspension of 223-2 (20.9 g, 136 mmol) and Zn (19.3g, 297mmol) in Et2O (500 mL) was added trichloroacetyl chloride (49.4 g, 271 mmol) drop wise in sonication at 25 °C . After stirring for 3 hr in a sonicator, the reaction mixture was filtered through a Celite®545 plug. The filtered cake was washed with ether and the filtrate was treated with sat. aq. NH4CI solution (100 mL). The mixture was concentrated, and the residue was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with sat. aq. NaHCO₃ and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EtOAc/PE = 1/4 as eluent to give 223-3 (23.5 g, 66%) as a yellow solid. TLC: R_f = 0.4 (EtOAc/PE = 1/4 (v/v)); MS (ESI): calcd. for C11H14CI2O3: 264; Found: 265 [M+l]⁺.

Step 3. Synthesis of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-one (223-4). To a solution of 223-3 (22.5 g, 85.2 mmol) in mixture of DME (600 mL) and NH4CI (aq.) (400 mL, 23g, 426 mmol) was added Zn (55 g, 852 mmol) below -5 °C and the reaction was stirred at rt overnight. The reaction mixture was filtered through a pad of Celite®545. The filtered cake was washed with DME and the filtrate was concentrated. The residue was diluted with sat. aq. NH4CI (200 mL) and extracted with EtOAc (200 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/PE = 1/3 as eluent to give 223-4 (14.5 g, 87%) as a brown oil. TLC: R/= 0.4 (EtOAc/PE = 1/3 (v/v)); MS (ESI): calcd. for C11H16O3: 196; Found: 197 [M+l]⁺.

Step 4. Synthesis of 8,ll-dioxadispiro[3.2.47.24]tridecan-2-ol (223-5): To a solution of 223-4 (11.5 g, 58.7 mmol) in MeOH (200 mL) was added NaBPL (4.46 g, 117.3 mmol) in small portions at rt. After stirring at rt for 16 h, the reaction mixture was treated with acetone (25 mL), followed by sat. aq. NH4CI solution (100 mL). The mixture was concentrated, and the residue was extracted with EtOAc (150 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified silica gel column chromatography using EtOAc/PE = 1/1 (v/v) to give 223-5 (9.0 g, 78%) as a colorless oil. TLC: R/= 0.3 (EtOAc/PE = 1/1 (v/v)); MS (ESI): calcd. for C11H18O3: 198; Found: 199 [M+l]⁺.

Step 5. Synthesis of 2-(benzyloxy)-8,H-dioxadispiro[3.2.47.24]tridecane (223-6): To a solution of 223-5 (8.0 g, 40.4 mmol) in THF (200 mL) was added NaH (3.23 g, 80.8 mmol) in an ice bath. After stirring at 0 °C for 3 h, BnBr (13.8 g, 80.8 mmol) was added, and the reaction was stirred at rt overnight. Subsequently, the reaction mixture was poured into icewater. The mixture was concentrated, and the residue was extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using EtOAc/PE = 1/8 (v/v) to give 223-6 (8.2 g, 71%) as a colorless oil. TLC: R/= 0.6 (EtOAc/PE = 1/5 (v/v)); MS (ESI): calcd. for C18H24O3: 288; Found: 289 [M+l]⁺. Step 6. Synthesis of 2-(benzyloxy)spiro[3.5]nonan-7-one (223-7): To a solution of 223-6 (8.2 g, 28.5 mmol) in THF (100 ml) was added aq. IN HC1 solution (100 mL). After stirring at 60 °C for 3 h, the reaction mixture was cooled to rt and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was dried in vacuo to give 223-7 (7.3 g, 100%) as a colorless oil. TLC: Rf= 0.3 (EtOAc/PE = 1/3 (v/v)); MS (ESI): calcd. for C16H20O2: 244; Found: 245 [M+l]⁺.

Step 7. Synthesis of 2-(benzyloxy)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (223-8). To a solution of 223-7 (1.0g, 0.35 mmol) in THF (30 mL) was added LiHMDS (0.7 mmol, 1.0 M, 7 mL) at -78°C. The reaction mixture was stirred at -78 °C for 1 h and then a solution of PhNTf2 (2.48 g, 0.7 mmol) in THF (20 mL) was added dropwise. The reaction mixture was warmed to 30 °C and stirred for 4 h. The reaction mixture was treated with sat. aq. NH4CI solution (5 mL) at 25 °C and then diluted with H2O (20 mL). The mixture was concentrated, and the residue was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EtOAc/PE = 1/8 as eluent to give 223-8 (850 mg, 63%) as a colorless oil. TLC: R/= 0.7 (EtOAc/PE = 1/5 (v/v)); MS (ESI): calcd. for C17H19F3O4S: 376; Found: 377 [M+l]⁺.

Step 8. Synthesis of 2-(2-(benzyloxy)spiro[3.5]non-6-en-7-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (223-9). A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (861 mg, 3.39 mmol), 223-8 (850 mg, 2.26 mmol), Pd(dppf)C12 (100 mg) and potassium acetate (665 mg, 6.78 mmol) in dioxane (100 mL) was stirred at 80 °C under an atmosphere of N2. After stirring at 80 °C overnight, the reaction mixture was cooled to rt and filtered through a Celite®545 plug. The filtered cake was washed with EtOAc and the filtrate was concentrated. The residue was diluted with sat. aq. NH4CI and extracted with EtOAc (25 mL x 3). The combined extracts were dried with anhydrous Na2SO4 and concentrated. The residue was dried in vacuo to give 223-9 (600 mg, crude) as a brown oil, which was used for the next step without further purification. MS (ESI): calcd. for C22H31BO3: 354; Found: 355 [M+l]⁺.

Step 9. Synthesis of 4-(2-(benzyloxy)spiro[3.5]non-6-en-7-yl)-N-(3-chloro-4- fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (223-10). To a solution of 4-bromo- N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (1.65 g, crude, 5.5 mmol) and 223-9 (800 mg, 2.42 mmol) in dioxane (50 ml) was added a solution of K₂CO3 (673 mg, 4.84 mmol) in H2O (10 ml) and Pd(dppf)C12 (100 mg). The mixture was stirred at 85 °C for 5 h under an atmosphere of N2 and then filtered through a Celite®545 plug. The filtrate was washed with EtOAc and the filtrate was concentrated. The residue was diluted with sat. aq. NaHCO₃ and extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using EtOAc/PE = 1/4 (v/v) as eluent to give 223-10 (700 mg, 60%) as a yellow oil. TLC: R/= 0.3 (EtOAc/PE = 1/2 (v/v)); MS (ESI): calcd. for C27H27CIFN3O2: 479; Found: 480 [M+l]⁺.

Step 10. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(2-hydroxyspiro[3.5]non-6-en-7-yl)- l-methyl-lH-imidazole-5-carboxamide (223-11). To a solution of 223-10 (700 mg, 1.46 mmol) and Nal (1.1 g, 7.31 mmol) in ACN (40 mL) was added BF3 Et2O (1.04 g, 7.31 mmol) at 0°C. The mixture was stirred at rt for 5 h and then quenched with sat. aq. Na2SC>3 solution. The mixture was concentrated, and the residue was diluted with water and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 223-11 (300 mg, 43%) as a yellow solid. MS (ESI): calcd. for C20H21CIFN3O2: 389; Found: 390 [M+l]⁺. Step 11. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(2-hydroxyspiro[3.5]nonan-7-yl)-l- methyl-lH-imidazole-5-carboxamide (Example 223). A mixture of 223-11 (300 mg, 0.77 mmol) and 10% Pd/C (300 mg) in EtOAc (100 mL) was stirred at 30 °C for 4 h under an atmosphere of H2. The reaction mixture was cooled to rt and saturated with N2. The mixture was then filtered through a Celite®545 and the filtered cake was washed with EtOAc. The filtrate was dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using MeOH/DCM = 1/19 (v/v) as eluent to give Example 223 (270 mg, 90%) and as a yellow solid. MS (ESI): calcd. for C20H23CIFN3O2: 391; Found: 392 [M+l]⁺. 1H NMR (400 MHz, DMSO-d6): 5 10.21 (s, 1H), 7.97 (dd, J = 6.8, 2.4 Hz, 1H), 7.63 (s, 1H), 7.58-7.53 (m, 1H), 7.41 (t, J = 9.0 Hz, 1H), 4.84 (d, J = 6.0 Hz, 1H), 4.21-4.01 (m, 1H), 3.67 (s, 3H), 2.80-2.64 (m, 1H), 2.18-2.08 (m, 1H), 1.96-1.85 (m, 1H), 1.64-1.33 (m, 10H) ppm.

Example 224. N-(3-chloro-4-fluorophenyl)-l-methyl-4-(2-oxospiro[3.5]nonan-7-yl)-lH- imidazole-5 -carboxamide

A mixture of Example 223 (300 mg, 0.77 mmol) and Dess-Martin periodinane (488 mg, 1.15 mmol) in DCM (20 ml) was stirred at rt for 20 h and then filtered through a plug of Celite®545. The filtered cake was washed with EtOAc and filtrate was dried over anhydrous Na₂SO₄. The solvent was removed, and the residue was purified by prep-HPLC to give Example 224 (240 mg, 80%) as an off-white solid. MS (ESI): calcd. for C20H21CIFN3O2: 389; Found: 390 [M+l]⁺. NMR (400 MHz, CD3OD): 57.93 (dd, J = 6.8, 2.4 Hz, 1H), 7.62 (s, 1H), 7.57-7.45 (m, 1H), 7.21 (t, J = 9.2 Hz, 1H), 3.77 (s, 3H), 2.98-2.70 (m, 5H), 1.88- 1.62 (m, 8H) ppm.

Example 225. N-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-((methylsulfonyl)methyl)- spiro[3.5]nonan-7-yl)-l-methyl-lH-imidazole-5-carboxamide

To a solution of methylsulphone (453 mg, 4.6 mmol) in THF (15 mL) was added n-BuLi (1.84 mL, 2.5 M, 4.6 mmol) at -78°C under an atmosphere of N2. After stirring at -78°C for 30 min, Example 224 (90 mg, 0.23 mmol) was added to the mixture in one portion. The resulting mixture was stirred at -78 °C for 3 h and then treated with sat. aq. NH4CI solution (5 mL). The mixture was warmed to rt and concentrated. The residue was diluted with water (15 mL) and extracted with EtOAc (15 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 prep-HPLC to give Example 225 (50 mg, 45%) as white solid. MS (ESI): calcd. for C22H27CIFN3O4S: 483; Found: 484 [M+l]⁺. NMR (400 MHz, CD3OD): 57.87 (dd, J = 6.8, 2.8 Hz, 1H), 7.63 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.39- 3.31 (m, 2H), 2.99 (s, 3H), 2.82-2.74 (m, 1H), 2.32-2.20 (m, 2H), 2.07-1.91 (m, 3H), 1.79- 1.60 (m, 5H), 1.50-1.42 (m, 2H) ppm.

Examples 225a and 225b. N-(3-chloro-4-fluorophenyl)-4-((2S,4s,7S)-2-hydroxy-2- ((methylsulfonyl)methyl)spiro[3.5]nonan-7-yl)-l-methyl-lH-imidazole-5-carboxamide

(225a) and N-(3-chloro-4-fluorophenyl)-4-((2R,4r,7R)-2-hydroxy-2- ((methylsulfonyl)methyl)spiro[3.5]nonan-7-yl)-l-methyl-lH-imidazole-5-carboxamide

(225b)

Example 225 (50 mg) was separated by SFC to give two single enantiomers Example 225a (14 mg, 56%) and Example 225b (13 mg, 52%). The stereochemistry was arbitrarily assigned.

Example 225a: MS (ESI): calcd. for C22H27CIFN3O4S: 483; Found: 484 [M+l]⁺. NMR (400 MHz, CD3OD): 57.87 (dd, J = 6.8, 2.8 Hz, 1H), 7.63 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (t,

J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.39-3.31 (m, 2H), 2.99 (s, 3H), 2.82-2.74 (m, 1H), 2.32-2.20 (m, 2H), 2.07-1.91 (m, 3H), 1.79-1.60 (m, 5H), 1.50-1.42 (m, 2H) ppm.

Example 225b: MS (ESI): calcd. for C22H27CIFN3O4S: 483; Found: 484 [M+l]⁺. NMR (400 MHz, CD3OD): 57.87 (dd, J = 6.8, 2.8 Hz, 1H), 7.63 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.39-3.31 (m, 2H), 2.99 (s, 3H), 2.82-2.74 (m, 1H), 2.32-2.20

(m, 2H), 2.07-1.91 (m, 3H), 1.79-1.60 (m, 5H), 1.50-1.42 (m, 2H) ppm.

Table 7. Analytical Data of Representative Examples 226-253

Example 254. 4-(5-(3-amino-l-methyl-lH-l,2,4-triazol-5-yl)-5-hydroxyoctahydro- pentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide

Step 1. Synthesis of 3-(2,5-dimethyl-lH-pyrrol-l-yl)-l-methyl-lH-l,2,4-triazole (254-2).

A mixture of l-methyl-lH-l,2,4-triazol-3-amine (254-1) (1.0 g, 10.2 mmol), hexane-2,5- dione (1.25 g, 11 mmol) and a catalytic amount of TsOH in toluene (60 mL) was refluxed overnight under Dean-Stark condenser. After refluxing overnight, the reaction mixture was cooled to rt and the solution was isolated and concentrated. The residue was dried in vacuo to give 254-2 (1.53 g, 85%) as a brown solid, which was used for the next step without further purification. MS (ESI): calcd. for C9H12N4: 176; Found: 177 [M+l]⁺.

Step 2. Synthesis of N-(3-chIoro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyI-lH-pyrrol-l-yl)- l-methyl-lH-l,2,4-triazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-l-methyl-lH- imidazole-5 -carboxamide (254-3). To a solution of 3-(2,5-dimethyl-lH-pyrrol-l-yl)-l- methyl-lH-l,2,4-triazole (254-2) (330 mg, 1.88 mmol) in THF (5 mL) was added n-BuLi (0.83 mL, 2.5 M, 2.07 mmol) at -80 °C under argon, the mixture was stirred at -80 °C to -30 °C for 1 h. Then to the resulting mixture was added a solution of Intermediate 8 (70 mg, 0.19 mmol) in THF (1 mL) at -80 °C by a syringe. The reaction mixture was allowed to warm to rt slowly and stirred overnight. Next day, the reaction mixture was quenched with water and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by prep- HPLC to give 253-3 (43 mg, 41%). MS (ESI): calcd. for C28H31CIFN7O2: 551; Found: 552 [M+l]⁺. ¹H NMR (400 MHz, CD3OD): 57.89 (dd, 7 = 6.8, 2.8 Hz, 1H), 7.68 (s, 1H), 7.52 (d, 7 = 9.7 Hz, 1H), 7.25 (t, 7 = 8.9 Hz, 1H), 5.79 (s, 2H), 4.62 (s, 2H), 4.09 (s, 3H), 3.78 (s, 3H), 3.36 (s, 1H), 2.67 (s, 2H), 2.56 (dd, 7 = 13.3, 7.5 Hz, 2H), 2.28 (s, 2H), 2.14 (s, 1H), 2.11 (s, 3H), 2.04 (d, 7= 7.2 Hz, 1H), 2.00 (d, 7 = 4.5 Hz, 1H), 1.97 - 1.84 (m, 2H) ppm.

Step 3. Synthesis of -(5-(3-amino-l-methyl-lH-l,2,4-triazol-5-yl)-5-hydroxyoctahydro- pentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (Example 254). To a solution of 254-3 (23 mg, 0.042 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (870 mg, 12.5 mmol) and triethylamine (1.69 mL, 12.2 mmol). The resulting mixture was refluxed for 2 days. After that, to the reaction mixture was added more hydroxylamine hydrochloride (870 mg, 12.5 mmol) and triethylamine (1.69 mL, 12.2 mmol). The resulting mixture was refluxed for 2 days. Then the last procedure was repeated. After 6 days, the conversion was full. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (25 mL). The mixture was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by prep-HPLC to give Example 254 (9.5 mg, 48%). MS (ESI): calcd. for C22H25CIFN7O2: 473; Found: 474 [M+l]⁺; NMR (600 MHz, DMSO-d₆ ): 5 10.16 (s, 1H), 7.94 (dd, 7 = 6.8, 2.6 Hz, 1H), 7.63 (s, 1H), 7.55 (ddd, 7 = 9.0, 4.3, 2.6 Hz, 1H), 7.39 (t, 7 = 9.1 Hz, 1H), 5.39 (s, 1H), 4.98 (s, 2H), 3.66 (d, 7 = 4.8 Hz, 6H), 3.22 (dd, 7 = 12.0, 6.0 Hz, 1H), 2.29 (dd, 7 = 13.3, 7.7 Hz, 2H), 2.07 (dd, 7 = 12.3, 6.5 Hz, 2H), 2.04 (s, 1H), 1.83 (q, 7 = 11.6 Hz, 2H), 1.78 (dd, 7 = 12.9, 3.9 Hz, 2H) ppm.

Example 255. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-methyl-2H-l,2,3-triazol-4- yl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide

Step 1. Synthesis of 4-bromo-5-(difluoromethyl)-2-methyl-2H-l,2,3-triazole (255-2). To a solution of 5-bromo-2-methyl-2H-l,2,3-triazole-4-carbaldehyde (255-1) (1.2 g, 6.33 mmol) in DCM (50 mL) was added dropwise a solution of 4-morpholinylsulfur trifluoride (2.77 g, 15.82 mmol, 1.93 mL, 2.5 eq.) in DCM (15 mL) at 0 °C. The reaction mixture was stirred 1 h at 0 °C, and left to warm gradually to rt. After stirring at rt for 16 h, the mixture was poured into saturated aq. NaHCO₃ solution (200 mL), and the mixture was extracted with DCM (30 mL x 2). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was dried in vacuo 255-2 (1.2 g, 89%) as a pale-yellow solid, which was used for the next step without further purification. MS (ESI): calcd. for C₄H₄BrF₂N₃: 211; Found: 212 [M+l]⁺.

Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-methyl-2H-l,2,3- triazol-4-yl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 255). To a solution of 255-2 (394.9 mg, 1.86 mmol) and tetramethylethylenediamine (1.77 mmol, 0.27 mL, 9.5 eq.) in anhydrous THF (15 mL), n-butyllithium (2.5 M in n-hexane, 1.77 mmol, 0.71 mL, 9.5 eq.) was added dropwise at -78 °C. The resulting mixture was stirred at the same temperature for 1 h. Then a solution of Intermediate 8 (70.0 mg, 0.186 mmol) in THF (2 mL) was added drop wise. The reaction mixture was stirred at -78 °C for 40 min, and left to warm gradually to rt. After stirring at rt for 12 h, the mixture was poured into saturated aq. NH₄C1 solution, and the resulting mixture was concentrated. The residue was extracted with EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 255 (24 mg, 26%) as an off-white solid. MS (ESI): calcd. for C₂3H₂₄C1F3N6O₂: 508; Found: 509 [M+l]⁺; ¹H NMR (400 MHz, DMSO-d₆ ): 5 10.21 (s, 1H), 7.96 (dd, 7 = 7.0, 2.5 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, 7 = 8.6, 4.9 Hz, 1H), 7.41 (t, 7 = 9.1 Hz, 1H), 7.20 (d, 7 = 54.0 Hz, 1H), 5.47 (s, 1H), 4.13 (s, 3H), 3.68 (s, 3H), 3.28 - 3.19 (m, 1H), 2.56 (s, 2H), 2.18 (dd, 7 = 13.2, 7.4 Hz, 2H), 2.09 (d, 7= 9.1 Hz, 2H), 2.03 - 1.73 (m, 4H) ppm. Example 256. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(5-(2-hydroxypropan-2-yl)-2- methyl-2H-l,2,3-triazol-4-yl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5- carboxamide

Step 1. Synthesis of 2-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)propan-2-ol (256-1). n-

BuLi (2.5 M in THF, 10 mL, 25 mmol) was added dropwise to a solution of 4,5-dibromo-2- methyl-2H-l,2,3-triazole (256-1) (5 g, 20.75 mmol) in THF (20 mL) at -80 °C. The resulting mixture was stirred at -80 °C -60 °C for 20 min. Than Me2CO was added to reaction mixture drop wise at -80 °C and stirred overnight at rt. The obtained mixture was concentrated, treated with sat. aq. NH4CI solution (50 mL), and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography using 0 to 30 % (v/v) EtOAc/Hexanes as eluent to give 256-2 (3.26 g, 71%) as a yellow oil. MS (ESI): calcd. for C₆HioBrN₃0: 219; Found: 220 [M+l]⁺.

Step 2. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(5-(2-hydroxypropan-2-yl)-2- methyl-2H-l,2,3-triazol-4-yl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5- carboxamide (Example 256). n-BuLi (2.5M in hexane, 1.5 mL, 3.73 mmol) was added dropwise to a solution of 256-2 (410 mg, 1.86 mmol) in Et20 (5 mL) at -80 °C. The obtained suspension was stirred at -80 °C -70 °C for 0.5 h. Then the solution of Intermediate 8 (100 mg, 0.266 mmol) in THF (1 mL) was added dropwise to the above suspension at -80 °C. The obtained mixture was warmed to rt and stirred overnight. Subsequently, the reaction mixture was treated with sat. aq. NH4CI (25 mL) and concentrated. The residue was diluted with water and extracted EtOAc (20 mL x 3). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to give Example 256 (25 mg, 18%) as a yellow solid. MS (ESI): calcd. for C25H30CIFN6O3, 516; found: 517 NMR (400 MHz, CD3OD): 57.90 (dd, J = 6.6, 2.6 Hz, 1H), 7.66 (s, 1H), 7.52 (dd, J = 7.7, 4.1 Hz, 1H), 7.26 (t, J = 8.9 Hz, 1H), 4.03 (d, J = 0.7 Hz, 3H), 3.78 (s, 3H), 2.68 (d, 7= 10.1 Hz, 3H), 2.46 (dd, 7 = 13.4, 7.3 Hz, 2H), 2.24 (d, 7 = 7.2 Hz, 2H), 1.95 (dt, 7 = 13.1, 6.7 Hz, 4H), 1.57 (s, 6H) ppm.

Example 257, 257a and 257b. N-(3-chloro-4-fluorophenyl)-4-(5-(5-(l,2-dihydroxyethyl)- 2-methyl-2H-l,2,3-triazol-4-yl)-5-hydroxyoctahydropentalen-2-yl)-l-methyl-lH- imidazole-5 -carboxamide (257), N-(3-chloro-4-fluorophenyl)-4-(5-(5-((R)-l,2- dihydroxyethyl)-2-methyl-2H-l,2,3-triazol-4-yl)-5-hydroxyoctahydropentalen-2-yl)-l- methyl-lH-imidazole-5-carboxamide (257a), and N-(3-chloro-4-fluorophenyl)-4-(5-(5- ((S)-l,2-dihydroxyethyl)-2-methyl-2H-l,2,3-triazol-4-yl)-5-hydroxyoctahydropentalen- 2-yl)-l-methyl-lH-imidazole-5-carboxamide (257b)

Step 1. Synthesis of 4-(5-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)-5- hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-l-methyl-lH-imidazole-5- carboxamide (257-1). To a solution of 4,5-dibromo-2-methyl-2H-l,2,3-triazole (1266 mg, 5.3 mmol) and TMEDA (614 mg, 5.3 mmol) in THF (10 mL) was added n-Butyllithium (1.91 mL, 4.77 mmol, 2.5 M) dropwise at -78°C, and the mixture was stirred for 1.5 h at - 78 °C in an atmosphere of Ar. Subsequently, a solution of Intermediate 8 (200 mg, 0.53 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise at -78 °C, the reaction mixture was stirred for 4 hours at -78 °C. Next, the reaction mixture was treated with sat. aq. NH4CI solution (30 mL) and concentrated. The residue was extracted with EtOAc (30 mL x 3), the combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (MeOH/DCM = 1/15 (v/v) to give 257-1 (250 mg, 88%) as an off-white solid. MS (ESI): calcd. for C22H23BrClFNeO2, 536; Found: 537 [M+l]⁺. ¹H NMR (400 MHz, CD3OD): 57.89 (dd, J = 6.4, 2.4 Hz, 1H), 7.64 (s, 1H), 7.54-7.48 (m, 1H), 7.24 (t, J = 8.8 Hz, 1H), 4.23 (s, 3H), 3.76 (s, 3H), 3.37-3.32 (m, 1H), 2.79-2.69 (m, 2H), 2.58-2.49 (m, 2H), 2.30-2.20 (m, 2H), 2.16-2.09 (m, 2H), 2.08-2.00 (m, 2H) ppm.

Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(2-methyl-5-vinyl-2H- l,2,3-triazol-4-yl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (257- 2). To a solution of 257-1 (200 mg, 0.37 mmol), TEA (224 mg, 2.22 mmol), potassium trifluoro(vinyl)borate (248 mg, 1.85 mmol) in ethanol (3 mL) was added Pd(dppf)Ch (27 mg, 0.037 mmol). The mixture was purged with Ar and stirred at 90 °C for 16 h under an atmosphere of Ar. The reaction mixture was concentrated, diluted with EtOAc, and filtered through a Celite®545 plug. The filtered cake was washed with EtOAc and the filtrated was dried with anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (MeOH/DCM = 1/15 (v/v) to give 257-2 (100 mg, 56%) as a brown solid. MS (ESI): calcd. for C24H26CIFN6O2, 484; Found: 485 [

CD3OD): 57.88 (d, J = 5.2 Hz, 1H), 7.66 (s, 1H), 7.54-7.44 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.00-6.88 (m, 1H), 5.92 (d, J = 18.0 Hz, 1H), 5.27 (d, J = 10.8 Hz, 1H), 4.06 (s, 3H), 3.77 (s, 3H), 3.24-3.10 (m, 1H), 2.59-2.39 (m, 4H), 2.28-2.14 (m, 2H), 1.95-1.75 (m, 4H) ppm. Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(5-(5-(l,2-dihydroxyethyl)-2-methyl- 2H-l,2,3-triazol-4-yl)-5-hydroxyoctahydropentalen-2-yl)-l-methyl-lH-imidazole-5- carboxamide (Example 257), N-(3-chloro-4-fluorophenyl)-4-(5-(5-((R)-l,2- dihydroxyethyl)-2-methyl-2H-l,2,3-triazol-4-yl)-5-hydroxyoctahydropentalen-2-yl)-l- methyl-lH-imidazole-5-carboxamide (Example 257a), and N-(3-chloro-4-fluorophenyl)- 4-(5-(5-((S)-l,2-dihydroxyethyl)-2-methyl-2H-l,2,3-triazol-4-yl)-5- hydroxyoctahydropentalen-2-yl)-l-methyl-lH-imidazole-5-carboxamide (Example 257b). To a solution of 257-2 (150 mg, 0.31 mmol), NMO (72 mg, 0.62 mmol) in acetone (2 mL) and water (2 mL) was added K2OSO42H2O (543 mg, 0.62 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with NaS O₃ solution (20 mL). The mixture was concentrated, and the residue was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (MeOH/DCM = 1/15 (v/v) to give Example 257 (68 mg, 42%) as an off-white solid. MS (ESI): calcd. for C24H28CIFN6O4, 518; Found: 519 [M+l]⁺.

NMR (400 MHz, CD3OD): 57.78 (dd, J = 6.8, 2.4 Hz, 1H), 7.55(s, 1H), 7.44-7.37 (m, 1H), 7.14 (t, J = 8.8 Hz, 1H), 4.92 (t, J = 6.8 Hz, 1H), 3.95 (s, 3H), 3.73-3.68 (m, 2H), 3.67 (s, 3H), 3.28- 3.22 (m, 1H), 2.59-2.48 (m, 2H), 2.43-2.30 (m, 2H), 2.19-2.08 (m, 2H), 1.88-1.71 (m, 4H) ppm.

Example 257 (68 mg) was separated by SFC to give two single diastereomers Example 257a (17 mg) as a white solid and Example 257b (16 mg) as a white solid. The corresponding stereochemistry was arbitrarily assigned.

Prep-SFC Condition: Instrument: SFC-80 (Thar, Waters); Column: CHIRALPAK AD (30*250 mm 5pm) (Daicel); Column temperature: 35 °C; Mobile phase: A = CO2, Co-Solvent B = MeOH (0.2% 7M NH₃ MeOH).

Sample solution: 100 mg of the solid in 20 mL of MeOH

Example 257a: tR = 1.39 min; MS (ESI): calcd. for C24H28CIFN6O4, 518; Found: 519 [M+l]⁺. ¹H NMR (400 MHz, CD3OD): 57.78 (dd, J = 6.8, 2.4 Hz, 1H), 7.55(s, 1H), 7.44- 7.37 (m, 1H), 7.14 (t, J = 8.8 Hz, 1H), 4.92 (t, J = 6.8 Hz, 1H), 3.95 (s, 3H), 3.73-3.68 (m, 2H), 3.67 (s, 3H), 3.28-3.22 (m, 1H), 2.59-2.48 (m, 2H), 2.43-2.30 (m, 2H), 2.19-2.08(m,

2H), 1.88-1.71 (m, 4H) ppm.

Example 257b: tR = 1.89 min; MS (ESI): calcd. for C24H28CIFN6O4, 518; Found: 519 [M+l]⁺. ¹H NMR (400 MHz, CD3OD): 57.78 (dd, J = 6.8, 2.4 Hz, 1H), 7.55(s, 1H), 7.44- 7.37 (m, 1H), 7.14 (t, J = 8.8 Hz, 1H), 4.92 (t, J = 6.8 Hz, 1H), 3.95 (s, 3H), 3.73-3.68 (m,

2H), 3.67 (s, 3H), 3.28-3.22 (m, 1H), 2.59-2.48 (m, 2H), 2.43-2.30 (m, 2H), 2.19-2.08 (m, 2H), 1.88-1.71 (m, 4H) ppm.

Table 8. Analytical Data of Representative Examples 258-354

Example 355. N-(3-chloro-4-fluorophenyl)-l-methyl-4-(2-oxohexahydro-l 'H-spiro- [oxazolidine-5,2'-pentalen]-5'-yl)-lH-imidazole-5-carboxamide

Step 1. Synthesis of N-(3-chloro-4-fluorophenyl)-4-(hexahydro-l'H-spiro[oxirane-2,2'- pentalen]-5'-yl)-l-methyl-lH-imidazole-5-carboxamide (355-1). Potassium 2- methylpropan-2-olate (597 mg, 5.3 mmol) in THF (8 mL) was added trimethylsulfoxonium iodide (1.17 g, 5.3 mmol). The mixture was stirred at rt for 1 h under an atmosphere of N2.

Subsequently, Intermediate 8 (500 mg, 1.3 mmol) was added and the reaction mixture was stirred at 60 °C for 2 h. Next, the reaction mixture was treated with sat. aq. NH4CI, concentrated, and extracted with EtOAc (15 mL x 3). The combined organic extracts were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography using 5% to 50% (v/v) EtOAc/Hexanes to give 355-1 (200 mg, 39%), a single isomer, as a pale-yellow solid. MS (ESI): calcd. for C20H2ICIFN3O2, 389; found: 390 [M+l]⁺.

Step 2. Synthesis of 4-(5-(aminomethyl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro- 4-fluorophenyl)-l-methyl-lH-imidazole-5-carboxamide (355-2). To a solution of 355-1 (100 mg, 0,26 mmol) in THF (3 mL) was added 28% aq. NH3 solution (3 mL). After stirring at 70°C in a sealed tube for 16 h, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give 355-2 (60 mg, 58%) as a brown oil. MS (ESI): calcd. for C20H24CIFN4O2, 406; found: 407 [M+l]⁺.

Step 3. Synthesis of N-(3-chloro-4-fluorophenyl)-l-methyl-4-(2-oxohexahydro-l'H- spiro[oxazolidine-5,2'-pentalen]-5'-yl)-lH-imidazole-5-carboxamide (example 355). To a solution of 355-2 (60 mg, 0.15 mmol) in DMF/DCM = 1/1 (v/v) (2 mL) was added CDI (24 mg, 0.15 mmol). After stirring at rt for 3 h, the reaction mixture was concentrated and the residue was purified by prep-HPLC to give Example 355 (8 mg, 13%) as a white solid. MS (ESI): calcd. for C21H22CIFN4O3, 432; found: 433 [M+l]⁺.

NMR (DMSO-d6, 400 MHz): 5 10.25 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.66 (s, 1H), 7.59-7.55 (m, 1H),7.41 (t, J = 9.2 Hz, 2H), 3.67 (s, 3H), 3.33-3.31 (m, 2H), 3.24-3.18 (m, 1H), 2.13-2.07 (m, 2H), 1.96-1.70 (m, 2H), 1.80-1.67 (m, 4H) ppm.

Example 356. N-(3-chloro-4-fluorophenyl)-l-methyl-4-(6'-oxohexahydro-l"H-dispiro-

[cyclopropane-1 ,5 ' -morpholine-2 ' ,2 " -pentalen] -5 " -yl)- lH-imidazole-5-car boxamide

Step 1. Synthesis of l-(((5-(5-((3-chloro-4-fhuorophenyl)carbamoyl)-l-methyl-lH- imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)methyl)amino)cyclopropane-l- carboxylic acid (356-1). To a solution of 355-1 (389 mg, 1.0 mmol) in THF/H2O = 5:1 (v/v) (5 mL) was added methyl 1 -aminocyclopropane- 1 -carboxylate (460 mg, 4 mmol) at rt. After stirring at 80°C in a sealed tube overnight, the reaction mixture was cooled to rt and added LiOH (84 mg, 2.0 mmol). The mixture was stirred at rt for 1 h, treated with aq. IN HC1 solution (2.5 mL), and concentrated. The residue was purified by prep-HPLC to give 356-1 (120 mg, 25%) as a white solid. MS (ESI): calcd. for C24H28CIFN4O4, 490; found: 491 [M+l]⁺. ¹H NMR (400 MHz, DMSO-d6): 5 10.22 (s, 1H),7.96 (dd, J = 6.8, 2.8 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.41 (t, J = 9.2 Hz, 1H), 3.67 (s, 3H), 3.24-3.22 (m, 2H), 2.62 (s, 2H), 2.33-2.32 (m, 2H), 2.06-2.04 (m, 2H), 1.84-1.81 (m, 2H), 1.71-1.69 (m, 2H), 1.39-1.34 (m, 2H), 1.07-1.05 (m, 2H), 0.87-0.84 (m, 2H) ppm.

Step 2. Synthesis of N-(3-chloro-4-fluorophenyl)-l-methyl-4-(6'-oxohexahydro-l"H- dispiro [cyclopropane-1 ,5 ' -morpholine-2 ' ,2 " -pentalen] -5 ' ' -yl)- lH-imidazole-5- carboxamide (Example 356). To a solution of 356-1 (49 mg, 0.1 mmol) in DCM (2 mL) was added DIEA (23 mg, 0.2 mmol) and HATU (49 mg, 0.13 mmol), and the mixture was stirred at rt overnight and concentrated. The residue was purified by prep-HPLC to give Example 356 (16 mg, 33.9%), a single isomer, as a white solid. MS (ESI): calcd. for C24H26CIFN4O3, 472; found: 473

6 10.25 (s, 1H), 7.96 (dd, 7 = 6.8, 2.4 Hz, 1H), 7.67 (s, 1H), 7.60-7.56 (m, 1H), 7.41 (t, 7 =9.2 Hz, 1H), 3.67 (s, 3H), 3.29-3.27 (m, 2H), 2.86-2.84 (m, 2H), 2.45-2.40 (m, 2H), 2.20-2.11 (m, 4H), 1.70- 1.65 (m, 4H), 1.17-1.11 (m, 2H), 0.88-0.85 (m, 2H) ppm.

Example 357. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(((5-(trifluoromethyl)- pyrimidin-2-yl)amino)methyl)octahydropentalen-2-yl)-l-methyl-lH-imidazole-5- carboxamide

A solution of 355-2 (100 mg, 0.25 mmol) in DMSO (3 mL) was added 2-chloro-5- (trifluoromethyl) pyrimidine (135 mg, 0.74 mmol) and CS2CO3 (241 mg, 0.74 mmol). The reaction was stirred at 80 °C overnight and concentrated. The residue was diluted with EtOAc and dried over anhydrous Na₂SO₄. The solvent was removed, and the residue was purified by prep-HPLC to give Example 357 (15 mg, 11%) as an off-white solid. MS (ESI): calcd. for C25H25CIF4N6O2, 552; found: 553 [M+l]⁺. NMR (400 MHz, DMSO-d₆ ): 5 10.22 (s, 1H), 8.60 (d, J = 6.4 Hz, 2H), 7.96 (dd, J = 6.8, 2.8 Hz, 1H), 7.70 (t, J = 6.0 Hz, 1H), 7.65 (s, 1H),

7.59-7.55 (m, 1H), 7.41 (t, 7 = 8.8 Hz, 1H), 4.63 (s, 1H), 3.67 (s, 3H), 3.42 (d, 7 = 6.0 Hz, 2H), 3.26-3.20 (m, 1H), 2.50-2.43 (m, 2H), 2.10-2.04 (m, 2H), 1.87-1.82 (m, 2H), 1.77-1.69 (m, 2H), 1.46-1.42 (m, 2H ) ppm.

Table 9. Analytical Data of Representative Examples 358-415

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), IX Pen/Strep (Invitrogen, cat#: 15140- 122), 10% FBS (Tissue Culture Biologies, cat#: 101), 250 pg/mL G418 (Alfa Aesar, cat#: J62671), Ipg/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)_? lx 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 IX 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 (Coming, cat#: 3904,) were seeded at 50,000 cells/well in 180 μL of treatment medium, and 20 pL 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 pM, 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 HB V-probe 5 '-FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTC/3IABkFQ -3 ' (IDT DNA), 10 pL/well of PerfeCTa® qPCR ToughMix® (Quanta Biosciences, Cat#: 95114- 05K), and 6 pL/well of DEPC water (Alfa Aesar, cat#: J62087) was prepared. Four pL of supernatant was added to 16 pL 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) IX DPBS in a 1:1 ratio, added 100 uL of the mixture to each well followed completely removal of all supernatant 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 |1M. Table 10 gives the viral load lowering EC50 values for exemplified compounds of the invention grouped in the following ranges: A indicates EC50 of <1 nM; B indicates EC50 of >1 to <10 nM; C indicates ECso of >10 to <100 nM; and D indicates ECso of >100 nM. Table 10. Viral load lowering for exemplified compounds of the invention

VII. Stereochemistry of Examples

AIA-225

5-Amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)- octahydropentalen-2-yl)-l-methyl-lH-pyrazole-4-carboxamide. To a solution of 5-amino-

N-(3-chloro-4-fluorophenyl)-3-(hexahydro-rH-spiro[oxirane-2,2'-pentalene]-5'-yl)-l-methyl- lH-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)-l -methyl- lH-pyrazole-4-carboxamide (100 mg, 45%) as a yellow solid. MS (ESI): calcd. for C21H26CIFN4O2S: 452; Found: 453 [M+l]⁺.

AIA-227-1, AIA-227-2

5-Amino-N-(3-chloro-4-fluorophenyl)-3-((2r,5r)-5-hydroxy-5-

(methylsulfonylmethyl)octahydropentalen-2-yl)-l-methyl-lH-pyrazole-4-carboxamide (AIA-227-1) and 5-Amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5- (methylsulfonylmethyl)octahydropentalen-2-yl)-l-methyl-lH-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- 1 H-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%) as a white solid. MS (m/z) calcd. for C21H26CIFN4O4S: 484, Found: 485 [M+l]⁺. 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:

NMR (400 MHz, DMSO-d₆): 5 8.95 (s, 1H), 7.91 (dd, 7 = 6.8, 2.4 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (t, 7 = 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:

NMR (400 MHz, DMSO- d₆) 5 8.94 (s, 1H), 7.91 (dd, 7 = 2.8, 2.4 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.34 (t, 7 = 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)-l-methyl-lH-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)-l-methyl-lH-pyrazole-4- carboxamide (26.0 g, 52%) as a white solid. MS (ESI): calcd. for C21H26CIFN4O4S: 484; Found: 485 [M+l]⁺;

NMR (400 MHz, DMSO-cfc): 5 8.96 (s, 1H), 7.92 (dd, 7 = 6.8, 2.8 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (t, 7 = 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 0.20 mm 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 P2i/c. The unit cell parameters were as follows: a= 6.6143(3), £>=14.0381(8), c=23.6870(14)A, <z=y=90.0°,β=97.702(3) °, V= 2179.5(2)A³, 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, wRz, GOF are 0.0457, 0.1293 and 1.024, respectively.

There is one C21H26FCIN4O4S 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

Formula I

, or a pharmaceutically acceptable salt thereof, wherein:

L¹ and L² are independently selected from the group consisting of a bond, C_1- 4alkylene, Ci^alkenylene, C_1-4alkynylene, haloC_1-4alkylene, hydroxyCi^alkylene, O, NR^C, C(O), C(O)O, C(O)NR^C, S(O)t, S(O)_tNR^c, C_1-4alkyleneS(O)tandhaloC_1-4alkyleneS(O)t;

L³ is C_1-6alkylene, C_2-6alkenylene or C_2-6alkynylene, wherein the C_1-6alkylene, C2- 6alkenylene, C_2-6alkynylene 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)-, C_1- 6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, R^aR^bN-C_1-6alkoxy, and haloC_1-6alkylNR⁰-;

X¹ is NR^xl, 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, C1-6 alkyl, and haloC_1-6 alkyl;

R^d is hydrogen, OH, C1-6 alkyl or C1-6 alkoxy;

R^xl is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, haloC_1-4 alkyl, or C3-6 monocycloalkyl;

R^Oa is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, R^aR^bN-, C_1-4alkyl and haloC_1-4alkyl;

R^6a is hydrogen, C1-4 alkyl, haloC_1-4 alkyl or C1-4 cycloalkyl;

R^6b is C_1-6alkyl, C_2-6alkenyl or C_2-6alkynyl, wherein the C_1-6alkyl, C_2-6alkenyl, 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-;

R°, 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, C_1-4alkyl, haloCi^alkyl, C_3-5monocycloalkyl, C_1-4alkoxy, and haloC_1- 4alkoxy;

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^xl and R^xl is hydrogen or methyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R^xl 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 zl 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

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

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

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

15. The compound of claims 14, wherein R⁷ is hydrogen, OH or C_1-4 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 C_1-4 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.