5-membered heteroaryl carboxamide compounds for treatment of hbv

Abstract

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

Description

Background Technology

[0001] Hepatitis B (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of chronic cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, approximately 2 billion people are infected with HBV, with about 360 million chronically infected, and HBV infection causes more than 500,000 deaths annually. HBV can be transmitted through bodily fluids: mother-to-child transmission, sexual transmission, and transmission through blood products. Children born to HBV-positive mothers may also be infected unless vaccinated at birth.

[0002] Hepatitis virus particles are formed by a lipid envelope surrounding the viral core, which is adorned with surface proteins (HBsAg). The core consists of a protein coat or capsid composed of 120 core protein (Cp) dimers, which also contains the relaxed circular DNA (rcDNA) viral genome, as well as viral and host proteins. In infected cells, the genome is found to be covalently closed circular DNA (cccDNA) in the host cell nucleus. cccDNA serves as a template for the viral RNA and therefore for the viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (so-called pregenomic RNA or pgRNA) and viral polymerase (P). After assembly, P reverse transcribes the pgRNA into rcDNA within the capsid to produce a DNA-filled viral core.

[0003] Currently, chronic HBV is primarily treated with nucleoside (nucleotide) analogs (e.g., entecavir), which suppress the virus while the patient maintains treatment, but do not eliminate the infection even after many years of treatment. Once a patient starts taking nucleoside (nucleotide) analogs, most must continue taking them, otherwise there is a risk of a life-threatening immune response due to viral rebound. Furthermore, nucleoside therapy may lead to antiviral resistance.

[0004] The only FDA-approved nucleoside (acid) analogue alternative is treatment with interferon-alpha or pegylated interferon-alpha. Unfortunately, the incidence and profile of adverse events associated with interferon-alpha can lead to poor tolerability, and many patients fail to complete the therapy. Moreover, only a small percentage of patients are considered suitable for interferon therapy because only a small fraction are likely to have a sustained clinical response to a course of interferon therapy. Therefore, interferon-based therapies are used only for a small fraction of all confirmed patients selected for treatment.

[0005] Therefore, current HBV treatments range from palliative care to observation and waiting. Nucleotide analogs suppress viral production and treat symptoms but do not affect infection. Interferon-alpha has serious side effects, is poorly tolerated by patients, and has only been successful in a small percentage of patients as a limited treatment strategy. Significant persistence requires more effective treatments for HBV infection. Summary of the Invention

[0006] This disclosure provides 5-membered heteroarylformamide compounds and pharmaceutical compositions thereof that can be used to disrupt the assembly of HBV core proteins, as well as methods for treating HBV infection.

[0007] In one aspect, this disclosure provides a compound of formula I:

[0008]

[0009] Or a pharmaceutically acceptable salt thereof, wherein the variables are described in the specific embodiments.

[0010] In another respect, this disclosure provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0011] In another aspect, this disclosure provides a method for treating HBV infection in a subject in need, comprising: administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, this disclosure provides a method for treating HBV infection in a subject in need, 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. Attached Figure Description

[0013] Figure 1 The ORTEP plot of compound CP-AIA-227-2 is shown.

[0014] Figure 2 The relative stereochemical scheme of compound CP-AIA-227-2 is shown. Detailed Implementation

[0015] The features and other details of this disclosure will now be described in more specific terms. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be referenced to other parts of this disclosure and interpreted as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0016] I. Definition

[0017] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups having 2 to 6 carbon atoms (referred to herein as C...). 2-6Alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl groups.

[0018] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group attached to an oxygen atom (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups having 1 to 6 carbon atoms or 1 to 4 carbon atoms, referred to herein as C14-C ... 1-6 Alkoxy and C 1-4 Alkoxy groups. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0019] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2-, and CH3OCH2-.

[0020] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbon groups having 1 to 6 carbon atoms or 1 to 4 carbon atoms, referred to herein as C14 and C24, respectively. 1-6 Alkyl and C 1-4 Alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. As used herein, the term "alkylene" refers to a dialkyl group.

[0021] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups having 2 to 6 carbon atoms (referred to herein as C...). 2-6 Alkyne groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, and methylpropynyl.

[0022] As used herein, the term "carbonyl" refers to the dimethyl-C(O)-.

[0023] As used herein, the term "cyano" refers to the -CN group.

[0024] As used herein, the term "cycloalkyl" refers to a saturated monocyclic hydrocarbon group having, for example, 3 to 6 carbons (referred to herein as C16). 3-6Monocyclic alkyl groups or bicyclic hydrocarbon ring structures having, for example, 8 to 12 carbons (referred to herein as C14-C ... 8-12 (Bicycloalkyl). For bicycloalkyl groups, the two rings can be connected by the same or different carbon atoms. Exemplary monocycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl. Exemplary bicycloalkyl groups include, but are not limited to, spiro[2.5]octyl, spiro[3.5]nonyl, bicyclo[2.2.2]octyl, bicyclo[4.1.0]heptyl, octahydrocyclopentadienyl, bicyclo[4.2.0]octyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

[0025] As used herein, the term "cycloalkenyl" refers to a partially unsaturated monocyclic hydrocarbon group having, for example, 4 to 6 carbons (referred to herein as C1). 4-6 Monocyclic alkenyl) or bicyclic hydrocarbon ring structures having, for example, 8 to 12 carbons (referred to herein as C) 8-12 (Bicyclic alkenyl). For bicyclic alkenyl groups: 1) one or both rings may contain one or more double bonds, and 2) the two rings may be connected by the same or different carbon atoms. Exemplary monocyclic alkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Exemplary bicyclic alkenyl groups include, but are not limited to, spiro[2.5]oct-5-enyl, spiro[2.5]oct-4-enyl, spiro[3.5]non-5-enyl, spiro[3.5]non-6-enyl, bicyclic[4.1.0]hept-3-enyl, bicyclic[4.1.0]hept-2-enyl, and bicyclic[2.2.2]oct-2-enyl.

[0026] As used herein, the term "carbocyclic group" refers to a group formed by adding a phenyl ring to a C-ring. 3-6 Monocycloalkyl or C 4-6 Bicyclic ring systems formed by the fusion of monocyclic alkenyl rings. Examples of carbocyclic groups include, but are not limited to, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1H-indenyl.

[0027] As used herein, the term “halogenated” or “halogen” refers to F, Cl, Br, or I.

[0028] As used herein, the term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogen atoms. For example, halogenated C 1-6 Alkyl groups are straight-chain or branched alkyl groups having 1 to 6 carbon atoms and being substituted with one or more halogen atoms. Examples include, but are not limited to, CH2F-, CHCl2-, -CHF2, CF3-, CF3CH2-, CH3CF2, CF3CCl2-, and CF3CF2-.

[0029] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O-, CF3CH2O-, and CF3CF2O-.

[0030] As used herein, the term "heteroaryl" refers to a 5- to 6-membered monocyclic aromatic ring system or an 8- to 12-membered bicyclic aromatic ring system containing 1 to 4 independently chosen heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the heteroaryl ring can be linked to adjacent groups via carbon or nitrogen. Examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also known as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also known 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. Examples of 8- to 12-membered bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, benzo[d]isooxazolyl, benzo[c]isooxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, inzolyl, benzo[d]imidazolyl, benzo[d]imidazolyl and benzo[d][1,2,3]triazolyl.

[0031] The term "heterocyclic alkyl" refers to a saturated 3- to 6-membered monocyclic or 8- to 12-membered bicyclic ring system (referred to herein as C14) containing 1 to 4 independently chosen heteroatoms such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) and SO2). 3-6 Monoheterocyclic alkyl and C 8-12 (Diheterocyclic alkyl). Where possible, the heterocyclic alkyl ring can be linked to an adjacent group via carbon or nitrogen. C 3-6 Examples of monoheterocyclic alkyl groups include, but are not limited to, azirropropyl, oxacyclopropyl, thioheteropropyl 1,1-dioxide, oxacyclobutyl, azirrobutyl, thioheterobutyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazineyl. 8-12 Examples of diheterocyclic alkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decyl and 1,5-dioxaspiro[5.5]undecyl.

[0032] The term "heterocyclic alkenyl" refers to a partially unsaturated 3- to 6-membered monocyclic or 8- to 12-membered bicyclic ring system containing 1 to 4 independently chosen heteroatoms such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) or S(O)2), referred to herein as C. 3-6 Monoheterocyclic alkenyl and C 8-12 Dicyclic alkenyl groups. Where possible, the heterocyclic alkenyl ring can be connected to an adjacent group via carbon or nitrogen. For dicyclic alkenyl groups: 1) one or both rings can contain one or more double bonds, and 2) the two rings can be connected via the same or different ring atoms. C 3-6 Examples of monoheterocyclic alkenyl groups include, but are not limited to, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-pyrazolyl, 2,3-dihydro-1H-pyrazolyl, 4,5-dihydro-1H-imidazolyl, 2,3-dihydro-1H-imidazolyl, 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl, 4,5-dihydrothiazolyl, 2,3-dihydrothiazolyl, 4,5-dihydroisothiazolyl, 2,3-dihydroisothiazolyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 4,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 4,5-dihydroisothiazolyl. Oxazolyl, 2,3-dihydroisoxazolyl, 3,4-dihydropyridyl, 2,3-dihydropyridyl, 2,3,4,5-tetrahydropyridyl, 1,6-dihydropyridazinyl, 4,5-dihydropyridazinyl, 3,4,5,6-tetrahydropyrimidinyl, 4,5-dihydropyrimidinyl, 1,2,5,6-tetrahydropyrimidinyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 2,3-dihydropyrazinyl, 1,2,3,6-tetrahydropyrazinyl, 4H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 4H-1,4-thiazinyl, and 3,4-dihydro-2H-1,4-thiazinyl. C 8-12 Examples of diheterocyclic alkenyl groups include, but are not limited to, 6,7-dihydroindolyl, 4,5-dihydroindolyl, 7,8-dihydroimidazo[1,2-a]pyridyl, 5,6-dihydroimidazo[1,2-a]pyridyl, 4,5-dihydrobenzo[d]imidazolyl, 6,7-dihydro-1H-indazolel, 4,5-dihydro-1H-indazolel, 4,5-dihydropyrazolo[1,5-a]pyridyl and 6,7-dihydropyrazolo[1,5-a]pyridyl.

[0033] As used herein, the term "heterocyclic group" refers to a group formed by (1) fusion of a phenyl ring with a 3- to 6-membered monocyclic heterocyclic alkyl group or a 4- to 7-membered monocyclic heterocyclic alkenyl ring, or (2) fusion of a 5- to 6-membered monocyclic heteroaryl ring with a C-shaped ring. 3-6 cycloalkyl, C 4-7Bicyclic ring systems formed by the fusion of cycloalkenyl, 3- to 6-membered monocyclic heterocyclic alkyl, or 4- to 6-membered monocyclic heterocyclic alkenyl rings. Where possible, these rings can be linked to adjacent groups via carbon or nitrogen. Examples of heterocyclic groups include, but are not limited to, isochoryl, 2H-quinolinyl, 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azacycloheptanetrienyl, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxacycloheptanetrienyl, 6,7-dihydro-5H,9H-[1,2,4]triazolo[3,4-c][1,4]oxacycloheptanetrienyl, 5,6,8,9-tetrahydro-7l2-[1,2,4]triazolo[4,3-d][1,4]diazacycloheptanetrienyl, 8, 9-Dihydro-5H-[1,2,4]triazolo[4,3-a]azacycloheptanetrienyl, 6,9-Dihydro-5H-[1,2,4]triazolo[4,3-a]azacycloheptanetrienyl, 5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl, 5,6-Dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, 5,6,7,8-Tetrahydroimidazo[1,2-a]pyridyl and 5H,9H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl.

[0034] As used herein, the term "hydroxyl (hydroxy and hydroxyl)" refers to the -OH group.

[0035] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, and HOCH2CH(OH)CH2-.

[0036] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, and HOCH2CH(OH)CH2O-.

[0037] As used in this article, the term "R" a R b NC 1-6 "alkyl-" refers to R as defined in this article. a R b An alkyl group substituted with an N- group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2-, and CH3CH(NH2)CH2-.

[0038] As used in this article, the term "R" a Rb NC 1-6 "Alkoxy" refers to the R defined in this article. a R b An alkoxy group substituted with an N- group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0039] As used in this article, the term "oxo" refers to the =O group.

[0040] As used herein, when the rings of a bicyclic ring exhibit floating connection points and / or floating substituents, for example, as... As shown, this indicates that the bicyclic rings can be connected via carbon atoms on either ring and substituents (e.g., one or more R atoms). 33 The group can be independently attached to one or two rings.

[0041] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds or pharmaceutical compositions disclosed herein can be administered to mammals such as humans, but also to other mammals such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). Mammals treated by the methods of this disclosure are ideally mammals desiring treatment for HBV infection.

[0042] The term “modulation” includes antagonism (e.g., inhibition), excitation, partial antagonism, and / or partial excitation.

[0043] The term "pharmaceutically acceptable" includes molecular entities and compositions that, when administered to animals or humans as required, will not produce adverse reactions, allergic reactions, or other harmful reactions. For human use, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0044] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic and absorption-retarding agents, fillers, etc., compatible with drug administration. The use of such media and agents in pharmaceutical active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0045] As used herein, the term "pharmaceutical composition" means a composition comprising at least one of the compounds disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0046] As used herein, the term "pharmaceutically acceptable salt" refers to a salt in which an acidic or basic group may be present in a compound used in a composition. Compounds that are inherently basic and are included in the compositions of this disclosure are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., those containing a pharmacologically acceptable anion. These non-toxic acid addition salts include, but are not limited to, malates, oxalates, hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, sucroseates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1′-methylene-di-(2-hydroxy-3-naphthylcarbamate)). The inherently acidic compounds included in the compositions of this disclosure are capable of forming basic salts with a variety of 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 including basic or acidic moieties in the compositions of this disclosure can also form pharmaceutically acceptable salts with various amino acids. The compounds of this disclosure may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0047] As used herein, the term "therapeuticly effective amount" or "effective amount" refers to the amount of the subject compound that will elicit a physiological or medical response in the tissue, system, or animal (e.g., a mammal or human) sought by an investigator, veterinarian, physician, or other clinical person. The compounds or pharmaceutical compositions disclosed herein are administered in a therapeutically effective amount to treat a disease. Alternatively, the therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0048] The term "treatment" includes any effect that improves the disease by disrupting the assembly of HBV core proteins, such as alleviating, reducing, modulating, or eliminating it. "Disruption" includes inhibiting HBV viral assembly and infection.

[0049] The compounds disclosed herein may contain one or more chiral centers and thus exist as stereoisomers. The term "stereoisomer" as used herein comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereocarbon atom, these compounds may be represented by the symbols "(+)", "(-)", "R", or "S", but those skilled in the art will recognize that the structure may implicitly represent the chiral center. This disclosure covers various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be represented in nomenclature by "(±)", but those skilled in the art will recognize that the structure may implicitly represent the chiral center.

[0050] The compounds disclosed herein may contain one or more double bonds, and thus exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bonds. (Symbols) The bond can be a single, double, or triple bond as described herein. Substituents surrounding a carbon-carbon double bond can be represented as having a “Z” or “E” configuration, where the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the structure describing the double bond encompasses both the “E” and “Z” isomers. Alternatively, substituents surrounding a carbon-carbon double bond can be referred to as “cis” or “trans”, where “cis” indicates that the substituent is on the same side of the double bond, and “trans” indicates that the substituent is on opposite sides of the double bond.

[0051] The compounds disclosed herein may contain a carbocyclic or heterocyclic ring, and thus exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around the carbocyclic or heterocyclic ring is indicated by “Z” or “E” configurations, wherein the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the structure depicting a carbocyclic or heterocyclic ring encompasses both “Z” and “E” isomers. Substituents around the carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, wherein the term “cis” indicates that the substituent is on the same side of the ring plane, and the term “trans” indicates that the substituent is on the opposite side of the ring plane. Mixtures of compounds in which the substituents are located on both the same and opposite sides of the ring plane are indicated as “cis / trans”.

[0052] Individual enantiomers and diastereomers of the compounds disclosed herein can be synthesized from commercially available starting materials containing asymmetric or stereocenters, or synthesized by preparing racemic compounds followed by resolution methods well known to those skilled in the art. Examples of such resolution methods include: (1) linking a mixture of enantiomers to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; (3) directly separating the optically enantiomer mixture on a chiral liquid chromatography column; or (4) dynamically resolving using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis is a chemical or enzymatic reaction well known in the art in which a single reactant forms a non-equimolar mixture of stereoisomers during the generation of a new stereocenter or during the transformation of an existing stereocenter. Stereoselective synthesis encompasses the selective transformation of enantiomers and diastereomers and can utilize chiral auxiliaries. For example, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0053] The compounds disclosed herein can exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and this disclosure is intended to include both solvated and non-solvated 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 yet another embodiment, the compound has a crystalline form.

[0054] This disclosure also includes isotopically labeled compounds of this disclosure that are identical to those described herein, except that one or more atoms are replaced with atoms having an atomic mass or mass number different from those commonly found in nature. Examples of isotopes that can be added to the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and36 Cl, etc. For example, compounds disclosed herein may have one or more deuterium-substituted H atoms.

[0055] Certain isotope-labeled public compounds (e.g., using) 3 H and 14 Compounds labeled with C can be used in the determination of compound and / or substrate tissue distribution. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavier isotopes such as deuterium (i.e., 2 Substitutions such as H can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents through procedures similar to those disclosed in the embodiments herein.

[0056] The term "prodrug" refers to a compound that is converted in vivo to a publicly disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of that compound. Conversion can occur through various mechanisms, such as esterases, amidases, phosphatases, oxidative and / or reductive metabolism, at various locations (e.g., in the intestinal lumen or during transport in the intestine, blood, or liver). Prodrugs are well-known in the art (e.g., see Rautio, Kumpulainen et al., Nature Reviews Drug Discovery, 2008, 7, 255).

[0057] II.5-membered heteroarylformamide compounds

[0058] In one aspect, this disclosure provides a compound of formula I.

[0059]

[0060] Or its pharmaceutically acceptable salt, wherein:

[0061] L is C 1-4 Alkylene or halogenated C 1-4 Alkylene;

[0062] L 1 and L 2 Independent as key, C 1-6 Alkylene, O, NR c C(O), C(O)O, C(O)NR c S(O) t Or S(O) t NR c;

[0063] X 1 It is NR x1 , O or S;

[0064] X 2 It is O, NR 13 CR 13 R 8 C(O) or S(O) t ;

[0065] X 3 It is O, NR 4 CR 4 R 8 C(O) or S(O) t ;

[0066] X 4 and X 6 Independently represented by O or S;

[0067] X 5 Is it O, S, or NR? 0 ;

[0068] R a R b and R c Each time it appears, it is independently selected from the following group: hydrogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-6 Monocycloalkyl;

[0069] R d It is hydrogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy;

[0070] R x1 It is hydrogen, C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl, halogenated C 1-4 Alkyl or C 3-6 Monocycloalkyl; or R x1 and R 2 Together they form -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O--CH2CH2OCH2-, -CH2CH2-NH--CH2NHCH2-, -CH2CH2CH2NH-, or -CH2CH2NHCH2- groups;

[0071] R 0a Each time it appears, it is independently selected from the following group: hydrogen, halogen, OH, CN, NO2, R aR b N-, C 1-4 Alkyl and Halogenated C 1-4 alkyl;

[0072] R 4a and R 6a Independent of hydrogen or C 1-4 alkyl;

[0073] R 0 R 6 and R 11 Each time it appears, it is independently selected from the following groups: hydrogen, halogen, OH, CN, NO2, oxo, R d N=, hydrazine, formyl, azide, silyl, siloxy, HOC(O)-, R a R b N-, R a R b NS(O) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, R a R b NC 1-6 Alkyl-, HOC(O)C 1-6 Alkyl-, R a R b NC 1-6 Alkyl NR c -、C 1-6 Alkyl NR a C 1-6 Alkyl NR c -、C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy-, R a R b NC 1-6 Alkoxy-, C 1-6 Alkoxy C 1-6 Alkyl-, Halogenated C 1-6 Alkoxy C 1-6 Alkyl-, R a R b NC(O)-, C 1-6 Alkyl C(O)-, C 1-6 Alkoxy C(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl S(O) q -、C 1-6 Alkyl S(O) t NRc -、C 1-6 Alkyl S(O) t C 1-6 Alkyl-, C 1-6 Alkyl S(O) t NR a C 1-6 Alkyl-, C 3-6 Cycloalkyl S(O) t C 1-6 Alkyl-, C 1-6 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-6 alkyl-;

[0074] R 1 It is a phenyl or a 5- to 6-membered monocyclic heteroaryl group, wherein the phenyl or 5- to 6-membered monocyclic heteroaryl group is optionally composed of one, two, or three independently selected R groups. 11 Group substitution;

[0075] R 2 and R 8 Independently selected from the following groups: hydrogen, halogen, CN, OH, R a R b N, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 3-5 Monocycloalkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy;

[0076] R 3 yes

[0077] R 4 It is R 5 -L 1 -、R 6 or R 9 ; or R 4 and R 8 The carbon atoms connected to them together form Group;

[0078] R 5 yes

[0079] R 9 It is R 14 S(O) q -L-、R 14 S(O) qNH-L- or R 14 C(O)NH-L-;

[0080] R 10 yes

[0081] R 12 yes

[0082] R 13 It is R 5 -L 1 -、R 10 -L 1 -、R 6 or R 9 ;

[0083] R 14 It is R a R b N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or R 5 -L 1 -;

[0084] q, r, t, and w are each independently selected from 0, 1, and 2 in each occurrence; and

[0085] v is independently selected from 0, 1, 2, and 3 each time it appears.

[0086] The following embodiments further describe compounds of Formula I or pharmaceutically acceptable salts thereof. It should be understood that all chemically permissible combinations of the embodiments described herein are considered further embodiments of the invention.

[0087] In some implementations, X 1 It is S.

[0088] In some implementations, X 1 It is NR x1 .

[0089] In some implementations, X 1 It is NR x1 And R x1 It is the hydrogen of the methyl group.

[0090] In some implementations, X 1 It is NR x1 And R x1 It is a methyl group.

[0091] In some implementations, X 2 It is CR 13 R 8 ;

[0092] In some implementations, X 3 It is CR 4 R 8 .

[0093] In some implementations, L 1 It is a key.

[0094] In some implementations, L 1 It is C 1-6 Alkylene.

[0095] In some implementations, r is 0.

[0096] In some implementations, R 1 yes R 11 Each time it appears, it is independently selected from the following group: halogen, CN, C. 1-6 Alkyl and Halogenated C 1-6 Alkyl; and z1 is 0, 1, 2 or 3.

[0097] In some implementations, R 11 Each time it appears, it is independently selected from the following group: halogens and CN.

[0098] In some implementations, R 11 Each time it appears, it is independently selected from the following groups: F, Cl, Br, and I.

[0099] In some implementations, R 1 Selected from the following group:

[0100]

[0101] In some implementations, R 1 yes

[0102] In some implementations, R 1 yes

[0103] In some implementations, X 1 It is NR x1 R x1 It is hydrogen or methyl, and R 1 yes

[0104] In some implementations, R 1It can be selected independently by one, two, or three halogens, CN, C 1-6 Alkyl and Halogenated C 1-6 Alkyl substituents of 5- to 6-membered monocyclic heteroaryl groups.

[0105] In some implementations, R 1 yes R 11 Each time it appears, it is independently selected from the following group: halogen, CN, C. 1-6 Alkyl and Halogenated C 1-6 Alkyl; and z1 is 0, 1, 2 or 3.

[0106] In some implementations, R 2 It is hydrogen.

[0107] In some implementations, R 2 It is R a R b N;

[0108] In some implementations, R 2 It is R a R b N, and R a and R b Independently selected from the following groups: hydrogen and C 1-6 alkyl.

[0109] In some implementations, R 2 It is NH2.

[0110] In some implementations, X 1 It is NR x1 R x1 It is hydrogen or methyl, R 1 yes And R 2 It is hydrogen.

[0111] In some implementations, X 1 It is NR x1 R x1 It is hydrogen or methyl, R 1 yes And R 2 It is NH2.

[0112] In some implementations, R 3 yes

[0113] In some implementations, R 3 yes

[0114] In some implementations, R 3 yes

[0115] In some implementations, R 3 yes

[0116] In some implementations, R 3 yes

[0117] In some implementations, R 3 yes

[0118] In some implementations, R 3 yes

[0119] In some implementations, R 3 yes

[0120] In some implementations, R 3 yes

[0121] In some implementations, R 3 yes

[0122] In some implementations, R 3 yes

[0123] In some implementations, R 4 It is R 5 -L 1 -

[0124] In some implementations, R 4 It is R 5 .

[0125] In some implementations, R 4 It is R 6 .

[0126] In some implementations, R 4 It is R 9 .

[0127] In some implementations, or R 4 and R 8 The carbon atoms connected to them together form Group.

[0128] In some implementations, R 5 yes

[0129] In some implementations, R 5 yes

[0130] In some implementations, R 5 yes

[0131] In some implementations, R 6 It is C 1-6 Alkyl S(O) t C 1-6 Alkyl- or C 1-6 Alkyl S(O) t NR a C 1-6 alkyl-.

[0132] In some implementations, R 8 It is hydrogen, OH or C 1-6 Alkyl group.

[0133] In some implementations, R 8 It is OH.

[0134] In some implementations, R 14 It is R a R b N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

[0135] In some implementations, R 14 It is R 5 -L 1 -

[0136] In some implementations, R 14 It is R 5 .

[0137] In some implementations, X 1 It is NR x1 ;R x1 It is hydrogen or methyl; R 1 yes R 2 It is H; R 3 yes and R 8 It is hydrogen, OH or C 1-6 Alkyl group.

[0138] In some implementations, X 1 It is NR x1 ;R x1 It is hydrogen or methyl; R 1 yes R 2 It is H; R 3 yes and R 8 It is OH.

[0139] In some implementations, X 1 It is NR x1 ;R x1 It is hydrogen or methyl; R 1 yes R 2 It is H; R 3 yes R 5 yes and R 8 It is hydrogen, OH or C 1-6 Alkyl group.

[0140] In some implementations, X 1 It is NR x1 ;R x1 It is hydrogen or methyl; R 1 yes R 2 It is H; R 3 yes R 5 yes and R 8 It is OH.

[0141] In some implementations, X 1 It is NR x1 ;R x1 It is hydrogen or methyl; R 1 yes R 2 It is NH2; R 3 yes R 6 It is C 1-6 Alkyl S(O) t C 1-6 Alkyl- or C 1-6 Alkyl S(O) t NR a C 1-6 Alkyl-; and R 8 It is hydrogen, OH or C 1-6 Alkyl group.

[0142] In some implementations, X 1 It is NR x1 ;R x1It is hydrogen or methyl; R 1 yes R 2 It is NH2; R 3 yes R 6 It is C 1-6 Alkyl S(O) t C 1-6 Alkyl- or C 1-6 Alkyl S(O) t NR a C 1-6 Alkyl-; and R 8 It is OH.

[0143] III. Pharmaceutical Compositions and Kits

[0144] On the other hand, this disclosure provides pharmaceutical compositions comprising compounds of formula I or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients. In particular, this disclosure provides pharmaceutical compositions comprising compounds of this disclosure formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, oral, 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 extent and severity of the condition being treated and on the characteristics of the specific compound used. For example, the disclosed compositions may be formulated as unit doses and / or may be formulated for oral or subcutaneous administration.

[0145] In another aspect, this disclosure provides a pharmaceutical composition comprising any combination of compounds according to the embodiments described herein, or pharmaceutically acceptable salts and / or stereoisomers thereof.

[0146] Exemplary pharmaceutical compositions of this disclosure can be used in the form of a pharmaceutical preparation containing one or more compounds of this disclosure as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application (e.g., in solid, semi-solid, or liquid form). The active ingredient can be compounded, for example, with a non-toxic, pharmaceutically acceptable carrier commonly used in tablets, granules, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce a desirable effect on the course or condition of the disease.

[0147] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium hydrogen phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the compounds of this disclosure or pharmaceutically acceptable non-toxic salts thereof. When these preformed compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, thus allowing the composition to be readily subdivided into equivalent effective unit dosage forms, such as tablets, pills, and capsules.

[0148] In solid dosage forms (capsules, tablets, pills, sugar pills, powders, granules, etc.) intended for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or calcium hydrogen phosphate and / or any of the following: (1) fillers or fillers such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants. Examples include glycerin, etc.; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate, etc.; (5) solution retarders, such as paraffin, etc.; (6) absorption promoters, such as quaternary ammonium compounds, etc.; (7) humectants, such as, for example, acetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents, such as kaolin and bentonite clay, etc.; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using such excipients, such as lactose or toffee and high molecular weight polyethylene glycol, etc.

[0149] Tablets can optionally be made by compression or molding with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium hydroxyacetic acid starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of a subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as sugar pills, capsules, pellets, and granules can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0150] Compositions for inhalation or inhalation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms may also contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, etc.), oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil, etc.), glycerin, tetrahydrofuranol, polyethylene glycol and dehydrated sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0151] In addition to the main composition, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0152] Formulations for rectal or vaginal application can be presented as suppositories, which can be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates. The suppository is solid at room temperature but liquid at body temperature, and thus will melt in the body cavity and release the active ingredient.

[0153] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed under aseptic conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0154] In addition to the main composition, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0155] In addition to the main composition, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamine powders or mixtures thereof. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0156] Alternatively, the compositions and compounds of this disclosure can be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Acoustic nebulizers can be used because they minimize the reagent's exposure to shear, which could lead to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by co-formulating an aqueous solution or aqueous suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers can vary depending on the specific subject composition required, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0157] 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 that can be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0158] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil, etc.), and injectable organic esters (such as ethyl oleate and cyclodextrin, etc.). Suitable flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining a suitable particle size in the case of dispersions, and by using surfactants.

[0159] On the other hand, this disclosure provides enteric drug formulations comprising the disclosed compounds and enteric-coated materials, as well as pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials are polymers that are substantially insoluble in the acidic environment of the stomach and soluble primarily in intestinal fluid at a specific pH. The small intestine is the portion of the gastrointestinal tract (intestine) located between the stomach and the large intestine, comprising the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the jejunum approximately 6.5, and the terminal ileum approximately 7.5. Therefore, enteric-coated materials are insoluble at pH values ​​below, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyethylene glycol acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate and methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez Es series), ethyl methacrylate-methyl methacrylate-trimethylchloroethyl acrylate ammonium copolymers, natural resins (such as corn gluten, shellac, and copal collophorium), and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit). (FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl30D, Coateric, and Aquateric, etc.). The solubility of each of the above materials is known or can be readily determined in vitro. The above is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not a comprehensive list, and that other enteric-coated materials would be suitable for the purposes of this disclosure.

[0160] Advantageously, this disclosure also provides kits for use by consumers, for example, who require treatment for HBV infection. Such kits include suitable dosage forms, such as those described above, and instructions for use describing methods of using such dosage forms to mediate, reduce, or prevent HBV infection. The instructions for use will guide consumers or healthcare professionals to administer the dosage form according to administration methods known to those skilled in the art. Advantageously, such kits can be packaged and sold as single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid sheet of material covered with a foil of a preferably transparent plastic material. During the packaging process, a recess is formed in the plastic foil. This recess has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the recess, and the relatively rigid sheet of material is sealed to the plastic foil on the foil side opposite to the direction in which the recess is formed. Thus, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the sheet is strong enough that an opening can be formed at the recess in the sheet by manually applying pressure to it, allowing the tablet or capsule to be removed from the blister pack. The tablet or capsule can then be removed through the opening.

[0161] Ideally, memory aids might be provided on the kit itself, for example, as numbers next to the tablets or capsules, so that the number corresponds to the number of days of the regimen in which the specified tablets or capsules should be taken. Another example of such a memory aid is a schedule printed on a card, for example, as shown below, “Week 1, Monday, Tuesday…etc…Week 2, Monday, Tuesday…etc.” Other variations of the memory aid would be readily apparent. A “daily dose” could be a single tablet or capsule taken on a given day, or several tablets or capsules. Furthermore, a daily dose of the first compound could consist of one tablet or capsule, while a daily dose of the second compound could consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0162] IV. Methods

[0163] In another aspect, a method for treating hepatitis B infection in a patient in need 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 additional, different disclosed compounds. In yet another embodiment, a method for treating hepatitis B infection in a patient in need 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.

[0164] For this intended use, the appropriate dosage is expected to vary, for example, depending on the specific compound used, 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 authority of the treating physician. Generally, the indicated dosage can range from about 0.1 μg / kg body weight to about 1000 μg / kg body weight. In some cases, the dosage of the compound may be less than 400 μg / kg body weight. In other cases, the dosage may be less than 200 μg / kg body weight. In still other cases, the dosage can range from about 0.1 μg / kg body weight to about 100 μg / kg body weight. The dosage can be conveniently administered once daily, or in split doses up to, for example, four times daily, or in a sustained-release form.

[0165] The compounds disclosed herein can be administered via any convenient route, particularly: for example, in tablet or capsule form, via suppository for intravenous, topical, oral, or intranasal administration, or for example, in the form of injectable solutions or suspensions for intravenous, intramuscular, subcutaneous, or intraperitoneal injection for parenteral administration. Suitable formulations and pharmaceutical compositions will include those formulations and pharmaceutical compositions conventionally formulated using one or more physiologically acceptable carriers or excipients, as well as those known and commercially available formulations and pharmaceutical compositions currently used in the clinical setting. Thus, the compounds can be formulated for oral, oral, topical, parenteral, rectal, or transdermal administration, or in forms suitable for administration by inhalation or blowing (oral or nasal).

[0166] For oral administration, pharmaceutical compositions may be formulated in tablet or capsule form using conventional methods with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn 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 carboxyacetate starch); or humectants (e.g., sodium lauryl sulfate). Tablets may be coated using methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups, or suspensions, or they may be presented as dry products prepared prior to use with water or other suitable solvents. Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous solvents (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g., methylparaben or propylparaben, or sorbic acid). Depending on the requirements, the preparation may also suitably contain buffer salts, flavorings, colorings, and sweeteners.

[0167] Preparations for oral administration can also be suitably formulated to deliver a controlled or sustained release of the active compound over an extended period of time. For oral administration, the composition can be in the form of tablets or lozenges formulated using conventional methods known to those skilled in the art.

[0168] The disclosed compounds can also be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Formulations for injection can be presented as unit dosage forms with added preservatives, such as in ampoules or multi-dose containers. The compositions can be in the form of suspensions, solutions, or emulsions, such as in oily or aqueous solvents, and may contain additives such as suspending agents, stabilizers, and / or dispersants. Alternatively, the compounds can be in powder form for preparation with a suitable solvent such as sterile, pyrogen-free water prior to use. The compounds can also be formulated as suppositories or retention enemas for rectal administration, which may contain, for example, conventional suppository bases such as cocoa butter or other glycerides.

[0169] This document also envisions methods and compositions that include a second active agent or the administration of a second active agent. For example, in addition to HBV infection, a subject or patient may further suffer from HBV infection-related comorbidities, namely illnesses and other adverse health conditions associated with, exacerbated by, or induced by HBV infection. This document envisions disclosed compounds in combination with at least one other pharmaceutical agent previously shown to be used to treat these HBV infection-related conditions.

[0170] In some cases, the disclosed compound may be administered as part of a combination therapy in conjunction with one or more antiviral agents. Example antiviral agents include nucleoside analogs, interferon-alpha, and other assembly effectors, such as heteroaryl dihydropyrimidines (HAPs), such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). For example, this document provides a method of treating a patient with hepatitis B infection, comprising administering to the patient a first amount of the disclosed compound and a second amount of an antiviral or other anti-HBV agent, such as a second amount of a second compound selected from the group consisting of HBV capsid assembly promoters (e.g., GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as described below)).

[0171]

[0172] NVR 3-778, NVR1221 (by code); and N890 (as described below):

[0173]

[0174] Other capsid inhibitors, such as those disclosed in the following patent applications incorporated herein by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014 033167 and WO2014033170; nucleoside (acid) analogs that interfere with viral polymerases, such as entecavir (Baraclude), lamivudine, (Epivir-HBV), telbivudine (Tyzeka, Sebivo), adefovir dipivoxil (Hepsera), tenofovir (Viread), tenofovir alafenamide fumarate (TAF), tenofovir prodrugs (e.g., AGX-1009), L-FMAU (clavudine), LB80380 (besififovir), and:

[0175]

[0176] Viral entry inhibitors, such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors, such as REP 9AC' and related nucleic acid-based amphiphilic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15, as described below:

[0177]

[0178] And as depicted below: BM601

[0179]

[0180] Nucleocapsid formation or integrity disruption agents, such as NZ-4 / W28F:

[0181]

[0182] cccDNA formation inhibitors, such as BSBI-25, CCC-0346, and CCC-0975 (as described below):

[0183]

[0184] Hbc-targeted transbodies, such as those described by Wang Y et al. at / / dx.doi.org / 10.1016 / j.intimp.2015.01.028, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro.Those described in Immunopharmacol [International Journal of Immunopharmacol] (2014); antiviral core protein mutants (such as Cp183-V124W and related mutations, as described in WO / 2013 / 010069 and WO2014 / 074906, which are incorporated herein by reference); HBx-interaction inhibitors, such as RNAi, antisenses, and nucleic acid-based polymers targeting HBV RNA; for example, RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisenses (ISIS-HBV), or nucleic acid-based polymers (REP 2139-Ca); immunostimulants, such as interferon α2a (Lordisin), Intron A (interferon α2b), Pegasys (pegylated interferon α2a), PEG IFN 2b, IFNλ1a, and PEG. IFNλ1a, Wellferon, interferon, cyclophosphamide, lymphotoxin β-receptor agonists such as CBE11 and BS1, etc.; non-interferon immunostimulants such as thymosin α-1 (Zadaxin) and interleukin-7 (CYT107); TLR-7 / 9 agonists such as GS-9620, CYT003, Resiquimod, etc.; cyclophilin inhibitors such as NVP018, etc.; OCB-030; SCY-635; arapovir; NIM811 and related cyclosporine analogues; vaccines Vaccines, such as GS-4774, TG1050, and core antigen vaccines; SMAC mimics, 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, and JMJD. HDM inhibitors and brominated domain antagonists; kinase inhibitors, such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING agonists; ribavirin; N-acetylcysteine; NOV-205 (BAM205); nitrozonide (Alinia), tezolinide; SB 9200 small molecule nucleic acid hybrid (SMNH); DV-601; arbidol; FXR agonists (such as GW4064 and Fexaramin); antibodies, therapeutic proteins, gene therapies, and biologics targeting viral components or interacting with host proteins.

[0185] In some embodiments, this disclosure provides a method of treating hepatitis B infection in patients in need, comprising administering a first compound selected from any of the disclosed compounds and one or more other HBV agents, each of which is selected from HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, nucleocapsid formation disruptors, cccDNA formation inhibitors, antiviral core protein mutants, HBc-directing transbodies, HBV RNA targeting RNAi, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimics, epigenetic regulators, kinase inhibitors, and STING agonists. In some embodiments, this disclosure provides a method of treating hepatitis B infection in patients in need, comprising administering an amount of the disclosed compound and administering another HBV capsid assembly promoter.

[0186] In some embodiments, the first and second amounts together constitute a pharmaceutically effective amount. The first amount, the second amount, or both may be equal to, higher than, or lower than the effective amount of each compound administered as a monotherapy. The therapeutically effective amounts of the disclosed compound and the antiviral drug may be administered to the subject together, i.e., simultaneously or separately, in a given order or via the same or different routes of administration. In some cases, it may be advantageous to begin administration of the disclosed compound first, for example, one or more days or one or more weeks before initiating administration of the antiviral drug. Moreover, additional drugs may be administered in combination with the above combination therapy.

[0187] In another embodiment, the disclosed compound may be conjugated to a detection moiety (e.g., a fluorophore moiety (such moiety may re-emit a certain light frequency after, for example, binding to a virus and / or after photon excitation) by direct covalent binding or binding via a molecular linker to the free carbon, nitrogen (e.g., amino group) or oxygen (e.g., active ester) of the disclosed compound). The envisioned fluorophore includes... 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, anthocyanins, indole-carbocyanins, anthraquinones, fluorescent proteins, aminocoumarins, methoxycoumarins, hydroxycoumarins, Cy2, Cy3, etc. Such disclosed compounds conjugated to the detection portion can be used, for example, in methods for detecting HBV or HBV infection pathways in vitro or in vivo; and / or in methods for evaluating the bioactivity of novel compounds.

[0188] V. Example

[0189] The compounds described herein can be prepared in many ways based on the teachings contained herein and synthetic steps known in the art. In the description of the synthetic methods described below, it should be understood that, unless otherwise stated, all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing steps, can be selected as standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods are therefore indicated. The starting materials used in the examples are either commercially available or readily prepared from known materials by standard methods.

[0190] At least some of the compounds identified as "intermediates" in this article are also conceived as compounds of this disclosure.

[0191] abbreviation:

[0192] AcOH (acetic acid)

[0193] ACN Acetonitrile

[0194] Boc2O ditert-butyl dicarbonate

[0195] nBuLi n-Butyllithium

[0196] DCM dichloromethane

[0197] DIAD (Diisopropyl Azodicarbonate)

[0198] DIEA (Diisopropylethylamine)

[0199] DMF N,N-dimethylformamide

[0200] DMSO (dimethyl sulfoxide)

[0201] DPPF 1,1'-bis(diphenylphosphine)ferrocene

[0202] EA, EtOAc (ethyl acetate)

[0203] Et3N Triethylamine

[0204] HATU (Azabenzotriazole Tetramethylurea Hexafluorophosphate)

[0205] h,hr hours

[0206] HPLC (High Performance Liquid Chromatography)

[0207] LCMS (Liquid Chromatography-Mass Spectrometry)

[0208] MeOH (methanol)

[0209] NMO N-methylmorpholine-N-oxide

[0210] NBS N-bromosuccinimide

[0211] PE petroleum ether

[0212] iPrOH isopropanol

[0213] rt,rt room temperature

[0214] SFC Supercritical Fluid Chromatography

[0215] TEA Triethylamine

[0216] TFA (trifluoroacetic acid)

[0217] THF Tetrahydrofuran

[0218] TLC (Thin Layer Chromatography)

[0219] XPhos 2-Dicyclohexylphosphine-2',4',6'-Triisopropylbiphenyl

[0220] Option I

[0221]

[0222] Option II

[0223]

[0224] Option III

[0225]

[0226] Option IV

[0227]

[0228] Option V

[0229]

[0230] Solution VI

[0231]

[0232] Option VII

[0233]

[0234] The final compound was analyzed using LCMS:

[0235] Method A: X-Bridge BEH C-18 (3x50mm x 2.5μm); Mobile phase: A; 0.025% formic acid / H2O; B: CH3CN; Injection volume: 2μL; Flow rate: 1.2mL / min; Column temperature: 50℃; Gradient program: 2% B to 98% B in 2.2 min, hold for 3 min, B concentration of 2% in 3.2 min, until reaching 4 min.

[0236] Method B: X-select CSH 18 (3x50mm x 2.5μm); Mobile phase: A: 0.025% formic acid / H2O; B: CH3CN; Injection volume: 2μL; Flow rate: 1.2mL / min; Column temperature: 50℃; Gradient program: 0% B to 98% B in 2 minutes, hold for 3 minutes, B concentration is 0% at 3.2 minutes, until 4 minutes are reached.

[0237] Method C: X-select CSH 18 (3x50mm x 2.5μm); Mobile phase: A: 0.05% formic acid / H2O:CH3CN (95:5); B: 0.05% formic acid / CH3CN; Injection volume: 2μL; Flow rate: 1.2mL / min; Column temperature: 50℃; Gradient program: 0% B to 98% B in 2 minutes, hold for 3 minutes, B concentration is 0% at 3.2 minutes, until 4 minutes are reached.

[0238] Method D: X-select CSH C18 (3x50mm x 2.5μm); Mobile phase: A: 2mM in ammonium bicarbonate; B: CH3CN; Injection volume: 2μL; Flow rate: 1.2mL / min; Column temperature: 50℃; Gradient program: 0% B to 98% B in 2 minutes, hold for 3 minutes, B concentration to 0% at 3.2 minutes, until reaching 4 minutes.

[0239] Method E: X-select CSH 18 (3x50mm x 2.5μm); Mobile phase: A: 0.05% formic acid / H2O; B: CH3CN; Injection volume: 2μL; Flow rate: 1.5mL / min; Column temperature: 50℃; Gradient program: 0% B to 100% B in 1.5 min, hold for 2.2 min, B concentration is 0% at 2.6 min, until 3 min.

[0240] General procedure for amidation:

[0241] Method A (Amide Coupling Using EDC·HCl): EDC·HCl (1.1 equivalents), HOBt (1.1 equivalents), and the corresponding amine (1 equivalent) were added to a stirred solution of carboxylic acid (1 equivalent) in 1,4-dioxane (5.84 mL / mmol) at 0 °C, and the mixture was stirred for 5 min. DIPEA (3 equivalents) was then added to the solution, and the resulting reaction mixture was stirred overnight at 90 °C. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and water, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude compound, which was purified by silica gel column chromatography / preparative HPLC to obtain the desired compound.

[0242] Method B (Amide Coupling with HATU): DIPEA (2-3 equivalents) and HATU (1.5-2.5 equivalents) were added to a stirred solution of the acid compound (1.1 to 1.2 equivalents) in DMF / DCM (1.01 mL / mmol) at 0 °C and stirred for 5 min. The corresponding amine (1 equivalent) was then added to the solution. The resulting reaction mixture was stirred at room temperature for 12-16 h. 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 sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was analyzed by preparative HPLC or... Column chromatography was used to purify the compound to obtain the desired compound.

[0243] Method C (AlMe3-mediated amidation): AlMe3 (2M in toluene, 2.5 equivalents) was added to a stirred solution of the corresponding aniline (1.1 equivalents) in DCM / toluene (3 mL / mmol) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 10 min and then continued to be stirred at room temperature for 1 h. The corresponding ester compound (1 equivalent) was added to this solution at 0 °C under an argon atmosphere, and the resulting reaction mixture was refluxed at 100 °C for 16 h. After completion, the reaction mixture was cooled to 0 °C; slowly quenched with 1N HCl aqueous solution; and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude compound was purified by washing with methanol to obtain the desired compound.

[0244] Method D (Amide Coupling Using Acyl Chloride / Derivative): TEA (1.5-3 equivalents) was added to a stirred solution of the amine compound (1 equivalent) in DCM (1.01 mL / mmol) at 0 °C and stirred for 5 min. The corresponding acyl chloride / carbamoyl chloride / chloroformate (1.1-1.5 equivalents) was slowly added to this solution at 0 °C, and the reaction mixture was stirred at room temperature until complete. 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 sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was analyzed by preparative HPLC or... Column chromatography was used to purify the compound to obtain the desired compound.

[0245] The general procedure for the Grignard reaction:

[0246] Method A (at lower temperatures): Under an inert atmosphere, Grignard reagent (10 equivalents) was slowly added via a glass syringe at -78°C to a stirred solution of the ketone compound (1 equivalent) in dry THF (0.2 mL / mmol). The reaction mixture was stirred at the same temperature for 4 hours, followed by stirring at room temperature for 2 hours. Afterward, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate; and concentrated on a rotary evaporator to give the crude compound. The crude compound was then... Purification by column chromatography or preparative HPLC is performed to obtain the desired compound.

[0247] General methods of Suzuki coupling:

[0248] Method A: Na₂CO₃ (2-3 equivalents) was added to a mixture of the halogenated compound (1 equivalent) and the corresponding boric acid / boronic ester (1.2-1.5 equivalents) in 1,4-dioxane:water (4:1) (2.17 mL / mmol), and the mixture was purified with argon for 15 min. PdCl₂ (dppf) (0.1 equivalent) was added to the solution, and purification with argon was continued for another 10 min. The resulting reaction mixture was stirred at 100 °C for 12-16 h. After the reaction was complete, the reaction mixture was subjected to… Filter at 545°C and evaporate to dryness. Place the residue in ethyl acetate, wash with water, then with brine, dry over anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is then... Purification by column chromatography or preparative HPLC is performed to obtain the desired compound.

[0249] The general procedure for hydrogenation:

[0250] Method A: 20% Pd / C (20 wt% olefin compound) was added to a stirred solution of an olefin compound (1 equivalent) in EtOAc (2.67 mL / mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 40-50 °C for 4-7 hours under a hydrogen atmosphere (100 psi). After completion, the reaction mixture was... The solution was filtered through a 545 filter and washed with EtOAc / methanol. The filtrate was concentrated under reduced pressure to obtain the compound, which was then purified by silica gel column chromatography or preparative HPLC to yield the desired compound.

[0251] The general procedure for ketone reduction:

[0252] Method A: NaBH4 (1-2 equivalents) was added to a stirred solution of the ketone compound (1 equivalent) in EtOH / MeOH (5 volumes) (4.7 mL / mmol) at 0 °C under an argon atmosphere, and the mixture was stirred at room temperature for 2-6 hours. After completion, the reaction mixture was concentrated under vacuum, and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography / preparative HPLC to obtain the desired compound. Note: THF (1 volume) was also added as a co-solvent for the substrate, which has poor solubility in alcohol solvents.

[0253] Intermediate 1

[0254]

[0255] 5-O-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yltrifluoromethanesulfonate. Tf₂O (89.8 g, 318.5 mmol) was added dropwise to a solution of 1,3,3a,4,6,6a-hexahydrocyclopentadien-2,5-dione (40.0 g, 289.5 mmol) and pyridine (24.0 g, 304.0 mmol) in DCM (600 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. Brine (300 mL) was added, and the aqueous layer was extracted with DCM (200 mL x 3). The organic layer was separated, dried over Na2SO4 and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using 8:1 (v / v) petroleum ether / ethyl acetate to obtain 5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yltrifluoromethanesulfonate, which is a yellow oil. 1H NMR (400MHz, CDCl3): δ5.63 (q, J = 1.92Hz, 1H), 3.57-3.50 (m, 1H), 3.14-3.00 (m, 2H), 2.67-2 .58(m,1H),2.56-2.40(m,2H),2.34-2.26(m,1H),2.17(ddd,J=19.14,7.34,1.63Hz,1H)ppm.

[0256] Intermediate 2

[0257]

[0258] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one. A mixture of 5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl trifluoromethanesulfonate (110.0 g, 407.0 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (108.5 g, 427.4 mmol), Pd(dppf)Cl2 (8.9 g, 12.2 mmol), and potassium acetate (119.7 g, 1221.0 mmol) in dioxane (1000 ml) was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was then... The mixture was filtered through a filter pad, and the filter cake was washed with EtOAc (250 mL x 3). The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography using 8:1 petroleum ether / ethyl acetate to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one, which was a yellow oil. 1 H NMR (400MHz, CDCl3): δ6.37(q,J=2.08Hz,1H),3.54-3.41(m,1H),3.05-2.93(m,1H),2.79(dd t,J=16.48,7.58,2.64,2.64Hz,1H),2.55-2.24(m,4H),2.07-1.95(m,1H),1.28(s,13H)ppm.

[0259] Intermediate 3

[0260]

[0261] Methyl 2,4-dibromo-1-methyl-1H-imidazolium-5-carboxylate. NBS (78.3 g, 414.8 mmol) and AIBN (1.95 g, 11.9 mmol) were added to a solution of methyl 1-methyl-1H-imidazolium-5-carboxylate (16.6 g, 118.5 mmol) in CHCl3 (200 mL). The reaction mixture was stirred at 60 °C for 24 hours. The mixture was concentrated and analyzed by column chromatography (R... f =0.4, PE:EA=5:1) purified to give methyl 2,4-dibromo-1-methyl-1H-imidazol-5-carboxylate (22.2 g, 63% yield), which is a yellow solid.

[0262] Intermediate 4

[0263]

[0264] N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide. HATU (63 g, 160 mmol) was added to a solution of 1-methyl-1H-imidazolium-5-carboxylic acid (10 g, 83 mmol), 3-chloro-4-fluoroaniline (18 g, 124 mmol), and Et3N (16 g, 160 mmol) in DMF (100 mL) at room temperature. The reaction mixture was stirred overnight at 25 °C and then poured into water (200 mL). A yellow solid formed from the solution, which was filtered and dried to provide N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide, a pale white solid. TLC; (50% ethyl acetate / petroleum ether) (Rf: 0.3). MS calculations: C 11 H9ClFN3O: 253.0; Measured: 254.1 [M+1] + .

[0265] Intermediate 5

[0266]

[0267] 2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. NBS (10 g, 60 mmol) and AIBN (0.25 g, 1.5 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (4 g, 15 mmol) in CHCl3 (100 mL) at room temperature. The reaction mixture was stirred at 50 °C for 18 hours. The mixture was evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography to give 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide, a yellow solid. TLC; 40% ethyl acetate / petroleum ether (R fMS is calculated as: C :0.3). 11 H7Br2ClFN3O: 408.9; Measured: 411.2 [M+2] + .

[0268] Alternative Synthesis of 2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. HATU (13.3 g, 35.0 mmol) and DIPEA (9.69 g, 175 mmol) were added to a solution of 2,4-dibromo-1-methyl-1H-imidazol-5-carboxylic acid (9.94 g, 35.0 mmol) in DMF (50 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. Subsequently, 3-chloro-4-fluoroaniline (6.1 g, 42.0 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was added dropwise to water (600 mL), and the resulting precipitate was filtered to provide 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (12.5 g, 87% yield), which was a yellow solid.

[0269] Intermediate 6

[0270]

[0271] 4-Bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. CH3MgI (2 mL, 4.0 mmol) was slowly added to a solution of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (1.1 g, 2.0 mmol) in THF (50 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours, then decanted 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 column chromatography to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide as a yellow solid. TLC; 50% ethyl acetate / petroleum ether (Rf: 0.3). MS calculations: C 11 H8BrClFN3O: 331.0; Actual measurement: 332.1 [M+1] + .

[0272] An alternative procedure for the synthesis of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized following the general amidation procedure (method C) described above to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide, a brown solid. TLC; 30% EtOAc / hexane (R f :0.45); 1¹H NMR (DMSO-d⁶, 400MHz): δ 10.41 (s, 1H), 7.96 (dd, J = 6.8, 2.4Hz, 1H), 7.85 (s, 1H), 7.63–7.60 (m, 1H), 7.43 (t, J = 9.6Hz, 1H), 3.75 (s, 3H); LCMS calculation: C 11 H8BrClFN3O: 331.0; Actual measurement: 332.1 [M+1] + .

[0273] Intermediate 7

[0274]

[0275] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. 4-Bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (600 mg, 1.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (448 mg, 1.8 mmol), Pd(dppf)Cl2 (62 mg, 0.077 mmol) and K3PO4 (814 mg, 3.6 mmol) were stirred at 100 °C for 4 hours under N2 in a mixture of dioxane (20 mL) and water (4 mL). EtOAc (20 mL) was then added to the mixture. The mixture was filtered, and the filtrate was washed with H2O (35 mL x 3). The organic layer was separated, dried over Na2SO4, and evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography using 20–50% petroleum ether / ethyl acetate to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, which was a brown solid. TLC; 5% MeOH / DCM (R f MS is calculated as: C :0.2). 19 H 17 ClFN3O2: 373.13. Actual measurement: 374.1 [M+1] + .

[0276] Alternative synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. To a solution of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (13.3 g, 40.0 mmol) in 1,4-dioxane / H₂O (v / v = 7:1, 120 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (12.2 g, 48.0 mmol), Pd(dppf)Cl₂ (2.9 g, 4.0 mmol), and Na₂CO₃ (10.6 g, 100.0 mmol) were added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The solid was washed with EA, and the filtrate was concentrated to give a crude product. This crude product was purified by silica gel column chromatography using 5% methanol / DCM (120 g silica gel column, 60 mL / min) to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (12.8 g, 85.6%), a brown solid. TLC: 7% methanol / DCM (R f :0.5); MS is calculated as: C 19 H 17 ClFN3O2: 373.1; Measured value: 374.3 [M+1] + .

[0277] Example 1

[0278]

[0279] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. Pd / C (30 mg, 10% Pd) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (300 mg, 0.8 mmol) in THF (20 mL). The mixture was stirred at 30 °C for 5 hours under H2. The mixture was filtered, and the filtrate was evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a brown solid, as a single diastereomer. TLC; 50% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.3).19 H 19 ClFN3O2: 375.2; Measured: 376.2 [M+1] + .

[0280] Alternative Synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide

[0281] Pd / C (6.4 g, 10%) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (12.8 g, 34.2 mmol) in THF (200 mL) under H2 conditions, and the mixture was stirred at room temperature for 4 hours. The mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography with 5% methanol / DCM (80 g silica gel column, 50 mL / min) to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a gray solid, as a single diastereomer (12.0 g, 93.3%). TLC: 7% Methanol / DCM (R) f :0.5); MS is calculated as: C 19 H 19 ClFN3O2: 375.2; MS measured: 376.3 [M+1] + .

[0282] Example 2

[0283]

[0284] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. NaBH4 (36 mg, 0.95 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (20 mg, 0.053 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 8 hours. The mixture was then evaporated under vacuum to give a yellow residue. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid, as a single diastereomer. TLC; 50% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.3). 19 H 21ClFN3O2: 377.1. Actual measurement: 378.2 [M+1] + . 1 H NMR (DMSO-d6, 400MHz): δ10.22 (s, 1H), 7.96 (dd, J = 6.8, 2.4Hz, 1H), 7.64 (s, 1H),7.58-7.54(m,1H),7.40(t,J=8.8Hz,1H),4.50(d,J=4.4Hz,1H),4.03(d d,J=6.8,2.4Hz,1H),3.66(s,3H),3.26-3.20(m,1H),2.32-2.28(m,2H),2.1 1-2.05(m,2H),1.95-1.89(m,2H),1.70-1.62(m,2H),1.30-1.23(m,2H)ppm.

[0285] Example 3

[0286]

[0287] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. n-BuLi (0.2 mL, 0.5 mmol) was added to a solution of methanesulfonylmethane (24 mg, 0.26 mmol) in THF (5 mL) at -78 °C. The solution was stirred at -78 °C for 30 min. Then, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (50 mg, 0.13 mmol) was added, and the reaction was slowly heated to room temperature and stirred for 5 h. The reaction mixture was quenched with H₂O (20 mL) and extracted with ethyl acetate. The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid as a single diastereomer. TLC; 20% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.4). 21 H 25 ClFN3O4S: 469.1; Measured: 470.2 [M+1] + ; 1H NMR (DMSO-d6, 400MHz): δ10.22(s,1H),7.96(dd,J=6.8,2.4Hz,1H),7.64(s,1H),7.59-7.55(m,1H),7.41(t,J=9.2Hz,1H),4.94(s,1H), 3.66(s,3H),3.24-3.19(m,3H),2.97(s,3H),2.49-2.44(m,2H),2.08-2.01(m,4H),1.78-1.75(m,2H),1.61(dd,J=13.2,4.0Hz,2H)ppm.

[0288] Example 4

[0289]

[0290] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. A solution of i-PrMgCl in THF (2.0 M, 0.5 mL, 1.0 mmol) was added to a solution of 4-iodo-1-methyl-1H-imidazolium (208 mg, 1.0 mmol) in THF (5 mL). The mixture was stirred at room temperature for 2 hours. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (46 mg, 0.08 mmol) in THF (2.0 mL) was added to this solution. The final mixture was stirred at room temperature overnight. The reaction mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid, as a single diastereomer. MS calculations showed that: C 23 H 25 ClFN5O2: 457.2; Measured value: 458.3 [M+1] + . 1H NMR(DMSO-d6,400MHz):10.20(s,1H),7.95(dd,J=6.8,2.4Hz,1H),7.64(s,1H),7.54-7.58(m,1H),7.38-7.42(m,2H),6.87(s,1H),4.53(s,1H), 3.67(s,3H),3.57(s,3H),3.16-3.24(m,1H),2.40-2.49(m,2H),2.17-2 .22(m,2H),2.02-2.08(m,2H),1.85-1.93(m,2H),1.59-1.63(m,2H)ppm.

[0291] Example 5

[0292]

[0293] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. A solution of n-BuLi in hexane (2.5 M, 0.4 mL, 1.0 mmol) was added to a solution of 1-methyl-1H-imidazolium (82 mg, 1.0 mmol) in THF (2 mL). The mixture was stirred at room temperature for 2 hours. Subsequently, a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (46 mg, 0.08 mmol) in THF (2.0 mL) was added to the mixture. The final mixture was stirred at room temperature overnight. The reaction mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid, as a single diastereomer. MS calculations showed that: C 23 H 25 ClFN5O2: 457.2; Measured value: 458.3 [M+1] + ; 1H NMR(CD3OD,400MHz):7.87(dd,J=6.4,2.4Hz,1H),7.65(s,1H),7.52-7.48(m,1H),7.23(t,J=8.8Hz,1H),6.98(d,J=1.2Hz,1H), 6.76(d,J=1.2Hz,1H),3.83(s,3H),3.75(s,3H),3.30-3.35(m,1H),2.56-2.58(m,4H),2.22-2.25(m,2H),1.83-1.93(m,4H)ppm.

[0294] Synthesis of Examples 6 to 15. Examples 6 to 15 in Table 1 were synthesized using the corresponding starting materials according to the procedures provided above.

[0295] Table 1. Examples 6 to 15

[0296]

[0297]

[0298]

[0299]

[0300]

[0301] Intermediate 8

[0302]

[0303] Ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydrocyclopentadien-2(1H)-ylidene)ethyl acetate. NaH (48 mg, 2 mmol) was slowly added to a solution of ethyl 2-(diethoxyphosphono)ethyl acetate (448 mg, 2 mmol) in dry THF (25 mL), followed by stirring at 0 °C for 0.5 h. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (375 mg, 1 mmol) was added to THF (5 mL), and stirring continued at room temperature for 3 h. Water was added, and the pH was adjusted to 6-7 with NH4Cl. The mixture was extracted with AcOEt, the organic phase was dried, and concentrated under vacuum. The residue was purified by column chromatography using 25–60% ethyl acetate / petroleum ether to give ethyl acetate 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydrocyclopentadien-2(1H)-ylidene)ethyl acetate, a pale yellow solid. TLC; 60% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.2). 23 H 25 ClFN3O3: 445.2; Measured: 446.3 [M+1] + .

[0304] Example 16

[0305]

[0306] Ethyl 2-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)ethyl acetate. Pd / C (50 mg) was added to a solution of ethyl 2-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydrocyclopentadien-2(1H)-ylidene)ethyl acetate (223 mg, 0.5 mmol) in THF (15 mL). The flask was then emptied and backfilled with H2. The solution was stirred overnight at room temperature. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give ethyl 2-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)ethyl acetate, a white solid. TLC; 60% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.2). 23 H 27 ClFN3O3: 447.2. Actual measurement: 448.3 [M+1] + .

[0307] Intermediate 9

[0308]

[0309] 2-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid. LiOH (42 mg, 1 mmol) was added to a solution of 2-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid (45 mg, 0.1 mmol) in CH3OH / H2O (5 mL / 1 mL). The solution was stirred at room temperature for 4 hours. Water was added, and the reaction mixture was adjusted to pH 5-6 with HCl (2 M). The reaction was extracted with ethyl acetate (10 mL × 3), the organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to give crude 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid, which was a pale yellow solid. TLC; 100% ethyl acetate / petroleum ether (R f :0.1). MS calculates C 21 H 23 ClFN3O3: 419.1; Measured: 420.2 [M+1] + .

[0310] Example 17

[0311]

[0312] 4-(5-(2-amino-2-oxoethyl)octahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. NH4Cl (54 mg, 1 mmol), HATU (38 mg, 0.1 mmol), and Et3N (101 mg, 1 mmol) were added to a solution of 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid (43 mg, 0.1 mmol) in anhydrous DCM (10 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the crude product was purified by preparative HPLC to give 4-(5-(2-amino-2-oxoethyl)octahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide, a white solid. TLC: 80% ethyl acetate / petroleum ether (R...) f MS is calculated as: C :0.3). 21 H 24ClFN4O2: 418.2; Measured: 419.3 [M+1] + . 1 H NMR (DMSO-d6, 400MHz): δ10.21 (s, 1H), 7.95 (dd, J = 7.2, 2.4Hz, 1H), 7.65 ( s,1H),7.58-7.55(m,1H),7.40(t,J=9.2Hz,1H),7.19(s,1H),6.65(s,1H), 3.66(s,3H),3.34-3.32(m,1H),2.43-2.36(m,2H),2.21-2.18(m,1H),2.10 -2.06(m,4H),1.99-1.92(m,2H),1.50-1.47(m,2H),0.93-0.90(m,2H)ppm.

[0313] Example 18

[0314]

[0315] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazin-1-yl)octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (50 mg, 0.13 mmol) in THF (3 mL), 1-methylpiperazine (110 mg, 1.1 mmol) and NaBH3CN (40 mg, 0.65 mmol) were added. The mixture was stirred overnight at 55 °C. The solvent was removed under vacuum to give a yellow residue. It was purified by column chromatography and preparative HPLC to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazin-1-yl)octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, which was a white solid. TLC: 10% DCM / MeOH(R) f MS is calculated as: C :0.3). 24 H 31 ClFN5O: 459.2; Measured: 460.3 [M+1] + ; 1H NMR (DMSO-d6, 400MHz): δ10.23(s,1H),7.95(dd,J=6.8,2.4Hz,1H), δ7.66(s,1H),7.59-7.55(m,1H),7.41(t,J=9.2Hz,1H ),3.67(s,3H),3.25(s,1H),2.49(s,1H),3.36-3.30(m,9H),2.18-2.00(m,8H),1.58-1.50(m,2H),1.17-1.09(m,2H)ppm.

[0316] Intermediate 10

[0317]

[0318] N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1′H-spiro[ethylene oxide-2,2'-cyclopentadienyl]-5′-yl)-1-methyl-1H-imidazol-5-carboxamide. Trimethylsulfonium iodide (1.47 g, 6.7 mmol) was added to a solution of t-BuOK (0.75 g, 6.7 mmol) in THF (20 mL). The mixture was stirred at room temperature for 1 hour. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadienyl-2-yl)-1H-imidazol-5-carboxamide (0.5 g, 1.3 mmol) was added, and the mixture was heated to 60 °C and maintained for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (2:1) to give N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1′H-spiro[ethylene oxide-2,2'-cyclopentadiene]-5′-yl)-1-methyl-1H-imidazolium-5-carboxamide, a white solid. TLC; 50% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.2). 20 H 21 ClFN3O2: 389.1; Measured: 390.2 [M+1] + .

[0319] Example 19

[0320]

[0321] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-cocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide isomer I. H2SO4 was added to a solution of N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1′H-spiro[ethylene oxide-2,2'-cocyclopentadien]-5'-yl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.26 mmol) in THF / H2O (6:1, 5 mL). 4( 0.1 mL), the mixture was stirred overnight at room temperature. The reaction was carried out via NaHCO3. 3( The solution was alkalized (in aqueous solution) and then extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-cyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide isomer I, a white solid. TLC; 5% MeOH / DCM (R f MS is calculated as: C :0.4). 20 H 23 ClFN3O3: 407.1; Measured: 408.2 [M+1] + ; 1 H NMR (DMSO-d6, 400MHz): δ10.21(s,1H),7.96(dd,J=7.2,2.8Hz,1H),7.65(s,1H),7.59-7.55(m,1H),7.41(t,J=8.8Hz,1H),4.54(t,J=5.6Hz,1H ),4.02(s,1H),3.67(s,3H),3.30(s,1H),3.25(d,J=5.6Hz,2H),2.65-2 .58(m,2H),2.10-2.03(m,2H),1.65-1.60(m,2H),1.52-1.42(m,4H)ppm.

[0322] Example 20

[0323]

[0324] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro- and cyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide isomer II. NaOH (80 mg, 2.0 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1H-spiro[ethylene oxide-2,2'- and cyclopentadien]-5′-yl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.26 mmol) in dioxane (2 mL) and water (0.5 mL). The mixture was stirred at 100 °C for 24 hours. After cooling, the pH was adjusted to 8 with 1 N HCl, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-naphthyl-2-yl)-1-methyl-1H-imidazolium-5-carboxamide isomer II, which was a pale yellow solid. TLC; 5% MeOH / DCM (R f MS is calculated as: C :0.4). 20 H 23 ClFN3O3: 407.1; Measured: 408.2 [M+1] + ; 1 H NMR (DMSO-d6, 400MHz): δ10.21 (s, 1H), 7.96 (dd, J = 7.2, 2.8Hz, 1H), 7.64 (s ,1H),7.58-7.55(m,1H),7.41(t,J=8.8Hz,1H),4.45(t,J=5.6Hz,1H),4.14 (s,1H),3.67(s,3H),3.23-3.19(m,3H),2.36-2.33(m,2H),2.07-2.04(m,2 H),1.89-1.84(m,2H),1.81-1.74(m,2H),1.33(dd,J=13.2,4.4Hz,2H)ppm.

[0325] Example 21

[0326]

[0327] 2-Chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. NCS (700 mg, 5.3 mmol) and AIBN (0.25 g, 1.5 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (200 mg, 0.53 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred overnight at 35 °C. The mixture was evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography to give 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a yellow solid. TLC: 40% ethyl acetate / petroleum ether (R) f MS is calculated as: C :0.3). 19 H 18 Cl2FN3O2: 409.1, Measured: 410.2 [M+1] + .

[0328] Example 22

[0329]

[0330] 2-Chloro-N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. NaBH4 (36 mg, 0.95 mmol) was added to a solution of 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (20 mg, 0.05 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 8 hours. The solvent was evaporated under vacuum to give a yellow residue. The residue was purified by preparative HPLC to give 2-chloro-N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid. TLC; 50% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.3). 19 H 20 Cl2FN3O2: 411.1; Actual measurement: 412.2 [M+1] + ; 1H NMR (DMSO-d6, 400MHz): δ10.39(s,1H),7.95(dd,J=6.8,4.8Hz,1H),7.57-7.54(m,1H),7.42(t,J=9.2Hz,1H),4.51(d,J=4.0Hz,1H),4.05(dd,J=11 .2,6.8Hz,1H),3.61(s,3H),3.22-3.16(m,1H),2.36-2.20(m,2H),2.10- 2.04(m,2H),1.93-1.86(m,2H),1.69-1.61(m,2H),1.33-1.26(m,2H)ppm.

[0331] Intermediate 11

[0332]

[0333] 2-Methyl-1H-imidazolium-4,5-dicarboxynitrile. A solution of 2,3-diaminocis-butenonitrile (54 g, 0.5 mol) and CH3C(OEt)3 (9.6 g, 0.8 mmol) in xylene (200 mL) was stirred at 130 °C for 6 hours. After cooling to room temperature, it was filtered to give 2-methyl-1H-imidazolium-4,5-dicarboxynitrile as a brown solid. TLC; 30% ethyl acetate / petroleum ether (R f MS calculation: C6H4N4: 132.0. Actual measurement: 133.0 [M+1] + .

[0334] Intermediate 12

[0335]

[0336] 1,2-Dimethyl-1H-imidazolium-4,5-dicarboxynitrile. Dimethyl sulfate (62 g, 0.49 mol) was added dropwise to a suspension of 1,2-dimethyl-1H-imidazolium-4,5-dicarboxynitrile (50 g, 0.38 mol) and NaHCO3 (160 g, 1.51 mol) in H2O (300 mL) at 55 °C, and the reaction was stirred at the same temperature for 6 hours. Ice water was added and the mixture was extracted with ethyl acetate (300 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 1,2-dimethyl-1H-imidazolium-4,5-dicarboxynitrile, which could be used for the next step without further purification. TLC; 30% ethyl acetate / petroleum ether (R f MS calculation: C7H7N4: 146.0; Actual measurement: 147.0 [M+1] + .

[0337] Intermediate 13

[0338]

[0339] 1,2-Dimethyl-1H-imidazolium-4,5-dicarboxylic acid. A solution of 1,2-dimethyl-1H-imidazolium-4,5-dicarboxynitrile (41 g, 0.28 mol) in 2M NaOH aqueous solution (45 g, 1.12 mol, 560 mL) was stirred at 100 °C for 6 hours. After cooling to room temperature, the solution was acidified with 6N HCl aqueous solution (pH = 1). After filtration, the solid was dried in an oven at 100 °C for 16 hours to obtain 1,2-dimethyl-1H-imidazolium-4,5-dicarboxylic acid, which was a white solid. MS calculation: C7H8N2O4: 184.0. Actual measurement: 185.1 [M+1] + .

[0340] Intermediate 14

[0341]

[0342] 1,2-Dimethyl-1H-imidazol-5-carboxylic acid. A suspension of 1,2-dimethyl-1H-imidazol-4,5-dicarboxylic acid (5 g, 27 mmol) in Ac₂O (150 mL) was stirred at 100 °C for 16 h. The reaction was concentrated to give a crude product, which was crystallized from acetone (100 mL) to give 1,2-dimethyl-1H-imidazol-5-carboxylic acid as a brown solid. MS calculation: C₆H₈N₂O₂: 140.1; Actual: 141.1 [M+1] + .

[0343] Intermediate 15

[0344]

[0345] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide. HATU (2.28 g, 6 mmol) was added to a solution of 2-dimethyl-1H-imidazol-5-carboxylic acid (560 mg, 4 mmol), 3-chloro-4-fluoroaniline (870 mg, 6 mmol), and DIEA (1.03 g, 8 mmol) in THF / DMF (15 mL / 3 mL), and the reaction was stirred at room temperature for 16 hours. Ice water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated to give a crude product, which was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / MeOH (R fMS calculation: C12H11ClFN3O: 267.1; Actual measurement: 268.1 [M+1] + .

[0346] Intermediate 16

[0347]

[0348] 4-Bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide. Br2 (1.5 g, 9.6 mmol) was added dropwise to a suspension of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide (510 mg, 1.91 mmol) and NaOAc (1.57 g, 19.1 mmol) in EtOH (40 mL) at 15 °C. The reaction mixture was then stirred at room temperature for 11 hours. The reaction was quenched with 0.5% NaHSO3 (aqueous solution) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to obtain a residue. This residue was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / MeOH (R f MS is calculated as: C :0.6). 12 H 10 BrClFN3O: 345.0; Measured: 346.2 [M+1] + .

[0349] Intermediate 17

[0350]

[0351] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. Pd(dppf)Cl2 (50 mg) was added to a solution of 4-bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazolium-5-carboxamide (400 mg, 1.16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (431 mg, 1.74 mmol) and Na2CO3 (246 mg, 2.32 mmol) in a mixture of dioxane (20 mL) and H2O (5 mL) under a nitrogen atmosphere. The reaction was stirred at 80 °C for 6 hours. After cooling to room temperature, the mixture was subjected to... Filter with a pad. Dilute the filtrate with water and extract with ethyl acetate (40 mL x 2). The combined organic layers were concentrated to give the residue, which was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / MeOH (R f MS is calculated as: C :0.3). 20 H 19 ClFN3O2: 387.1. Actual measurement: 388.2 [M+1] + .

[0352] Example 23

[0353]

[0354] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. A mixture of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (300 mg, 0.77 mmol) and Pd / C (300 mg) was stirred in ethyl acetate (300 ml) at 30 °C for 6 hours under H2. The reaction mixture was cooled to room temperature and passed through... Filtered through a 545 filter pad, washed with ethyl acetate and concentrated to give a crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / CH3OH (R f MS is calculated as: C :0.5). 20 H 21 ClFN3O2: 589.2; Measured value: 390.2 [M+1] + .

[0355] Example 24

[0356]

[0357] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazol-5-carboxamide. NaBH4 (11 mg, 0.27 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (35 mg, 0.09 mmol) in MeOH (2 mL) cooled to 0 °C. The reaction was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was concentrated to give a crude compound, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / CH3OH(R) f MS is calculated as: C :0.4). 20 H 23 ClFN3O2: 391.1; Measured: 392.1 [M+1] + ; 1 H NMR (CD3OD, 400MHz): δ7.86 (dd, J=2.4Hz, 6.4Hz, 1H), 7.52-7.46 (m, 1H), 7.23 (t, J=8.8Hz, 1H), 4.17-4.10 (m, 1H) ,3.63(s,3H),3.32-3.20(m,1H),2.40-2.38(m,5H),2.24-2.01(m,4H),1.75-1.62(m,2H),1.41-1.37(m,2H)ppm.

[0358] Synthesis of Examples 25 and 26. Examples 25 and 26 in Table 2 were synthesized using the corresponding starting materials according to the procedures provided above.

[0359] Table 2. Examples 25 to 26

[0360]

[0361] Example 27

[0362]

[0363] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazol-5-carboxamide. n-BuLi (2.5 M, 0.5 mL, 1.25 mmol) in hexane was added to a solution of 1-methyl-1H-imidazolium (101 mg, 1.23 mmol) in THF (2 mL) at -78 °C. The reaction was stirred at -78 °C for 1 hour. N,N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (60 mg, 0.154 mmol) was added to this solution in a single addition. The reaction was stirred at -78 °C for 1 hour, then allowed to warm to room temperature overnight. The mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazol-5-carboxamide, a white solid, as a single diastereomer. MS calculations showed that: C 24 H 27 ClFN5O2: 471.1; Actual measurement: 472.3 [M+1] + ; 1 H NMR (DMSO-d6, 400MHz): δ10.10(s,1H),7.95(dd,J=6.8,2.8Hz,1H),7.57-7.53(m,1H),7.39(t,J=9.2Hz,1H),7.00(s,1H),6.65(s,1H ),5.23(s,1H),3.73(s,3H),3.55(s,3H),3.21-3.18(m,1H),2.43-2.41(m,4H),2.31(s,1H),2.06-2.03(m,2H),1.82-1.77(m,4H)ppm.

[0364] Synthesis of Examples 28 to 30. Examples 28 to 30 in Table 3 were synthesized using the corresponding starting materials according to the procedures provided above.

[0365] Table 3. Examples 28 to 30

[0366]

[0367]

[0368] Intermediate 18

[0369]

[0370] 2-Bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide. A solution of 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxylic acid (500 mg, 2.2 mmol) in SOCl2 (6 mL) was stirred at 80 °C for 4 hours. The reaction was concentrated to remove volatiles. The residue was dissolved in anhydrous DCM (5 mL). 3-Chloro-4-fluoroaniline (473 mg, 3.3 mmol) and Et3N (440 mg, 4.4 mmol) were added to the solution. The reaction was stirred at room temperature for 1 hour, followed by concentration to remove the solvent. The residue was diluted with ethyl acetate and washed with brine. The ethyl acetate solution was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (40 g silica gel column, eluted with petroleum ether / ethyl acetate) to give 2-bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a brown solid. TLC; 50%, ethyl acetate / petroleum ether (R f MS is calculated as: C :0.3). 13 H 10 BrClFN3O: 357.0; Actual measurement: 357.9 [M+1] + .

[0371] Intermediate 19

[0372]

[0373] N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide. To 2-bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (660 mg, 1.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (4.0 g 15% purity, 2.4 mmol) and K3PO4. 4(Pd(dppf)Cl2 (95 mg, 0.13 mmol) was added to a solution of dioxane (15 mL) and H2O (3 mL), and the reaction was stirred overnight at 80 °C under a nitrogen atmosphere. Volatile substances were removed under vacuum, and the residue was purified by silica gel column chromatography (40 g silica gel column, eluted with petroleum ether / ethyl acetate) to give N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid. TLC: 70% ethyl acetate / petroleum ether (R f MS is calculated as: C :0.2). 21 H 19 ClFN3O2: 399.1; Actual measurement: 400.3 [M+1] + .

[0374] Example 31

[0375]

[0376] N-(3-chloro-4-fluorophenyl)-2-(5-oxo-octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide. Pd / C (100 mg, 100% w / w) was added to a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (100 mg, 0.3 mmol) in ethyl acetate (25 mL), and the reaction solution was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was then filtered, and the filtrate was concentrated to give a crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid. TLC: 10% MeOH / DCM (Rf: 0.6). MS calculations: C 21 H 21 ClFN3O2: 401.1; Actual measurement: 402.2 [M+1] + . 1H NMR (CD3OD, 400MHz): δ7.83(dd,J=6.8,2.8Hz,1H),7.51-7.47(m,1H),7.23(t,J=9.2Hz,1H),4.16(t,J=7.2Hz,2H),3.64-3.55 (m,1H),2.88-2.78(m,3H),2.66-2.58(m,2H),2.56-2.49(m,2H),2.39-2.32(m,2H),2.25-2.19(m,2H),1.75-1.67(m,4H)ppm.

[0377] Example 32

[0378]

[0379] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomers I and II. NaBH4 (11 mg, 0.3 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (60 mg, 0.2 mmol) in MeOH (5 mL), and the solution was stirred at room temperature for 3 hours. After the starting material was exhausted, the volatiles were removed under vacuum, and the residue was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomers I and II.

[0380] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomer I. MS calculation: C 21 H 23 ClFN3O2: 403.1; Actual measurement: 404.2 [M+1] + ; 1H NMR (CD3OD, 400MHz): δ7.82(dd,J=6.8,2.8Hz,1H),7.49-7.45(m,1H),7.22(t,J=9.2Hz,1H),4.45-4.42(m,1H),4.15(t,J=7.2 Hz,2H),3.38-3.31(m,1H),2.87-2.84(m,2H),2.66-2.58(m,4H),2.23-2.16(m,2H),1.71-1.68(m,4H),1.56-1.48(m,2H)ppm.

[0381] Example 33

[0382]

[0383] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomer II. MS calculation: C 21 H 23 ClFN3O2: 403.1; Actual measurement: 404.2 [M+1] + ; 1 H NMR (CD3OD, 400MHz): δ7.82(dd,J=6.8,2.8Hz,1H),7.49-7.45(m,1H),7.22(t,J=8.8Hz,1H),4.18-4.14(m,3H),3.48-3.42(m,1H),2. 88-2.84(m,2H),2.66-2.60(m,2H),2.48-2.46(m,2H),2.26-2.19(m,2H),2.15-2.09(m,2H),1.77-1.69(m,2H),1.45-1.38(m,2H)ppm.

[0384] Example 34

[0385]

[0386] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-(trifluoromethyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (100 mg, 0.25 mmol) in THF (2 mL), TBAF (0.75 mL (1 M), 0.75 mmol) and TMSCF3 (213 mg, 1.5 mmol) were added, and the mixture was stirred overnight at 60 °C. After cooling to room temperature, another batch of TMSCF3 (213 mg, 1.5 mmol) was added, and stirring was continued at 60 °C for 6 hours. After cooling to room temperature, another batch of TMSCF3 was added. 3( 213 mg (1.5 mmol) and stirred overnight at 60 °C. After the starting material was completely exhausted, the reaction was concentrated. The residue was diluted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a crude compound, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-(trifluoromethyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid as a single diastereomer. TLC: 5% MeOH / DCM (R f MS is calculated as: C :0.4). 22 H 22 ClF4N3O2: 471.1; Actual measurement: 472.2 [M+1] + ; 1 H NMR (CD3OD, 400MHz): δ7.83(dd,J=6.8,2.8Hz,1H),7.49-7.45(m,1H),7.22(t,J=9.2Hz,1H),4.16(t,J=7.2Hz,2H),3.43-3.38(m, 1H),2.86(t,J=7.2Hz,2H),2.74-2.72(m,2H),2.66-2.60(m,2H),2.26-2.14(m,4H),1.98-1.90(m,2H),1.79(d,J=13.6Hz,2H)ppm.

[0387] Example 35

[0388]

[0389] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide. n-BuLi (0.32 mL, 0.8 mmol) was added to a solution of dimethyl sulfoxide (75 mg, 0.8 mmol) in 1 mL of THF at -78 °C under a nitrogen atmosphere, and the reaction was stirred at -78 °C for 1 hour. N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide (40 mg, 0.1 mmol) was added to 1 mL of THF at -78 °C, and the reaction was stirred at -78 °C for 30 minutes. The reaction was then warmed to room temperature and stirred for 2 hours. The reaction was quenched with water and concentrated. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid, as a single diastereomer. TLC: 5% MeOH / DCM (R f MS calculation shows: Chemical formula: C 23 H 27 ClFN3O4S: 495.1; Actual measurement: 496.2 [M+1] + ; 1 H NMR (DMSO-d6, 400MHz): δ9.74(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.57-7.53(m,1H),7.39(t,J=8.8Hz,1H),4.96(s,1H),4.08(t,J=7.2Hz,2H),3 .39-3.33(m,1H),3.26(s,2H),2.99(s,3H),2.75(t,J=7.2Hz,2H),2.54- 2.47(m,4H),2.08-2.03(m,4H),1.86-1.78(m,2H),1.65-1.61(m,2H)ppm.

[0390] Synthesis of Examples 36 to 49. Examples 36 to 49 in Table 4 were synthesized using the corresponding starting materials according to the procedures provided above.

[0391] Table 4. Examples 36 to 49

[0392]

[0393]

[0394]

[0395]

[0396]

[0397] The general procedure for alkylation, method A

[0398] K₂CO₃ (2 equivalents) and KI (0.5 equivalents) were added to a stirred solution of Ar-OH (1 equivalent) and the halogenated compound (2 equivalents) in acetonitrile / DMF (4 mL / mmol). The reaction mixture was stirred at 60 °C to 80 °C for 12-16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0399] General methods of alkylation, Method B

[0400] Cs₂CO₃ (2.5 equivalents) was added to a stirred solution of Ar-OH (1 equivalent) and the halogenated compound (2 equivalents) in DMF / ACN (6 mL / mmol). The reaction mixture was stirred at room temperature / 60 °C for 2 to 4 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0401] Intermediate 20

[0402]

[0403] 1-Methyl-3-nitro-1H-pyrazole. NaOtBu (19.11 g, 199.1 mmol) was added to a stirred solution of 3-nitro-1H-pyrazole (15 g, 132.7 mmol) in DMF (150 mL) at 0 °C, and the reaction was stirred for 20 min. MeI (9.91 mL, 159.24 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 1-methyl-3-nitro-1H-pyrazole (10 g, 59%) as a creamy white solid. TLC: 20% EtOAc / hexane (R f :0.2). 1H NMR (400MHz, DMSO-d6): δ7.98 (s, 1H), 7.03 (d, J = 2.0Hz, 1H), 3.97 (s, 3H) ppm.

[0404] Example 50

[0405]

[0406] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazole-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. LDA (2M in THF, 60 mL, 120 mmol) was added dropwise to a stirred solution of methyl-3-nitro-1H-pyrazole (10.16 g, 80 mmol) in 100 mL of dry THF at -78 °C under an inert atmosphere, and the reaction mixture was stirred for 2 hours. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (3 g, 8 mmol) in THF was added to the mixture at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 hour. The reaction progress was monitored by TLC and LCMC. After completion, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, as a single diastereomer (2 g, 50%), as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3). 1 ¹H-NMR (DMSO-d6, 400MHz): δ 10.23 (s, 1H), 7.96 (dd, J = 6.8Hz, 2.4Hz, 1H), 7.66 (s, 1H), 7.59–7.55 (m, 1H), 7.40 (t, J = 9.2Hz, 1H), 6.93 (s, 1H), 5.60 (s, 1H), 4.05 (s, 3H), 3.68 (s, 3H), 3.29–3.24 (m, 1H), 2.51–2.49 (m, 2H), 2.30–2.24 (m, 2H), 2.13–2.07 (m, 2H), 1.94–1.85 (m, 4H) ppm; MS calculation: C 23 H 24 ClFN6O4: 502.2; Measured: 503.3 [M+1] + .

[0407] Example 51

[0408]

[0409] 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. 10% Pd / C (0.5 g) and NaBH4 (1.06 g, 27.88 mmol) were added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (2 g, 3.98 mmol) in MeOH (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was filtered through a diatomaceous earth pad and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4,5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (1.5 g, 80%), as a creamy white solid. TLC: 10% MeOH / DCM (R f :0.1). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.25 (s, 1H), 7.95 (d, J = 4.4Hz, 1H), 7.76 (s, 1H), 7.58–7.54 (m, 1H), 7.41 (t, J = 9.2Hz, 1H), 6.62–5.57 (br s, 2H), 5.39 (s, 1H), 5.17 (s, 1H), 3.69 (s, 6H), 3.32–3.31 (m, 1H, combined), 2.50–2.32 (m, 2H, combined), 2.29–2.11 (m, 4H), 1.85–1.83 (m, 4H) ppm; MS calculation: C 23 H 26 ClFN6O2; 472.2; Measured: 471.2 [M-1]-.

[0410] Example 52

[0411]

[0412] 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. Selectfluor (0.149 g, 0.42 mmol) and DIPEA (0.147 mL, 0.84 mmol) were added to a stirred solution of 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.2 g, 0.42 mmol) in ACN (5 mL). The reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.02 g, 10%), which was an off-white solid. TLC: 10% MeOH / DCM (R f :0.3). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.19 (s, 1H), 7.95 (dd, J = 6.8, 2.4Hz, 1H), 7.63 (s, 1H), 7.57–7.53 (m, 1H), 7.39 (t, J = 9.6Hz, 1H), 5.21 (s, 1H), 4.47 (s, 2H), 3.66 (s, 3H), 3.60 (s, 3H), 3.30–3.14 (m, 1H), 2.50–2.40 (m, 2H, combined), 2.23–2.16 (m, 2H), 2.07–2.04 (m, 2H), 1.96–1.83 (m, 4H). MS calculation: C 23 H 25 ClF2N6O2: 490.2; Actual measurement: 473.1 [M-H2O+1] + .

[0413] Intermediate 21

[0414]

[0415] Methyl 3-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)propionate. n-BuLi (1.19 g, 18.6 mmol) was added to a stirred solution of methyl propionate (1.56 g, 18.6 mmol) in 40 mL of dry THF at -78 °C under an inert atmosphere, and the reaction mixture was stirred for 30 min. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (1 g, 2.66 mmol) in THF was added to the mixture at -78 °C. The resulting reaction mixture was stirred at -78 °C for 2 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give methyl 3-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)propionate, a white solid, as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.3); 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.23 (s, 1H), 7.95 (d, J = 6.4Hz, 1H), 7.74–7.68 (m, 1H), 7.59–7.55 (m, 1H), 7.40 (t, J = 8.8Hz, 1H), 5.79 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.28–3.23 (m, 1H), 2.58–2.54 (m, 2H), 2.09–2.06 (m, 4H), 1.80–1.76 (m, 4H) ppm. MS calculation: C 23 H 23 ClFN3O4: 459.1; Measured: 460.2 [M+1] + .

[0416] Example 53

[0417]

[0418] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. TEA (2 g, 19.82 mmol) and 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)propionate (1.3 g, 2.83 mmol) were added to a stirred solution of methylhydrazine sulfate (2.85 g, 19.82 mmol) in EtOH (20 mL). The reaction mixture was stirred at 50 °C for 24 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.65 g, 49%), a white solid. TLC: 8% MeOH / DCM (R f :0.2); 1 ¹H NMR (400MHz, DMSO-d6): δ 10.18 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 4.4Hz, 1H), 7.64 (s, 1H), 7.61–7.55 (m, 1H), 7.39 (t, J = 8.8Hz, 1H), 5.28 (s, 1H), 5.13 (s, 1H), 3.66 (s, 6H), 3.38–3.18 (m, 1H, combined), 2.60–2.38 (m, 2H, combined), 2.20–2.01 (m, 4H), 1.91–1.75 (m, 4H) ppm. MS calculation: C 23 H 25 ClFN5O3: 473.2; Measured: 473.9 [M+1] + .

[0419] Example 54

[0420]

[0421] The title compound was synthesized by alkylation of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-isopropoxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. 1 H NMR (400MHz, DMSO-d6): δ10.21(s,1H),7.99-7.94(m,1H),7.64(s,1H),7.60 -7.54(m,1H),7.40(t,J=9.2Hz,1H),5.47(s,1H),5.20(s,1H),4.61-4.54(m, 1H),3.71(s,3H),3.67(s,3H),3.29-3.18(m,1H),2.48-2.39(m,2H),2.20-2 .04(m,4H),1.90-1.78(m,4H),1.21(d,J=6.4Hz,6H)ppm; TLC: 10%MeOH / DCM(R f :0.3); MS is calculated as: C 26 H 31 ClFN5O3: 515.2; Measured value: 516.1 [M+1] + .

[0422] Example 55

[0423]

[0424] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. MeMgBr (3M in DEE, 0.59 mL, 1.78 mmol) was slowly added at 0 °C to a stirred solution of 2-((5-(5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)ethyl acetate (0.5 g, 0.89 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was obtained by... The solution was purified by column chromatography and then by preparative HPLC to N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.501 g, 61%), which was an off-white solid. TLC: 5% MeOH / DCM (R f :0.4); 1 ¹H NMR (400MHz, DMSO-d6): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8Hz, 2.4Hz, 1H), 7.65 (s, 1H), 7.59–7.52 (m, 1H), 7.40 (t, J = 9.6Hz, 1H), 5.52 (s, 1H), 5.23 (s, 1H), 4.53 (s, 1H), 3.75–3.70 (m, 5H), 3.67 (s, 3H), 3.26–3.20 (m, 1H), 2.50–2.44 (m, 2H), 2.20–2.06 (m, 4H), 1.90–1.80 (m, 4H), 1.13 (s, 6H) ppm. MS calculation: C 27 H 33 ClFN5O4: 545.2; Measured value: 546.3 [M+1] + .

[0425] Intermediate 22

[0426]

[0427] 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. n-BuLi (2M in THF, 7.8 mL, 15.96 mmol) was added dropwise to a stirred solution of 3,5-dibromo-1-methyl-1H-pyrazol (3.8 g, 15.96 mmol) in dry THF (50 mL) at -78 °C under an inert atmosphere. The reaction mixture was stirred at the same temperature for 35 min. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (1 g, 2.65 mmol) in THF was slowly added at -78 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was diluted with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide, as a single diastereomer (0.46 g, 32.39%). TLC: 5% MeOH / DCM (R f :0.3) 1 ¹H NMR (400MHz, DMSO-d6): δ 10.21 (s, 1H), 7.95 (dd, J = 6.8, 2.4Hz, 1H), 7.65 (s, 1H), 7.58–7.55 (m, 1H), 7.40 (t, J = 9.2Hz, 1H), 6.23 (s, 1H), 5.37 (s, 1H), 3.87 (s, 3H), 3.67 (s, 3H), 3.29–3.23 (m, 1H), 2.50–2.46 (m, 2H, combined), 2.22–2.07 (m, 4H), 1.87–1.83 (m, 4H) ppm; MS calculation: C 23 H 24 BrClFN5O2: 535.1; Measured: 536.1 [M+1] + .

[0428] Example 56

[0429]

[0430] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(prop-1-yn-1-yl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Tributyl(1-propynyl)tin (153.7 mg, 0.46 mmol) was added to a stirred solution of 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (50 mg, 0.09 mmol) in 1,4-dioxane (3 mL). The mixture was purified with argon for 15 minutes. Pd(PPh3)4 (10.39 mg, 0.009 mmol) was then added, and the mixture was further purified with argon for 10 minutes. The reaction mixture was stirred in a microwave oven at 140 °C for 45 minutes. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was obtained by... Column chromatography purification yielded N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(prop-1-yn-1-yl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (6 mg, 12%), a creamy-white solid. TLC: 5% MeOH / DCM (R f :0.4); 1 ¹H NMR (400MHz, CD₃OD): δ 7.92–7.87 (m, 1H), 7.66 (s, 1H), 7.55–7.48 (m, 1H), 7.24 (t, J = 8.8 Hz, 1H), 6.21 (s, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.38–3.26 (m, 1H, combined), 2.62–2.52 (m, 2H), 2.43–2.34 (m, 2H), 2.32–2.22 (m, 2H), 1.99 (s, 3H), 1.97–1.82 (m, 4H) ppm (amide and OH protons not observed); MS calculation: C 26 H 27 ClFN5O2: 495.2; Actual measurement: 496.0.

[0431] Example 57

[0432]

[0433] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Zn(CN)2 (49.4 mg, 0.42 mmol) and zinc dust (4.5 mg, 0.07 mmol) were added to a stirred solution of 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (150 mg, 0.28 mmol) in DMA (3 mL). The mixture was purified with argon for 10 minutes. Pd2(dba)3 (12.8 mg, 0.014 mmol) and dppf (15.5 mg, 0.028 mmol) were added to the solution, and the mixture was further purified with argon for 10 minutes. The resulting mixture was stirred at 130 °C for 12 hours. The reaction progress was monitored by TLC. After completion, the mixture was filtered through a diatomaceous earth mat and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid, TLC: 5% MeOH / DCM(R f :0.4); 1 ¹H NMR (400MHz, DMSO-d6): δ 10.20 (s, 1H), 7.98–7.91 (m, 1H), 7.64 (s, 1H), 7.59–7.52 (m, 1H), 7.38 (t, J = 8.8Hz, 1H), 6.85 (s, 1H), 5.50 (s, 1H), 3.99 (s, 3H), 3.66 (s, 3H), 3.42–3.16 (m, 1H, combined), 2.59–2.34 (m, 2H, combined), 2.28–2.02 (m, 4H), 1.95–1.76 (m, 4H) ppm; MS calculation: C 24 H 24 ClFN6O2: 482.2; Measured: 483.1 [M+1] + .

[0434] Example 58

[0435]

[0436] 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in DEE, 0.13 mL, 0.419 mmol) was slowly added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (50 mg, 0.103 mmol) in dry THF (5 mL) at 0 °C under an inert atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (40 mg, 77.2%), a creamy white solid. TLC: 5% MeOH / DCM (R f :0.4); 1 ¹H NMR (400MHz, DMSO-d6): δ 10.20 (s, 1H), 7.98–7.92 (m, 1H), 7.65 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 8.0Hz, 1H), 6.53 (s, 1H), 5.39 (s, 1H), 4.00 (s, 3H), 3.68 (s, 3H), 3.40–3.20 (m, 1H, combined), 2.55–2.20 (m, 2H, combined), 2.42 (s, 3H), 2.28–2.20 (m, 2H), 2.15–2.05 (m, 2H), 1.94–1.85 (m, 4H) ppm. MS calculation: C 25 H 27 ClFN5O3: 499.2; Actual measurement: 482.1 [M-H2O+1] + .

[0437] Example 59

[0438]

[0439] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in DEE, 0.66 mL, 2 mmol) was slowly added at 0 °C to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.2 mmol) in dry THF (5 mL) under an inert atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (40 mg, 39%), a white solid. TLC: 5% MeOH / DCM (R f :0.2); 1 ¹H NMR (400MHz, DMSO-d6): δ 10.20 (s, 1H), 7.96 (d, J = 5, 2Hz, 1H), 7.65 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 9.2Hz, 1H), 6.01 (s, 1H), 5.18 (s, 1H), 4.67 (s, 1H), 3.83 (s, 3H), 3.68 (s, 3H), 3.28–3.20 (m, 1H), 2.55–2.40 (m, 2H, combined), 2.22–2.16 (m, 2H), 2.10–2.08 (m, 2H), 1.90–1.84 (m, 4H), 1.36 (s, 6H) ppm; MS calculation: C 26 H 31 ClFN5O3: 515.2; Measured: 516.2 [M+1] + .

[0440] Example 60

[0441]

[0442] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. NaBH4 (3 mg, 0.08 mmol) was added at 0 °C to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (20 mg, 0.04 mmol) in MeOH (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography followed by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (5 mg, 25%). TLC: 10% MeOH / DCM (R f :0.4); 1 H NMR (400MHz, DMSO-d6): δ 10.21 (s, 1H), 7.96 (d, J = 4.0Hz, 1H), 7.65 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 9.2Hz, 1H), 6.00 (s, 1H), 5.19 (s, 1H), 4.84 (d, J = 4.8Hz, 1H), 4.57 (t, J = 5.6Hz, 1H), 3.83 (s, 3H), 3.67 (s, 3H), 3.30–3.20 (m, 1H, combined), 2.55–2.40 (m, 2H, combined), 2.20–2.05 (m, 4H), 1.88–1.82 (m, 4H), 1.29 (d, J = 6.4Hz, 3H) ppm; MS calculated as C 25 H 29 ClFN5O3: 501.2; Actual measurement: 502.1 [M+1] + .

[0443] Example 61

[0444]

[0445] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Selectfluor (2.99 g, 8.45 mmol) was added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (2 g, 4.22 mmol) in DMF (40 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. crude compound through Column chromatography purification yielded N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.55 g, 38%), a white solid. TLC: 10% MeOH / DCM (R f :0.2); 1 ¹H NMR (400MHz, DMSO-d6): δ 10.21 (s, 1H), 10.00–9.80 (m, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.58–7.54 (m, 1H), 7.40 (t, J = 8.0 Hz, 1H), 5.30 (s, 1H), 3.67 (s, 3H), 3.65 (s, 3H), 3.25–3.20 (m, 1H, combined), 2.60–2.45 (m, 2H, combined), 2.25–2.18 (m, 2H), 2.09–2.06 (m, 2H), 1.96–1.87 (m, 4H) ppm; MS calculation: C 23 H 24 ClF2N5O3: 491.2; Measured: 492.1 [M+1] + .

[0446] Example 62

[0447]

[0448] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-1-methyl-3-(3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized using the general procedure for alkylation described above (Method B). TLC: 10% MeOH / DCM (R f :0.3); 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.20 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.64 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 6.62 (d, J = 6.8 Hz, 1H), 5.39 (s, 1H), 4.45–4.35 (m, 1H), 4.30–4.24 (m, 1H), 4.18–4.12 (m, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 3.26–3.18 (m, 1H), 2.60–2.50 (m, 2H, combined). 2.25-2.20 (m, 2H), 2.10-2.06 (m, 2H), 1.94-1.88 (m, 4H) ppm; MS calculated as C 26 H 27 ClF5N5O4: 603.2; Actual measurement: 586.2 [M-H2O+1] + .

[0449] Intermediate 23

[0450]

[0451] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. LDA (5.33 mL, 10.66 mmol) was added dropwise to a stirred solution of 4-fluoro-3-iodo-1-methyl-1H-pyrazol (2.42 g, 10.66 mmol) in dry THF (30 mL) at -78 °C, and the reaction mixture was stirred at the same temperature for 2 hours. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (0.4 g, 1.06 mmol) in THF was added to the mixture at -78 °C. The reaction mixture was stirred at the same temperature and subsequently at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.250 g, 40.62%), a white solid, as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.3). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.20 (s, 1H), 7.98–7.94 (m, 1H), 7.65 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 9.2Hz, 1H), 5.44 (s, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 3.28–3.18 (m, 1H), 2.55–2.40 (m, 2H, combined), 2.24–2.18 (m, 2H), 2.10–2.06 (m, 2H), 1.98–1.90 (m, 4H) ppm. MS calculation: C 23 H 23 ClF2IN5O2: 601.1; Observed result: 602.1 [M+1] + .

[0452] Example 63

[0453]

[0454] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-((2-hydroxy-2-methylpropyl)amino)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. K₂CO₃ (99 mg, 0.415 mmol) and L-proline (7.6 mg, 0.066 mmol) were added to a mixture of N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.166 mmol) and 1-amino-2-methylprop-2-ol (29.6 mg, 0.33 mmol) in DMSO (3 mL). The solution was purified with argon for 10 min. CuI (6.3 mg, 0.033 mmol) was added to the solution, and purification with argon was continued for another 10 min. The resulting reaction mixture was stirred at 90 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-((2-hydroxy-2-methylpropyl)amino)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (20 mg, 21%). TLC: 10% MeOH / DCM (R f :0.2). 1 H NMR (400MHz, DMSO-d6) δ10.21 (s, 1H), 7.95 (d, J = 6.8Hz, 1H), 7.64 (s, 1H), 7.58-7. 54(m,1H),7.40(t,J=9.2Hz,1H),5.25(s,1H),4.53(t,J=6.4Hz,1H),4.45(s,1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.26–3.22 (m, 1H), 2.94 (d, J = 6.0 Hz, 2H), 2.55–2.40 (m, 2H, combined), 2.25–2.20 (m, 2H), 2.12–2.06 (m, 2H), 1.98–1.85 (m, 4H), 1.10 (s, 6H) ppm. MS calculation: C 27 H 33 ClF2N6O3: 562.2; Measured value: 563.2 [M+1] + .

[0455] Example 64

[0456]

[0457] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Zn(CN)₂ (0.073 g, 0.623 mmol) and zinc dust (0.0054 g, 0.083 mmol) were added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.25 g, 0.415 mmol) in DMA (5 mL), which was then purified with argon for 10 minutes. Pd2(dba)3 (0.038 g, 0.0415 mmol) and dppf (0.023 g, 0.0415 mmol) were added to the solution, and the mixture was further purified with argon for 10 min. The resulting reaction mixture was stirred at 120 °C for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.160 g, 77%), which was an off-white solid. TLC: 5% MeOH / DCM (R f MS is calculated as: C :0.4). 24 H 23 ClF2N6O2: 500.2; Actual measurement: 501.1 [M+1] + .

[0458] Example 65

[0459]

[0460] 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in diethoxyethane, 0.5 mL, 1.5 mmol) was slowly added at 0 °C under an inert atmosphere to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.15 g, 0.3 mmol) in dry THF (5 mL). The reaction mixture was stirred at 50 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.105 g, 67%), as a white solid. TLC: 5% MeOH / DCM (R f :0.2). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.21 (s, 1H), 7.96 (d, J = 6.4Hz, 1H), 7.65 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 6.4Hz, 1H), 5.49 (s, 1H), 3.99 (s, 3H), 3.67 (s, 3H), 3.32–3.20 (m, 1H), 2.60–2.50 (m, 2H, combined), 2.41 (s, 3H), 2.35–2.20 (m, 2H), 2.10–2.05 (m, 2H), 2.00–1.94 (m, 4H) ppm; LCMS calculation: C 25 H 26 ClF2N5O3: 517.2; Measured: 518.1 [M+1] + .

[0461] Example 66

[0462]

[0463] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in diethoxyethane, 0.32 mL, 0.96 mmol) was slowly added at 0 °C to a stirred solution of 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.1 g, 0.193 mmol) in dry THF (3 mL). The reaction mixture was stirred at 50 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated ammonium chloride (water) solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (12 mg, 12%), as a white solid. TLC: 5% MeOH / DCM (R f :0.2); 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.27 (s, 1H), 7.96 (d, J = 6.4Hz, 1H), 7.92–7.62 (m, 1H), 7.60–7.54 (m, 1H), 7.41 (t, J = 9.2Hz, 1H), 5.31 (s, 1H), 4.81 (br.s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.30–3.20 (m, 1H, combined), 2.60–2.45 (m, 2H, combined), 2.30–2.10 (m, 4H), 1.96–1.90 (m, 4H), 1.41 (s, 6H) ppm; MS calculated as C 26 H 30 ClF2N5O3: 533.2; Measured value: 534.1 [M+1] + .

[0464] Intermediate 24

[0465]

[0466] Ethyl 2-((5-(-5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propionate. The title compound was synthesized according to the general procedure for alkylation (Method B). TLC: 5% MeOH / DCM (R f :0.5); MS is calculated as: C 28 H 33 ClFN5O5: 573.2; Measured value: 572.4 [M⁻¹] - .

[0467] Example 67

[0468]

[0469] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(((1-hydroxyprop-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. NaBH4 (0.133 g, 3.49 mmol) was added at 0 °C to a stirred solution of ethyl 2-((5-(-5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propionate (0.2 g, 0.349 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated NH4Cl and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography followed by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(((1-hydroxypropyl-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (60 mg, 32.4%). The racemic compound was submitted for chiral preparative HPLC purification to give two diastereomers: Example 68 (diastereomer 1) and Example 69 (diastereomer 2) (Table 5).

[0470] Table 5. Examples 68 and 69

[0471]

[0472] Intermediate 25

[0473]

[0474] 1-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethylamine. 5-Bromo-1-methyl-1H-pyrazol-4-carboxaldehyde (2.0 g, 10.59 mmol) was added to a stirred solution of dimethylamine hydrochloride (4.32 g, 52.96 mmol, 5.0 equivalent), triethylamine (52.95 mmol, 7.38 mL, 5.0 equivalent), and acetic acid (1.91 g, 31.78 mmol, 1.83 mL, 3.0 equivalent) in 30 mL of dry DCM at room temperature. The resulting mixture was stirred for 20 minutes, followed by a single addition of sodium triacetoxyborohydride (13.47 g, 63.55 mmol, 6.0 equivalent). The resulting suspension was stirred overnight. After the reaction was complete, the mixture was poured into a stirred aqueous solution of NaHCO3. The organic phase was separated, washed with brine, and concentrated under reduced pressure to give 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethylamine (2.2 g, 90.0% purity, 9.08 mmol, 86% yield). MS calculation yielded C7H... 12 BrN3: 217.0; Measured: 218.1 [M+1] + .

[0475] Example 70

[0476]

[0477] N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Butyllithium (2.5 M in n-hexane, 1.7 mmol, 0.68 mL, 8.0 equivalents) was added dropwise to a solution of 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethylamine (372.65 mg, 1.71 mmol, 8.0 equivalents) in anhydrous THF (10 mL) at -78 °C. The resulting mixture was stirred for 30 min, then heated to -60 °C over 30 min, and subsequently cooled to -78 °C. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (80 mg, 213.58 μmol) in THF (2 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and then extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried over Na2SO4 and evaporated under vacuum to give 0.12 g of crude product. N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (26.0 mg, 50.48 μmol, 23.6% yield) was purified by preparative HPLC as a single diastereomer. MS calculation: C26H32ClFN6O2: 514.1; Measured: 515.2 [M+1] + ; 1 H NMR (400MHz, chloroform-d): δ7.78(dd,J=6.5,2.6Hz,1H),7.51(s,1H),7.48(s,1H),7. 42–7.35(m,1H),7.22(s,1H),7.16(t,J=8.7Hz,1H),3.90(s,3H),3.85(s,3H),3 .37(s,2H),3.23(dq,J=12.1,6.1Hz,1H),2.87(s,2H),2.50–2.33(m,4H),2.32 –2.25(m,2H),2.21(s,6H),2.12(s,1H),2.09(s,1H),2.03(d,J=4.6Hz,1H)ppm.

[0478] Example 71

[0479]

[0480] N-(3-chloro-4-fluorophenyl)-4-(5-(1,3-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. n-Butyllithium (2.5 M in n-hexane, 2.2 mmol, 0.88 mL, 11.0 equivalents) was added dropwise to a solution of 1,3-dimethyl-1H-pyrazol (211.0 mg, 2.2 mmol) in anhydrous THF (20 mL) at -78 °C. The resulting mixture was stirred for 10 min and then warmed to -5 °C over 30 min. The reaction mixture was cooled to -78°C and a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (75.0 mg, 199.56 μmol) in THF (2 mL) was added dropwise. The mixture was stirred at -78°C for 30 min and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and then extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na₂SO₄ and evaporated under vacuum to give 0.1 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(1,3-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (6.7 mg, 14.2 μmol, 7.1% yield). MS calculations yielded C1. 24 H 27 ClFN5O2: 471.2; Actual measurement: 454.2 [M-H2O+1] + ; 1 H NMR (400MHz, chloroform-d): δ7.79(d,J=6.8Hz,2H),7.55(s,1H),7.37(s,1H),7.15(t,J=8.6Hz,1H),5.87(s,1H),3.96(s,3H),3.85(s ,3H),3.29(s,1H),3.00(s,2H),2.74(s,2H),2.31(dd,J=21.5,13.4Hz,5H),2.21(d,J=2.1Hz,3H),2.13(d,J=13.3Hz,2H)ppm.

[0481] Example 72

[0482]

[0483] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. To a solution of diisopropylamine (207.41 mg, 2.05 mmol, 290.0 μl, 11.0 equivalents) in anhydrous THF (20 mL), n-butyllithium (2.5 M in n-hexane, 2.05 mmol, 0.82 mL, 11.0 equivalents) was added dropwise at -78 °C. The resulting mixture was stirred for 10 min and then warmed to -10 °C over 10 min. The mixture was cooled to -78 °C and a solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazol (307.67 mg, 2.05 mmol) in THF (1 mL) was added. The reaction mixture was stirred at -70°C for 1 hour, followed by dropwise addition of a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (70.0 mg, 186.26 μmol) in THF (2 mL). The mixture was stirred at -70°C for 30 minutes and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na₂SO₄ and evaporated under vacuum to give 0.15 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (20.1 mg, 38.22 μmol, 21% yield). MS calculations showed: C 24 H 24 ClF4N5O2: 525.2; Measured: 526.2 [M+1] + ; 1 ¹H NMR (400MHz, chloroform-d): δ 7.77 (dd, J = 6.5, 2.5Hz, 1H), 7.58 (s, 1H), 7.40–7.33 (m, 1H), 7.31 (s, 1H), 7.15 (td, J = 8.7, 1.7Hz, 1H), 6.34 (s, 1H), 4.10 (s, 3H), 3.81 (d, J = 1.7Hz, 3H), 3.30 (tt, J = 11.8, 6.6Hz, 1H), 2.84–2.67 (m, 3H), 2.39–2.14 (m, 8H) ppm.

[0484] Example 73

[0485]

[0486] 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. To a solution of 3-chloro-1-methyl-1H-pyrazol (124.04 mg, 1.06 mmol) in tetrahydrofuran (10 mL), n-butyllithium (1.06 mmol, 430.0 μl, 2.5 M in hexane, 4.0 equivalents) was added dropwise at -78 °C, and the resulting mixture was stirred for 10 minutes. The reaction temperature was then increased to -30 °C and stirred for 30 minutes. The reaction mixture was cooled to -78°C and a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (100 mg, 266.06 μmol) in tetrahydrofuran (2 mL) was added dropwise, with stirring continued for 15 minutes. The resulting mixture was warmed to room temperature and quenched with saturated ammonium chloride. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to give 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (2.2 mg, 95.0% purity, 4.24 μmol, 1.6% yield). MS calculations showed: C 23 H 24 Cl2FN5O2: 491.1; Actual measurement: 493.0 [M+2] + ; 1 H NMR (400MHz, methanol-d4): δ7.89(dd,J=6.7,2.6Hz,1H),7.66(s,1H),7.55–7.47(m,1H),7.25(t,J=9.0Hz,1H),6.15(s,1H),3.94 (s,3H),3.78(s,3H),3.68–3.42(m,1H),2.59(s,2H),2.37(dd,J=13.4,7.2Hz,2H),2.32–2.21(m,2H),2.04–1.82(m,4H)ppm.

[0487] Example 74

[0488]

[0489] 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. n-Butyllithium (109.0 mg, 1.7 mmol, 680.0 μl, 8.0 equivalent) was added dropwise to a solution of 3-tert-butyl-1-methyl-1H-pyrazol (234.46 mg, 1.7 mmol) in tetrahydrofuran (10 mL) at -78 °C, and the mixture was stirred for 10 minutes. The reaction temperature was then increased to -60 °C and stirred for 1 hour. The mixture was then cooled to -78°C and 4-[-5-oxo-octahydrocyclopentadien-2-yl]-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (79.69 mg, 212.05 μmol) was added dropwise to a solution of tetrahydrofuran (2 mL). The reaction mixture was stirred at -78°C for 15 minutes. The resulting mixture was warmed to room temperature and quenched with saturated ammonium chloride. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give a crude product, which was purified by preparative HPLC to give 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (2.8 mg, 97.8% purity, 5.33 μmol, 2.5% yield). MS calculations yielded C1. 27 H 33 ClFN5O2: 513.2; Measured: 512.0 [MH] – ; 1 HNMR (400MHz, methanol-d4): δ7.88 (dd, J=6.5, 2.7Hz, 1H), 7.65 (s, 1H), 7.51 (d, J= 2.4Hz,2H),7.25(t,J=8.9Hz,1H),6.14(d,J=2.4Hz,1H),4.09(s,2H),3.77(s ,3H),2.67(s,1H),2.58(s,2H),2.22(d,J=8.2Hz,2H),2.05(s,1H),1.86(t,J =6.6Hz,2H),1.81–1.71(m,2H),1.56–1.46(m,2H),1.29(d,J=2.1Hz,9H)ppm.

[0490] Intermediate 26

[0491]

[0492] A mixture of 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole, 1,4-dimethyl-1H-pyrazole-3-amine (2.1 g, 18.9 mmol), hexane-2,5-dione (2.22 mL, 18.9 mmol), and catalytically active TsOH in toluene (100 mL) was refluxed overnight using a Dean-Stark condenser. The reaction mixture was then cooled to room temperature and carefully decanted from the insoluble material. The resulting solution was evaporated under reduced pressure and further dried under vacuum for several hours to provide 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole.

[0493] Intermediate 27

[0494]

[0495] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. n-BuLi (0.85 mL, 2.5 M, 2.1 mmol) was added to a solution of 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole (400 mg, 2.1 mmol) in THF (8 mL) at -78 °C under argon. The mixture was stirred at -50 °C for 2.5 hours. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (80 mg, 0.2 mmol) in THF (1.5 mL) was added to the resulting mixture at -78 °C. The resulting mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude compound (420 mg), which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (11 mg, 9% yield).

[0496] Example 75

[0497]

[0498] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. Hydroxylamine hydrochloride (270 mg, 3.9 mmol) and KOH solution (4.7 mL, 4.5% in EtOH:H₂O 1:1, 3.8 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (11 mg, 0.02 mmol) in EtOH (1 mL). The resulting mixture was refluxed for 2 days. Following this, additional hydroxylamine hydrochloride (270 mg, 3.9 mmol) and triethylamine (0.528 mL, 3.85 mmol) were added, and the resulting mixture was refluxed for 2 days. The previous step was repeated. EtOH was evaporated from the cooled reaction mixture, the product was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give a crude compound, which was purified by preparative HPLC to give 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (2.7 mg, 28% yield). MS calculation: C₂₄H₂₈ClFN₆O₂: 486.2; Measured: 485.2 [M⁻¹] - ¹H NMR (600MHz, acetonitrile-d³): δ 8.30 (s, ¹H), 7.88 (dd, J = 6.8, 2.6Hz, ¹H), 7.53 (ddd, J = 9.0, 4.2, 2.6Hz, ¹H), 7.46 (s, ¹H), 7.26 (t, J = 9.0Hz, ¹H), 3.74 (d, J = 14.5Hz, 6H), 3.54 (s ,2H),3.29(dt,J=11.6,5.5Hz,1H),3.04(s,1H),2.70(s,2H),2.28(dd,J=13.6,8. 3Hz, 2H), 2.13 (s, 3H), 2.07 (dt, J=4.9, 2.5Hz, 2H), 1.85 (qt, J=6.1, 3.5Hz, 2H) ppm.

[0499] Intermediate 28

[0500]

[0501] 3-(2,5-Dimethyl-1H-pyrrolo-1-yl)-1-ethyl-1H-pyrazole. The title compound is synthesized according to the procedure described for 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole.

[0502] Intermediate 29

[0503]

[0504] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-ethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized according to the procedure described for N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. (25 mg, 95% purity, 22% yield). MS calculations: C 30 H 34 ClFN6O2: 564.2; Measured: 563.1 [MH] - ; 1 H NMR (600MHz, DMSO-d6) δ10.20(s,1H),7.94(dd,J=6.8,2.6Hz,1H),7.64(s,1H),7.55(ddd,J= 9.0,4.3,2.6Hz,1H),7.38(t,J=9.1Hz,1H),6.08(s,1H),5.70(s,2H),5.43(s,1H),4.29(q,J =7.1Hz,2H),3.66(s,3H),3.23(dt,J=12.2,6.1Hz,1H),2.51(dd,2H),2.23(dd,J=13.1,7.8H z,2H),2.08(dt,J=7.7,6.8Hz,2H),2.01(s,6H),1.93–1.80(m,4H),1.34(t,J=7.1Hz,3H)ppm.

[0505] Example 76

[0506]

[0507] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized according to the procedure described for 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MS calculation: C24H28ClFN6O2: 486.2; Found: 485.0 [M-1] - ; 1 ¹H NMR (400MHz, chloroform-d): δ 7.77 (dd, J = 6.5, 2.6 Hz, 1H), 7.52 (s, 1H), 7.43–7.30 (m, 2H), 7.15 (t, J = 8.7 Hz, 1H), 5.42 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.50 (s, 1H), 3.26 (dd, J = 11.7, 5.2 Hz, 1H), 2.73 (s, 3H), 2.35–2.04 (m, 8H), 1.39 (t, J = 7.1 Hz, 3H) ppm.

[0508] Example 77

[0509]

[0510] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized according to the method provided for 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MS calculations showed: C 25 H 30 ClFN6O2: 500.2; Actual measurement: 499.2 [M⁻¹] - ; 1H NMR (400MHz, chloroform-d): δ7.78(d,J=7.4Hz,1H),7.49(s,2H),7.35(d,J=8.0Hz,1H),7.16(t,J=8.7Hz,1H),5.42(s,1H),5.03– 4.89(m,1H),3.85(s,3H),3.28(s,1H),2.74(s,2H),2.38–2.22(m,7H),2.10(d,J=12.7Hz,4H),1.42(d,J=6.6Hz,6H)ppm.

[0511] Example 78

[0512]

[0513] N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. n-Butyllithium (2.5 M in n-hexane, 4.26 mmol, 1.71 mL, 20.0 equivalents) was added dropwise to a solution of (R)-1-(1-methyl-1H-pyrazol-3-yl)ethanol (268.91 mg, 2.13 mmol, 10.0 equivalents) in anhydrous THF (10 mL) at -78 °C. The resulting mixture was stirred for 30 min and then warmed to -30 °C over 30 min. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (80.0 mg, 212.87 μmol) in THF (2 mL) was added dropwise to the cooled (-78 °C) reaction mixture. The resulting mixture was stirred at -78 °C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into saturated NH4Cl and extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried over Na₂SO₄ and evaporated under vacuum to give 0.35 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (9.4 mg, 18.73 μmol, 8.8% yield). MS calculations showed that: C 25 H 29 ClFN5O3: 501.2; Actual measurement: 484.2 [M-18+1] + ; 1¹H NMR (600 MHz, acetonitrile-d³) δ 8.41 (d, J = 41.1 Hz, 1H), 7.88 (dd, J = 6.8, 2.6 Hz, 1H), 7.53 (ddd, J = 9.0, 4.3, 2.7 Hz, 1H), 7.45 (s, 1H), 7.25 (td, J = 9.0, 1.2 Hz, 1H), 6.08 (s, 1H), 4.72 (q, J = 6.5 Hz, 1H), 3.90 (d, J = 1.2 Hz, 3H) ,3.72(s,3H),3.41(s,1H),3.33(tt,J=12.0,6.1Hz,1H),3.19–2.85(m,2H),2.61(h,J=10.1,9.3Hz,2H) ,2.32(ddd,J=11.8,7.9,2.8Hz,2H),2.21(d,J=7.0Hz,1H),2.01(d,J=4.6Hz,2H),1.45–1.33(m,3H)ppm.

[0514] Intermediate 30

[0515]

[0516] 2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol. A solution of TBAF (1M in THF, 9.08 mmol, 0.91 mL, 0.1 equivalent) in THF was added dropwise to a solution of 1-methyl-1H-pyrazol-3-carboxaldehyde (1.0 g, 9.08 mmol) and TMSCF3 (1.94 g, 13.62 mmol, 1.5 equivalent) in 20 mL of THF. The reaction mixture was stirred at 0 °C for 30 min and then gradually warmed to room temperature. After 12 hours, an additional portion of TBAF (1M in THF, 5.0 mL) was added, the mixture was decanted into water, and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na₂SO₄ and then evaporated under vacuum to give 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol, which was an oil (1.4 g, 95.0% purity, 7.38 mmol, 81% yield). The crude product was used directly without further purification. MS calculation: C₆H₇F₃N₂O: 180.1; Actual: 181.2 [M+1] +

[0517] Example 79

[0518]

[0519] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Butyllithium (2.5 M in n-hexane, 3.2 mmol, 1.28 mL, 20.0 equivalents) was added dropwise to a solution of 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol (288.36 mg, 1.6 mmol, 10.0 equivalents) in anhydrous THF (10 mL) at -78 °C. The resulting mixture was stirred for 30 minutes and then warmed to -20 °C over 30 minutes. The mixture was cooled to -78°C, and a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (60 mg, 160.09 μmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried over Na₂SO₄ and evaporated under vacuum to give 0.2 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (6.5 mg, 11.69 μmol, 7.3% yield). MS calculations yielded C1. 24 H 24 ClF4N5O3: 541.2; Measured value: 542.2 [M+1] + ; 1 ¹H NMR (400MHz, acetonitrile-d³): δ 8.33 (s, 1H), 7.89 (dd, J = 6.7, 2.7Hz, 1H), 7.54 (ddd, J = 9.0, 4.2, 2.6Hz, 1H), 7.49 (s, 1H), 7.27 (t, J = 9.0Hz, 1H), 6.25 (s, 1H), 5.03 (q, J = 7.3Hz, 1H) ,4.54(s,1H),3.98(s,3H),3.74(s,3H),3.51(d,J=44.4Hz,1H),3.34(dq,J=11.9,5. 9Hz, 1H), 2.81 (s, 2H), 2.34 (dd, J=13.2, 7.7Hz, 2H), 2.04 (dd, J=8.8, 3.6Hz, 2H) ppm.

[0520] Example 80

[0521]

[0522] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(methyl-d3)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Magnesium (42.65 mg, 1.75 mmol) was stirred in a three-necked flask equipped with a thermometer and a dropping funnel in dry diethyl ether (10 mL). Trideuterium methyl iodide (231.27 mg, 1.6 mmol, 100.0 μl, 10.0 equivalent) in diethyl ether (2 mL) was added to the dropping funnel, and small crystals of iodine were added to the magnesium suspension. The magnesium suspension was briefly warmed, and then the 1,1,1-trideuterium methyl iodide solution was added dropwise to the flask. After the addition was complete, the mixture was refluxed for 30 minutes, and then cooled to -40 °C. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (60.0 mg, 159.65 μmol) in THF (1.5 mL) was added dropwise to the reaction mixture, which was allowed to reach room temperature and incubated overnight. The mixture was partitioned between ammonium chloride aqueous solution (20 mL) and MTBE (50 mL) and extracted with EtOAc. The combined organic solutions were dried over Na2SO4 and evaporated under vacuum to give 0.075 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(methyl-d3)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (15.4 mg, 39.0 μmol, 24% yield). MS calculations: C 20 H 20 D3ClFN3O2: 394.2; Measured: 395.2 [M+1] + ; 1 H NMR (400MHz, methanol-d4): δ7.89(dd,J=6.7,2.6Hz,1H),7.66(s,1H),7.52(ddd,J=9.0,4.2,2.6Hz,1H),7.25(t,J=8.9Hz,1H),3.77(s,3H),3.36 (s,1H),2.61–2.45(m,2H),2.31–2.19(m,2H),1.88(dd,J=12.6,8.0Hz,2H),1.73(td,J=12.3,8.7Hz,2H),1.61(dd,J=12.6,6.7Hz,2H)ppm.

[0523] Synthesis of Examples 81 to 113. Examples 81 to 113 in Table 6 were synthesized using the corresponding starting materials according to the procedures provided above.

[0524] Table 6. Examples 81 to 113

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] Example 114

[0542]

[0543] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide: t-BuLi (1.3M, 19.5mL, 25.0mmol) was added dropwise to a solution of 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol (5.8g, 25.0mmol) in dry Et2O (65mL), and the mixture was stirred at -78°C under a N2 atmosphere for 5 minutes. Subsequently, a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (940.0mg, 2.5mmol) in dry THF (3mL) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 4 hours. The mixture was quenched with NH₄Cl solution (3 mL) and concentrated under vacuum to give a crude product, which was purified by column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (600.0 mg, 46%), a white solid as a single diastereomer. MS calculations yielded C1. 24 H 24 ClF4N5O2: 525.2; Measured value: 525.9 [M+1] + ; 1 H NMR (400MHz, d6-DMSO): δ10.23(s,1H),7.96(dd,J=6.8,2.0Hz,1H),7.77(s,1H),7.65(s,1H),7.61-7.54(m,1H),7.41(t,J=9.2 Hz,1H),4.87(s,1H),3.83(s,3H),3.68(s,3H),3.28-3.17(m,1H),2.48-2.41(m,2H),2.41-2.03(m,4H),1.93-1.77(m,4H)ppm.

[0544] Example 115

[0545]

[0546] N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Zn(CN)₂ (1.7 g, 14.0 mmol), t-BuXPhos (300.0 mg, 0.7 mmol), and a third-generation t-BuXPhos precatalyst (560.0 mg, 0.7 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (740.0 mg, 1.4 mmol) in dioxane / H₂O (45 mL, v / v = 2:1). The reaction was stirred at 60 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, washed with methanol, and concentrated to obtain a crude product. This crude product was purified by column chromatography and reversed-phase chromatography to give N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (270.0 mg, 37.3%), a white solid. TLC: 7% MeOH / DCM (Rf: 0.3); MS calculations: C 25 H 24 F4N6O2: 516.2; Measured value: 517.0 [M+1] + 499.0 [M–18+1] + ; 1HNMR (400MHz, CD3OD): δ8.09 (dd, J=5.6, 2.8Hz, 1H), 7.91-7.81 (m, 1H), 7.66 (s, 1H), 7.65 (s, 1H), 7.37 (t, J=9.2Hz, 1H), 3 .86(s,3H),3.77(s,3H),3.37-3.33(m,1H),2.60-2.54(m,2H),2.34-2.29(m,2H),2.27-2.20(m,2H),1.94-1.89(m,4H)ppm.

[0547] Intermediate 31

[0548]

[0549] N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. tBuXPhos-Pd-G3 (6.3 g, 8 mmol) and t-BuXPhos (3.4 g, 8 mmol) were added to a solution of Zn(CN)2 (9.4 g, 80 mmol) and N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (6 g, 16 mmol) in dioxane (250 mL) under N2. The mixture was stirred overnight at 85 °C. It was then cooled, filtered, washed with EA, and the organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography using 1–5% MeOH / DCM (v / v) to give N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (4 g, 68%), as a yellow solid. TLC: 5% EtOH / DCM (Rf: 0.5); MS calculations: C 20 H 19 FN4O2: 366.1; Measured: 367.1 [M+1] + .

[0550] Synthesis of Examples 116 to 222. Examples 116 to 222 were synthesized using the corresponding starting materials in Table 7 according to the procedures provided above.

[0551] Table 7. Examples 116 to 222

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605] VI. Biological Data

[0606] Determination of the activity of the test compound against viruses produced by HepAD38 cells.

[0607] HepAD8A cells grown in T-150 flasks (Corning, catalog number: 430825) containing growth medium (DMEM / F12(1:1)(Hyclone, cat#:SH30023.02), 1X penicillin / streptomycin (Invitrogen, catalog number: 15140-122), 10% FBS (Tissue Culture Biologics, catalog number: 101), 250 μg / mL G418 (Alfa Aesar, catalog number: J62671), and 1 μg / mL tetracycline (Teknova, catalog number: T3320)) were isolated using 0.25% trypsin-EDTA (Invitrogen, catalog number: 25200-056). Tetracycline-free treatment medium (15 mL DMEM / F12 (1:1), 1x penicillin / streptomycin, containing 2% FBS, approved Tet system (Clontech, catalog number: 631106)) was then added to the mixture and transferred to 50 mL conical tubes (Falcon, catalog number: 21008-918), and then rotated at 1300 rpm for 5 min. The clumps of cells were then resuspended / washed twice with 50 mL 1X DPBS (Invitrogen, catalog number: 14190-136) and twice with 50 mL treatment medium. HepAD38 cells were then resuspended in 10 mL treatment medium, rinsed with a syringe, and counted. 50,000 cells / well were seeded in 180 μL of treatment medium in 96-well clear-bottom TC plates (Corning, catalog number: 3904), with 20 μL added. 10% DMSO (Sigma, catalog number: D4540) was used as a control, or the test compound was added to 10% DMSO in a 10X solution in the treatment medium to make the final compound concentration start from 10 μM. The plates were incubated in a 5% CO2 incubator at 37°C for 5 days.

[0608] Subsequently, viral load was determined by quantitative PCR (qPCR) of the HBV core sequence. A mixture containing the forward primer HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3' (IDT DNA), the reverse primer HBV-r 5′-AAGGAAAGAAGTCAGAAGGCAAAA-3′ (IDT DNA), and a fluorescent TaqMan assay was prepared. tm HBV probe 5′-FAM / AGCTCCAAA / ZEN / TTCTTTATAAGGGTCGATGTC / 3IABkFQ-3′ (IDTDNA), 10 μL / well qPCR PCR reaction mixtures were prepared using Quanta Biosciences (catalog number: 95114-05K) and 6 μL / well DEPC water (Alfa Aesar, catalog number: J62087). 4 μL of supernatant was added to a 16 μL reaction mixture in a qPCR plate (Applied Biosystems, catalog number: 4309849), sealed with a membrane (Applied Biosystems, catalog number: 4311971), centrifuged for a few seconds, and then run on an Applied Biosystems VIIA7. The PCR mixture was incubated at 45°C for 5 min, then at 95°C for 10 min, followed by 40 cycles of incubation at 95°C for 10 sec and at 60°C for 20 sec. Viral load was quantified using ViiATM7 software according to known HBV DNA standards. The viral load from the supernatant of wells containing treated cells was compared to the viral load from the supernatant of DMSO control wells (≥3 cells / plate). Cell viability was determined using a modified CellTiter-Glo luminescent cell viability assay (Promega, catalog number: G7573). A suitable amount of CellTiter-Glo (CTG) 1X DPBS was mixed at a 1:1 ratio, and 100 μL of the mixture was added to each well. All supernatant was then completely removed from each well without touching the cell surface. The plates were incubated at room temperature on a microplate shaker for 10 minutes, and then read using a microplate reader (TECAN M1000 or Envision). EC 50 value or CC 50 The value is calculated through curve fitting using a four-parameter nonlinear logistic regression model (GraphPad Prism or Dotmatics). 50 All values ​​are >10μM.

[0609] Table 8 shows the viral load reduction EC of the exemplary compounds of the present invention grouped according to the following ranges. 50 Value: A represents EC 50 <10 nM; B indicates EC ≥10 to <50 nM. 50 C indicates EC ≥50 to <500 nM 50

[0610] Table 8. Viral load reduction of exemplary compounds of the present invention

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619] VII. Stereochemistry of the Examples

[0620] AIA-225

[0621]

[0622] 5-Amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide. Add NaSMe (138.6 mg, 1.98 mmol) to a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(hexahydro-1′H-spiro[ethylene oxide-2,2′-cyclopentadien]-5′-yl)-1-methyl-1H-pyrazole-4-carboxamide (200 mg, 0.495 mmol) in THF / H₂O (6 mL / 2 mL). Stir the mixture overnight at room temperature. The solvent was removed, and the crude product was purified by silica gel column chromatography using 3:1 (v / v) petroleum ether / ethyl acetate to give 5-amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 44.7%), a yellow solid. MS (m / z): Calculated: 452.1, Found: 452.2 [M+1] + .

[0623] AIA-227-1, AIA-227-2

[0624]

[0625] 5-Amino-N-(3-chloro-4-fluorophenyl)-3-((2r,5r)-5-hydroxy-5-(methanesulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-1) and 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methanesulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-2). To a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol) in DCM (5 mL), m-CPBA (114.8 mg, 0.66 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was removed, and the crude material was purified by silica gel column chromatography using 3:1 (v / v) DCM / MeOH to give AIA-227 (40 mg, 37.3%) as a white solid. MS (m / z): Calculated: 484.1, Found: 484.3 [M+1] + AIA-227 was separated by SFC to obtain AIA-227-1 (4 mg), a white solid, and AIA-227-2 (4 mg), a white solid. AIA-227-1: 1 H NMR (400MHz, DMSO-d6): δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,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: 1 H NMR (400MHz, DMSO-d6): δ8.94(s,1H),7.91(dd,J=2.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.97(s,2H),4.87(s,1H),3.4 9(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

[0626]

[0627] Alternative synthesis of 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methanesulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide. n-BuLi (327.5 mL, 818.7 mmol, 2.5 M) was added dropwise to a solution of dimethyl sulfoxide (77.0 g, 818.7 mmol) in THF (800 mL) at -78 °C. The resulting solution was warmed to -20 °C and stirred for 1 h. The reaction was cooled to -78 °C and AIA-002 (40.0 g, 102.3 mmol) was added over 2 hours to a solution of anhydrous tetrahydrofuran (1200 mL). The mixture was warmed to room temperature and stirred for another 4 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (200 mL). The solvent was removed, followed by dilution with water, extraction with ethyl acetate (3 x 200 mL), drying to Na₂SO₄, filtration, and concentration to obtain the crude product. The crude product was purified by column chromatography using 0–5% (v / v) methanol / DCM and basic preparative HPLC to give 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methanesulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (26.0 g, 52.4%), a white solid. MS (m / z): Calculated: 484.1, MS measured: 485.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ8.96(s,1H),7.92(dd,J=6.8,2.8Hz,1H),7.54-7.50(m,1H),7.35(t,J=8.8Hz,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.

[0628] Crystals of compound AIA-227-2 with dimensions of 0.08 x 0.10 x 0.20 mm were obtained from EtOH after 20 days of volatilization and used for X-ray diffraction data collection. Data were collected at room temperature using CuKα radiation in ω / φ scan mode on a BrukerSMART CCD surface detector diffractometer. 10,846 reflections were collected, of which 3,754 reflections were unique (Rint = 0.0507).

[0629] This crystal belongs to the monoclinic system, space group P21 / c. The cell parameters are as follows: a = 6.6143(3), b = 14.0381(8). α=γ=90.0°, β=97.702(3), Z = 4.

[0630] The structure was solved using a direct method, and all non-H atoms were solved using the full matrix least squares method with the SHELXTL program. 2 Fine-tuning was performed. All H atoms were placed in geometrically ideal positions and confined to their parent atoms. A multi-scan absorption correction method was used, with the maximum and minimum transmission parameters being 0.7531 and 0.6017, respectively. The final R, wR², and GOF values ​​were 0.0457, 0.1293, and 1.024, respectively.

[0631] There exists a C in the asymmetric element. 21 H 26 The FClN4O4S molecules, and the hydrogen bonds between them, play an important role in the stable stacking of the crystal structure.

[0632] ORTEP plot of compound AIA-227-2 Figure 1 Presented in [the text]. The relative stereochemical scheme of compound AIA-227-2 is in [the text]. Figure 2 The stereochemical description of the chemical structures in the relevant embodiments is shown in the figure.

[0633] By incorporating via reference

[0634] All publications and patents mentioned herein, including those listed below, are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent were specifically and individually incorporated by reference. In case of conflict, the definitions herein, including any definitions herein, shall prevail.

[0635] equivalent

[0636] Although specific embodiments of this disclosure have been discussed, the above description is illustrative and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of this disclosure should be determined by reference to the full scope of the claims together with their equivalents and the description together with such variations.

[0637] Unless otherwise stated, all figures for the amounts of expressed components, reaction conditions, etc., used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximate values ​​and may vary depending on the desired properties sought through this disclosure.

Claims

1. A compound of formula I, ， Or its pharmaceutically acceptable salt, wherein: L is C 1-4 Alkylene or halogenated C 1-4 Alkylene; L 1 and L 2 Independent as key, C 1-6 Alkylene, O, NR c C(O), C(O)O, C(O)NR c S(O) t Or S(O) t NR c ; X 1 It is NR x1 ; X 3 is CR 4 R 8 ; R a R b and R c Each time it appears, it is independently selected from the following group: hydrogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-6 Monocycloalkyl; R d It is hydrogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy; R x1 Is it hydrogen or C? 1-4 Alkyl; or R x1 and R 2 Together with the atoms they are attached to, they form groups selected from -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2CH2-NH-, -CH2NHCH2-, -CH2CH2CH2NH-, and -CH2CH2NHCH2-. R 0a Each time it appears, it is independently selected from the following group: hydrogen, halogen, OH, CN, NO2, R a R b N-, C 1-4 Alkyl and Halogenated C 1-4 alkyl; R 6a Independent of hydrogen or C 1-4 alkyl; R 0 and R 6 Each time it appears, it is independently selected from the following groups: hydrogen, halogen, OH, CN, NO2, oxo, R d N=, hydrazine, formyl, azide, silyl, siloxy, HOC(O)-, R a R b N-, R a R b NS(O) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, R a R b NC 1-6 Alkyl-, HOC(O)C 1-6 Alkyl-, R a R b NC 1-6 Alkyl NR c -、C 1-6 Alkyl NR a C 1-6 Alkyl NR c -、C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy-, R a R b NC 1-6 Alkoxy-, C 1-6 Alkoxy C 1-6 Alkyl-, Halogenated C 1-6 Alkoxy C 1-6 Alkyl-, R a R b NC(O)-, C 1-6 Alkyl C(O)-, C 1-6 Alkoxy C(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl S(O) q -、C 1-6 Alkyl S(O) t NR c -、C 1-6 Alkyl S(O) t C 1-6 Alkyl-, C 1-6 Alkyl S(O) t NR a C 1-6 Alkyl-, C 3-6 Cycloalkyl S(O) t C 1-6 Alkyl-, C 1-6 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-6 alkyl-; R 1 It is a phenyl group, wherein the phenyl group is selected by one, two or three independently chosen R groups. 11 Group substitution; Each R 11 It is C 1-6 Alkyl, halogen, or CN; R 2 and R 8 Independently selected from the following groups: hydrogen, halogen, CN, OH, R a R b N, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 3-5 Monocycloalkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy; R 3 yes ; R 4 It is R 5 -L 1 -、R 6 Or R 9 ; R 5 yes ; R 9 is R 14 S(O) q -L-, R 14 S(O) q NH-L- or R 14 C(O)NH-L-; R 14 It is R a R b N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or R 5 -L 1 -;and q, r, t, and w are each independently selected from 0, 1, and 2 when they appear.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R x1 It is either hydrogen or methyl.

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

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein r is 0.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 yes ;R 11 Each time it appears, it is independently selected from the following group: halogen and CN; and z1 is 0, 1, 2 or 3.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein for each occurrence, R 11 Select independently from the following groups: CN, F, Cl, Br, and I.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 yes .

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 yes .

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 yes .

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is R 6 .

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is R 5 -L 1 - 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is R 9 .

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 It is hydrogen, OH or C 1-4 Alkyl group.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 8 It is OH.

17. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatitis B (HBV) infection.

19. Use of the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating hepatitis B (HBV) infection.

20. A compound: ， Or its stereoisomer, or its pharmaceutically acceptable salt.

21. The compound of claim 20, wherein it is a single stereoisomer or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound of claim 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. Use of the compound of claim 20 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hepatitis B (HBV) infection.

24. Use of the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating hepatitis B (HBV) infection.