5-membered heteroaryl carboxamide compounds for treatment of hbv

Abstract

To provide 5-membered heteroaryl carboxamide compounds for treatment of HBV.SOLUTION: The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds and pharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating Hepatitis B (HBV) infections. In another aspect, the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.SELECTED DRAWING: None

Description

[Background technology]

[0001] background Hepatitis B virus (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of cirrhosis and liver cancer (hepatocellular carcinoma). Globally, approximately 2 billion people are infected with HBV, approximately 360 million are chronically infected, and more than 500,000 people die from HBV infection each year. HBV can be transmitted from mother to child via bodily fluids, sexual intercourse, and blood products. Children born to HBV-positive mothers can become infected unless vaccinated at birth.

[0002] Hepatitis virus particles consist of a lipid envelope interspersed with surface proteins (HBsAg) surrounding a viral core. The core is composed of a protein shell or capsid composed of 120 core protein (Cp) dimers, thereby containing the relaxed circular DNA (rcDNA) viral genome and viral and host proteins. In infected cells, the genome is found in the host cell nucleus as a covalently closed circular DNA (cccDNA). The cccDNA is a template for viral RNA and therefore viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P)). After assembly, P reverse-transcribes the pgRNA into rcDNA within the capsid to create a DNA-filled viral core.

[0003] Currently, chronic HBV is primarily treated with nucleoside(t)ide analogs (e.g., entecavir) that suppress the virus, but patients continue to receive treatment, and even after many years of treatment, the infection is not eliminated. Once patients begin taking nucleoside(t)ide analogs, most patients must continue to receive the analogs or risk developing life-threatening immune responses due to viral rebound. Furthermore, nucleoside therapy can lead to the development of antiviral drug resistance.

[0004] The only alternative approved by the FDA for nucleoside(t)ide analogues is treatment with interferon alpha or pegylated interferon alpha.Unfortunately, the incidence of adverse events and the profile of interferon alpha can reduce tolerability, and many patients are unable to complete treatment.In addition, only a small subset of patients are likely to have a sustained clinical response to the course of interferon treatment, so only a small percentage of patients are considered suitable for interferon treatment.As a result, interferon-based treatment is used in only a small percentage of all diagnosed patients who are selected for treatment.

[0005] Therefore, current HBV treatments can range from symptomatic to observational. Nucleotide analogs suppress viral production and treat symptoms, but leave the infection untreated. Interferon alpha is associated with severe side effects, is poorly tolerated by patients, and is a limited treatment strategy that is successful in only a small proportion of patients. There is a clear continuing need for more effective treatments for HBV infection. Summary of the Invention [Means for solving the problem]

[0006] Abstract The present disclosure relates, in part, to five-membered heteroaryl carboxamide compounds and pharmaceutical compositions thereof useful for disrupting HBV core protein assembly, and methods for treating HBV infection. provide.

[0007] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are described in the detailed description.

[0008] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In another aspect, the disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the ORTEP plot for compound CP-AIA-227-2.

[0012] [Figure 2] FIG. 2 shows the relative stereochemical scheme of compound CP-AIA-227-2. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description The features and other details of the present disclosure will now be described more specifically.Before further describing the present disclosure, certain terms used in the specification, examples and appended claims will be summarized here.These definitions should be read in light of the remainder of the disclosure and 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.

[0014] I. Definition The term "alkenyl," as used herein, refers to an unsaturated, straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include those described herein as C 2~6 These include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to as alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0015] The term "alkoxy," as used herein, refers to a straight or branched chain alkyl group attached to oxygen (e.g., alkyl-O-). Exemplary alkoxy groups include , respectively, herein C 1~6 Alkoxy and C 1~4 Examples of alkoxy groups include, but are not limited to, alkoxy groups of 1 to 6 or 1 to 4 carbon atoms, referred to as alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0016] The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2-, and CH3OCH2-.

[0017] The term "alkyl," as used herein, refers to a saturated, straight-chain or branched hydrocarbon. Exemplary alkyl groups include those described herein as C 1~6 Alkyl, and C 1~4 These include, but are not limited to, straight-chain or branched hydrocarbons of 1 to 6 or 1 to 4 carbon atoms, referred to as alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The term "alkylene," as used herein, refers to a biradical alkyl group.

[0018] The term "alkynyl," as used herein, refers to an unsaturated, straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include those described herein as C 2~6 These include, but are not limited to, straight or branched chain groups of 2 to 6 carbon atoms, referred to as alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0019] The term "carbonyl," as used herein, refers to the divalent group --C(O)--.

[0020] The term "cyano," as used herein, refers to the group --CN.

[0021] The term "cycloalkyl" as used herein includes, for example, C 3~6A saturated monocyclic hydrocarbon group of 3 to 6 carbons referred to as monocycloalkyl, or, for example, C 8~12 This refers to a bicyclic hydrocarbon ring structure of 8 to 12 carbons called bicycloalkyl. For bicyclic cycloalkyl groups, the two rings may be attached through the same or different carbons. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl. Exemplary bicyclic cycloalkyl groups include, but are not limited to, spiro[2.5]octanyl, spiro[3.5]nonanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, octahydropentalenyl, bicyclo[4.2.0]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl.

[0022] The term "cycloalkenyl" as used herein includes, for example, C 4~6 Partially unsaturated monocyclic hydrocarbon groups of 4 to 6 carbons referred to as monocycloalkenyl, or, for example, C 8~12 Bicyclic cycloalkenyl groups refer to bicyclic hydrocarbon ring structures of 8 to 12 carbons called bicycloalkenyl. 1) one or both rings may contain one or more double bonds, and 2) the two rings may be joined through the same or different ring carbons. Exemplary monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Exemplary bicyclic cycloalkenyl 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, bicyclo[4.1.0]hept-3-enyl, bicyclo[4.1.0]hept-2-enyl, and bicyclo[2.2.2]oct-2-enyl.

[0023] The term "carbocyclyl" as used herein refers to a phenyl ring at C 3~6 Monocycloalkyl or C 4~6 It refers to a bicyclic ring system formed by fusion to a monocycloalkenyl ring. Examples of carbocyclyl include, but are not limited to, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, and 1H-indenyl.

[0024] The term "halo" or "halogen" as used herein refers to F, Cl, Br, or I.

[0025] The term "haloalkyl," as used herein, refers to an alkyl group that is substituted with one or more halogen atoms. For example, haloC 1~6 Alkyl refers to a straight or branched alkyl group of 1 to 6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, CH2F-, CHCl2-, -CHF2, CF3-, CF3CH2-, CH3CF2, CF3CCl2-, and CF3CF2-.

[0026] The term "haloalkoxy," as used herein, refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CC10-, CF30-, CHF20-CF3CH20-, and CF3CF20-.

[0027] The term "heteroaryl," as used herein, refers to a 5- to 6-membered monocyclic or 8- to 12-membered bicyclic aromatic ring system containing 1 to 4 independently selected heteroatoms, such as nitrogen, oxygen, and sulfur. The heteroaryl ring may be attached to the adjacent group through either carbon or nitrogen, where possible. Examples of 5-6 membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also called thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also called 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 8-12 membered bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, benzo[d]isoxazolyl, benzo[c]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d]imidazolyl, benzo[d]imidazolyl, and benzo[d][1,2,3]triazolyl.

[0028] The term "heterocycloalkyl" refers to a heterocycloalkyl group, as used herein, containing 1 to 4 independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) and SO). 3~6 Monoheterocycloalkyl and C 8~12 This refers to a saturated 3- to 6-membered monocyclic or 8- to 12-membered bicyclic ring system, termed a biheterocycloalkyl. Where possible, the heterocycloalkyl ring may be linked to adjacent groups through a carbon or nitrogen. C 3~6Examples of monoheterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl 1,1-dioxide, oxetanyl, azetidinyl, thietanyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazinyl. 8~12 Examples of biheterocycloalkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decanyl and 1,5-dioxaspiro[5.5]undecanyl.

[0029] The term "heterocycloalkenyl" refers to any alkyl group, as defined herein, containing one to four independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) or S(O)). 3~6 Monoheterocycloalkenyl and C 8~12 This refers to a partially unsaturated 3- to 6-membered monocyclic or 8- to 12-membered bicyclic ring system, termed biheterocycloalkenyl. Where possible, the heterocycloalkenyl ring may be attached to the adjacent group through a carbon or nitrogen atom. Regarding bicyclic heterocycloalkenyl groups: 1) either one or both rings may contain one or more double bonds, and 2) the two rings may be attached through the same or different ring atoms. C 3~6Examples of monoheterocycloalkenyl groups include 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-dihydroisoxazolyl, 2,3-dihydro Examples of aryl groups include, but are not limited to, isoxazolyl, 3,4-dihydropyridinyl, 2,3-dihydropyridinyl, 2,3,4,5-tetrahydropyridinyl, 1,6-dihydropyridazinyl, 4,5-dihydropyridazinyl, 3,4,5,6-tetrahydropyridazinyl, 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. 8~12 Examples of biheterocycloalkenyl groups include, but are not limited to, 6,7-dihydroindolyl, 4,5-dihydroindolyl, 7,8-dihydroimidazo[1,2-a]pyridinyl, 5,6-dihydroimidazo[1,2-a]pyridinyl, 4,5-dihydrobenzo[d]imidazolyl, 6,7-dihydro-1H-indazolyl, 4,5-dihydro-1H-indazolyl, 4,5-dihydropyrazolo[1,5-a]pyridinyl, and 6,7-dihydropyrazolo[1,5-a]pyridinyl.

[0030] The term "heterocyclyl," as used herein, refers to (1) a phenyl ring fused to a 3- to 6-membered monocyclic heterocycloalkyl or a 4- to 7-membered monocyclic heterocycloalkenyl ring, or (2) a 5- to 6-membered monocyclic heteroaryl ring fused to a C 3~6Cycloalkyl, C 4~7 "Cycloalkenyl" refers to a bicyclic ring system formed by condensing a cycloalkenyl ring to either a 3- to 6-membered monocyclic heterocycloalkyl or a 4- to 6-membered monocyclic heterocycloalkenyl ring. Where possible, the ring may be attached to the adjacent group through a carbon or nitrogen. Examples of heterocyclyl include isochromanyl, 2H-quinolinyl, 6,7,8,9 -Tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepane, 6,7-dihydro-5H,9H-[1,2,4]triazolo[3,4-c][1,4]oxazepane, 5,6,8,9-tetrahydro-7l2-[1,2,4]triazolo[4,3-d][1,4]diazepine, 8,9-dihydro-5H-[1,2,4]triazolo[4,3-a]azepine azepine, 6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]azepine, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, and 5H,9H-[1,2,4]triazolo[3,4-c][1,4]oxazepine.

[0031] The terms "hydroxy" and "hydroxyl," as used herein, refer to an --OH group.

[0032] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH-, HOCHCH-, CHCH(OH)CH-, and HOCHCH(OH)CH-.

[0033] The term "hydroxyalkoxy," as used herein, refers to an alkoxy group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCHO-, HOCHCHO-, CHCH(OH)CHO-, and HOCHCH(OH)CHO-.

[0034] "R a R b NC 1~6 The term "alkyl-" as used herein refers to R as defined herein. a R b It refers to 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-.

[0035] "R a R b NC 1~6 The term "alkoxy" as used herein means R as defined herein. a R b It refers to an alkoxy group substituted with an N-group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CHO-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CHO-.

[0036] The term "oxo," as used herein, refers to the group =O.

[0037] As used herein, for example, [ka] When a bicyclic ring is shown with a floating point of attachment and / or floating substituents, such as 33 This means that the group(s) can be independently attached to either or both rings.

[0038] "Individual," "patient," or "subject" are used interchangeably and include mammals. The compounds or pharmaceutical compositions of the present disclosure can be administered to mammals such as humans, and can also be administered to other mammals, such as animals requiring veterinary treatment, including domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammal treated in the methods of the present disclosure is desirably a mammal for which treatment of HBV infection is desired.

[0039] The term "modulation" includes antagonism (eg, inhibition), agonism, partial antagonism and / or partial agonism.

[0040] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0041] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition can also contain other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0042] The term "pharmaceutical composition," as used herein, refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0043] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. 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., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present composition that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present composition that contain a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure can contain both acidic and basic groups; for example, one amino group and one carboxylic acid group. In such cases, the compound can exist as an acid addition salt, zwitterion, or base salt.

[0044] The term "therapeutically effective amount" or "effective amount," as used herein, refers to the amount of the compound that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is being sought by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount needed to achieve the desired therapeutic and / or prophylactic effect.

[0045] The term "treating" includes any effect, e.g., alleviation, reduction, modulation, or elimination, via disruption of HBV core protein assembly that results in amelioration of disease. "Disruption" includes inhibition of HBV viral assembly and infection.

[0046] The compounds of the present disclosure may contain one or more chiral centers and therefore can exist as stereoisomers. The term "stereoisomer," as used herein, consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)," "(-)," "R," or "S," depending on the configuration of substituents around the stereogenic carbon atom, although those of skill in the art will recognize that the structure may imply chiral centers. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in the nomenclature, although those of skill in the art will recognize that the structure may imply chiral centers.

[0047] The compounds of the present disclosure may contain one or more double bonds and, therefore, may exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. [ka] As described herein, denotes a bond that may be a single bond, a double bond, or a triple bond. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond can be designated as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond.

[0048] The compounds of the present disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, a structure depicting a carbocyclic or heterocyclic ring encompasses both the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring can also be designated "cis" or "trans", where "cis" refers to substituents on the same side of the plane of the ring and "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring is designated "cis / trans".

[0049] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods include: (1) coupling the enantiomeric mixture to a chiral auxiliary and resolving the resulting diastereomer; These methods are exemplified by (1) separating a mixture of enantiomers by recrystallization or chromatography and liberating the optically pure product from the auxiliary; (2) forming a salt with an optically active resolving agent; (3) directly separating the mixture of enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers while creating a new stereocenter or converting an existing one, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0050] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present disclosure is intended to encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0051] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those listed herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, for example, 2 H, 3 H, 13 C.14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. For example, compounds of the present disclosure can have one or more H atoms replaced with deuterium.

[0052] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because they are easy to prepare and detect. Additionally, heavier isotopes such as deuterium (i.e., 2 H) can confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and, therefore, may be preferred in certain circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared following procedures similar to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0053] The term "prodrug" refers to a compound that is converted in vivo to produce a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The conversion can occur by various mechanisms (e.g., by esterase, amidase, phosphatase, oxidative and / or reductive metabolism, etc.) and at various locations (e.g., in the intestinal lumen, or during transport through the intestine, blood, or liver). Prodrugs are well known in the art (see, for example, Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery, 2008, vol. 7, p. 255).

[0054] II. Five-membered heteroarylcarboxamide compounds In one aspect, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof [wherein: L is C 1~4 Alkylene or HaloC 1~4 is alkylene, L 1 and L 2 are independently bonded, 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 and X 1 is NR x1 , O or S; X 2 O, NR 13 , C.R. 13 R 8 , C(O) or S(O) t and X 3 O, NR 4 , C.R. 4 R 8 , C(O) or S(O) t and X 4 and X 6 are independently O or S, X 5 is O, S or NR 0 and R a , R b and R c is hydrogen, C 1~6 Alkyl, HaloC 1~6 Alkyl and C 3~6 independently selected at each occurrence from the group consisting of: monocycloalkyl; R d is hydrogen, OH, C 1~6 Alkyl or C 1~6 is an alkoxy, R x1 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, HaloC 1~4 Alkyl or C 3~6 monocycloalkyl or R x1 and R 2 together form a -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O- -CH2CH2OCH2-, -CH2CH2-NH- -CH2NHCH2-, -CH2CH2CH2NH- or -CH2CH2NHCH2- group, R 0a are hydrogen, halogens, OH, CN, NO2, R a R b N-, C 1~4 Alkyl and HaloC 1~4 independently selected at each occurrence from the group consisting of alkyl, R 4a and R 6a are independently hydrogen or C 1~4 is alkyl, R 0 , R 6 and R 11 is hydrogen, halogen, OH, CN, NO2, oxo, R d N=hydrazino, formyl, azido, 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, HaloC 1~6 Alkyl, hydroxy 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 -, C1~6 Alkyl NR a C 1~6 Alkyl NR c -, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy-, R a R b NC 1~6 Alkoxy-, C 1~6 Alkoxy C 1~6 Alkyl-, HaloC 1~6 Alkoxy C 1~6 Alkyl-, R a R b NC(O)-, C 1~6 Alkyl C(O)-, C 1~6 AlkoxyC(O)-, C 1~6 Alkyl C(O)O-, C 1~6 AlkylS(O) q -, C 1~6 AlkylS(O) t NR c -, C 1~6 AlkylS(O) t C 1~6 Alkyl-, C 1~6 AlkylS(O) t NR a C 1~6 Alkyl-, C 3~6 CycloalkylS(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 independently selected at each occurrence from the group consisting of alkyl-, R 1 is phenyl or a 5- to 6-membered monocyclic heteroaryl, and said phenyl or 5- to 6-membered monocyclic heteroaryl is selected from one, two, or three independently selected R 11 optionally substituted with a group, R 2 and R 8 is hydrogen, halo, CN, OH, R a R b N.C. 1~4 Alkyl, HaloC1~4 Alkyl, C 3~5 Monocycloalkyl, C 1~4 Alkoxy and HaloC 1~4 independently selected from the group consisting of alkoxy; R 3 teeth, [ka] and R 4 is R 5 -L 1 -, R 6 Or R 9 or R 4 and R 8 together with the carbon atoms to which they are attached, [ka] [ka] Forming a base, R 5 teeth, [ka] and R 9 is R 14 S(O) q -L-, R 14 S(O) q NH-L- or R 14 C(O)NH-L-, R 10 teeth, [ka] and R 12 teeth, [ka] and R 13 is R 5 -L 1 -, R 10 -L1 -, R 6 or R 9 and R 14 is R a R b N-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, or R 5 -L 1 - and q, r, t, and w are independently selected at each occurrence from 0, 1, and 2; v is independently selected at each occurrence from 0, 1, 2, and 3. to provide.

[0055] The following embodiments further describe compounds of Formula I, or pharmaceutically acceptable salts thereof. It should be recognized that all chemically permissible combinations of the embodiments described herein are contemplated as additional embodiments of the present invention.

[0056] In certain embodiments, X 1 is S.

[0057] In certain embodiments, X 1 is NR x1 is.

[0058] In certain embodiments, X 1 is NR x1 and R x1 is the hydrogen of methyl.

[0059] In certain embodiments, X 1 is NR x1 and R x1 is methyl.

[0060] In certain embodiments, X 2 is CR 13 R8 is.

[0061] In certain embodiments, X 3 is CR 4 R 8 is.

[0062] In certain embodiments, L 1 is a bond.

[0063] In certain embodiments, L 1 is C 1~6 It is alkylene.

[0064] In certain embodiments, r is 0.

[0065] In certain embodiments, R 1 teeth, [ka] [In the formula, R 11 are halogens, CN, C 1~6 Alkyl and HaloC 1~6 independently selected at each occurrence from the group consisting of alkyl, z1 is 0, 1, 2 or 3].

[0066] In certain embodiments, R 11 is independently selected at each occurrence from the group consisting of halogen and CN.

[0067] In certain embodiments, R 11 is independently selected at each occurrence from the group consisting of F, Cl, Br and I.

[0068] In certain embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0069] In certain embodiments, R 1 teeth, [ka] is.

[0070] In certain embodiments, R 1 teeth, [ka] is.

[0071] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] is.

[0072] In certain embodiments, R 1 are halogens, CN, C 1~6 Alkyl and haloC 1~6 and 5-6 membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0073] In certain embodiments, R 1 teeth, [ka] [In the formula, R 11 are halogens, CN, C 1~6 Alkyl and haloC 1~6 independently selected at each occurrence from the group consisting of alkyl, z1 is 0, 1, 2 or 3].

[0074] In certain embodiments, R 2 is hydrogen.

[0075] In certain embodiments, R 2 is R a R b It's N.

[0076] In certain embodiments, R 2 is R a R b N and R a and R b is hydrogen and C 1~6 alkyl.

[0077] In certain embodiments, R 2 is NH2.

[0078] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth [ka] and R 2 is hydrogen.

[0079] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth [ka] and R 2 is NH2.

[0080] In certain embodiments, R 3 teeth, [ka] is.

[0081] In certain embodiments, R 3 teeth, [ka] is.

[0082] In certain embodiments, R 3 teeth, [ka] is.

[0083] In certain embodiments, R 3 teeth, [ka] is.

[0084] In certain embodiments, R 3 teeth, [ka] is.

[0085] In certain embodiments, R 3 teeth, [ka] is.

[0086] In certain embodiments, R 3 teeth, [ka] is.

[0087] In certain embodiments, R 3 teeth, [ka] is.

[0088] In certain embodiments, R 3 teeth, [ka] is.

[0089] In certain embodiments, R 3 teeth, [ka] is.

[0090] In certain embodiments, R 3 teeth, [ka] is.

[0091] In certain embodiments, R 4 is R 5 -L 1 -It is.

[0092] In certain embodiments, R 4 is R 5 is.

[0093] In certain embodiments, R 4 is R 6 is.

[0094] In certain embodiments, R 4 is R 9 is.

[0095] In certain embodiments, or R 4 and R 8 together with the carbon atoms to which they are attached, [ka] Form a group.

[0096] In certain embodiments, R 5 teeth, [ka] is.

[0097] In certain embodiments, R 5 teeth, [ka] is.

[0098] In certain embodiments, R 5 teeth, [ka] is.

[0099] In certain embodiments, R 6 is C 1~6 AlkylS(O) t C 1~6 Alkyl- or C 1~6 AlkylS(O) t NR a C 1~6 It is alkyl-.

[0100] In certain embodiments, R 8 is hydrogen, OH or C 1~6 It is an alkoxy.

[0101] In certain embodiments, R 8 is OH.

[0102] In certain embodiments, R 14 is R a R b N-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, or C 1~6 It is haloalkoxy.

[0103] In certain embodiments, R 14 is R 5 -L 1 -It is.

[0104] In certain embodiments, R 14 is R 5 is.

[0105] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] and R 2 is H and R 3 teeth, [ka] and R 8 is hydrogen, OH or C 1~6 It is an alkoxy.

[0106] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] and R 2 is H and R 3 teeth, [ka] and R 8 is OH.

[0107] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] and R 2 is H and R 3 teeth, [ka] and R 5 teeth, [ka] and R 8 is hydrogen, OH or C 1~6 It is an alkoxy.

[0108] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] and R 2 is H and R 3 teeth, [ka] and R 5 teeth, [ka] and R 8 is OH.

[0109] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] and R 2 is NH2 and R 3 teeth, [ka] and R 6 is C 1~6 AlkylS(O) t C 1~6 Alkyl- or C 1~6 AlkylS(O)t NR a C 1~6 alkyl-, and R 8 is hydrogen, OH or C 1~6 It is an alkoxy.

[0110] In certain embodiments, X 1 is NR x1 and R x1 is hydrogen or methyl, and R 1 teeth, [ka] and R 2 is NH2 and R 3 teeth, [ka] and R 6 is C 1~6 AlkylS(O) t C 1~6 Alkyl- or C 1~6 AlkylS(O) t NR a C 1~6 alkyl-, and R 8 is OH.

[0111] III. Pharmaceutical Compositions and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present disclosure provides a pharmaceutical composition comprising a compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most appropriate administration form in any given case will depend on the extent and severity of the condition being treated and the nature of the specific compound used. For example, the disclosed compositions can be formulated as a unit dose and / or formulated for oral or subcutaneous administration.

[0112] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to any combination of the examples described herein, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0113] The exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, containing one or more compounds of the present disclosure as an active ingredient, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application. The active ingredient can be formulated with a conventional non-toxic, pharmaceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the process or condition of the disease.

[0114] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical carrier, such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, this means that the active ingredient is uniformly dispersed throughout the composition, thereby allowing the composition to be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0115] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or silicic acid; or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be utilized as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, etc.

[0116] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the present composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings, and other coatings well known in the pharmaceutical formulation art.

[0117] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or their mixtures, and powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the present composition, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrin and their mixtures.

[0118] Suspensions may contain, in addition to the present compositions, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0119] Formulations for rectal or vaginal administration can be prepared by mixing the composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and can be presented as a suppository that is solid at room temperature but liquid at body temperature and therefore melts in the body cavity and releases the active agent.

[0120] The dosage form for transdermal administration of the present composition includes powder, spray, ointment, paste, cream, lotion, gel, solution, patch and inhalant.The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservative, buffer or propellant that may be required.

[0121] Ointments, pastes, creams and gels may contain, in addition to the present composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0122] Powders and sprays can contain, in addition to the present composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0123] Alternatively, the compositions and compounds of the present disclosure can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers can be used because they minimize exposure of the drug to shear, which can result in degradation of the compound contained in the composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition, but typically include non-ionic surfactants (Tween®, Pluronic®, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols, and the like. Aerosols are generally prepared from isotonic solutions.

[0124] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the 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 immediately before use (which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents).

[0125] Examples of suitable aqueous and non-aqueous carriers that can be utilized in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0126] In another aspect, the present disclosure provides an enteral pharmaceutical formulation comprising the disclosed compound and an enteric substance, and a pharmaceutically acceptable carrier or excipient thereof. The enteric substance refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluid at a specific pH. The small intestine is the portion of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Thus, for example, the enteric material is not soluble up to a pH of 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), polyvinyl acetate (PA), and the like. cellulose acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorum, and some commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit Examples of suitable enteric substances include PEG-100, PEG-100E, PEG-100F, PEG-100H ...

[0127] Advantageously, the present disclosure also provides kits for use by consumers in need of, for example, treatment of HBV infection. Such kits include an appropriate dosage form, such as those described above, and instructions describing how to use such dosage form to regulate, reduce, or prevent HBV infection. The instructions direct the consumer or medical professional to administer the dosage form according to an administration mode known to those skilled in the art. Such kits can be advantageously packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packaged. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed to the plastic foil on the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. The strength of the sheet is preferably such that the tablets or capsules can be removed from the blister pack by applying manual pressure on the recesses, which forms openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through said openings.

[0128] For example, it may be desirable to provide a memory aid on the kit in the form of numbers adjacent to the tablets or capsules, the numbers corresponding to the days of the regimen in which the so-identified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "Week 1, Monday, Tuesday...etc...Week 2, Monday, Tuesday...", etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule, while a daily dose of a second compound can consist of several tablets or capsules, or vice versa. The memory aid should reflect this.

[0129] IV. Method In a further aspect, a method of treating a hepatitis B infection in a patient in need thereof is selected from administering to the subject or patient an effective amount of a disclosed compound; and / or a disclosed first compound, and optionally an additional, different disclosed compound(s). In another embodiment, a method of treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to the 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.

[0130] For use according to this embodiment, the appropriate dosage will vary depending, for example, on the particular compound used, the method of administration, and the nature and severity of the infection being treated, as well as the specific infection being treated, and is within the jurisdiction of the attending physician. Typically, the specified dosage may be in the range of about 0.1 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 may be in the range of about 0.1 to about 100 μg / kg body weight. This dosage can be conveniently administered once daily or in divided doses, for example, up to four times daily, or in sustained-release form.

[0131] The compound of the present disclosure can be administered by any conventional route, particularly enteral, topical, oral, nasal, for example, in the form of tablet or capsule, by suppository, or parenterally, for example, in the form of injectable solution or suspension for intravenous, intramuscular, subcutaneous or intraperitoneal injection.Suitable formulations and pharmaceutical compositions include those that are formulated in a conventional manner using one or more physiologically acceptable carriers or additives, and those that are known, commercially available, and currently used in clinical situations.Therefore, the compound can be formulated in a suitable form for oral, buccal, topical, parenteral, rectal or transdermal administration, or for administration by inhalation or insufflation (either oral or nasal).

[0132] For oral administration, the pharmaceutical compositions may be in the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable additives such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups, or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid). The preparations can also contain buffer salts, flavoring agents, coloring agents, and sweetening agents, as appropriate.

[0133] Preparations for oral administration can also be suitably formulated so as to provide controlled or sustained release of the active compound(s) over an extended period of time. For buccal administration, the compositions can be in the form of tablets or lozenges formulated in conventional manner known to those skilled in the art.

[0134] The disclosed compounds can be administered parenterally by injection, for example, by bolus injection or continuous infusion. It can also be formulated for administration.The preparation for injection can be presented in a unit dosage form, for example, in ampoules or in multi-dose containers, with added preservatives.The composition can be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain additives such as suspending agents, stabilizing agents and / or dispersing agents.Alternatively, the compound can be in powder form, for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.The compound can also be formulated as a suppository or retention enema, for example, containing a conventional suppository base, for example, cocoa butter or other glycerides, for rectal administration.

[0135] Also contemplated herein are methods and compositions comprising administering a second active agent or a second active agent.For example, in addition to being infected with HBV, a subject or patient may also have HBV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or accelerated by HBV infection.Contemplated herein are the disclosed compounds in combination with at least one other drug that has been shown to treat these HBV infection-related conditions.

[0136] In some cases, the disclosed compounds can be administered as part of a combination therapy in combination with one or more antiviral agents. Exemplary antiviral agents include nucleoside analogs, interferon alpha, and other assembly effectors, such as heteroaryldihydropyrimidines (HAPs), such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). Provided herein, for example, are methods for treating a patient suffering from a hepatitis B infection, comprising administering to the patient a first amount of a disclosed compound and a second amount of an antiviral or other anti-HBV agent, such as a second amount of a second compound selected from the group consisting of: another HBV capsid assembly promoter (e.g., GLS4, BAY41-4109, AT-130, DVR-23 (e.g., as depicted below): [ka] ;NVR3-778, NVR1221 (by code); and N890 (as pictured below): [ka] other capsid inhibitors, such as those described in the following patent applications, which are incorporated herein by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO20 those disclosed in WO2014033176, WO2014033167, and WO2014033170; nucleoside(t)ide 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), prodrugs of tenofavir (e.g., AGX-1009), L-FMAU (Clevudine), LB80380 (Vesifovir), and [ka] 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 depicted below: [ka] ; and the BM601 pictured below: [ka] nucleocapsid formation or integrity disruptors, such as NZ-4 / W28F: [ka] cccDNA formation inhibitors, such as BSBI-25, CCC-0346, CCC-0975 (as depicted below): [ka]

[0137] transbodies directed against HBc, such as those described in Wang Y et al., Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014) (published at http: / / dx.doi.org / 10.1016 / j.intimp.2015.01.028); antiviral core protein mutants (e.g., Cp183-V124W and related mutations described in WO / 2013 / 010069, WO2014 / 074906, each of which is incorporated by reference); inhibitors of HBx-interactions, such as HBV RNA-targeting, RNAi, antisense, and nucleic acid-based polymers; for example, RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid-based polymers (REP2139-Ca); immunostimulants, such as interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), pegylated IFN2b, IFN lambda 1a, and PEG IFN lambda 1a, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1; non-interferon immune enhancers such as thymosin alpha-1 (Zadaxin) and interleukin-7 (CYT107); TLR-7 / 9 agonists such as GS-9620, CYT003, resiquimod; cyclophilin inhibitors such as NVP018; OCB-030; SCY-635; alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, core antigen vaccines; SMAC mimetics such as birinapant and other IAP-antagonists;Epigenetic modulators, such as KMT inhibitors (EZH1 / 2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g., OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors and bromodomain antagonists; kinase inhibitors, such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM and ATR kinase inhibitors; STING agonists; ribavirin; N-acetylcysteine; NOV-205 (BAM205); nitazoxanide (Alinia), tizoxanide; SB9200 small molecule nucleic acid hybrid (SMNH); DV-601; arbidol; FXR agonists (e.g., GW4064 and fexaramine); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting with host proteins.

[0138] In some embodiments, the present disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering to the patient a first compound selected from any one of the disclosed compounds and an HBV capsid assembly enhancer, an HBF viral polymerase interfering nucleoside, a viral entry inhibitor, an HBsAg secretion inhibitor, a nucleocapsid formation disruptor, a cccDNA formation inhibitor, an antiviral core protein mutant, a transbody directed against HBc, an RNAi targeting HBV RNA, an immunostimulant, a TLR-7 / 9 agonist, a cyclophilin inhibitor, an HBV vaccine, a SMAC mimetic, or an epigenetic modulator. and one or more other HBV agents, each selected from the group consisting of a hydroxybenzoate, a hydroxybenzoate inhibitor ...

[0139] In some embodiments, the first and second amounts together constitute a pharmaceutically effective amount.The first amount, the second amount, or both can be the same, greater than, or less than the effective amount of each compound administered as monotherapy.The therapeutically effective amount of the disclosed compound and antiviral drug can be administered to a subject in combination, i.e., simultaneously or separately in any given order, by the same or different administration route.In some cases, it may be advantageous to first start administering the disclosed compound, for example, one day, several days, or several weeks before starting to administer antiviral drug.In addition, additional drugs can be given together with the above combined therapy.

[0140] In another embodiment, the disclosed compounds can be conjugated (e.g., covalently attached, directly or via a molecular linker, to a free carbon, nitrogen (e.g., amino group), or oxygen (e.g., active ester) of the disclosed compounds) with a detection moiety, such as a fluorophore moiety (such moiety can re-emit a certain light frequency, e.g., upon binding to a virus and / or photon excitation). Contemplated fluorophores include AlexaFluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinone, fluorescent protein, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated with a detection moiety can be used, for example, in vitro or in vivo. It can be used in vivo, for example, in methods for detecting HBV or biological pathways of HBV infection, and / or in methods for evaluating new compounds for biological activity. [Example]

[0141] V. Working Example The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art.In the following description of synthetic methods, it should be understood that all proposed reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and work-up procedures, can be selected to be standard conditions for the reaction unless otherwise specified.It is understood by those skilled in the art of organic synthesis that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions.Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods will be shown accordingly.The starting materials for the examples are commercially available or can be easily prepared from known materials by standard methods.

[0142] At least some of the compounds identified herein as "intermediates" are contemplated as compounds of the present invention.

[0143] Abbreviation: AcOH acetic acid ACN Acetonitrile Boc2O di-tert-butyl dicarbonate nBuLi n-butyllithium DCM dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPPF 1,1'-bis(diphenylphosphino)ferrocene EA, EtOAc, ethyl acetate Et3N Triethylamine HATU Hexafluorophosphate azabenzotriazole tetramethyluronium h, hr hours HPLC High-Performance Liquid Chromatography LCMS Liquid Chromatography-Mass Spectrometry MeOH Methanol NMO N-methylmorpholine-N-oxide NBS N-Bromosuccinimide PE Petroleum Ether iPrOH isopropanol rt, rt room temperature SFC Supercritical Fluid Chromatography TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0144] [ka] [ka] [ka] [ka]

[0145] For the analysis of the final compounds, an LCMS method was used.

[0146] Method A: X-Bridge BEH C-18 (3 × 50 mm × 2.5 μm), mobile phase: A; 0.025% formic acid in H2O, B; CH3CN, injection volume: 2 μL, flow rate: 1.2 mL / min, column temperature: 50 °C, gradient program: 2% B to 98% B in 2.2 min, hold until 3 min, B concentration at 3.2 min up to 2% for 4 min.

[0147] Method B: X-select CSH 18 (3 × 50 mm × 2.5 μm), mobile phase: A; 0.025% formic acid in H2O, B; CH3CN, injection volume: 2 μL, flow rate: 1.2 mL / min, column temperature: 50 °C, gradient program: 0% B to 98% B in 2 min, hold until 3 min, B concentration at 3.2 min up to 0% for 4 min.

[0148] Method C: X-select CSH 18 (3 × 50 mm × 2.5 μm), mobile phase: A; 0.05% formic acid in H2O:CH3CN (95:5), B; 0.05% formic acid in CH3CN, injection volume: 2 μL, flow rate: 1.2 mL / min, column temperature: 50 °C, gradient program: 0% B to 98% B in 2 min, hold for 3 min, B concentration at 3.2 min up to 0% B for 4 min.

[0149] Method D: X-select CSH C18 (3 × 50 mm × 2.5 μm), mobile phase: A; 2 mM in ammonium bicarbonate, B; CH3CN, injection volume: 2 μL, flow rate: 1.2 mL / min, column temperature: 50 °C, gradient program: 0% B to 98% B in 2 min, hold until 3 min, B concentration at 3.2 min up to 0% B for 4 min.

[0150] Method E: X-select CSH 18 (3 × 50 mm × 2.5 μm), mobile phase: A; 0.05% formic acid in H2O, B; CH3CN, injection volume: 2 μL, flow rate: 1.5 mL / min, column temperature: 50 °C, gradient program: 0% B to 100% B in 1.5 min, hold until 2.2 min, B concentration at 2.6 min up to 0% for 3 min.

[0151] General Procedure for Amidation

[0152] Method A (amide coupling using EDC·HCl): To a stirred solution of carboxylic acid (1 equiv.) in 1,4-dioxane (5.84 mL / mmol), EDC·HCl (1.1 equiv.), HOBt (1.1 equiv.), and the corresponding amine (1 equiv.) were added at 0°C and stirred for 5 min. To this solution, DIPEA (3 equiv.) was added, and the resulting reaction mixture was stirred at 90°C overnight. Upon completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution, water, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude compound, which was purified by silica gel column chromatography / preparative HPLC to give the desired compound.

[0153] Method B (amide coupling using HATU): To a stirred solution of the acid compound (1.1-1.2 equiv.) in DMF / DCM (1.01 mL / mmol) at 0°C, DIPEA (2-3 equiv.) and HATU (1.5-2.5 equiv.) were added and stirred for 5 minutes. To this solution, the corresponding amine (1 equiv.) was added. The resulting reaction mixture was stirred at room temperature for 12-16 hours. 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 purified by either preparative HPLC or CombiFlash® column chromatography to give the desired compound.

[0154] Method C (AlMe3-mediated amidation): To a stirred solution of the corresponding aniline (1.1 equiv.) in DCM / toluene (3 mL / mmol) was added AlMe3 (2 M in toluene, 2.5 equiv.) under an argon atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and stirring was continued at room temperature for 1 h. To this solution, the corresponding ester compound (1 equiv.) was added under an argon atmosphere at 0 °C. 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 1 N aqueous HCl, and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude compound was purified by washing with methanol to give the desired compound.

[0155] Method D (amide coupling using acid chlorides / derivatives): To a stirred solution of an amine compound (1 equiv.) in DCM (1.01 mL / mmol), TEA (1.5-3 equiv.) was added at 0°C and stirred for 5 minutes. To this solution, the corresponding acid chloride / carbamic acid chloride / chloroformate (1.1-1.5 equiv.) was slowly added at 0°C, and the reaction mixture was stirred at room temperature until completion. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate / DCM. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by either preparative HPLC or CombiFlash® column chromatography to give the desired compound.

[0156] General Procedure for the Grignard Reaction

[0157] Method A (at lower temperature): To a stirred solution of keto compound (1 equiv.) in dry THF (0.2 mL / mmol) was slowly added Grignard reagent (10 equiv.) via glass syringe at −78° C. under an inert atmosphere, and the reaction mixture was stirred at the same temperature for 4 h and then at room temperature for 2 h. After completion, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate / DCM. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated on a rotavapor to give the crude compound. The crude compound was purified by either CombiFlash® column chromatography or preparative HPLC to give the desired compound.

[0158] General Method for Suzuki Coupling

[0159] Method A: To a mixture of a halo compound (1 equiv.) and the corresponding boronic acid / boronic ester (1.2–1.5 equiv.) in 1,4-dioxane:water (4:1) (2.17 mL / mmol) was added Na2CO3 (2–3 equiv.) and purged with argon for 15 minutes. To this solution was added PdCl2(dppf) (0.1 equiv.) and purging with argon continued for another 10 minutes. The resulting reaction mixture was stirred at 100 °C for 12–16 hours. After completion of the reaction, the reaction mixture was filtered through Celite® 545 and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water followed by brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by either CombiFlash® column chromatography or preparative HPLC to give the desired compound.

[0160] General Procedure for Hydrogenation

[0161] Method A: To a stirred solution of olefin compound (1 equiv.) in EtOAc (2.67 mL / mmol) under a nitrogen atmosphere was added 20% Pd / C (20% w / w of olefin compound). The reaction mixture was stirred under a hydrogen atmosphere (100 psi) at 40-50°C for 4-7 hours. Upon completion, the reaction mixture was filtered through a pad of Celite® 545 and washed with EtOAc / methanol. The filtrate was concentrated under reduced pressure to give the compound, which was purified by silica gel column chromatography or preparative HPLC to give the desired compound.

[0162] General Procedure for Keto Reduction

[0163] Method A: To a stirred solution of keto compound (1 equiv.) in EtOH / MeOH (5 vol.) (4.7 mL / mmol) under argon atmosphere at 0°C, NaBH4 (1-2 equiv.) was added and stirred at room temperature for 2-6 h. Upon completion, the reaction mixture was concentrated in vacuo, 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 in vacuo, and purified by silica gel column chromatography / preparative HPLC to afford the desired compound. Note: THF (1 vol.) was also added as a co-solvent for substrates with poor solubility in alcoholic solvents.

[0164] Intermediate 1 [ka]

[0165] 5-Oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate. To a solution of 1,3,3a,4,6,6a-hexahydropentalene-2,5-dione (40.0 g, 289.5 mmol) and pyridine (24.0 g, 304.0 mmol) in DCM (600 mL) was added TfO (89.8 g, 318.5 mmol) dropwise 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 × 3). The organic layer was separated, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography using 8:1 (v / v) petroleum ether / ethyl acetate to give 5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 5.63 (q, J = 1.92 Hz, 1 H), 3.57 - 3.50 (m, 1 H), 3.14 - 3.00 (m, 2 H), 2.67 - 2.58 (m, 1 H), 2.56 -2.40 (m, 2 H), 2.34 - 2.26 (m, 1 H), 2.17 (ddd, J = 19.14, 7.34, 1.63 Hz, 1 H) ppm.

[0166] Intermediate 2 [ka]

[0167] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(1H)-one. A mixture of 5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate (110.0 g, 407.0 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (108.5 g, 427.4 mmol), Pd(dppf)Cl (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 N atmosphere for 2 hours. The reaction mixture was filtered through a pad of Celite®, and the filter cake was washed with EtOAc (250 mL × 3). The filtrate was concentrated in vacuo 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-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(1H)-one as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 6.37 (q, J = 2.08 Hz, 1 H), 3.54 - 3.41 (m, 1 H), 3.05 - 2.93 (m, 1 H), 2.79 (ddt, J = 16.48, 7.58, 2.64, 2.64 Hz, 1 H), 2.55 - 2.24 (m, 4 H), 2.07 - 1.95 (m, 1 H), 1.28 (s, 13 H) ppm.

[0168] Intermediate 3 [ka]

[0169] Methyl 2,4-dibromo-1-methyl-1H-imidazole-5-carboxylate. To a solution of methyl 1-methyl-1H-imidazole-5-carboxylate (16.6 g, 118.5 mmol) in CHCl3 (200 mL) was added NBS (78.3 g, 414.8 mmol) and AIBN (1.95 g, 11.9 mmol). The reaction mixture was stirred at 60 °C for 24 h. The mixture was concentrated and purified by column chromatography (R f =0.4, PE:EA=5:1) to give methyl 2,4-dibromo-1-methyl-1H-imidazole-5-carboxylate (22.2 g, 63% yield) as a yellow solid.

[0170] Intermediate 4 [ka]

[0171] N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 1-methyl-1H-imidazole-5-carboxylic acid (10 g, 83 mmol), 3-chloro-4-fluoroaniline (18 g, 124 mmol), and EtN (16 g, 160 mmol) in DMF (100 mL) was added HATU (63 g, 160 mmol) 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 give N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a pale white solid. TLC: (50% ethyl acetate / petroleum ether) (Rf: 0.3). C 11 MS calculated for H9ClFN3O: 253.0; Found: 254.1 [M+1] + .

[0172] Intermediate 5 [ka]

[0173] 2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (4 g, 15 mmol) in CHCl3 (100 mL) was added NBS (10 g, 60 mmol) and AIBN (0.25 g, 1.5 mmol) at room temperature. The reaction mixture was stirred at 50°C for 18 hours. The mixture was evaporated in vacuo to give a yellow residue. The residue was purified by silica gel chromatography to give 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a yellow solid. TLC: 40% ethyl acetate / petroleum ether (R f :0.3). C 11 MS calculated for HBrClFN0: 408.9; found: 411.2 [M+2] + .

[0174] Alternative synthesis of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 2,4-dibromo-1-methyl-1H-imidazole-5-carboxylic acid (9.94 g, 35.0 mmol) in DMF (50 mL) was added HATU (13.3 g, 35.0 mmol) and DIPEA (9.69 g, 175 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 1 hour. Then, 3-chloro-4-fluoroaniline (6.1 g, 42.0 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was added dropwise to water (600 mL) and the resulting precipitate was filtered to give 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (12.5 g, 87% yield) as a yellow solid.

[0175] Intermediate 6 [ka]

[0176] 4-Bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (1.1 g, 2.0 mmol) in THF (50 mL) was slowly added CHMgI (2 mL, 4.0 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 4 hours, then poured into water (50 ml) and extracted with ethyl acetate (20 mL×3). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a yellow solid. TLC: 50% ethyl acetate / petroleum ether (Rf: 0.3). C 11 MS calculated for HBrClFN0: 331.0; Found: 332.1 [M+1] + .

[0177] Alternative procedure for the synthesis of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was synthesized following the general procedure described above for amidation (Method C) to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a brown solid. TLC: 30% EtOAc / hexane (R f :0.45); 1 H NMR (DMSO-d 6, 400 MHz): δ 10.41 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.85 (s, 1H), 7.63-7.60 (m, 1H), 7.43 (t, J = 9.6 Hz, 1H), 3.75 (s, 3H);C 11 LCMS calculated for HBrClFN0: 331 .0; Actual value: 332.1 [M+1] + .

[0178] Intermediate 7 [ka]

[0179] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide. A mixture of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (600 mg, 1.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(1H)-one (448 mg, 1.8 mmol), Pd(dppf)Cl (62 mg, 0.077 mmol), and KPO (814 mg, 3.6 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 100° C. for 4 hours under N. Then, EtOAc (20 mL) was added to the mixture. The mixture was filtered, and the filtrate was washed with HO (35 mL × 3). The organic layer was separated, dried over NaSO, and evaporated in vacuo 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-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide as a brown solid. TLC; 5% MeOH / DCM (R f :0.2). C 19 H 17 MS calculated for ClFN3O2: 373.13. Found: 374.1 [M+1] + .

[0180] Alternative synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide. To a solution of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (13.3 g, 40.0 mmol) in 1,4-dioxane / HO (v / v=7:1, 120 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(1H)-one (12.2 g, 48.0 mmol), Pd(dppf)Cl (2.9 g, 4.0 mmol), and NaCO (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 pad of Celite. The solid was washed with EA and the filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel using 5% methanol in 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-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide (12.8 g, 85.6%) as a brown solid. TLC: 7% methanol / DCM (R f :0.5);C 19 H 17 MS calculated for ClFN3O2: 373.1; Found: 374.3 [M+1] + .

[0181] Example 1 [ka]

[0182] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide (300 mg, 0.8 mmol) in THF (20 ml) was added Pd / C (30 mg, 10% Pd). The mixture was stirred under H2 at 30 °C for 5 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to give a yellow residue. The residue was purified by silica gel chromatography to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide as a brown solid as a single diastereomer. TLC: 50% ethyl acetate / petroleum ether (R f :0.3). C 19 H 19 MS calculated for ClFN3O2: 375.2; found: 376.2 [M+1] + .

[0183] Alternative synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide (12.8 g, 34.2 mmol) in THF (200 mL) was added Pd / C (6.4 g, 10%) under H2, and the mixture was stirred at room temperature for 4 h. The mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel using 5% methanol in DCM (80 g silica gel column, 50 mL / min) to give a grey solid, N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide, as a single diastereomer (12.0 g, 93.3%). TLC: 7% methanol / DCM (R f :0.5);C 19 H 19 MS calculated for ClFN3O2: 375.2; MS found: 376.3 [M+1] + .

[0184] Example 2 [ka]

[0185] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (20 mg, 0.053 mmol) in MeOH (2 ml) was added NaBH (36 mg, 0.95 mmol). The mixture was stirred at room temperature for 8 hours. The mixture was evaporated in vacuo to give a yellow residue. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid as a single diastereomer. TLC: 50% ethyl acetate / petroleum ether (R f :0.3). C 19 H 21 MS calculated for ClFN3O2: 377.1. Found: 378.2 [M+1] + . 1 H NMR (DMSO-d6, 400 MHz): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.64 (s, 1H), 7.58-7.54 (m, 1H), 7.40 (t, J = 8.8Hz, 1H), 4.50 (d, J = 4.4 Hz, 1H), 4.03 (dd, J = 6.8, 2.4 Hz, 1H), 3.66 (s, 3H), 3.26-3.20 (m, 1H), 2.32-2.28 (m, 2H), 2.11-2.05 (m, 2H), 1.95-1.89 (m, 2H), 1.70-1.62 (m, 2H), 1.30-1.23 (m, 2H) ppm.

[0186] Example 3 [ka]

[0187] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((methylsulfonyl)methyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of methylsulfonylmethane (24 mg, 0.26 mmol) in THF (5 mL) was added n-BuLi (0.2 mL, 0.5 mmol) at −78° C. The solution was stirred at −78° C. for 30 minutes. Then, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (50 mg, 0.13 mmol) was added, and the reaction was allowed to warm slowly to room temperature and stirred for 5 hours. The reaction mixture was quenched with HO (20 mL) and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((methylsulfonyl)methyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid as a single diastereomer. TLC: 20% ethyl acetate / petroleum ether (R f :0.4). C 21 H 25 MS calculated for ClFN3O4S: 469.1; found: 470.2 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.64 (s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J = 9.2 Hz, 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, 4.0 Hz, 2H) ppm.

[0188] Example 4 [ka]

[0189] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 4-iodo-1-methyl-1H-imidazole (208 mg, 1.0 mmol) in THF (5 mL) was added a solution of i-PrMgCl in THF (2.0 M, 0.5 mL, 1.0 mmol). The mixture was stirred at room temperature for 2 hours. To this solution was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (46 mg, 0.08 mmol) in THF (2.0 mL). The final mixture was stirred at room temperature overnight. The reaction mixture was quenched with methanol (2.0 mL) and Concentration in air was performed. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid as a single diastereomer. 23 H 25 MS calculated for ClFN5O2: 457.2; found: 458.3 [M+1] + . 1 H NMR (DMSO-d6, 400 MHz): 10.20 (s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 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.

[0190] Example 5 [ka]

[0191] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in THF (2 mL) was added a solution of n-BuLi in hexane (2.5 M, 0.4 mL, 1.0 mmol). The mixture was stirred at room temperature for 2 hours. Then, to this mixture was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (46 mg, 0.08 mmol) in THF (2.0 mL). The final mixture was stirred at room temperature overnight. The reaction mixture was quenched with methanol (2.0 mL) and concentrated in vacuo. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid as a single diastereomer. 23 H 25 MS calculated for ClFN5O2: 457.2; Found: 458.3 [M+1] + ; 1H NMR (CD3OD, 400 MHz): 7.87 (dd, J = 6.4, 2.4 Hz, 1H), 7.65 (s, 1H), 7.52-7.48 (m, 1H), 7.23 (t, J = 8.8 Hz, 1H), 6.98 (d, J = 1.2 Hz, 1H), 6.76 (d, J = 1.2 Hz, 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.

[0192] Synthesis of Examples 6-15. Examples 6-15 in Table 1 were synthesized according to the procedures provided above using the corresponding starting materials. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0193] Intermediate 8 [ka]

[0194] Ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1 -methyl-1H-imidazol-4-yl)hexahydropentalen-2(1H)-ylidene)acetate. To a solution of ethyl 2-(diethoxyphosphoryl)acetate (448 mg, 2 mmol) in dry THF (25 mL), NaH (48 mg, 2 mmol) was slowly added, followed by stirring at 0 °C for 0.5 h. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (375 mg, 1 mmol) in THF (5 mL) was added, and stirring was 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, and the organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography using 25-60% ethyl acetate / petroleum ether to give ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydropentalen-2(1H)-ylidene)acetate as a pale yellow solid. TLC: 60% ethyl acetate / petroleum ether (R f :0.2). C 23 H 25 MS calculated for ClFN3O3: 445.2; Found: 446.3 [M+1] + .

[0195] Example 16 [ka]

[0196] Ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)acetate. To a solution of -(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydropentalen-2(1H)-ylidene)acetate (223 mg, 0.5 mmol) in THF (15 mL) was added Pd / C (50 mg). The flask was then evacuated and filled with H2. The solution was stirred at room temperature overnight. 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)octahydropentalen-2-yl)acetate as a white solid. TLC: 60% ethyl acetate / petroleum ether (R f :0.2). C 23 H 27 MS calculated for ClFN3O3: 447.2. Found: 448.3 [M+1] + .

[0197] Intermediate 9 [ka]

[0198] 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)acetic acid. To a solution of ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)acetate (45 mg, 0.1 mmol) in CH3OH / HO (5 mL / 1 mL) was added LiOH (42 mg, 1 mmol). The solution was stirred at room temperature for 4 h. 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 x 3), and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)acetic acid as a pale yellow solid. TLC: 100% ethyl acetate / petroleum ether (R f :0.1). C 21 H 23 MS calculated for ClFN3O3: 419.1; Found: 420.2 [M+1] + .

[0199] Example 17 [ka]

[0200] 4-(5-(2-Amino-2-oxoethyl)octahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydropentalen-2-yl)acetic acid (43 mg, 0.1 mmol) in anhydrous DCM (10 mL) was added NH4Cl (54 mg, 1 mmol), HATU (38 mg, 0.1 mmol), and Et3N (101 mg, 1 mmol), and 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)octahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a white solid. TLC: 80% ethyl acetate / petroleum ether (R f :0.3). C 21 H 24 MS calculated for ClFN4O2: 418.2; Found: 419.3 [M+1] + . 1 H NMR (DMSO-d6, 400 MHz): δ 10.21 (s, 1H), 7.95 (dd, J = 7.2, 2.4 Hz, 1H), 7.65 (s, 1H), 7.58-7.55 (m, 1H), 7.40 (t, J = 9.2 Hz, 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.

[0201] Example 18 [ka]

[0202] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazin-1-yl)octahydropentalen-2-yl)-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (50 mg, 0.13 mmol) in THF (3 ml) was added 1-methylpiperazine (110 mg, 1.1 mmol) and NaBHCN (40 mg, 0.65 mmol). The mixture was stirred at 55° C. overnight. The solvent was removed in vacuo to give a yellow residue. This was purified by column chromatography and preparative HPLC to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazin-1-yl)octahydropentalen-2-yl)-1H-imidazole-5-carboxamide as a white solid. TLC: 10% DCM / MeOH(R f :0.3). C 24 H 31 MS calculated for ClFNO: 459.2; Found: 460.3 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 10.23 (s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 1H), δ 7.66 (s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J = 9.2 Hz, 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.

[0203] Intermediate 10 [ka]

[0204] N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1'H-spiro[oxirane-2,2'-pentalen]-5'-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of t-BuOK (0.75 g, 6.7 mmol) in THF (20 mL) was added trimethysulfonium iodide (1.47 g, N-(3-chloro-4-furan, 6.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (0.5 g, 1.3 mmol) was added and the mixture was heated to 60° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL×3). The combined organic phase was concentrated in vacuo. 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[oxirane-2,2′-pentalen]-5′-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid. TLC: 50% ethyl acetate / petroleum ether (R 2 ). f :0.2). C 20 H 21 MS calculated for ClFN3O2: 389.1; Found: 390.2 [M+1] + .

[0205] Example 19 [ka]

[0206] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide isomer I. To a solution of N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1′H-spiro[oxirane-2,2′-pentalen]-5′-yl)-1-methyl-1H-imidazole-5-carboxamide (100 mg, 0.26 mmol) in THF / HO (6:1, 5 mL) was added HSO (0.1 mL) and the mixture was stirred at room temperature overnight. The reaction was made basic with NaHCO (aq) and then extracted with ethyl acetate. The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide Isomer I as a white solid. TLC; 5% MeOH / DCM (R f :0.4). C 20 H 23 MS calculated for ClFN3O3: 407.1; Found: 408.2 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 10.21 (s, 1H), 7.96 (dd, J = 7.2, 2.8 Hz, 1H), 7.65 (s, 1H), 7.59-7.55 (m, 1H), 7.41 (t, J =8.8 Hz, 1H), 4.54 (t, J = 5.6 Hz, 1H), 4.02 (s, 1H), 3.67 (s, 3H), 3.30 (s, 1H), 3.25 (d, J = 5.6 Hz, 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.

[0207] Example 20 [ka]

[0208] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide isomer II. To a solution of N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1H-spiro[oxirane-2,2'-pentalen]-5'-yl)-1-methyl-1H-imidazole-5-carboxamide (100 mg, 0.26 mmol) in dioxane (2 mL) and water (0.5 mL), NaOH (80 mg, 2.0 mmol) was added, and the mixture was stirred at 100°C for 24 hours. After cooling, the pH was adjusted to 8 with 1N HCl and extracted with ethyl acetate. The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-pentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide Isomer II as a pale yellow solid. TLC; 5% MeOH / DCM (R f :0.4). C 20 H 23 MS calculated for ClFN3O3: 407.1; Found: 408.2 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 10.21 (s, 1H), 7.96 (dd, J = 7.2, 2.8 Hz, 1H), 7.64 (s, 1H), 7.58-7.55 (m, 1 H), 7.41 (t, J =8.8 Hz, 1H), 4.45 (t, J = 5.6 Hz, 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, 2H), 1.89-1.84 (m, 2H), 1.81-1.74 (m, 2H), 1.33 (dd, J = 13.2, 4.4 Hz, 2H) ppm.

[0209] Example 21 [ka]

[0210] 2-Chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (200 mg, 0.53 mmol) in DMF (5 mL) was added NCS (700 mg, 5.3 mmol) and AIBN (0.25 g, 1.5 mmol) at room temperature. The reaction mixture was stirred at 35° C. overnight. The mixture was evaporated in vacuo to give a yellow residue. The residue was purified by silica gel chromatography to give 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide as a yellow solid. TLC: 40% ethyl acetate / Petroleum ether (R f :0.3). C 19 H 18 MS calculated for Cl2FN3O2: 409.1, found: 410.2 [M+1] + .

[0211] Example 22 [ka]

[0212] 2-Chloro-N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (20 mg, 0.05 mmol) in MeOH (2 ml) was added NaBH (36 mg, 0.95 mmol). The mixture was stirred at room temperature for 8 hours. The solvent was evaporated in vacuo to give a yellow residue. The residue was purified by preparative HPLC to give 2-chloro-N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid. TLC: 50% ethyl acetate / petroleum ether (R f :0.3). C 19 H 20 MS calculated for Cl2FN3O2: 411.1; Found: 412.2 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 10.39 (s, 1H), 7.95 (dd, J = 6.8, 4.8 Hz, 1H), 7.57-7.54 (m, 1H), 7.42 (t, J = 9.2Hz, 1H), 4.51 (d, J = 4.0 Hz, 1H), 4.05 (dd, J = 11.2, 6.8 Hz, 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.

[0213] Intermediate 11 [ka]

[0214] 2-Methyl-1H-imidazole-4,5-dicarbonitrile. A solution of 2,3-diaminomaleonitrile (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 h. After cooling to room temperature, it was filtered to give 2-methyl-1H-imidazole-4,5-dicarbonitrile as a brown solid. TLC: 30% ethyl acetate / petroleum ether (R f : 0.4). MS calculated for C6H4N4: 132.0. Found: 133.0 [M+1] + .

[0215] Intermediate 12 [ka]

[0216] 1,2-Dimethyl-1H-imidazole-4,5-dicarbonitrile. To a suspension of 1,2-methyl-1H-imidazole-4,5-dicarbonitrile (50 g, 0.38 mol) and NaHCO3 (160 g, 1.51 mol) in HO (300 mL), dimethyl sulfate (62 g, 0.49 mol) was added dropwise at 55 °C, and the reaction was stirred at the same temperature for 6 h. Ice water was added and extracted with ethyl acetate (300 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 1,2-dimethyl-1H-imidazole-4,5-dicarbonitrile, which was used in the next step without further purification. TLC: 30% ethyl acetate / petroleum ether (R f : 0.5). MS calculated for C7H7N4: 146.0; Found: 147.0 [M+1] + .

[0217] Intermediate 13 [ka]

[0218] 1,2-Dimethyl-1H-imidazole-4,5-dicarboxylic acid. A solution of 1,2-dimethyl-1H-imidazole-4,5-dicarbonitrile (41 g, 0.28 mol) in 2 M aqueous NaOH (45 g, 1.12 mol, 560 mL) was stirred at 100° C. for 6 hours. After cooling to room temperature, the solution was acidified (pH=1) with 6 N aqueous HCl. After filtration, the solid was dried in an oven at 100° C. for 16 hours to give 1,2-dimethyl-1H-imidazole-4,5-dicarboxylic acid as a white solid. MS calculated for C7H8N2O4: 184.0. Found: 185.1 [M+1] + .

[0219] Intermediate 14 [ka]

[0220] 1,2-Dimethyl-1H-imidazole-5-carboxylic acid. A suspension of 1,2-dimethyl-1H-imidazole-4,5-dicarboxylic acid (5 g, 27 mmol) in AcO (150 mL) was stirred at 100 °C for 16 h. The reaction was concentrated to give the crude product, which was crystallized from acetone (100 mL) to give 1,2-dimethyl-1H-imidazole-5-carboxylic acid as a brown solid. MS calculated for C H N O: 140.1; found: 141.1 [M+1] + .

[0221] Intermediate 15 [ka]

[0222] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazole-5-carboxamide. To a solution of 2-dimethyl-1H-imidazole-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) was added HATU (2.28 g, 6 mmol), 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 × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the 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-imidazole-5-carboxamide as a white solid. TLC: 10% ethyl acetate / MeOH(R f : 0.4). MS calculated for C12H11ClFN3O: 267.1; found: 268.1 [M+1] + .

[0223] Intermediate 16 [ka]

[0224] 4-Bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazole-5-carboxamide. To a suspension of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazole-5-carboxamide (510 mg, 1.91 mmol) and NaOAc (1.57 g, 19.1 mmol) in EtOH (40 mL) was added Br (1.5 g, 9.6 mmol) dropwise at 15 °C. The reaction mixture was then stirred at room temperature for 11 hours. The reaction was quenched with 0.5% NaHSO (aq) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated to give a residue, which 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-imidazole-5-carboxamide as a white solid. TLC: 10% ethyl acetate / MeOH (R f :0.6). C 12 H 10 MS calculated for BrClFN3O: 345.0; Found: 346.2 [M+1] + .

[0225] Intermediate 17 [ka]

[0226] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide. To a solution of 4-bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazole-5-carboxamide (400 mg, 1.16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(1H)-one (431 mg, 1.74 mmol), and NaCO (246 mg, 2.32 mmol) in a mixture of dioxane (20 mL) and HO (5 mL), Pd(dppf)Cl (50 mg) was added under a nitrogen atmosphere, and the reaction was stirred at 80 °C for 6 h. After cooling to room temperature, the mixture was filtered through a pad of Celite®. The filtrate was diluted with water and extracted with ethyl acetate (40 mL × 2). The combined organic layers were concentrated to give a 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-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide as a white solid. TLC: 10% ethyl acetate / MeOH (R f :0.3). C 20 H 19 MS calculated for ClFN3O2: 387.1. Found: 388.2 [M+1] + .

[0227] Example 23 [ka]

[0228] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide. A mixture of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1H-imidazole-5-carboxamide (300 mg, 0.77 mmol) and Pd / C (300 mg) in ethyl acetate (300 ml) was stirred under H at 30° C. for 6 hours. The reaction mixture was cooled to room temperature, filtered through a pad of Celite® 545, washed with ethyl acetate, and concentrated to give the crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide as a white solid. TLC: 10% ethyl acetate / CH3OH (R f :0.5). C 20 H 21 MS calculated for ClFN3O2: 589.2; Found: 390.2 [M+1] + .

[0229] Example 24 [ka]

[0230] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1,2-dimethyl-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (35 mg, 0.09 mmol) in MeOH (2 mL) cooled to 0 °C was added NaBH (11 mg, 0.27 mmol). 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 the crude compound, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1,2-dimethyl-1H-imidazole-5-carboxamide as a white solid. TLC: 10% ethyl acetate / CHOH(R f :0.4). C 20 H 23 MS calculated for ClFN3O2: 391.1; Found: 392.1 [M+1] + ; 1 H NMR (CD3OD, 400 MHz): δ 7.86 (dd, J = 2.4 Hz, 6.4 Hz, 1H), 7.52-7.46 (m, 1H), 7.23 (t, J = 8.8 Hz, 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.

[0231] Synthesis of Examples 25-26. Examples 25-26 in Table 2 were synthesized according to the procedures provided above using the corresponding starting materials. [Table 2]

[0232] Example 27 [ka]

[0233] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydropentalen-2-yl)-1,2-dimethyl-1H-imidazole-5-carboxamide. To a solution of 1-methyl-1H-imidazole (101 mg, 1.23 mmol) in THF (2 mL) was added n-BuLi in hexanes (2.5 M, 0.5 mL, 1.25 mmol) at −78° C. The reaction was stirred at −78° C. for 1 hour. To this solution was added N N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (60 mg, 0.154 mmol) in one portion. The reaction was stirred at −78° C. for 1 hour and then allowed to warm to room temperature overnight. The mixture was quenched with methanol (2.0 mL) and concentrated in vacuo. The residue was purified by preparative HPLC to afford a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydropentalen-2-yl)-1,2-dimethyl-1H-imidazole-5-carboxamide, as a single diastereomer. 24 H 27 MS calculated for ClFN5O2: 471.1; Found: 472.3 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 10.10 (s, 1H), 7.95 (dd, J = 6.8, 2.8 Hz, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J = 9.2 Hz, 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.

[0234] Synthesis of Examples 28-30. Examples 28-30 in Table 3 were synthesized according to the procedures provided above using the corresponding starting materials. [Table 3-1] [Table 3-2]

[0235] Intermediate 18 [ka]

[0236] 2-Bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide. A solution of 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-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). To this was added 3-chloro-4-fluoroaniline (473 mg, 3.3 mmol) and Et3N (440 mg, 4.4 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated 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]imidazole-3-carboxamide as a brown solid. TLC: 50%, ethyl acetate / petroleum ether (R f :0.3). C13 H 10 MS calculated for BrClFNO: 357.0; Found: 357.9 [M+1] + .

[0237] Intermediate 19 [ka]

[0238] N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide. To a solution of 2-bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (660 mg, 1.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydropentalen-2(1H)-one (4.0 g, 15% purity, 2.4 mmol) and KPO (785 mg, 3.7 mmol) in dioxane (15 mL) and HO (3 mL) was added Pd(dppf)Cl (95 mg, 0.13 mmol) and the reaction was stirred at 80 °C under a nitrogen atmosphere overnight. The volatiles were removed in vacuo 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-hexahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide as a white solid. TLC: 70% ethyl acetate / petroleum ether (R f :0.2). C 21 H 19 MS calculated for ClFN3O2: 399.1; Found: 400.3 [M+1] + .

[0239] Example 31 [ka]

[0240] N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (100 mg, 0.3 mmol) in ethyl acetate (25 mL) was added Pd / C (100 mg, 100% w / w), and the reaction solution was stirred under a hydrogen atmosphere at room temperature overnight. The reaction was then filtered and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide as a white solid. TLC: 10% MeOH / DCM (Rf: 0.6). 21 H 21 MS calculated for ClFN3O2: 401.1; Found: 402.2 [M+1] + . 1 H NMR (CD3OD, 400 MHz): δ 7.83 (dd, J = 6.8, 2.8 Hz, 1H), 7.51-7.47 (m, 1H), 7.23 (t, J = 9.2 Hz, 1H), 4.16 (t, J = 7.2 Hz, 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.

[0241] Example 32 [ka]

[0242] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide Isomer I and Isomer II. To a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (60 mg, 0.2 mmol) in MeOH (5 mL) was added NaBH (11 mg, 0.3 mmol), and the solution was stirred at room temperature for 3 h. After the starting material was consumed, the volatiles were removed in vacuo and the residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide Isomer I and Isomer II.

[0243] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide isomer I.C 21 H 23 MS calculated for ClFN3O2: 403.1; Found: 404.2 [M+1] + ; 1 H NMR (CD3OD, 400 MHz): δ 7.82 (dd, J = 6.8, 2.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.22 (t, J = 9.2 Hz, 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.

[0244] Example 33 [ka]

[0245] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide isomer II.C 21 H 23 MS calculated for ClFN3O2: 40 3.1; Actual value: 404.2 [M+1] + ; 1 H NMR (CD3OD, 400 MHz): δ 7.82 (dd, J = 6.8, 2.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.22 (t, J = 8.8 Hz, 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.

[0246] Example 34 [ka]

[0247] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-(trifluoromethyl)octahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (100 mg, 0.25 mmol) in THF (2 mL) was added TBAF (0.75 mL (1 M), 0.75 mmol) and TMSCF (213 mg, 1.5 mmol), and the mixture was stirred at 60 °C overnight. After cooling to room temperature, another batch of TMSCF (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 TMSCF (213 mg, 1.5 mmol) was added and the reaction was continued at 60 °C overnight. After complete consumption of the starting material, the reaction was concentrated. The residue was diluted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous Na SO , filtered, and concentrated to give the crude compound, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-(trifluoromethyl)octahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide as a white solid as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.4). C 22 H 22 MS calculated for ClF4N3O2: 471.1; Found: 472.2 [M+1] + ; 1 H NMR (CD3OD, 400 MHz): δ 7.83 (dd, J = 6.8, 2.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.22 (t, J = 9.2 Hz, 1H), 4.16 (t, J = 7.2 Hz, 2H), 3.43-3.38 (m, 1H), 2.86 (t, J = 7.2 Hz, 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 = 13.6 Hz, 2H) ppm.

[0248] Example 35 [ka]

[0249] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-((methylsulfonyl)methyl)octahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide. To a solution of dimethyl sulfone (75 mg, 0.8 mmol) in THF (1 mL) was added n-BuLi (0.32 mL, 0.8 mmol) under a nitrogen atmosphere at −78° C., and the reaction was stirred at −78° C. for 1 h. N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (40 mg, 0.1 mmol) in THF (1 mL) was added 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-((methylsulfonyl)methyl)octahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide as a white solid as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.4). Chemical formula:C 23 H 27 MS calculated for ClFN3O4S: 495.1; Found: 496.2 [M+1] + ; 1H NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 7.91 (dd, J = 6.8, 2.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.08 (t, J = 7.2 Hz, 2H), 3.39-3.33 (m, 1H), 3.26 (s, 2H), 2.99 (s, 3H), 2.75 (t, J = 7.2 Hz, 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.

[0250] Synthesis of Examples 36-49. Examples 36-49 in Table 4 were synthesized according to the procedures provided above using the corresponding starting materials. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0251] General Procedure for Alkylation, Method A

[0252] To a stirred solution of Ar-OH (1 equiv.) and halo compound (2 equiv.) in acetonitrile / DMF (4 mL / mmol) was added K2CO3 (2 equiv.) and KI (0.5 equiv.). The reaction mixture was stirred at 60-80 °C for 1216 h. The reaction progress was monitored by TLC. Upon 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 give the crude compound, which was purified by silica gel column chromatography or preparative HPLC to give the desired compound.

[0253] General Procedure for Alkylation, Method B

[0254] To a stirred solution of Ar-OH (1 equiv.) and halo compound (2 equiv.) in DMF / ACN (6 mL / mmol) was added Cs2CO3 (2.5 equiv.). The reaction mixture was stirred at room temperature / 60 °C for 2-4 h. The reaction progress was monitored by TLC. Upon 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 give the crude compound, which was purified by silica gel column chromatography or preparative HPLC to give the desired compound.

[0255] Intermediate 20 [ka]

[0256] 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 minutes. MeI (9.91 mL 159.24 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water. The mixture was quenched with hexane 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 an off-white solid. TLC: 20% EtOAc / hexane (R f :0.2). 1 H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.03 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H) ppm.

[0257] Example 50 [ka]

[0258] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. LDA (2 M 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 dry THF (100 mL) under an inert atmosphere at −78° C., and the reaction mixture was stirred for 2 hours. To this was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (3 g, 8 mmol) in THF at −78° C. The resulting reaction mixture was stirred at −78° C. for 1 hour. The progress of the reaction was monitored by TLC and LCMS. Upon 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (2 g, 50%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.3). 1 H-NMR (DMSO-d6, 400 MHz): δ 10.23 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.66 (s, 1H), 7.59-7.55 (m, 1H), 7.40 (t, J = 9.2 Hz, 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;C 23H 24 About ClFN6O4 MS calculated: 502.2; Measured: 503.3 [M+1] + .

[0259] Example 51 [ka]

[0260] 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-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 minutes. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of Celite 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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (1.5 g, 80%) as an off-white solid. TLC: 10% MeOH / DCM (R f :0.1). 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 7.95 (d, J = 4.4 Hz, 1H), 7.76 (s, 1H), 7.58-7.54 (m, 1H), 7.41 (t, J = 9.2 Hz, 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, merged),2.50-2.32(m, 2H, merged), 2.29-2.11 (m, 4H), 1.85-1.83 (m, 4H) ppm;C 23 H 26 MS calculated for ClFN6O2: 472.2; Found: 471.2[M-1] - .

[0261] Example 52 [ka]

[0262] 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. Dissolved in Selectfluor (0.149 g, 0.42 mmol) and DIPEA (0.147 mL, 0. To a stirred solution of 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (0.2 g, 0.42 mmol) in ACN (5 mL) was added. The reaction mixture was stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC and LCMS. 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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (0.02 g, 10%) as an off-white solid. TLC: 10% MeOH (R f :0.3). 1 H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 1H), 7.63 (s, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J = 9.6 Hz, 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, merged), 2.23-2.16 (m, 2H), 2.07-2.04 (m, 2H), 1.96-1.83 (m, 4H).C 23 H 25 ClF2N6 MS calculated for O2: 490.2; Found: 473.1 [M-H2O+1] + .

[0263] Intermediate 21 [ka]

[0264] Methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate. n-BuLi (1.19 g, 18.6 mmol) was added to a stirred solution of methyl propiolate (1.56 g, 18.6 mmol) in dry THF (40 mL) at −78° C. under an inert atmosphere, and the reaction mixture was stirred for 30 minutes. To this was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (1 g, 2.66 mmol) in THF at −78° C. The resulting reaction mixture was stirred at −78° C. for 2 hours. The progress of the reaction was monitored by TLC and LCMS. 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-hydroxyoctahydropentalen-2-yl)propiolate as an off-white solid as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.3); 1 H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.59-7.55 (m, 1H), 7.40 (t, J = 8.8 Hz, 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.C 23 H 23 MS calculated for ClFN3O4: 459.1; Found: 460.2 [M+1] + .

[0265] Example 53 [ka]

[0266] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. TEA (2 g, 19.82 mmol) and 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate (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 hours. The progress of the reaction was monitored by TLC and LCMS. Upon 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.65 g, 49%) as a white solid. TLC: 8% MeOH / DCM (R f :0.2); 1 H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 4.4 Hz, 1H), 7.64 (s, 1H), 7.61-7.55 (m, 1H), 7.39 (t, J = 8.8 Hz, 1H), 5.28 (s, 1H), 5.13 (s, 1H), 3.66 (s, 6H), 3.38-3.18 (m, 1H, merged), 2.60-2.38 (m, 2H, merged), 2.20-2.01 (m, 4H), 1.91-1.75 (m, 4H) ppm.C 23H 25 MS calculated for ClFN5O3: 473.2; Found: 473.9 [M+1] + .

[0267] Example 54 [ka]

[0268] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-isopropoxy-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was prepared by the reaction of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy- Synthesized using Method A by alkylation of 1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.99-7.94 (m, 1H), 7.64 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 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 = 6.4 Hz, 6H) ppm;TLC:10%MeOH / DCM(R f :0.3);C 26 H 31 MS calculated for ClFN5O3: 515.2; Found: 516.1 [M+1] + .

[0269] Example 55 [ka]

[0270] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgBr (3 M in DEE, 0.59 mL, 1.78 mmol) was added slowly to a stirred solution of ethyl 2-((5-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)acetate (0.5 g, 0.89 mmol) in dry THF (5 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched 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. The crude compound was purified by CombiFlash® column chromatography followed by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.501 g, 61%) as an off-white solid. TLC: 5% MeOH (R f :0.4); 1 H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.65 (s, 1H), 7.59-7.52 (m, 1H), 7.40 (t, J = 9.6 Hz, 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.C 27 H 33 MS calculated for ClFN5O4: 545.2; Found: 546.3 [M+1] + .

[0271] Intermediate 22 [ka]

[0272] 4-(5-(3-Bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. n-BuLi (2 M in THF, 7.8 mL, 15.96 mmol) was added dropwise to a stirred solution of 3,5-dibromo-1-methyl-1H-pyrazole (3.8 g, 15.96 mmol) in dry THF (50 mL) at −78° C. under an inert atmosphere, and the reaction mixture was stirred at the same temperature for 35 min. To this was slowly added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (1 g, 2.65 mmol) in THF at −78° C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride 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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (0.46 g, 32.39%). TLC: 5% MeOH / DCM (R f :0.3) 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.95 (dd, J = 6.8, 2.4 Hz, 1H), 7.65 (s, 1H), 7.58-7.55 (m, 1H), 7.40 (t, J = 9.2 Hz, 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, merged), 2.22-2.07 (m, 4H), 1.87-1.83 (m, 4H) ppm;C23 H 24 MS calculated for BrClFN5O2: 535.1; Found: 536.1 [M+1] + .

[0273] Example 56 [ka]

[0274] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl) N-(3-(prop-1-yn-1-yl)-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (50 mg, 0.09 mmol) in 1,4 dioxane (3 mL), and the mixture was purged with argon for 15 minutes. Pd(PPh3)4 (10.39 mg, 0.009 mmol) was then added, and purging with argon was continued for another 10 minutes. The reaction mixture was stirred in a microwave at 140° C. for 45 minutes. The progress of the reaction was monitored by TLC and LCMS. 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 purified by CombiFlash® column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(prop-1-yn-1-yl)-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (6 mg, 12%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.4); 1 H NMR (400 MHz, 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, merged), 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);C 26 H 27 MS calculated for ClFN5O2: 495.2; found :496.0.

[0275] Example 57 [ka]

[0276] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. Zn(CN) (49.4 mg, 0.42 mmol) and Zn powder (4.5 mg, 0.07 mmol) were added to a stirred solution of 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (150 mg, 0.28 mmol) in DMA (3 mL), and the mixture was purged with argon for 10 minutes. To this solution, Pd2(dba)3 (12.8 mg, 0.014 mmol) and dppf (15.5 mg, 0.028 mmol) were added and purging with argon was continued for another 10 min. The resulting mixture was stirred at 130 °C for 12 h. The progress of the reaction was monitored by TLC. Upon completion, the mixture was filtered through a pad of Celite 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 and washed with brine. The mixture was washed, 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-octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as an off-white solid. TLC: 5% MeOH (R f :0.4); 1 H NMR (400 MHz, DMSO-d6): δ10.20 (s, 1H), 7.98-7.91 (m, 1H), 7.64 (s, 1H), 7.59-7.52 (m, 1H), 7.38 (t, J = 8.8 Hz, 1H), 6.85 (s, 1H), 5.50 (s, 1H), 3.99 (s, 3H), 3.66 (s, 3H), 3.42-3.16 (m, 1H, merged), 2.59-2.34 (m, 2H, merged), 2.28-2.02 (m, 4H), 1.95-1.76 (m, 4H)ppm;C 24 H 24 MS calculated for ClFN6O2: 482.2; found :483.1[M+1] + .

[0277] Example 58 [ka]

[0278] 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3 M in DEE, 0.13 mL, 0.419 mmol) was added slowly to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (50 mg, 0.103 mmol) in dry THF (5 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride 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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (40 mg, 77.2%) as an off-white solid. TLC: 5% MeOH (R ) in DCM f :0.4);1 H NMR (400 MHz, DMSO-d6): δ10.20 (s, 1H), 7.98-7.92 (m, 1H), 7.65 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.53 (s, 1H), 5.39 (s, 1H), 4.00 (s, 3H), 3.68 (s, 3H), 3.40-3.20 (m, 1H, merged), 2.55-2.20 (m, 2H, merged), 2.42 (s, 3H), 2.28-2.20 (m, 2H), 2.15-2.05 (m, 2H), 1.94-1.85 (m, 4H) ppm.C 25 H 27 ClFN5O3についてのMS calculated value :499.2; actual measured value: 482.1[M-H2O+1] + .

[0279] Example 59

change

[0280] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3 M in DEE, 0.66 mL, 2 mmol) was added slowly to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (100 mg, 0.2 mmol) in dry THF (5 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride 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-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (40 mg, 39%) as an off-white solid. TLC: 5% MeOH (R ) in DCM f :0.2); 1 H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 7.96 (d, J = 5,2 Hz, 1H), 7.65 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 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, merged), 2.22-2.16 (m, 2H), 2.10-2.08 (m, 2H),1.90-1.84 (m, 4H), 1.36 (s, 6H) ppm;C 26 H 31MS calculated for ClFN5O3: 515.2; found :516.2[M+1] + .

[0281] Example 60 [ka]

[0282] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydropenta NaBH4 (3 mg, 0.08 mmol) was added to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (20 mg, 0.04 mmol) in MeOH (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (5 mg, 25%). TLC: 10% MeOH / DCM (R f :0.4); 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.96 (d, J = 4.0 Hz, 1H), 7.65 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 6.00 (s, 1H), 5.19 (s, 1H), 4.84 (d, J = 4.8 Hz, 1H), 4.57 (t, J = 5.6 Hz, 1H), 3.83 (s, 3H), 3.67 (s, 3H), 3.30-3.20 (m, 1H, merged), 2.55-2.40 (m, 2H, merged), 2.20-2.05 (m, 4H), 1.88-1.82 (m, 4H), 1.29 (d, J = 6.4 Hz, 3H) ppm;C 25 H 29 ClFN5O3についてのMS calculated value: 501.2; measured value: 502.1[M+1] + .

[0283] Example 61

change

[0284] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (2 g, 4.22 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. Upon 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. The crude compound was purified by CombiFlash column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.55 g, 38%) as a white solid. TLC: 10% MeOH (R f :0.2); 1 H NMR (400 MHz, 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, merged), 2.60-2.45 (m, 2H, merged), 2.25-2.18 (m, 2H), 2.09-2.06 (m, 2H), 1.96-1.87 (m, 4H) ppm;C 23 H24 MS calculated for ClF2N5O3: 491.2; found: 492. 1[M+1] + .

[0285] Example 62 [ka]

[0286] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-1-methyl-3-(3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was synthesized by following the general procedure described above for alkylation (Method B). TLC: 10% MeOH / DCM (R f :0.3); 1 H NMR (400 MHz, 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, C 26 H 27 MS calculated for ClF5N5O4: 603.2; Found: 586.2 [M-H2O+1] + .

[0287] Intermediate 23 [ka]

[0288] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a stirred solution of 4-fluoro-3-iodo-1-methyl-1H-pyrazole (2.42 g, 10.66 mmol) in dry THF (30 mL) was added LDA (5.33 mL, 10.66 mmol) at -78 °C. l) was added dropwise, and the reaction mixture was stirred at the same temperature for 2 hours. To this was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (0.4 g, 1.06 mmol) in THF at -78°C. The reaction mixture was stirred at the same temperature and then at room temperature for 3 hours. The progress of the reaction 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-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.250 g, 40.62%) as an off-white solid as a single diastereomer. TLC: 5% MeOH / DCM (R f :0.3). 1 H NMR (400 MHz, DMSO-d6): δ10.20 (s, 1H), 7.98-7.94 (m, 1H), 7.65 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 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, merged), 2.24-2.18 (m, 2H), 2.10-2.06 (m, 2H), 1.98-1.90 (m, 4H) ppm.C 23 H 23 MS calculated for ClF2IN5O2: 601.1; observed: 602.1 [M+1] + .

[0289] Example 63 [ka]

[0290] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-((2-hydroxy-2-methylpropyl)amino)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-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-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (100 mg, 0.166 mmol) and 1-amino-2-methylpropan-2-ol (29.6 mg, 0.33 mmol) in DMSO (3 mL), and the solution was purged with argon for 10 minutes. To this solution was added CuI (6.3 mg, 0.033 mmol), and purging with argon was continued for another 10 minutes. The resulting reaction mixture was stirred at 90 °C for 16 hours. The progress of the reaction 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-hydroxyoctahydropentane. (20 mg, 21%). TLC: 10% MeOH / DCM (R f :0.2). 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.95 (d, J = 6.8 Hz, 1H), 7.64 (s, 1H), 7.58-7.54 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 5.25 (s, 1H), 4.53 (t, J = 6.4 Hz, 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, merged), 2.25-2.20 (m, 2H), 2.12-2.06 (m, 2H), 1.98-1.85 (m, 4H), 1.10 (s, 6H) ppm.C 27 H 33 MS calculated for ClF2N6O3: 562.2; Found: 563.2 [M+1] + .

[0291] Example 64 [ka]

[0292] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. Zn(CN) (0.073 g, 0.623 mmol) and Zn powder (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-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.25 g, 0.415 mmol) in DMA (5 mL), which was purged with argon for 10 minutes. To this solution was added Pd2(dba)3 (0.038 g, 0.0415 mmol) and dppf (0.023 g, 0.0415 mmol), and argon purging was continued for another 10 minutes. The resulting reaction mixture was stirred at 120 °C for 16 hours. The reaction progress was monitored by TLC. Upon 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-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.160 g, 77%) as an off-white solid. TLC: 5% MeOH (R f :0.4). C 24 H 23 MS calculated for ClF2N6O2: 500.2; Found: 501.1 [M+1] + .

[0293] Example 65 [ka]

[0294] 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3 M in diethoxyethane, 0.5 mL, 1.5 mmol) was added slowly to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.15 g, 0.3 mmol) in dry THF (5 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at 50° C. for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride 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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (0.105 g, 67%) as an off-white solid. TLC: 5% MeOH (R ) in DCM f :0.2). 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.65 (s, 1H), 7.60-7.54 (m, 1H), 7.40 (t, J = 6.4 Hz, 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, merged), 2.41 (s, 3H), 2.35-2.20 (m, 2H), 2.10-2.05 (m, 2H), 2.00-1.94 (m, 4H) ppm;C 25 H 26LCMS calculated for ClF2N5O3: 517.2; Found: 518.1 [M+1] + .

[0295] Example 66 [ka]

[0296] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3 M in diethoxyethane, 0.32 mL, 0.96 mmol) l) was added slowly to a stirred solution of 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (0.1 g, 0.193 mmol) in dry THF (3 mL) at 0° C. under an inert atmosphere. The reaction mixture was stirred at 50° C. for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with a saturated (aqueous) solution of ammonium chloride 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-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (12 mg, 12%) as an off-white solid. TLC: 5% MeOH (R f :0.2); 1 H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.92-7.62 (m, 1H), 7.60-7.54 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 5.31 (s, 1H), 4.81 (br. s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.30-3.20 (m, 1H, merged) 2.60-2.45 (m, 2H, merged), 2.30-2.10 (m, 4H), 1.96-1.90 (m, 4H), 1.41 (s, 6H) ppm;C 26 H 30 MS calculated for ClF2N5O3: 533.2; Found: 534.1 [M+1] + .

[0297] Intermediate 24 [ka]

[0298] Ethyl 2-((5-(-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propanoate. The title compound was synthesized according to the general procedure for alkylation (Method B). TLC: 5% MeOH / DCM (R f :0.5);C 28 H 33 MS calculated for ClFN5O5: 573.2; Found: 572.4 [M-1] - .

[0299] Example 67 [ka]

[0300] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-((1-hydroxypropan-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. NaBH4 (0.133 g, 3.49 mmol) was added to a stirred solution of ethyl 2-((5-(-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propanoate (0.2 g, 0.349 mmol) in MeOH (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction 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-hydroxypropan-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (60 mg, 32.4%). The racemic compound was subjected to chiral preparative HPLC purification to give two diastereomers, Example 68 (Diastereomer 1) and Example 69 (Diastereomer 2) (Table 5). [Table 5]

[0301] Intermediate 25 [ka]

[0302] 1-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethanamine. 5-Bromo-1-methyl-1H-pyrazole-4-carbaldehyde (2.0 g, 10.59 mmol) was dissolved in dimethylamine hydrochloride (4.32 g, 52.96 mmol, 5.0 equiv.), triethylamine (52.95 mmol, 7.38 mL, 5.0 equiv.), and acetic acid (1.91 g, 31.78 mmol, 1.83 mL, 3.0 equiv.) in dry DC HCl. To the stirred solution in 30 mL of Methanol was added at room temperature. The resulting mixture was stirred for 20 minutes, after which sodium triacetoxyborohydride (13.47 g, 63.55 mmol, 6.0 equiv.) was added portionwise. The resulting suspension was stirred overnight. After the reaction was complete, the mixture was poured into a stirring 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-dimethylmethanamine (2.2 g, 90.0% purity, 9.08 mmol, 86% yield). CH 12 MS calculated for BrN3: 217.0; Found: 218.1 [M+1] + .

[0303] Example 70 [ka]

[0304] N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. n-Butyllithium (2.5 M in n-hexane, 1.7 mmol, 0.68 mL, 8.0 equiv) was added dropwise to a solution of 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethanamine (372.65 mg, 1.71 mmol, 8.0 equiv) in anhydrous THF (10 mL) at −78° C. The resulting mixture was stirred for 30 minutes, then warmed to −60° C. for 30 minutes, and then cooled to −78° C. To the reaction mixture was added dropwise a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (80 mg, 213.58 μmol) in THF (2 mL). The reaction mixture was stirred at −78° C. for 1 hour and gradually warmed to room temperature. After 12 hours, the mixture was poured into saturated NH4Cl solution and then extracted with EtOAc (3×10 mL). The combined organic solution was dried over Na2SO4 and evaporated in vacuo to give 0.12 g of crude product. Purification using preparative HPLC afforded N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (26.0 mg, 50.48 μmol, 23.6% yield) as a single diastereomer. MS calculated for CHCIFNO: 514.1; found: 515.2 [M+1] + ; 1 H NMR (400 MHz, Chloroform-d): δ 7.78 (dd, J = 6.5, 2.6 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 7.42 - 7.35 (m, 1H), 7.22 (s, 1H), 7.16 (t, J = 8.7 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.37 (s, 2H), 3.23 (dq, J = 12.1, 6.1 Hz, 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 = 4.6 Hz, 1H) ppm.

[0305] Example 71

change

[0306] N-(3-chloro-4-fluorophenyl)-4-(5-(1,3-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 1,3-dimethyl-1H-pyrazole (211.0 mg, 2.2 mmol) in anhydrous THF (20 mL) was added n-butyllithium (2.5 M in n-hexane, 2.2 mmol, 0.88 mL, 11.0 equiv.) dropwise at −78° C. The resulting mixture was stirred for 10 minutes and then warmed to −5° C. over 30 minutes. The reaction mixture was cooled to -78 °C, and a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-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 gradually warmed to room temperature. After 12 h, the mixture was poured into saturated NH4Cl solution and then extracted with EtOAc (3 × 20 mL). The combined organic solution was dried over Na2SO4 and evaporated in vacuo 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-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (6.7 mg, 14.2 μmol, 7.1% yield). 24 H 27 MS calculated for ClFN5O2: 471.2; Found: 454.2 [M-H2O+1] + ; 1 H NMR (400 MHz, Chloroform-d): δ 7.79 (d, J = 6.8 Hz, 2H), 7.55 (s, 1H), 7.37 (s, 1H), 7.15 (t, J = 8.6 Hz, 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, 13.4 Hz, 5H), 2.21 (d, J = 2.1 Hz, 3H), 2.13 (d, J = 13.3 Hz, 2H) ppm.

[0307] Example 72 [ka]

[0308] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of diisopropylamine (207.41 mg, 2.05 mmol, 290.0 μL, 11.0 equiv.) in anhydrous THF (20 mL) was added n-butyllithium (2.5 M in n-hexane, 2.05 mmol, 0.82 mL, 11.0 equiv.) dropwise at −78° C. The resulting mixture was stirred for 10 minutes and then warmed to −10° C. over 10 minutes. The mixture was cooled to −78° C. and 1-methyl-3-(trifluoromethyl)-1H-pyrazole (307.67 mg, A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (70.0 mg, 186.26 μmol) in THF (1 mL) was added. The reaction mixture was stirred at −70° C. for 1 hour, and then a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (70.0 mg, 186.26 μmol) in THF (2 mL) was added dropwise. 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 saturated NH4Cl solution and extracted with EtOAc (3×20 mL). The combined organic solution was dried over Na2SO4 and evaporated in vacuo to give 0.15 g of crude product, which was purified using preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (20.1 mg, 38.22 μmol, 21% yield). 24 H24 MS calculated for ClF4N5O2: 525.2; Found: 526.2 [M+1] + ; 1 H NMR (400 MHz, Chloroform-d): δ 7.77 (dd, J = 6.5, 2.5 Hz, 1H), 7.58 (s, 1H), 7.40 - 7.33 (m, 1H), 7.31 (s, 1H), 7.15 (td, J = 8.7, 1.7 Hz, 1H), 6.34 (s, 1H), 4.10 (s, 3H), 3.81 (d, J = 1.7 Hz, 3H), 3.30 (tt, J = 11.8, 6.6 Hz, 1H), 2.84 - 2.67 (m, 3H), 2.39 - 2.14 (m, 8H) ppm.

[0309] Example 73 [ka]

[0310] 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 3-chloro-1-methyl-1H-pyrazole (124.04 mg, 1.06 mmol) in tetrahydrofuran (10 mL) at −78° C. was added dropwise n-butyllithium (1.06 mmol, 430.0 μL, 2.5 M in hexanes, 4.0 equiv.) and the resulting mixture was stirred for 10 minutes. The reaction temperature was raised 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-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (100 mg, 266.06 μmol) in tetrahydrofuran (2 mL) was added dropwise, and stirring was 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 in vacuo to give the crude product, which was purified using preparative HPLC to give 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (2.2 mg, 95.0% purity, 4.24 μmol, 1.6% yield). 23 H 24 MS calculated for ClFN0: 491.1; Found: 493.0 [M+2] + ; 1 H NMR (400 MHz, Methanol-d4): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.47 (m, 1H), 7.25 (t, J = 9.0 Hz, 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, 7.2 Hz, 2H), 2.32 - 2.21 (m, 2H), 2.04 - 1.82 (m, 4H) ppm.

[0311] Example 74 [ka]

[0312] 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 3-tert-butyl-1-methyl-1H-pyrazole (234.46 mg, 1.7 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (109.0 mg, 1.7 mmol, 680.0 μL, 8.0 equiv) dropwise at −78° C. and the mixture was stirred for 10 minutes. The temperature of the reaction was raised to −60° C. and stirred for 1 hour. The mixture was then cooled to -78°C and a solution of 4-[-5-oxo-octahydropentalen-2-yl]-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (79.69 mg, 212.05 μmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction 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 in vacuo to give the crude product, which was purified using preparative HPLC to give 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (2.8 mg, 97.8% purity, 5.33 μmol, 2.5% yield). 27 H 33MS calculated for ClFN5O2: 513.2; Found: 512.0 [MH] - ; 1 H NMR (400 MHz, Methanol-d4): δ 7.88 (dd, J = 6.5, 2.7 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 2.4 Hz, 2H), 7.25 (t, J = 8.9 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 4.09 (s, 2H), 3.77 (s, 3H), 2.67 (s, 1H), 2.58 (s, 2H), 2.22 (d, J = 8.2 Hz, 2H), 2.05 (s, 1H), 1.86 (t, J = 6.6 Hz, 2H), 1.81 - 1.71 (m, 2H), 1.56 - 1.46 (m, 2H), 1.29 (d, J = 2.1 Hz, 9H) ppm.

[0313] Intermediate 26 [ka]

[0314] 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazole. 1,4-Dimethyl-1H-pyrazol-3-amine (2.1 g, 18.9 mmol) and hexane-2,5-dione (2.22 mL, 18.9 mmol) and catalyst A mixture of 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 give 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazole.

[0315] Intermediate 27 [ka]

[0316] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazole (400 mg, 2.1 mmol) in THF (8 mL) was added n-BuLi (0.85 mL, 2.5 M, 2.1 mmol) under argon at −78° C. The mixture was stirred at −50° C. for 2.5 hours. To the resulting mixture was added a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (80 mg, 0.2 mmol) in THF (1.5 mL) 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 × 3). The organic layer was washed with brine, dried over anhydrous NaSO and concentrated to give the crude compound (420 mg), which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (11 mg, 9% yield).

[0317] Example 75 [ka]

[0318] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl) N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (11 mg, 0.02 mmol) in EtOH (1 mL) was added hydroxylamine hydrochloride (270 mg, 3.9 mmol) and KOH solution (4.7 mL, 4.5% in 1:1 EtOH:HO, 3.8 mmol). The resulting mixture was refluxed for 2 days. Additional hydroxylamine hydrochloride (270 mg, 3.9 mmol) and triethylamine (0.528 mL, 3.85 mmol) were then added, and the resulting mixture was refluxed for 2 days. The final step was repeated. EtOH was evaporated from the cooled reaction mixture, and the product was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude compound, which was purified by preparative HPLC to give 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (2.7 mg, 28% yield). MS calculated for CHClFNO2: 486.2; found: 485.2 [M-1] - ; 1H NMR (600 MHz, Acetonitrile-d3): δ 8.30 (s, 1H), 7.88 (dd, J = 6.8, 2.6 Hz, 1H), 7.53 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.46 (s, 1H), 7.26 (t, J = 9.0 Hz, 1H), 3.74 (d, J = 14.5 Hz, 6H), 3.54 (s, 2H), 3.29 (dt, J = 11.6, 5.5 Hz, 1H), 3.04 (s, 1H), 2.70 (s, 2H), 2.28 (dd, J = 13.6, 8.3 Hz, 2H), 2.13 (s, 3H), 2.07 (dt, J = 4.9, 2.5 Hz, 2H), 1.85 (qt, J = 6.1, 3.5 Hz, 2H) ppm.

[0319] Intermediate 28 [ka]

[0320] 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-ethyl-1H-pyrazole The title compound was synthesized following the procedure described for 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazole.

[0321] Intermediate 29 [ka]

[0322] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethyl-1H-pyrazol-5-yl)-5-hydro N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-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-pyrrol-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. (25 mg, purity 95%, yield 22%). C 30 H 34 MS calculated for ClFN6O2: 564.2; Found: 563.1 [MH] - ; 1 H NMR (600 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.94 (dd, J = 6.8, 2.6 Hz, 1H), 7.64 (s, 1H), 7.55 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 6.08 (s, 1H), 5.70 (s, 2H), 5.43 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 3.23 (dt, J = 12.2, 6.1 Hz, 1H), 2.51 (dd, 2H), 2.23 (dd, J = 13.1, 7.8 Hz, 2H), 2.08 (dt, J = 7.7, 6.8 Hz, 2H), 2.01 (s, 6H), 1.93 - 1.80 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H) ppm.

[0323] Example 76 [ka]

[0324] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was synthesized according to the procedure provided for 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. MS calculated for CHCIFNO: 486.2; found: 485.0 [M-1] - ; 1 H NMR (400 MHz, 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.

[0325] Example 77 [ka]

[0326] 4-(5-(3-amino-1-isopropyl-1H-pyrazol-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-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-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. C 25 H 30 MS calculated for ClFN6O2: 500.2; Found: 499.2 [M-1] - ; 1 H NMR (400 MHz, Chloroform-d): δ 7.78 (d, J = 7.4 Hz, 1H), 7.49 (s, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.7 Hz, 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 = 12.7 Hz, 4H), 1.42 (d, J = 6.6 Hz, 6H) ppm.

[0327] Example 78 [ka]

[0328] N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of (R)-1-(1-methyl-1H-pyrazol-3-yl)ethanol (268.91 mg, 2.13 mmol, 10.0 equiv) in anhydrous THF (10 mL) was added n-butyllithium (2.5 M in n-hexane, 4.26 mmol, 1.71 mL, 20.0 equiv) dropwise at −78° C. The resulting mixture was stirred for 30 minutes and then warmed to −30° C. over 30 minutes. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-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 h and then gradually warmed to room temperature. After 12 h, the mixture was poured into saturated NH4Cl and extracted with EtOAc (3 × 10 mL). The combined organic solution was dried over Na2SO4 and evaporated in vacuo to give 0.35 g of crude product, which was purified using preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (9.4 mg, 18.73 μmol, 8.8% yield). 25 H 29 MS calculated for ClFN5O3: 501.2; Found: 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, 6.1 Hz, 1H), 3.19 - 2.85 (m, 2H), 2.61 (h, J = 10.1, 9.3 Hz, 2H), 2.32 (ddd, J = 11.8, 7.9, 2.8 Hz, 2H), 2.21 (d, J = 7.0 Hz, 1H), 2.01 (d, J = 4.6 Hz, 2H), 1.45 - 1.33 (m, 3H) ppm.

[0329] Intermediate 30

Chemical Structure

[0330] 2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol. To a solution of 1-methyl-1H-pyrazole-3-carbaldehyde (1.0 g, 9.08 mmol) and TMSCF3 (1.94 g, 13.62 mmol, 1.5 equiv.) in THF (20 mL) was added dropwise a solution of TBAF (1 M in THF, 908.24 μmol, 0.91 mL, 0.1 equiv.) in THF at -20 °C. The reaction mixture was stirred at 0 °C for 30 min and then gradually warmed to room temperature. After 12 h, additional TBAF (1 M in THF, 5.0 mL) was added, and the mixture was poured into water and extracted with EtOAc (3 × 20 mL). The combined organic solution was dried over NaSO and evaporated in vacuo to give 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol as an oil (1.4 g, 95.0% purity, 7.38 mmol, 81% yield). The crude product was used directly without any further purification. MS calculated for C6H7F3N2O: 180.1; Found: 181.2 [M+1] +

[0331] Example 79 [ka]

[0332] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. n-Butyllithium (2.5 M in n-hexane, 3.2 mmol, 1.28 mL, 20.0 equiv) 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 equiv) 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-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (60 mg, 160.09 μmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h and gradually warmed to room temperature. After 12 h, the mixture was poured into saturated NH4Cl solution and extracted with EtOAc (3 × 10 mL). The combined organic solution was dried over Na2SO4 and evaporated in vacuo 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide was obtained (6.5 mg, 11.69 μmol, yield 7.3%). 24 H 24 MS calculated for ClF4N5O3: 541.2; Found: 542.2 [M+1] + ; 1 H NMR (400 MHz, Acetonitrile-d3): δ 8.33 (s, 1H), 7.89 (dd, J = 6.7, 2.7 Hz, 1H), 7.54 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.49 (s, 1H), 7.27 (t, J = 9.0 Hz, 1H), 6.25 (s, 1H), 5.03 (q, J = 7.3 Hz, 1H), 4.54 (s, 1H), 3.98 (s, 3H), 3.74 (s, 3H), 3.51 (d, J = 44.4 Hz, 1H), 3.34 (dq, J = 11.9, 5.9 Hz, 1H), 2.81 (s, 2H), 2.34 (dd, J = 13.2, 7.7 Hz, 2H), 2.04 (dd, J = 8.8, 3.6 Hz, 2H) ppm.

[0333] Example 80

change

[0334] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(methyl-d3)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. Magnesium (42.65 mg, 1.75 mmol) was stirred in dry diethyl ether (10 mL) in a three-neck flask equipped with a thermometer and a dropping funnel. Trideuteriomethyl iodide (231.27 mg, 1.6 mmol, 100.0 μL, 10.0 equiv.) in diethyl ether (2 mL) was added to the dropping funnel, and a small crystal of iodine was added to the magnesium suspension. The magnesium suspension was briefly warmed, and then the 1,1,1-trideuteromethyl iodide solution was added dropwise to the flask. After the addition was complete, the mixture was warmed to reflux for 30 minutes and then cooled to -40 °C. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (60.0 mg, 159.65 μmol) in THF (1.5 mL) was added dropwise to the reaction mixture, which was allowed to warm to room temperature overnight. The mixture was partitioned between aqueous ammonium chloride (20 mL) and MTBE (50 mL) and extracted with EtOAc. The combined organic solution was dried over Na2SO4 and evaporated in vacuo 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (15.4 mg, 39.0 μmol, 24% yield). C 20 H 20 MS calculated for D3ClFN3O2: 394.2; Found: 395.2 [M+1] + ; 1 H NMR (400 MHz, Methanol-d4): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H), 7.66 (s, 1H), 7.52 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.25 (t, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.36 (s, 1H), 2.61 - 2.45 (m, 2H), 2.31 - 2.19 (m, 2H), 1.88 (dd, J = 12.6, 8.0 Hz, 2H), 1.73 (td, J = 12.3, 8.7 Hz, 2H), 1.61 (dd, J = 12.6, 6.7 Hz, 2H) ppm.

[0335] Synthesis of Examples 81-113. Examples 81-113 in Table 6 were synthesized according to the procedures provided above. Therefore, it was synthesized using the corresponding starting materials. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17]

[0336] Example 114 [ka]

[0337] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide: To a solution of 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (5.8 g, 25.0 mmol) in dry EtO (65 mL) was added t-BuLi (1.3 M, 19.5 mL, 25.0 mmol) dropwise and the mixture was stirred at −78° C. under N atmosphere for 5 min. Then, a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (940.0 mg, 2.5 mmol) in dry THF (3 mL) 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 in vacuo to give the 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (600.0 mg, 46%) as a white solid as a single diastereomer. 24 H 24 MS calculated for ClF4N5O2: 525.2; Found: 525.9 [M+1] + ; 1 H NMR (400 MHz, d6-DMSO): δ 10.23 (s, 1H), 7.96 (dd, J = 6.8, 2. 0 Hz, 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.

[0338] Example 115 [ka]

[0339] N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (740.0 mg, 1.4 mmol) in dioxane / HO (45 mL, v / v = 2:1) was added Zn(CN) (1.7 g, 14.0 mmol), t-BuXPhos (300.0 mg, 0.7 mmol), and third-generation t-BuXPhos precatalyst (560.0 mg, 0.7 mmol). The reaction was stirred at 60 °C for 4 h. The reaction was cooled to room temperature, filtered through a pad of Celite, washed with methanol, and concentrated to give the crude product, which was purified by column chromatography and reverse phase chromatography to give N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (270.0 mg, 37.3%) as a white solid. TLC: 7% MeOH / DCM (Rf: 0.3); C 25 H 24 MS calculated for F4N6O2: 516.2; Found: 517.0 [M+1] + , 499.0[M-18+1] + ;1H NMR (400 MHz, CD3OD): δ 8.09 (dd, J = 5.6, 2.8 Hz, 1H), 7.91-7.81 (m, 1H), 7.66 (s, 1H), 7.65 (s, 1H), 7.37 (t, J = 9.2 Hz, 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.

[0340] Intermediate 31 [ka]

[0341] N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-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-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (6 g, 16 mmol) in dioxane (250 mL) under N2. The mixture was stirred at 85 °C overnight. It was then cooled, filtered, washed with EA, and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography using 1-5% MeOH / DCM (v / v) to give N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (4 g, 68%) as a yellow solid. TLC: 5% EtOH / DCM (Rf: 0.5); C 20 H 19 MS calculated for FN4O2: 366.1; Found: 367.1 [M+1] + .

[0342] Synthesis of Examples 116-222. Examples 116-222 in Table 7 were synthesized according to the procedures provided above using the corresponding starting materials. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14] [Table 7-15] [Table 7-16] Table 7-17 Table 7-18 Table 7-19 Table 7-20 Table 7-21 Table 7-22 Table 7-23 Table 7-24 Table 7-25 Table 7-26 Table 7-27 Table 7-28 Table 7-29 Table 7-30 Table 7-31 Table 7-32 Table 7-33 Table 7-34 Table 7-35 Table 7-36 Table 7-37 Table 7-38 Table 7-39 Table 7-40 Table 7-41 Table 7-42 Table 7-43 Table 7-44 Table 7-45 Table 7-46 Table 7-47 Table 7-48 Table 7-49 Table 7-50 [Table 7-51] [Table 7-52] [Table 7-53] [Table 7-54] [Table 7-55]

[0343] VI. Biological Data

[0344] Assay to measure the activity of test compounds on virus production from HepAD38 cells

[0345] HepAD38 cells grown in a T-150 flask (Corning, catalog number: 430825) containing growth medium (DMEM / F12 (1:1) (Hyclone, catalog number: SH30023.02), 1x Pen / Strep (Invitrogen, catalog number: 15140-122), 10% FBS (Tissue Culture Biologics, catalog number: 101), 250 μg / mL G418 (Alfa Aesar, catalog number: J62671), 1 μg / mL tetracycline (Teknova, catalog number: T3320)) were detached using 0.25% trypsin-EDTA (Invitrogen, catalog number: 25200-056). Tetracycline-free treatment medium (15 mL of DMEM / F12 (1:1), 1x Pen / Strep, 2% FBS, certified Tet-system (Clontech, Catalog No.: 631106)) was then added to the mix, transferred to a 50 mL conical tube (Falcon, Catalog No.: 21008-918), and spun at 1300 rpm for 5 minutes. The pelleted cells were then resuspended / washed twice with 50 mL of 1x DPBS (Invitrogen, Catalog No.: 14190-136) and twice with 50 mL of treatment medium. HepAD38 cells were then resuspended in 10 mL of treatment medium, placed in a syringe, and counted. Wells of a 96-well clear-bottom TC plate (Corning, Cat. No.: 3904) were seeded with 50,000 cells / well in 180 μL of treatment medium, and 20 μL of 10% DMSO (Sigma, Cat. No.: D4540) was added as a control or a 10× solution of test compound in 10% DMSO in treatment medium was added to give a final compound concentration starting at 10 μM, and the plates were incubated at 37°C in a 5% CO incubator for 5 days.

[0346] Viral production was then assayed by quantitative PCR (qPCR) of the HBV core sequence. A PCR reaction mixture containing the forward primer HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3' (IDT DNA), the reverse primer HBV-r 5'-AAGGAAAGAAGTCAGAAGGCAAAA-3' (IDT DNA), the Fluorescent TaqMan™ Probes HBV-probe 5'-FAM / AGCTCCAAA / ZEN / TTCTTTATAAGGGTCGATGTC / 3IABkFQ-3' (IDT DNA), 10 μL / well of PerfeCTa® qPCR ToughMix® (Quanta Biosciences, catalog number: 95114-05K), and 6 μL / well of DEPC water (Alfa Aesar, catalog number: J62087) was prepared. 4 μL of supernatant was added to 16 μL of reaction mixture in a qPCR plate (Applied Biosytems, Cat. No.: 4309849), sealed with film (Applied Biosystems, Cat. No.: 4311971), centrifuged for a few seconds, and then run on an Applied Biosystems VIIA7. The PCR mixture was incubated at 45°C for 5 minutes, then at 95°C for 10 minutes, followed by 40 cycles of 95°C for 10 seconds and 60°C for 20 seconds. ViiA™ 7 software was used to analyze the PCR results. Viral load was quantified against known HBV DNA standards using a modified CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat. No. G7573). The viral load in supernatants from wells with treated cells was compared with the viral load in supernatants from DMSO control wells (≥3 per plate). Cell viability assays were performed using a modified CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat. No. G7573). An appropriate amount of CellTiter-Glo (CTG) and 1x DPBS was mixed at a 1:1 ratio, and 100 μL of the mixture was added to each well. Following this, all supernatant in each well was completely removed without contacting the cell surface. The plate was incubated on an orbital shaker for 10 minutes at room temperature, and then the plate was read using a plate reader (TECAN M1000 or Envision). EC values ​​were calculated via curve fitting of a four-parameter nonlinear logistic regression model (GraphPad Prism or Dotmatics). 50 or CC 50 The CC value was calculated. 50 All values ​​were >10 μM.

[0347] Table 8 shows the viral load reduction EC for exemplary compounds of the present invention, grouped into the following ranges: 50 Values ​​shown: A is EC 50 B indicates EC<10nM; B indicates EC<10~<50nM 50 C indicates an EC of ≥ 50 to < 500 nM. 50 Shows.

[0348] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8]

[0349] VII. Stereochemistry of Examples

[0350] AIA-225 [ka]

[0351] 5-Amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydropentalen-2-yl)-1-methyl-1H-pyra Pyrazole-4-carboxamide. To a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(hexahydro-1'H-spiro[oxirane-2,2'-pentalen]-5'-yl)-1-methyl-1H-pyrazole-4-carboxamide (200 mg, 0.495 mmol) in THF / HO (6 mL / 2 mL) was added NaSMe (138.6 mg, 1.98 mmol). The mixture was stirred at room temperature overnight. 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)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 44.7%) as a yellow solid. MS (m / z): calculated: 452.1, found: 452.2 [M+1] + .

[0352] AIA-227-1, AIA-227-2 [ka]

[0353] 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2r,5r)-5-hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-1) and 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-2). To a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol) in DCM (5 mL) was added m-CPBA (114.8 mg, 0.66 mmol). The mixture was stirred at room temperature overnight. 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 give AIA-227-1 (4 mg) as a white solid and AIA-227-2 (4 mg) as a white solid. AIA-227-1: 1 H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 7.91 (dd, J = 6.8, 2.4 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (t, J = 9.2 Hz, 1H), 5.97 (s, 2H), 4.79 (s, 1H), 3.59 - 3.53 (m, 1H), 3.49 (s, 3H), 3.35 (s, 2H), 2.97 (s, 3H), 2.67 - 2.60 (m, 2H), 2.18 - 2.12 (m, 2H), 2.07 - 2.02 (m, 2H), 1.45 - 1.36 (m, 4H) ppm. AIA-227-2: 1 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 7.91 (dd, J = 2.8, 2.4 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.34 (t, J = 9.2 Hz, 1H), 5.97 (s, 2H), 4.87 (s, 1H), 3.49 (s, 3H), 3.43 - 3.35 (m, 1H), 3.25 (s, 2H), 2.97 (s, 3H), 2.49 (s, 2H), 2.15 - 2.09 (m, 2H), 2.02 - 1.97 (m, 2H), 1.73 - 1.60 (m, 4H) ppm.

[0354] AIA-227-2

Chem.

[0355] Alternate synthesis of 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide. To a solution of dimethyl sulfone (77.0 g, 818.7 mmol) in THF (800 mL) was added n-BuLi (327.5 mL, 818.7 mmol, 2.5 M) dropwise at −78° C. The resulting solution was warmed to −20° C. and stirred for 1 h. The reaction was cooled to −78° C. and a solution of AIA-002 (40.0 g, 102.3 mmol) in anhydrous tetrahydrofuran (1200 mL) was added over 2 h. The mixture was warmed to room temperature and stirred for an additional 4 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL). Removal of the solvent, followed by dilution with water, extraction with ethyl acetate (3 x 200 mL), drying over Na2SO4, filtration, and concentration gave the crude product. The crude product was purified by column chromatography using 0-5% (v / v) methanol in DCM and basic preparative HPLC to give 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydropentalen-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (26.0 g, 52.4%) as a white solid. MS (m / z): calculated: 484.1, MS found: 485.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 7.92 (dd, J = 6.8, 2.8 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.35 (t, J = 8.8 Hz, 1H), 5.98 (s, 2H), 4.88 (s, 1H), 3.49 (s, 3H), 3.42 - 3.37 (m, 1H), 3.25 (s, 2H), 2.97 (s, 3H), 2.15 - 2.10 (m, 2H), 2.03 - 1.97 (m, 2H), 1.73 - 1.60 (m, 4H) ppm.

[0356] After 20 days of stripping, crystals of compound AIA-227-2 with a size of 0.08 × 0.10 × 0.20 mm were obtained from EtOH and used for X-ray diffraction data collection. Data were collected on a Bruker SMART CCD area-detector diffractometer at room temperature using CuKα radiation in ω / φ scan mode. 10,846 reflections were collected, of which 3,754 were unique (Rint = 0.0507).

[0357] The crystals belong to the monoclinic system with space group P21 / c. The unit cell parameters were: a = 6.6143(3), b = 14.0381(8), c = 23.6870(14) Å, α = γ = 90.0°, β = 97.702(3)°, V = 2179.5(2) Å. 3 , Z=4.

[0358] The structure was solved by direct methods, and all non-H atoms were fitted to F by full-matrix least-squares using the SHELXTL program. 2 All H atoms were placed in geometrically ideal positions and constrained to lie on their parent atoms. A multiscan absorption correction method was used, with maximum and minimum transmission parameters of 0.7531 and 0.6, respectively. The final R, wR2, and GOF were 0.0457, 0.1293, and 1.024, respectively.

[0359] One C in the asymmetric unit 21 H 26 FClN4O4S molecules are present and hydrogen bonds can be found between them, which play an important role in the stable packing of the crystal structure.

[0360] The ORTEP plot for compound AIA-227-2 is presented in Figure 1. The relative stereochemical scheme of compound AIA-227-2 is shown in Figure 2. The stereochemical depictions of the chemical structures of the relevant examples are based on this configuration.

[0361] Incorporation by Reference All publications and patent documents mentioned herein, including those listed below, are incorporated by reference herein in their entirety for all purposes as if each individual publication or patent document was specifically and individually incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control.

[0362] equivalent While specific embodiments of the present disclosure have been discussed, the foregoing specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, together with such variations.

[0363] Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure, unless otherwise indicated. In one embodiment, for example, the following items are provided: (Item 1) Compounds of Formula I [ka] or a pharmaceutically acceptable salt thereof [wherein: L is C 1~4 Alkylene or HaloC 1~4 is alkylene, L 1 and L 2 are independently bonded, 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 and X 1 is NR x1 and X 3 is CR 4 R 8 and X 4 and X 6 are independently O or S, X 5 is O, S or NR 0 and R a , R b and R c is hydrogen, C 1~6 Alkyl, HaloC 1~6 Alkyl and C 3~6 independently selected at each occurrence from the group consisting of: monocycloalkyl; R d is hydrogen, OH, C 1~6 Alkyl or C 1~6 is an alkoxy, R x1 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenyl, C 1~4 Alkynyl, HaloC 1~4 Alkyl or C 3~6 monocycloalkyl or R x1 and R 2 together form a -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O- -CH2CH2OCH2-, -CH2CH2-NH- -CH2NHCH2-, -CH2CH2CH2NH- or -CH2CH2NHCH2- group, R 0a are hydrogen, halogens, OH, CN, NO2, R a R b N-, C 1~4 Alkyl and HaloC 1~4 independently selected at each occurrence from the group consisting of alkyl, R 4a and R 6a are independently hydrogen or C 1~4 is alkyl, R 0 , R 6 and R 11 is hydrogen, halogen, OH, CN, NO2, oxo, R d N=hydrazino, formyl, azido, 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, HaloC 1~6 Alkyl, hydroxy 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, HaloC 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy-, R a R b NC 1~6 Alkoxy-, C 1~6 Alkoxy C 1~6 Alkyl-, HaloC 1~6 Alkoxy C 1~6 Alkyl-, R a R b NC( O)-, C 1~6 Alkyl C(O)-, C 1~6 AlkoxyC(O)-, C 1~6 Alkyl C(O)O-, C 1~6 AlkylS(O) q -, C 1~6 AlkylS(O) t NR c -, C 1~6 AlkylS(O) t C 1~6 Alkyl-, C 1~6 AlkylS(O)t NR a C 1~6 Alkyl-, C 3~6 CycloalkylS(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 independently selected at each occurrence from the group consisting of alkyl-, R 1 is phenyl or a 5- to 6-membered monocyclic heteroaryl, and said phenyl or 5- to 6-membered monocyclic heteroaryl is selected from one, two, or three independently selected R 11 optionally substituted with a group, R 2 and R 8 is hydrogen, halo, CN, OH, R a R b N.C. 1~4 Alkyl, HaloC 1~4 Alkyl, C 3~5 Monocycloalkyl, C 1~4 Alkoxy and HaloC 1~4 independently selected from the group consisting of alkoxy; R 3 teeth [ka] and R 4 is R 5 -L 1 -, R 6 or R 9 and R 5 teeth, [ka] and R 9 is R 14 S(O) q -L-, R 14 S(O) q NH-L- or R 14 C(O)NH-L-, R14 is R a R b N-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, or R 5 -L 1 - and q, r, t, and w are independently selected at each occurrence from 0, 1, and 2; v is independently selected at each occurrence from 0, 1, 2 and 3]. (Item 2) R x1 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof. (Item 3) R x1 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, wherein is methyl. (Item 4) 4. The compound according to any one of items 1 to 3, wherein r is 0, or a pharmaceutically acceptable salt thereof. (Item 5) R 2 5. The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. (Item 6) R 1 but, [ka] and R 11 But halogen, CN, C 1~6 Alkyl and HaloC 1~6 independently selected at each occurrence from the group consisting of alkyl, 6. The compound according to any one of items 1 to 5, wherein z1 is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof. (Item 7) For each occurrence, R 11is independently selected from the group consisting of CN, F, Cl, Br and I, or a pharmaceutically acceptable salt thereof. (Item 8) R 1 but, [ka] 8. The compound according to item 7, wherein: (Item 9) R 1 but, [ka] 8. The compound according to item 7, wherein: (Item 10) R 3 but, [ka] 10. The compound according to any one of items 1 to 9, wherein: (Item 11) R 4 R 6 11. The compound according to any one of items 1 to 10, wherein: (Item 12) R 4 R 5 -L 1 11. The compound according to any one of items 1 to 10, wherein: (Item 13) L 1 13. The compound according to item 12, or a pharmaceutically acceptable salt thereof, wherein is a bond. (Item 14) R 4 R 9 11. The compound according to any one of items 1 to 10, wherein: (Item 15) R 8 is hydrogen, OH or C 1~615. The compound according to any one of items 1 to 14, or a pharmaceutically acceptable salt thereof, which is alkoxy. (Item 16) R 8 16. The compound according to item 15, or a pharmaceutically acceptable salt thereof, wherein is OH. (Item 17) 17. A pharmaceutical composition comprising a compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 18) 17. A method of treating hepatitis B (HBV) infection in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof. (Item 19) 18. A method for treating hepatitis B (HBV) infection in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of item 17.

Claims

[Claim 1] The invention described in the specification.

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