Five-membered heteroarylcarboxamide compounds for HBV treatment

Abstract

The present disclosure provides, in part, five-membered heteroarylcarboxamide compounds useful for disrupting HBV core protein assembly, and pharmaceutical compositions thereof, and methods for treating hepatitis B (HBV) infection. In another aspect, the present disclosure provides a method of treating HBV infection in a subject in need thereof, the method 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.

Description

[Background technology]

[0001] background Hepatitis B virus (HBV) causes viral hepatitis, which can 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, about 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 through bodily fluids, through sexual intercourse, and through blood products. Children born to HBV-positive mothers can also become infected unless they are vaccinated at birth.

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

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

[0004] The only FDA-approved alternative to nucleoside(tide) analogs is treatment using interferon-alpha or pegylated interferon-alpha. Unfortunately, the incidence of adverse events and the profile of interferon-alpha can lead to poor tolerability, and many patients are unable to complete treatment. Furthermore, only a small subset of patients are likely to have a sustained clinical response to the course of interferon treatment, meaning that 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 observation. Nucleotide analogs suppress viral production and treat symptoms, but the infection remains untreated. Interferon-alpha has severe side effects, is poorly tolerated by patients, and has only been successful in a limited number of patients as a treatment strategy. There is clearly a continued need for more effective treatments for HBV infection. [Overview of the Initiative] [Means for solving the problem]

[0006] Abstract The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds useful for disrupting HBV core protein aggregates, pharmaceutical compositions thereof, and methods of treating HBV infections.

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

Chemical formula

[0008] 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.

[0009] In another aspect, the present disclosure provides a method of treating an HBV infection in a subject that needs to be treated for an HBV infection, the method 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 that needs to be treated for an HBV infection, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Brief Description of the Drawings

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

[0012] [Figure 2] Figure 2 shows the relative stereochemistry scheme of compound CP-AIA-227-2.

Modes for Carrying Out the Invention

[0013] Detailed Description Herein, the features and other details of this disclosure are described in more detail. Before further description of this disclosure, certain terms used in this specification, examples and appended claims are summarized here. These definitions should be taken as understood by those skilled in the art, in consideration of the remainder of this disclosure. 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 As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups are represented herein by C 2~6 Examples of alkenyl groups include, but are not limited to, linear or branched groups consisting of 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, buttenyl, and pentenyl.

[0015] As used herein, the term "alkoxy" refers to a linear or branched alkyl group (e.g., alkyl-O-) bonded to oxygen. Exemplary alkoxy groups are represented herein by C, respectively. 1~6 Alkoxy and C 1~4 Examples of alkoxy groups include, but are not limited to, alkoxy groups consisting of 1 to 6 or 1 to 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

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

[0017] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbons. Exemplary alkyl groups are, as used herein, C, respectively.1~6 Alkyl, and C 1~4 Examples of alkyl groups include, but are not limited to, linear or branched hydrocarbons having 1 to 6 or 1 to 4 carbon atoms. 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. As used herein, the term "alkylene" refers to a bivalent (biradical) alkyl group.

[0018] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Examples of alkynyl groups are given herein by C 2~6 Examples of alkynyl groups include, but are not limited to, linear or branched groups consisting of 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

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

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

[0021] When the term "cycloalkyl" is used herein, for example, C 3~6 A saturated monocyclic hydrocarbon group consisting of 3 to 6 carbon atoms, called a monocycloalkyl, or, for example, C as used herein. 8~12Refers to a bicyclic hydrocarbon ring structure of 8 to 12 carbons called bicycloalkyl. For a bicyclic cycloalkyl group, the two rings may be bonded via 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, for example, herein C 4~6 A partially unsaturated monocyclic hydrocarbon group of 4 to 6 carbons called monocycloalkenyl, or, for example, herein C 8~12 Refers to a bicyclic hydrocarbon ring structure of 8 to 12 carbons called bicycloalkenyl. For a bicyclic cycloalkenyl group: 1) either one or both rings may contain one or more double bonds, and 2) the two rings may be bonded via 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, when used in this specification, a phenyl ring C 3~6 Monocycloalkyl or C 4~6Refers to a bicyclic ring system formed by condensing with a monocyclic alkenyl 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 substituted with one or more halogen atoms. For example, haloC 1~6 Alkyl refers to a straight-chain 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, CCl3O-, CF3O-, CHF2O-CF3CH2O-, and CF3CF2O-.

[0027] As used herein, the term "heteroaryl" refers to a 5-6 member monocyclic or 8-12 member bicyclic aromatic ring system containing 1-4 independently selected heteroatoms, e.g., nitrogen, oxygen, and sulfur. Heteroaryl rings may be bonded to adjacent groups, if possible, via carbon or nitrogen. Examples of 5-6 member 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), pyridadinyl, 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" here refers to a compound containing 1 to 4 independently selected heteroatoms, such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) and SO2), as defined herein. 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 called a biheterocycloalkyl. If possible, the heterocycloalkyl ring may be linked to adjacent groups via carbon or nitrogen. 3~6Examples of monoheterocycloalkyl groups include, but are not limited to, azilidinyl, oxyranil, thiranil 1,1-dioxide, oxetanil, azetidinil, thietanil 1,1-dioxide, pyrrolidinyl, tetrahydrofuranil, piperidinyl, tetrahydro-2H-pyranil, morpholinil, thiomorpholinil, 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" is used herein to mean a compound containing 1 to 4 independently selected heteroatoms, e.g., nitrogen, oxygen, and sulfur (including its oxidation state: S(O) or S(O)2), as defined herein. 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 called a biheterocycloalkenyl. Where possible, the heterocycloalkenyl ring may be bonded to adjacent groups via carbon or nitrogen. With respect to bicyclic heterocycloalkenyl groups: 1) either one or both rings may contain one or more double bonds, and 2) the two rings may be bonded via the same or different ring atoms. 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-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 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-dihydropyridinyl, 2,3-dihydropyridinyl, 1,2,3,6-tetrahydropyrimidinyl, 4H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 4H-1,4-thiadinyl, and 3,4-dihydro-2H-1,4-thiadinyl. 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] As used herein, the term "heterocyclyl" means (1) a phenyl ring condensed into 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 C 3~6Cycloalkyl, C 4~7 Cycloalkenyls refer to bicyclic ring systems formed by condensation with either a 3- to 6-membered monocyclic heterocycloalkyl or a 4- to 6-membered monocyclic heterocycloalkenyl ring. If possible, the rings may be bonded to adjacent groups via carbon or nitrogen. Examples of heterocyclyls include isochromanil, 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, and 8,9-dihydro-5H-[1 Examples include, but are not limited to, [2,4]triazolo[4,3-a]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] As used herein, the terms "hydroxy" and "hydroxyl" refer to the -OH group.

[0032] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, and HOCH2CH(OH)CH2-.

[0033] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, and HOCH2CH(OH)CH2O-.

[0034] "R a R b NC 1~6 The term "alkyl-" as used herein means R as defined herein. a R b This refers to alkyl groups 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 This refers to an alkoxy group substituted with an N-group. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0036] As used herein, the term "oxo" refers to the base = O.

[0037] When used herein, for example, [ka] When a bicyclic ring is shown with floating bonds and / or floating substituents, as in the example above, it is possible that the bicyclic ring is bonded via carbon atoms on either ring, and substituents (e.g., R) 33 This means that each base(s) can independently bond with either or both of the rings.

[0038] The terms “individual,” “patient,” or “subject” are interchangeable and may include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds or pharmaceutical compositions of this disclosure may be administered to mammals such as humans and may also be administered to other mammals, such as animals requiring veterinary treatment, such as domesticated 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 mammals treated in the methods of this disclosure are preferably mammals for which treatment of HBV infection is desired.

[0039] The term "modulation" includes antagonistism (e.g., inhibition), agonism, partial antagonistism, and / or partial agonism.

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

[0041] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable additive,” as used herein, refer to any solvent, dispersion medium, coating, isotonic and absorption retardant, filler, etc., that is compatible with the pharmaceutically active substance. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide auxiliary, additional, or enhanced therapeutic functions.

[0042] When used herein, the term "pharmaceutical composition" means a composition comprising at least one compound, such as those disclosed herein, formulated with one or more pharmaceutically acceptable excipients.

[0043] The term "pharmaceutically acceptable salt(s)" as used herein refers to a salt(s) of an acidic or basic group that may be present in a compound used in a composition. Compounds in this composition that are basic can form 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 include, but are not limited to, malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, superphosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bicarbonate tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucarons, sugarates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), which form salts containing pharmaceutically acceptable anions. Compounds contained in this composition that are acidic can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron. Compounds contained in this composition that contain basic or acidic moieties can also form pharmaceutically acceptable salts with various amino acids. Compounds of this disclosure may contain both acidic and basic groups; for example, one amino group and one carboxylic acid group. In such cases, the compound may exist as an acid addition salt, an amphoteric ion, or a salt of a base.

[0044] The terms “therapeutic effective dose” or “effective dose,” as used herein, refer to the amount of the Compound that elicits a biological or medical response in a tissue, system or animal (e.g., mammal or human) as explored by researchers, veterinarians, physicians or other clinicians. The Compounds or Pharmaceutical Compositions of this Disclosure are administered in therapeutic effective doses to treat a disease. Instead, the therapeutic effective dose of a Compound is the amount required to achieve the desired therapeutic and / or prophylactic effect.

[0045] The term "treat" includes any effect, e.g., reduction, decrease, modulation, or elimination, through the disruption of the HBV core protein assembly, resulting in improvement of the disease. "Disruption" includes the inhibition of the HBV virus assembly and infection.

[0046] The compounds of this disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. The term “stereoisomer,” as used herein, comprises all enantiomers or diastereomers. These compounds may be designated by the symbols “(+)”, “(-)”, “R” or “S” depending on the stereoconfiguration of substituents around the stereogenic carbon atom, but those skilled in the art will recognize that the structure may imply a chiral center. This disclosure encompasses various stereoisomers and mixtures thereof of these compounds. Mixtures of enantiomers or diastereomers may be denoted “(±)” in nomenclature, but those skilled in the art will recognize that the structure may imply a chiral center.

[0047] The compounds of this 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] Where used herein, indicates a bond that may be a single, double, or triple bond. Substituents around a carbon-carbon double bond are designated as existing in a "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures illustrating a double bond encompass both "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" represents a substituent on the same side of the double bond and "trans" represents a substituent on the opposite side of the double bond.

[0048] The compounds of this disclosure may contain a carbocyclic or heterocyclic ring 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 existing in a "Z" or "E" stereoconfiguration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures illustrating a carbocyclic or heterocyclic ring encompass both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the ring face and "trans" refers to substituents on opposite sides of the ring face. A mixture of compounds in which substituents are located on both the same and opposite sides of the ring face is designated "cis / trans."

[0049] Individual enantiomers and diastereomers of the compounds of this disclosure can be prepared by synthesis from commercially available starting materials containing chiral or stereogenic centers, or by preparing racemic mixtures and then performing resolution methods well known to those skilled in the art. These resolution methods include (1) attaching the enantiomer mixture to a chiral auxiliary and separating the resulting diastereomer mixture by recrystallization or chromatography to liberate the optically pure product from the auxiliary; (2) forming a salt using an optically active resolving agent; (3) directly separating the optical enantiomer mixture using a chiral liquid chromatography column; or (4) kinetically resolving using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be separated into their constituent enantiomers by well known methods, such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms an heterogeneous mixture of stereoisomers while creating a new stereocenter or transforming an existing stereocenter, 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 and unsolvated forms with pharmaceutically acceptable solvents, such as water and ethanol, and this 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 yet another embodiment, the compound is crystalline.

[0051] This disclosure also includes isotopically labeled compounds of the disclosure, which are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 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 is one example. For instance, the compounds of this disclosure may have one or more H atoms replaced by deutherium.

[0052] A specific isotope-labeled compound (for example, 3 H and 14 Compounds labeled with 1C are useful in compound and / or substrate tissue distribution assays. Tritium-labeled compounds (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavier isotopes, such as deutherium (i.e., 2 Substitution using H) can result in certain therapeutic benefits (e.g., extension of in vivo half-life or reduction of required dose) derived from higher metabolic stability, and may therefore be preferable in certain situations. The isotope-labeled compounds of this disclosure can generally be prepared by using isotope-labeled reagents instead of unisotope-labeled reagents, following procedures similar to those disclosed in the examples herein.

[0053] The term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur through various mechanisms (e.g., by esterases, amidases, phosphatases, oxidative and / or reductive metabolism, etc.) and at various locations (e.g., in the intestinal lumen, or during transport in the intestines, 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 embodiment, the present disclosure relates to a compound of formula I. [ka] or a pharmaceutically acceptable salt thereof [in the formula, L is C 1~4 Alkylene or Halo C 1~4 It is alkylene, L 1 and L 2 Independently, combined, 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 CR 13 R 8 , C(O) or S(O) t And, X 3 O, NR 4 CR 4 R 8 , C(O) or S(O) t And, X 4 and X 6is, independently, O or S, X 5 is O, S or NR 0 and R a 、R b and R c is, independently, selected from the group consisting of hydrogen, C 1~6 alkyl, haloC 1~6 alkyl and C 3~6 monocycloalkyl each time it appears, R d is hydrogen, OH, C 1~6 alkyl or C 1~6 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 is hydrogen, halogen, OH, CN, NO2, R a R b N-, C 1~4 alkyl and haloC[[ID=5​​​​​​​​​​​​​​​​​​​​​​N-, R a R b NS(O) t -, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo C 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, Halo C 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy-, R a R b NC 1~6 Alkoxy-, C 1~6 Alkoxy C 1~6 Alkyl-, Halo C 1~6 Alkoxy C 1~6 Alkyl-, R a R b NC(O)-, C 1~6 Alkyl C(O)-, C 1~6 Alkoxy C(O)-, C 1~6 Alkyl C(O)O-, C 1~6 Alkyl S(O) q -, C 1~6 Alkyl S(O) t NR c -, C 1~6 Alkyl S(O) t C 1~6 Alkyl-, C 1~6 Alkyl S(O) t NR a C 1~6 Alkyl-, C 3~6 Cycloalkyl S(O) t C 1~6 Alkyl-, C 1~6 Alkyl C(O)C 1~6 Alkyl-, and C 1~6Alkyl C(O)OC 1~6 Each element is independently selected from the group consisting of alkyl-, R 1 is a phenyl or a 5-6 member monocyclic heteroaryl, wherein the phenyl or 5-6 member monocyclic heteroaryl is 1, 2, or 3 independently selected R 11 It is replaced as needed in the base, R 2 and R 8 These are hydrogen, halo, CN, OH, and R. a R b N, C 1~4 Alkyl, Halo C 1~4 Alkyl, C 3~5 Monocycloalkyl, C 1~4 Alkoxy and Halo C 1~4 Independently selected from the group consisting of alkoxys, R 3 teeth, [ka] And, R 4 is R 5 -L 1 -, R 6 Or R 9 is or R 4 and R 8 Together with the carbon atoms to which they are bonded, [ka] [ka] Forming a base, R 5 teeth, [ka] And, R 9 R 14 S(O) q -L-, R 14 S(O) q NH-L-, or R 14It is C(O)NH-L-, R 10 teeth, [ka] And, R 12 teeth, [ka] And, R 13 R 5 -L 1 -, R 10 -L 1 -, R 6 or R 9 And, R 14 R a R b N-, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 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 from 0, 1, and 2, respectively. v is independently selected from 0, 1, 2, and 3 each time it appears. To provide.

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

[0056] In a particular embodiment, X 1 S is.

[0057] In a particular embodiment, X 1 is NR x1 That is the case.

[0058] In a particular embodiment, X 1 is NR x1 And R x1 It is a hydrogen atom of methyl.

[0059] In a particular embodiment, X 1 is NR x1 And R x1 It is methyl.

[0060] In a particular embodiment, X 2 CR 13 R 8 That is the case.

[0061] In a particular embodiment, X 3 CR 4 R 8 That is the case.

[0062] In a particular embodiment, L 1 It is a combination.

[0063] In a particular embodiment, L 1 is C 1~6 It is alkylene.

[0064] In a particular embodiment, r is 0.

[0065] In a particular embodiment, R 1 teeth, [ka] [In the formula, R 11 Halogen, CN, C 1~6 Alkyl and Halo C 1~6 Each element is independently selected from the group consisting of alkyl groups, z1 is 0, 1, 2, or 3.

[0066] In a particular embodiment, R 11Each element is independently selected from the group consisting of halogens and CN.

[0067] In a particular embodiment, R 11 Each element is independently selected from the group consisting of F, Cl, Br, and I.

[0068] In a particular embodiment, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0069] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0070] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0071] In a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth, [ka] That is the case.

[0072] In a particular embodiment, R 1 Halogen, CN, C 1~6 alkyl and halo C 1~6 It is a 5-6 member monocyclic heteroaryl molecule that is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups.

[0073] In a particular embodiment, R1 teeth, [ka] [In the formula, R 11 Halogen, CN, C 1~6 alkyl and halo C 1~6 Each element is independently selected from the group consisting of alkyl groups, z1 is 0, 1, 2, or 3.

[0074] In a particular embodiment, R 2 It is hydrogen.

[0075] In a particular embodiment, R 2 R a R b It is N.

[0076] In a particular embodiment, R 2 is R a R b N is R a and R b is hydrogen and C 1~6 It is independently selected from the group consisting of alkyl groups.

[0077] In a particular embodiment, R 2 It is NH2.

[0078] In a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth [ka] And R 2 It is hydrogen.

[0079] In a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth [ka] And R 2 It is NH2.

[0080] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0081] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0082] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0083] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0084] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0085] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0086] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0087] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0088] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0089] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0090] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0091] In a particular embodiment, R 4 R 5 -L 1 - is

[0092] In a particular embodiment, R 4 R 5 That is the case.

[0093] In a particular embodiment, R 4 R 6 That is the case.

[0094] In a particular embodiment, R 4 R 9 That is the case.

[0095] In a particular embodiment, or R 4 and R 8 Together with the carbon atoms to which they are bonded, [ka] To form a base.

[0096] In a particular embodiment, R 5 teeth, [ka] That is the case.

[0097] In a particular embodiment, R 5 teeth, [ka] That is the case.

[0098] In a particular embodiment, R 5 teeth, [ka] That is the case.

[0099] In a particular embodiment, R 6 is C 1~6 Alkyl S(O) t C 1~6 Alkyl- or C 1~6 Alkyl S(O) t NR a C 1~6 It is alkyl-.

[0100] In a particular embodiment, R 8 is hydrogen, OH or C 1~6 It is an alkoxy.

[0101] In a particular embodiment, R 8 It is OH.

[0102] In a particular embodiment, R 14R a R b N-, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, or C 1~6 It is a haloalkoxy.

[0103] In a particular embodiment, R 14 is R 5 -L 1 - is

[0104] In a particular embodiment, R 14 is R 5 That is the case.

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

[0106] In a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth, [ka] And R 2 H is R 3 teeth, [ka] And R 8 It is OH.

[0107] In a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth, [ka] And R 2 H is 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 a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth, [ka] And R 2 H is R 3 teeth, [ka] And R 5 teeth, [ka] And R 8 It is OH.

[0109] In a particular embodiment, X 1 is NR x1 And Rx1 R is hydrogen or methyl, 1 teeth, [ka] And R 2 NH2 is R 3 teeth, [ka] And R 6 C 1~6 Alkyl S(O) t C 1~6 Alkyl- or C 1~6 Alkyl S(O) t NR a C 1~6 It is alkyl-, R 8 is hydrogen, OH or C 1~6 It is an alkoxy.

[0110] In a particular embodiment, X 1 is NR x1 And R x1 R is hydrogen or methyl, 1 teeth, [ka] And R 2 NH2 is R 3 teeth, [ka] And R 6 C 1~6 Alkyl S(O) t C 1~6 Alkyl- or C 1~6 Alkyl S(O) t NR a C 1~6 It is alkyl-, R 8 It is OH.

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

[0112] In another aspect, the present disclosure provides pharmaceutical compositions comprising compounds in any combination of the examples described herein, or pharmaceutically acceptable salts and / or stereoisomers thereof.

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

[0114] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier, such as a conventional tableting agent, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other pharmaceutical diluents, such as water, to form a solid preliminary formulation composition containing a homogeneous mixture of the compound of the Disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, 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, sugar-coated tablets, powders, granules, etc.), the composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants (5) Decomposing agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (6) Dissolution retarders, such as paraffin; (7) Absorption enhancers, such as quaternary ammonium compounds; (8) Wetting agents, such as acetyl alcohol and glycerol monostearate; (9) Absorbents, such as kaolin and bentonite clay; (10) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (11) Colorants. In the case of capsules, tablets and pills, the composition may also contain buffers. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0116] Tablets can be prepared by compression or molding, along with one or more auxiliary components as needed. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of the composition moistened with an inert liquid diluent in appropriate equipment. Tablets, and other solid dosage forms such as sugar-coated tablets, capsules, pills, and granules, can be prepared, as needed, by notching or by using coatings and shells, such as enteric coatings, as well as other coatings known in pharmaceutical formulation technology.

[0117] Compositions for inhalation or inhalation include pharmaceutically acceptable liquids and suspensions in aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, liquids, suspensions, syrups, and elixirs. In addition to the present composition, the liquid dosage forms may contain solubilizers and emulsifiers commonly used in the art, such as inert diluents, such as water or other solvents, 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 mixtures thereof.

[0118] The suspension may contain, in addition to the composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, 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, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, and can be presented as suppositories that are solid at room temperature but liquid at body temperature, and therefore melt in a body cavity to release the activator.

[0120] Dosage forms for transdermal administration of this composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or sprays as needed.

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

[0122] Powders and sprays may contain, in addition to the composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may further contain conventional spraying agents such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0123] The compositions and compounds of this disclosure may be administered by aerosol instead. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon sprays) suspensions may be used. Ultrasonic nebulizers may be used because they minimize exposure of the drug to shear, which can lead to the degradation of the compounds contained in the compositions. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the specific requirements of the composition but typically include nonionic surfactants (Tween®, Pluronic®, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids, e.g., glycine, buffers, salts, sugars, or sugar alcohols. 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 nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders (which may contain antioxidants, buffers, bacteriostatic agents, solutes to be isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners) that can be reconstituted immediately before use into an injectable sterile solution or dispersion.

[0125] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), as well as organic esters for injection (e.g., ethyl oleate), and cyclodextrins. Appropriate fluidity can be maintained, for example, by the use of a coating substance (e.g., lecithin), by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant.

[0126] In another embodiment, the present disclosure provides enteral pharmaceutical formulations comprising the disclosed compounds and enteromaterials, as well as pharmaceutically acceptable carriers or excipients thereof. Enteromaterials refer to polymers that are substantially insoluble in the acidic environment of the stomach and are 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 approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Therefore, for example, intestinal substances are not soluble up to a pH of approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Examples of intestinal substances include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, 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), and ethyl methacrylate. Examples include methyacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal colophorium, as well as several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric).The solubility of each of the above substances is either publicly known or readily determinable in vitro. While the above is a list of possible substances, those skilled in the art who are interested in this disclosure will recognize that the list is not exhaustive and that other intestinal substances exist that serve the purposes of this disclosure.

[0127] Advantageously, this disclosure also provides kits for use by consumers requiring treatment for HBV infection, for example. Such kits include a suitable dosage form, such as those described above, and instructions describing how to use such dosage forms to modulate, reduce, or prevent HBV infection. The instructions instruct consumers or healthcare professionals to administer the dosage forms according to a mode of administration known to those skilled in the art. Such kits may be advantageously packaged and sold in single or multi-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 for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of a relatively rigid material covered with a foil, preferably a clear plastic material. During the packaging process, a depression is formed in the plastic foil. The depression has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the depression, and the sheet of the relatively rigid material is sealed against the plastic foil with the foil side opposite to the direction in which the depression was formed. As a result, the tablet or capsule is sealed in a recess between the plastic foil and the sheet. The strength of the sheet is preferably such that the tablet or capsule can be removed from the blister pack by applying pressure by hand over the recess, forming an opening in the sheet at the location of the recess. The tablet or capsule can then be removed through the opening.

[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, where the numbers correspond to the number of days in the regimen on which the identified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday... etc... Week 2, Monday, Tuesday..." Other variations of the memory aid will be readily apparent. The "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0129] IV. Method In a further embodiment, a method is provided for treating hepatitis B infection in a patient requiring treatment for hepatitis B infection, comprising the steps of selecting an effective amount of a disclosed compound for administration to a subject or patient, and / or administering a first disclosed compound and, if necessary, additional different compounds(s) disclosed. In another embodiment, a method is provided for treating hepatitis B infection in a patient requiring treatment for hepatitis B infection, comprising the steps of administering to a subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound or two or more disclosed compounds and pharmaceutically acceptable excipients.

[0130] For use in this manner, the appropriate dosage is expected to vary depending on, for example, the specific compound used, the method of administration, the nature and severity of the infection being treated, and the specific infection being treated, and is within the authority 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 yet 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 of up to four times daily, for example, or in a sustained-release form.

[0131] The compounds of this disclosure can be administered by any conventional route, particularly enterally, topically, orally, or nasally, for example, in the form of tablets or capsules, suppositories, or parenterally, for example, in the form of injectable solutions or suspensions for intravenous, intramuscular, subcutaneous, or intraperitoneal injection. Suitable formulations and pharmaceutical compositions include those conventionally formulated using one or more physiologically acceptable carriers or excipients, and those that are known, commercially available, and currently used in clinical settings. Accordingly, the compounds can be formulated in forms suitable for oral, oral buccal, topical, parenteral, rectal, or transdermal administration, or by inhalation or inhalation (either orally or nasally).

[0132] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets or capsules, prepared by conventional means using pharmaceutically acceptable additives, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., potato starch or sodium 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 dried products to be prepared using water or other suitable vehicles 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), emulsifiers (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 p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). The preparations may also optionally contain buffer salts, flavorings, colorants, and sweeteners.

[0133] Preparations for oral administration can also be appropriately formulated to control or sustained release of the active compound(s) over a long period of time. For oral buccal administration, the composition may be in the form of tablets or lozenges formulated in conventional ways known to those skilled in the art.

[0134] The disclosed compounds can also be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as ampoules or multi-dose containers, with preservatives added. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain additives, such as suspending agents, stabilizers and / or dispersants. Alternatively, the compounds may be in powder form for preparation with a suitable vehicle before use, such as sterile water free of pyrogens. The compounds can also be formulated for rectal administration, for example, as suppositories or retained enemas containing conventional suppository bases, such as cocoa butter or other glycerides.

[0135] Methods and compositions comprising administering a second activator or a second activator are also envisioned herein. For example, in addition to being infected with HBV, a subject or patient may have further HBV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or promoted by, HBV infection. Disclosed compounds in combination with at least one other agent that has been shown to treat these HBV infection-related conditions are envisioned herein.

[0136] In some cases, the disclosed compounds can be administered as part of combination therapy in combination with one or more antiviral agents. Exemplary antiviral agents include nucleoside analogs, interferon-α, and other aggregation effectors, e.g., heteroaryldihydropyrimidines (HAPs), e.g., methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridine-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). This specification provides, for example, a method for treating a patient with hepatitis B infection, comprising the step of administering to the patient a first amount of the disclosed compound and a second amount of an antiviral agent or other anti-HBV agent, e.g., a second amount of a second compound selected from the group consisting of: another HBV capsid aggregation promoter (e.g., GLS4, BAY41-4109, AT-130, DVR-23 (e.g., as described below): [ka] ;NVR3-778, NVR1221 (by code); and N890 (as depicted below): [ka] Other capsid inhibitors, for example, those disclosed in the following patent applications incorporated herein by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167, and WO2014033170. ;Nucreoside analogs interfered with by viral polymerase, e.g., entecavir (Baraclude), lamivudine (Epivir-HBV), terbivudine (Tyzeka), Sebivo, adefovir dipivoxil (Hepsera), tenofovir (Viread), tenofovir alafenamide fumarate (TAF), tenofavir prodrugs (e.g., AGX-1009), L-FMAU (Klevudine), LB80380 (Besifovir), and [ka] ; Viral entry inhibitors, e.g., Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors, e.g., REP 9AC' and related nucleic acid-based amphiphilic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15, as described below: [ka] ;and BM601 as depicted below: [ka] ; Nucleocapsid formation or integrity disruptors, e.g., NZ-4 / W28F: [ka] cccDNA formation inhibitors, e.g., BSBI-25, CCC-0346, CCC-0975 (as described below): [ka]

[0137] Transbodies targeting HBc, e.g., 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 / / dx.doi.org / 10.1016 / j.intimp.2015.01.028); antiviral core protein variants (e.g., Cp183-V124W and related mutations described in WO / 2013 / 010069 and WO2014 / 074906, respectively, incorporated by reference); inhibitors of HBx-interaction, e.g., HBV RNA-targeting RNAi, antisense, and nucleic acid-based polymers; e.g., RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid-based polymer (REP2139-Ca); immunostimulants, e.g., interferon alpha 2a (Roferon), intron A (interferon alpha 2b), pegasys (pegylated interferon alpha 2a), pegylated IFN 2b, IFN lambda 1a, and PEG IFN-Lambda 1a, Wellferon, Loferon, Infergen; lymphotoxin beta-agonists, e.g., CBE11 and BS1); non-interferon immunostimulants, e.g., thymosin alpha-1 (Zadaxin) and interleukin-7 (CYT107); TLR-7 / 9 agonists, e.g., GS-9620, CYT003, resikimod; cyclophylline inhibitors, e.g., NVP018; OCB-030; SCY-635; arispolivir; NIM811 and related cyclosporine analogs; vaccines, e.g., GS-4774, TG1050, core antigen vaccines; SMAC mimetic drugs, e.g., virinapant and other IAP antagonists;Epigenetic modulators, e.g., 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, e.g., TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM and ATR kinase inhibitors; STING agonists; ribavirin; N-acetylcysteine; NOV-205 (BAM205); nitazoxanides (Alinia), tizoxanides; SB9200 small molecule nucleic acid hybrids (SMNH); DV-601; Arbidol; FXR agonists (e.g., GW4064 and fexalamine); antibodies, therapeutic proteins, gene therapies, and biologics targeting or interacting with viral components.

[0138] In some embodiments, the Disclosure provides a method for treating hepatitis B infection in a patient requiring treatment for hepatitis B infection, comprising the steps of administering a first compound selected from any one of the disclosed compounds, and one or more other HBV agents selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, nucleocapsid formation disruptors, cccDNA formation inhibitors, antiviral core protein variants, HBc-targeting transbodies, RNAi-targeted HBV RNA, immunostimulants, TLR-7 / 9 agonists, cyclophyllin inhibitors, HBV vaccines, SMAC mimetic drugs, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the Disclosure provides a method for treating hepatitis B infection in a patient requiring treatment for hepatitis B infection, comprising the steps of administering a certain amount of the disclosed compound and administering another HBV capsid assembly promoter.

[0139] In some embodiments, the first and second amounts together constitute a pharmacokinetic dose. The first amount, the second amount, or both may be equal to, greater than, or less than the effective dose of each compound administered as monotherapy. The disclosed compound and antiviral agent in therapeutic doses can be administered concomitantly to a subject, i.e., simultaneously or separately in any given order, by the same or different routes of administration. In some cases, it may be advantageous to initiate administration of the disclosed compound first, for example, one day, several days, or several weeks before initiating administration of the antiviral agent. Furthermore, additional drugs may be administered in conjunction with the aforementioned combination therapy.

[0140] In another embodiment, the disclosed compounds can be conjugated with a detection moiety, such as a fluorophore moiety (such a moiety can, for example, re-emit a specific optical frequency upon binding to a virus and / or photon excitation) (for example, covalently bonded directly or via a molecular linker to the free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of the disclosed compound). Intended fluorophores include AlexaFluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinone, fluorescent proteins, 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, in methods for detecting, for example, HBV or the biological pathway of HBV infection, and / or in methods for evaluating novel compounds for their biological activity. [Examples]

[0141] V. Examples 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 descriptions of synthetic methods, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and workup procedures, can be selected to be standard conditions for the reaction unless otherwise specified. It will be understood by those skilled in organic synthesis that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art, and alternative methods will therefore be shown. Starting materials for the examples are commercially available or readily prepared from materials known by standard methods.

[0142] At least some of the compounds identified as “intermediates” in this specification are intended to be compounds of the present invention.

[0143] Abbreviation: Acetic acid (ACOH) 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, HCl ethyl acetate Et3N triethylamine HATU Hexafluorophosphate azabenzotriazole tetramethyluronium h, hr time HPLC (High-Performance Liquid Chromatography) LC-MS (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] LC-MS was used for the analysis of the final compound.

[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 at 2.2 mins, hold until 3 mins, B concentration increased to a maximum of 2% at 3.2 mins up to 4 mins.

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

[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 minutes, hold until 3 minutes, B concentration reduced to 0% up to 4 minutes at 3.2 minutes.

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

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

[0151] General procedure for amidation

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

[0153] Method B (Amide coupling using HATU): To a stirred solution of an acid compound (1.1-1.2 equivalents) in DMF / DCM (1.01 mL / mmol), DIPEA (2-3 equivalents) and HATU (1.5-2.5 equivalents) were added at 0°C and stirred for 5 minutes. The corresponding amine (1 equivalent) was added to this solution. 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 obtain the crude compound. The crude compound was purified by either preparative HPLC or CombiFlash® column chromatography to obtain the desired compound.

[0154] Method C (Amidation mediated by AlMe3): To a stirred solution of the corresponding aniline (1.1 equivalents) in DCM / toluene (3 mL / mmol), AlMe3 (2 M, 2.5 equivalents in toluene) was added at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C for 10 minutes, and stirring was continued at room temperature for 1 hour. To this solution, the corresponding ester compound (1 equivalent) was added at 0°C under an argon atmosphere, and the resulting reaction mixture was refluxed at 100°C for 16 hours. After completion, the reaction mixture was cooled to 0°C, slowly quenched with 1N HCl aqueous solution, and extracted with ethyl acetate. The combined organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude compound was purified by washing with methanol to obtain the desired compound.

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

[0156] General procedure for the Grignard reaction

[0157] Method A (at lower temperatures): To a stirred solution of keto compound (1 equivalent) in dry THF (0.2 mL / mmol), Grignard reagent (10 equivalents) was slowly added at -78°C via a glass syringe under an inert atmosphere. The reaction mixture was stirred at the same temperature for 4 hours, then at room temperature for 2 hours. 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 in rotavapor to obtain the crude compound. The crude compound was purified by either CombiFlash® column chromatography or preparative HPLC to obtain the desired compound.

[0158] General method for Suzuki coupling

[0159] Method A: A mixture of a halo compound (1 equivalent) and the corresponding boronic acid / boronic acid ester (1.2-1.5 equivalents) in 1,4-dioxane:water (4:1) (2.17 mL / mmol) was mixed with Na2CO3 (2-3 equivalents) and purged with argon for 15 minutes. To this solution, PdCl2 (dppf) (0.1 equivalent) was added and purging with argon was continued for another 10 minutes. The resulting reaction mixture was stirred at 100°C for 12-16 hours. After the reaction was complete, 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 obtain the desired compound.

[0160] General procedures for hydrogenation

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

[0162] General procedure for keto reduction

[0163] Method A: A keto compound (1 equivalent) was stirred in EtOH / MeOH (5 volumes) (4.7 mL / mmol). Under an argon atmosphere, NaBH4 (1-2 equivalents) was added at 0°C and stirred at room temperature for 2-6 hours. After completion, the reaction mixture was concentrated under vacuum, the resulting residue was diluted with water, and extracted using ethyl acetate. The combined organic layer was collected, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography / preparative HPLC to obtain the desired compound. Note: THF (1 volume) was also added as a co-solvent for substrates with low solubility in alcohol solvents.

[0164] Intermediate 1 [ka]

[0165] 5-Oxo-1,3a,4,5,6,6a-Hexahydropentalene-2-yltrifluoromethanesulfonate. 1,3,3a,4,6,6a-Hexahydropentalene-2,5-dione (40.0 g, 289.5 mmol) and pyridine (24.0 g, 304.0 mmol) were dissolved in 600 ml of DCM, to which Tf2O (89.8 g, 318.5 mmol) was added 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 3 x 200 mL DCM. The organic layer was separated, dried over Na2SO4, and concentrated to obtain the crude product, which was purified by silica gel column chromatography using 8:1 (v / v) petroleum ether / ethyl acetate to obtain 5-oxo-1,3a,4,5,6,6a-hexahydropentalene-2-yltrifluoromethanesulfonate as a yellow oily substance. 1H NMR (400 MHz, CDCl3): δ 5.63 (q, J = 1.92 Hz, 1 H), 3.57 - 3.50 (m, 1 H), 3.14 - 3.00 (m, 2 H), 2.67 - 2.58 (m, 1 H), 2.56 -2.40 (m, 2 H), 2.34 - 2.26 (m, 1 H), 2.17 (ddd, J = 19.14, 7.34, 1.63 Hz, 1 H) ppm.

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

[0168] Intermediate 3 [ka]

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

[0170] Intermediate 4 [ka]

[0171] N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. HATU (63 g, 160 mmol) was added at room temperature to a solution of 1-methyl-1H-imidazole-5-carboxylic acid (10 g, 83 mmol), 3-chloro-4-fluoroaniline (18 g, 124 mmol), and Et3N (16 g, 160 mmol) in DMF (100 mL). 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 obtain 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 calculation value for H9ClFN3O: 253.0; Measured value: 254.1 [M+1] + .

[0172] Intermediate 5 [ka]

[0173] 2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (4 g, 15 mmol) was dissolved in CHCl3 (100 mL), to which NBS (10 g, 60 mmol) and AIBN (0.25 g, 1.5 mmol) were added at room temperature. The reaction mixture was stirred at 50°C for 18 hours. The mixture was evaporated under vacuum to obtain a yellow residue. The residue was purified by silica gel chromatography to obtain 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 calculation value for H7Br2ClFN3O: 408.9; Measured value: 411.2 [M+2] + .

[0174] Synthesis of an alternative to 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), HATU (13.3 g, 35.0 mmol) and DIPEA (9.69 g, 175 mmol) were added 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 overnight at room temperature. The mixture was added dropwise to water (600 mL), and the resulting precipitate was filtered to obtain 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (12.5 g, yield 87%) as a yellow solid.

[0175] Intermediate 6 [ka]

[0176] 4-Bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. 2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (1.1 g, 2.0 mmol) was dissolved in THF (50 mL) and CH3MgI (2 mL, 4.0 mmol) was slowly added 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 x 3). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography to obtain 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 calculation value for H8BrClFN3O: 331.0; Measured value: 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 according to the general procedure (Method C) described above for amidation to obtain 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a brown solid. TLC; 30% HCl / hexane(R) f :0.45); 1 1H NMR (DMSO-d 6, 400 MHz): δ 10.41 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.85 (s, 1H), 7.63-7.60 (m, 1H), 7.43 (t, J = 9.6 Hz, 1H), 3.75 (s, 3H);C 11 LCMS calculated value for H8BrClFN3O: 331.0; measured 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)Cl2 (62 mg, 0.077 mmol), and K3PO4 (814 mg, 3.6 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 100 °C for 4 hours under N2. Then, ELISA (20 mL) was added to the mixture. The mixture was filtered, and the filtrate was washed with H2O (35 mL x 3). The organic layer was separated, dried over Na2SO4, and evaporated under vacuum to obtain a yellow residue. The residue was purified by silica gel column chromatography using 20-50% petroleum ether / ethyl acetate to obtain 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 calculation value for ClFN3O2: 373.13. Measured value: 374.1[M+1] + .

[0180] Synthesis of an alternative to 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 / H2O (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)Cl2 (2.9 g, 4.0 mmol), and Na2CO3 (10.6 g, 100.0 mmol) were added, respectively, and the mixture was stirred overnight at 100°C. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The solid was washed with EA, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography using 5% methanol in DCM (120 g silica gel column, 60 mL / min) to obtain 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 calculation value for ClFN3O2: 373.1; Measured value: 374.3 [M+1] + .

[0181] Example 1 [ka]

[0182] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-octahydropentalen-2-yl)-1H-imidazole-5-carboxamide. 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 mixed with 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 under vacuum to obtain a yellow residue. The residue was purified by silica gel chromatography to obtain a brown solid, N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide, as a single diastereomer. TLC; 50% ethyl acetate / petroleum ether (R f :0.3). C 19 H 19 MS calculation value for ClFN3O2: 375.2; Measured value: 376.2 [M+1] + .

[0183] Alternative synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentarene-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), Pd / C (6.4 g, 10%) was added under H2, and the mixture was stirred at room temperature for 4 hours. The mixture was filtered through a Celite pad and washed with methanol. The filtrate was concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography using 5% methanol in DCM (80 g silica gel column, 50 mL / min) to obtain a gray 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 calculation value for ClFN3O2: 375.2; MS measured value: 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. NaBH4 (36 mg, 0.95 mmol) was added 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). The mixture was stirred at room temperature for 8 hours. The mixture was evaporated under vacuum to obtain a yellow residue. The residue was purified by preparative HPLC to obtain a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide, as a single diastereomer. TLC; 50% ethyl acetate / petroleum ether (R f :0.3). C 19 H 21 MS calculation value for ClFN3O2: 377.1. Measured value: 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), n-BuLi (0.2 mL, 0.5 mmol) was added 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 mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate. The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC to obtain a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((methylsulfonyl)methyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide, as a single diastereomer. TLC; 20% ethyl acetate / petroleum ether (R f :0.4). C 21 H 25 MS calculation value for ClFN3O4S: 469.1; Measured value: 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-imidazole-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. A solution of 4-iodo-1-methyl-1H-imidazole (208 mg, 1.0 mmol) in THF (5 mL) was mixed with 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, 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) was added. The final mixture was stirred overnight at room temperature. The reaction mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to obtain a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazole-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide, as a single diastereomer. 23 H 25 MS calculation value for ClFN5O2: 457.2; Measured value: 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-imidazole-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), a solution of n-BuLi in hexane (2.5 M, 0.4 mL, 1.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. Next, 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) was added to this mixture. The final mixture was stirred overnight at room temperature. The reaction mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to obtain a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazole-2-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide, as a single diastereomer. 23 H 25 MS calculation value for ClFN5O2: 457.2; Measured value: 458.3 [M+1] + ; 1 H 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 using the corresponding starting materials according to the previously provided procedure. [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-imidazole-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, and the mixture was stirred at 0°C for 0.5 hours. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (375 mg, 1 mmol) was added to THF (5 mL), and stirring was continued at room temperature for 3 hours. Water was added, and the pH was adjusted to 6-7 with NH4Cl. The mixture was extracted with AcOEt, the organic phase was dried, and concentrated under vacuum. The residue was purified by column chromatography using 25-60% ethyl acetate / petroleum ether to obtain ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-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 calculation value for ClFN3O3: 445.2; Measured value: 446.3 [M+1] + .

[0195] Example 16 [ka]

[0196] Ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)octahydropentalen-2-yl)acetate. Pd / C (50 mg) was added to a solution of ethyl 2-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)hexahydropentalen-2(1H)-ylidene)acetate (223 mg, 0.5 mmol) in THF (15 mL). The flask was then evacuated and filled with H2. The solution was stirred overnight at room temperature. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to obtain ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-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 calculation value for ClFN3O3: 447.2. Measured value: 448.3 [M+1] + .

[0197] Intermediate 9 [ka]

[0198] 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)octahydropentalen-2-yl)acetic acid. To a solution of ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)octahydropentalen-2-yl)acetate (45 mg, 0.1 mmol) in CH3OH / H2O (5 mL / 1 mL), LiOH (42 mg, 1 mmol) was added. The solution was stirred at room temperature for 4 hours. Water was added, and the reaction mixture was adjusted to pH 5-6 with HCl (2 M). The reaction product was extracted with ethyl acetate (10 mL x 3), the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-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 calculation value for ClFN3O3: 419.1; Measured value: 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. 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)octahydropentalen-2-yl)acetic acid (43 mg, 0.1 mmol) was dissolved in anhydrous DCM (10 mL), to which NH4Cl (54 mg, 1 mmol), HATU (38 mg, 0.1 mmol), and Et3N (101 mg, 1 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After removing the solvent, the crude product was purified by preparative HPLC to obtain 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 calculation value for ClFN4O2: 418.2; Measured value: 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-methylpiperazine-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), 1-methylpiperazine (110 mg, 1.1 mmol) and NaBH3CN (40 mg, 0.65 mmol) were added. The mixture was stirred overnight at 55°C. The solvent was removed under vacuum to obtain a yellow residue. This was purified by column chromatography and preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazine-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 calculation value for ClFN5O: 459.2; Measured value: 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[oxiran-2,2'-pentalen]-5'-yl)-1-methyl-1H-imidazole-5-carboxamide. Trimethylsulfonium iodide (1.47 g, 6.7 mmol) was added to a solution of t-BuOK (0.75 g, 6.7 mmol) in THF (20 mL). The mixture was stirred at room temperature for 1 hour. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (0.5 g, 1.3 mmol) was added, and the mixture was heated at 60°C for 2 hours. The reaction product was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (2:1) to obtain N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1'H-spiro[oxiran-2,2'-pentalen]-5'-yl)-1-methyl-1H-imidazole-5-carboxamide as a white solid. TLC; 50% ethyl acetate / petroleum ether (R f :0.2). C 20 H 21 MS calculation value for ClFN3O2: 389.1; Measured value: 390.2 [M+1] + .

[0205] Example 19 [ka]

[0206] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide isomer I. N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1'H-spiro[oxiran-2,2'-pentalen]-5'-yl)-1-methyl-1H-imidazole-5-carboxamide (100 mg, 0.26 mmol) was dissolved in THF / H2O (6:1, 5 mL), to which H2SO4 (0.1 mL) was added, and the mixture was stirred overnight at room temperature. The reaction product was made basic with NaHCO3 (aqueous solution) and then extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydropentalen-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 calculation value for ClFN3O3: 407.1; Measured value: 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, 1 H), 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)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide isomer II. N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1H-spiro[oxiran-2,2'-pentalen]-5'-yl)-1-methyl-1H-imidazole-5-carboxamide (100 mg, 0.26 mmol) was dissolved 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 the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain 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 calculation value for ClFN3O3: 407.1; Measured value: 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. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (200 mg, 0.53 mmol) was dissolved in DMF (5 mL), to which NCS (700 mg, 5.3 mmol) and AIBN (0.25 g, 1.5 mmol) were added at room temperature. The reaction mixture was stirred overnight at 35°C. The mixture was evaporated under vacuum to obtain a yellow residue. The residue was purified by silica gel chromatography to obtain 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 calculation value for Cl2FN3O2: 409.1, measured value: 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. 2-Chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (20 mg, 0.05 mmol) was dissolved in MeOH (2 ml) and NaBH4 (36 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 8 hours. The solvent was evaporated under vacuum to obtain a yellow residue. The residue was purified by preparative HPLC to obtain 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 calculation value for Cl2FN3O2: 411.1; Measured value: 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 hours. After cooling to room temperature, the solution was filtered to obtain 2-methyl-1H-imidazole-4,5-dicarbonitrile as a brown solid. TLC; 30% ethyl acetate / petroleum ether (R f :0.4). MS calculation value for C6H4N4: 132.0. Measured value: 133.0 [M+1] + .

[0215] Intermediate 12 [ka]

[0216] 1,2-dimethyl-1H-imidazole-4,5-dicarbonitride. To a suspension of methyl-1H-imidazole-4,5-dicarbonitride (50 g, 0.38 mol) and NaHCO3 (160 g, 1.51 mol) in H2O (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 hours. Ice water was added, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1,2-dimethyl-1H-imidazole-4,5-dicarbonitride, which was used in the next step without further purification. TLC; 30% ethyl acetate / petroleum ether (R f :0.5). MS calculation value for C7H7N4: 146.0; measured value: 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-dicarbonitrate (41 g, 0.28 mol) in a 2 M NaOH aqueous solution (45 g, 1.12 mol, 560 mL) was stirred at 100°C for 6 hours. After cooling to room temperature, the solution was acidified (pH=1) with a 6 N HCl aqueous solution. After filtration, the solid was dried in an oven at 100°C for 16 hours to obtain 1,2-dimethyl-1H-imidazole-4,5-dicarboxylic acid as a white solid. MS calculation value for C7H8N2O4: 184.0. Measured value: 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 Ac2O (150 mL) was stirred at 100°C for 16 hours. The reaction mixture was concentrated to obtain the crude product, which was crystallized from acetone (100 mL) to obtain 1,2-dimethyl-1H-imidazole-5-carboxylic acid as a brown solid. MS calculation value for C6H8N2O2: 140.1; measured value: 141.1 [M+1] + .

[0221] Intermediate 15 [ka]

[0222] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazole-5-carboxamide. 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) were dissolved in THF / DMF (15 ml / 3 mL), to which HATU (2.28 g, 6 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Ice water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the crude product, which was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to obtain 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 calculation value for C12H11ClFN3O: 267.1; measured value: 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), Br2 (1.5 g, 9.6 mmol) was added dropwise at 15 °C. The reaction mixture was then stirred at room temperature for 11 hours. The reaction product was quenched with 0.5% NaHSO3 (aqueous solution) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain a residue. This residue was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to obtain 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 calculation value for BrClFN3O: 345.0; Measured value: 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. 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 Na2CO3 (246 mg, 2.32 mmol) were dissolved in a mixture of dioxane (20 mL) and H2O (5 mL). Pd(dppf)Cl2 (50 mg) was added under a nitrogen atmosphere, and the reaction mixture was stirred at 80°C for 6 hours. After cooling to room temperature, the mixture was filtered through a Celite® pad. The filtrate was diluted with water and extracted with ethyl acetate (40 mL x 2). The combined organic layers were concentrated to obtain a residue, which was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to obtain 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 calculation value for ClFN3O2: 387.1. Measured value: 388.2 [M+1] + .

[0227] Example 23 [ka]

[0228] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-octahydropentalen-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 H2 at 30°C for 6 hours. The reaction mixture was cooled to room temperature, filtered through a Celite® 545 pad, washed with ethyl acetate, and concentrated to obtain the crude product. This was purified by preparative HPLC to obtain 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 calculation value for ClFN3O2: 589.2; Measured value: 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. NaBH4 (11 mg, 0.27 mmol) was added 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. The reaction mixture 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 obtain the crude compound, which was purified by preparative HPLC to obtain 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 / CH3OH(R f :0.4). C 20 H 23 MS calculation value for ClFN3O2: 391.1; Measured value: 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 using the corresponding starting materials according to the previously provided procedure. [Table 2]

[0232] Example 27 [ka]

[0233] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazole-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), n-BuLi (2.5 M, 0.5 mL, 1.25 mmol) in hexane was added at -78°C. The reaction mixture was stirred at -78°C for 1 hour. To this solution, N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (60 mg, 0.154 mmol) was added all at once. The reaction mixture was stirred at -78°C for 1 hour, then warmed overnight to room temperature. The mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to obtain a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazole-2-yl)octahydropentalen-2-yl)-1,2-dimethyl-1H-imidazole-5-carboxamide, as a single diastereomer. 24 H 27 MS calculation value for ClFN5O2: 471.1; Measured value: 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 using the corresponding starting materials according to the previously provided procedures. [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 mixture was concentrated and volatile matter was removed. The residue was dissolved in anhydrous DCM (5 mL). To this, 3-chloro-4-fluoroaniline (473 mg, 3.3 mmol) and Et3N (440 mg, 4.4 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, 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 obtain 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). C 13 H 10 MS calculation value for BrClFN3O: 357.0; Measured value: 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 K3PO4 (785 mg, 3.7 mmol) in dioxane (15 mL) and H2O (3 mL), Pd(dppf)Cl2 (95 mg, 0.13 mmol) was added, and the reaction mixture was stirred overnight at 80°C under a nitrogen atmosphere. The volatile components were removed under vacuum, and the residue was purified by silica gel column chromatography (40 g silica gel column, eluted with petroleum ether / ethyl acetate) to obtain 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 calculation value for ClFN3O2: 399.1; Measured value: 400.3 [M+1] + .

[0239] Example 31 [ka]

[0240] N-(3-chloro-4-fluorophenyl)-2-(5-oxo-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-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), Pd / C (100 mg, 100% w / w) was added, and the reaction solution was stirred overnight at room temperature under a hydrogen atmosphere. Next, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC to obtain 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). C 21 H 21 MS calculation value for ClFN3O2: 401.1; Measured value: 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 isomers I and II. 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 mixed with NaBH4 (11 mg, 0.3 mmol), and the solution was stirred at room temperature for 3 hours. After the starting material was consumed, volatiles were removed under vacuum, and the residue was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydropentalen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide isomers I and 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 calculation value for ClFN3O2: 403.1; Measured 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 = 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-hydroxyoctahydropentarene-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide isomer II. C 21 H 23 MS calculation value for ClFN3O2: 403.1; Measured 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), TBAF (0.75 mL (1 M), 0.75 mmol) and TMSCF3 (213 mg, 1.5 mmol) were added, and the mixture was stirred overnight at 60°C. After cooling to room temperature, another batch of TMSCF3 (213 mg, 1.5 mmol) was added, and stirring was continued at 60°C for 6 hours. After cooling to room temperature, another batch of TMSCF3 (213 mg, 1.5 mmol) was added, and the reaction was continued overnight at 60°C. After the starting materials were completely consumed, the reaction product was concentrated. The residue was diluted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound, which was purified by preparative HPLC to obtain a white solid, 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 single diastereomer. TLC: 5% MeOH / DCM(R f :0.4). C 22 H 22 MS calculation value for ClF4N3O2: 471.1; Measured value: 472.2 [M+1] + ; 1H 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), n-BuLi (0.32 mL, 0.8 mmol) was added at -78°C under a nitrogen atmosphere, and the reaction mixture was stirred at -78°C for 1 hour. 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) was added to THF (1 mL) at -78°C, and the reaction mixture was stirred at -78°C for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water and concentrated. The residue was purified by preparative HPLC to obtain a white solid, 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 single diastereomer. TLC: 5% MeOH / DCM(R) f :0.4). Chemical formula:C23 H 27 MS calculation value for ClFN3O4S: 495.1; Measured value: 496.2 [M+1] + ; 1 H 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 using the corresponding starting materials according to the previously provided procedures. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0251] General procedure and method A for alkylation

[0252] To a stirred solution of Ar-OH (1 equivalent) and halo compound (2 equivalents) in acetonitrile / DMF (4 mL / mmol), K2CO3 (2 equivalents) and KI (0.5 equivalents) were added. The reaction mixture was stirred at 60°C to 80°C for 12 to 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0253] General procedure for alkylation, method B

[0254] To a stirred solution of Ar-OH (1 equivalent) and a halo compound (2 equivalents) in DMF / ACN (6 mL / mmol), Cs2CO3 (2.5 equivalents) was added. The reaction mixture was stirred at room temperature / 60°C for 2-4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was then purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0255] Intermediate 20 [ka]

[0256] 1-Methyl-3-nitro-1H-pyrazole. NaOtBu (19.11 g, 199.1 mmol) was added at 0°C to a stirred solution of 3-nitro-1H-pyrazole (15 g, 132.7 mmol) in DMF (150 mL), and the reaction mixture was stirred for 20 minutes. Then, MeI (9.91 mL, 159.24 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to obtain 1-methyl-3-nitro-1H-pyrazole (10 g, 59%) as an off-white solid. TLC: 20% siRNA / 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-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. LDA (2M in THF, 60 mL, 120 mmol) was added dropwise to a stirred solution of methyl-3-nitro-1H-pyrazole (10.16 g, 80 mmol) in dry THF (100 mL) under an inert atmosphere at -78°C, and the reaction mixture was stirred for 2 hours. To this, 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 was added at -78°C. The resulting reaction mixture was stirred at -78°C for 1 hour. The reaction was monitored by TLC and LC-MS. After completion, the reaction product was quenched with a 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 obtain N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazole-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) salt;C 23 H 24MS calculation value for ClFN6O4: 502.2; Measured value: 503.3 [M+1] + .

[0259] Example 51 [ka]

[0260] 4-(5-(3-amino-1-methyl-1H-pyrazole-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 under a nitrogen atmosphere to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (2 g, 3.98 mmol) in MeOH (20 mL). The reaction mixture was stirred at 0°C for 30 minutes. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was filtered through a Celite pad and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to obtain 4-5-(3-amino-1-methyl-1H-pyrazole-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 calculation value for ClFN6O2: 472.2; Measured value: 471.2 [M-1] - .

[0261] Example 52 [ka]

[0262] 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. Selectfluor (0.149 g, 0.42 mmol) and DIPEA (0.147 mL, 0.84 mmol) were added to a stirred solution of 4-(5-(3-amino-1-methyl-1H-pyrazole-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). The reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to obtain 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazole-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) in DCM 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 MS calculation value for ClF2N6O2: 490.2; Measured value: 473.1 [M-H2O+1] + .

[0263] Intermediate 21 [ka]

[0264] Methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate. n-BuLi (1.19 g, 18.6 mmol) was added to a stirred solution of methyl propioate (1.56 g, 18.6 mmol) in dry THF (40 mL) under an inert atmosphere at -78°C, and the reaction mixture was stirred for 30 minutes. To this, 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 was added 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 a 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 obtain an off-white solid, methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)-2-hydroxyoctahydropentalen-2-yl)propiolate, as a single diastereomer. TLC: 5% MeOH / DCM(R f :0.3); 1H 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 calculation value for ClFN3O4: 459.1; Measured value: 460.2 [M+1] + .

[0265] Example 53 [ka]

[0266] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazole-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-imidazole-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. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazole-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 23 H 25 MS calculation value for ClFN5O3: 473.2; Measured value: 473.9 [M+1] + .

[0267] Example 54 [ka]

[0268] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-isopropoxy-1-methyl-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was synthesized using Method A by alkylation of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazole-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 calculation value for ClFN5O3: 515.2; Measured value: 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-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgBr (3M in DEE, 0.59 mL, 1.78 mmol) was slowly added at 0°C under an inert atmosphere to a stirred solution of ethyl 2-((5-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazole-3-yl)oxy) acetate (0.5 g, 0.89 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.501 g, 61%) as an off-white solid. TLC: 5% MeOH(R) in DCM 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.C27 H 33 MS calculation value for ClFN5O4: 545.2; Measured value: 546.3 [M+1] + .

[0271] Intermediate 22 [ka]

[0272] 4-(5-(3-bromo-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. n-BuLi (2M in THF, 7.8 mL, 15.96 mmol) was added dropwise to a stirred solution of 3,5-dibromo-1-methyl-1H-pyrazole (3.8 g, 15.96 mmol) in dry THF (50 mL) under an inert atmosphere at -78°C, and the reaction mixture was stirred at the same temperature for 35 minutes. To this, 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 was slowly added 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 obtain the crude compound. The crude compound was purified by silica gel column chromatography to obtain 4-(5-(3-bromo-1-methyl-1H-pyrazole-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) 1H 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;C 23 H 24 MS calculation value for BrClFN5O2: 535.1; Measured value: 536.1 [M+1] + .

[0273] Example 56 [ka]

[0274] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(propa-1-in-1-yl)-1H-pyrazole-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-pyrazole-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. Next, Pd(PPh3)4 (10.39 mg, 0.009 mmol) was added, and argon purging was continued for a further 10 minutes. The reaction mixture was stirred in microwave at 140°C for 45 minutes. The progress of the reaction was monitored by TLC and LC-MS. 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(propa-1-in-1-yl)-1H-pyrazole-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); 1H 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 calculation value for ClFN5O2: 495.2; measured value: 496.0.

[0275] Example 57 [ka]

[0276] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. Zn(CN)2 (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-pyrazole-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 argon purging was continued for a further 10 minutes. The resulting mixture was stirred at 130°C for 12 hours. The progress of the reaction was monitored by TLC. After completion, the mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to obtain N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazole-5-yl)-5-hydroxy-octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as an off-white solid. TLC: 5% MeOH(R) in DCM f :0.4); 1H 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 calculation value for ClFN6O2: 482.2; Measured value: 483.1 [M+1] + .

[0277] Example 58 [ka]

[0278] 4-(5-(3-acetyl-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3M in DEE, 0.13 mL, 0.419 mmol) was slowly added at 0°C under an inert atmosphere to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (50 mg, 0.103 mmol) in dry THF (5 mL). 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 obtain 4-(5-(3-acetyl-1-methyl-1H-pyrazole-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 MS calculation value for ClFN5O3: 499.2; Measured value: 482.1 [M-H2O+1]+ .

[0279] Example 59 [ka]

[0280] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3M in DEE, 0.66 mL, 2 mmol) was slowly added at 0°C under an inert atmosphere to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazole-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). 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-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); 1H 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 31 ClFN5O3についてのMS calculated value: 515.2; measured value: 516.2[M+1] + .

[0281] Example 60

change

[0282] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. NaBH4 (3 mg, 0.08 mmol) was added at 0°C to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazole-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). 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazole-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 H29 MS calculation value for ClFN5O3: 501.2; Measured value: 502.1 [M+1] + .

[0283] Example 61 [ka]

[0284] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazole-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-pyrazole-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 progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH / DCM. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by CombiFlash® column chromatography to obtain N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.55 g, 38%) as a white solid. TLC: 10% MeOH(R) in DCM f :0.2); 1H 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 H 24 MS calculation value for ClF2N5O3: 491.2; Measured value: 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-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. The title compound was synthesized by following the general procedure (Method B) described above for alkylation. TLC: 10% MeOH / DCM(R f :0.3); 1H 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, 3H), 3.26-3.18 (m, 1H), 2.60-2.50 (m, 2H, merged). 2.25-2.20 (m, 2H), 2.10-2.06 (m, 2H), 1.94-1.88 (m, 4H) ppm;C 26 H 27 ClF5N5O4についてのMS calculated value: 603.2; measured value: 586.2[M-H2O+1] + .

[0287] Intermediate 23

change

[0288] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazole-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), LDA (5.33 mL, 10.66 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at the same temperature for 2 hours. To this, 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 was added at -78 °C. The reaction mixture was stirred at the same temperature, then at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with a 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 obtain an off-white solid, N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.250 g, 40.62%), 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 23MS calculation value for ClF2IN5O2: 601.1; Observed value: 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-pyrazole-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-pyrazole-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. CuI (6.3 mg, 0.033 mmol) was added to this solution, and argon purging 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-((2-hydroxy-2-methylpropyl)amino)-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (20 mg, 21%). TLC: 10% MeOH / DCM(R f :0.2). 1H 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 ClF2N6O3についてのMS calculated value: 562.2; measured value: 563.2[M+1] + .

[0291] Example 64

change

[0292] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. Zn(CN)2 (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-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.25 g, 0.415 mmol) in DMA (5 mL), and the mixture was purged with argon for 10 minutes. To this solution, Pd2(dba)3 (0.038 g, 0.0415 mmol) and dppf (0.023 g, 0.0415 mmol) were added, and argon purging was continued for another 10 minutes. The resulting reaction mixture was stirred at 120°C for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazole-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) in DCM f :0.4). C 24 H 23 MS calculation value for ClF2N6O2: 500.2; Measured value: 501.1 [M+1] + .

[0293] Example 65 [ka]

[0294] 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3M in diethoxyethane, 0.5 mL, 1.5 mmol) was slowly added at 0°C under an inert atmosphere to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.15 g, 0.3 mmol) in dry THF (5 mL). The reaction mixture was stirred at 50°C for 3 hours. The 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 obtain 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazole-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 value for ClF2N5O3: 517.2; measured value: 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-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. MeMgI (3M in diethoxyethane, 0.32 mL, 0.96 mmol) was slowly added at 0°C under an inert atmosphere to a stirred solution of 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazole-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). The reaction mixture was stirred at 50°C for 3 hours. 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (12 mg, 12%) as an off-white solid. TLC: 5% MeOH(R) in DCM f :0.2); 1H 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) salt;C 26 H 30 MS calculation value for ClF2N5O3: 533.2; Measured value: 534.1 [M+1] + .

[0297] Intermediate 24 [ka]

[0298] Ethyl 2-((5-(-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazole-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 calculation value for ClFN5O5: 573.2; Measured value: 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-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. NaBH4 (0.133 g, 3.49 mmol) was added at 0°C to a stirred solution of ethyl 2-((5-(-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazole-4-yl)-2-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-pyrazole-3-yl)oxy)propanoate (0.2 g, 0.349 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction product 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 obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-((1-hydroxypropane-2-yl)oxy)-1-methyl-1H-pyrazole-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 obtain 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-pyrazole-4-yl)-N,N-dimethylmethaneamine. 5-bromo-1-methyl-1H-pyrazole-4-carbaldehyde (2.0 g, 10.59 mmol) was added at room temperature to a stirred solution in 30 mL of dry DCM containing dimethylamine hydrochloride (4.32 g, 52.96 mmol, 5.0 equivalents), triethylamine (52.95 mmol, 7.38 mL, 5.0 equivalents), and acetic acid (1.91 g, 31.78 mmol, 1.83 mL, 3.0 equivalents). The resulting mixture was stirred for 20 minutes, after which sodium triacetoxyborohydride (13.47 g, 63.55 mmol, 6.0 equivalents) was added little by little. The resulting suspension was stirred overnight. After the reaction was complete, the mixture was poured into a stirred aqueous solution of NaHCO3. The organic phase was separated, washed with brine, and concentrated under reduced pressure to obtain 1-(5-bromo-1-methyl-1H-pyrazole-4-yl)-N,N-dimethylmethaneamine (2.2 g, purity 90.0%, 9.08 mmol, yield 86%). C7H 12 MS calculation value for BrN3: 217.0; Measured value: 218.1 [M+1] + .

[0303] Example 70 [ka]

[0304] N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. n-butyllithium (2.5 M, 1.7 mmol, 0.68 mL, 8.0 equivalents in n-hexane) was added dropwise at -78°C to a solution of 1-(5-bromo-1-methyl-1H-pyrazole-4-yl)-N,N-dimethylmethaneamine (372.65 mg, 1.71 mmol, 8.0 equivalents) in anhydrous THF (10 mL). The resulting mixture was stirred for 30 minutes, then heated to -60°C for 30 minutes, and then cooled to -78°C. To the reaction mixture, 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) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and then extracted with HCl (3 × 10 mL). The combined organic solution was dried over Na2SO4 and evaporated under vacuum to obtain 0.12 g of crude product. Purification using preparative HPLC yielded N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (26.0 mg, 50.48 μmol, yield 23.6%) as a single diastereomer. MS calculation value for C26H32ClFN6O2: 514.1; measured value: 515.2 [M+1] + ; 1H 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-pyrazole-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), n-butyllithium (2.5 M, 2.2 mmol, 0.88 mL, 11.0 equivalents in n-hexane) was added dropwise at -78°C. The resulting mixture was stirred for 10 minutes and then warmed to -5°C 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 (75.0 mg, 199.56 μmol) in THF (2 mL) was added dropwise. The mixture was stirred at -78°C for 30 minutes and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and then extracted with Â(3 × 20 mL). The combined organic solution was dried with Na2SO4 and evaporated in a vacuum to obtain 0.1 g of crude product, which was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(5-(1,3-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (6.7 mg, 14.2 μmol, yield 7.1%). 24 H 27 MS calculation value for ClFN5O2: 471.2; Measured value: 454.2 [M-H2O+1] + ; 1H 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

change

[0308] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-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 equivalents) in anhydrous THF (20 mL), n-butyllithium (2.5 M in n-hexane, 2.05 mmol, 0.82 mL, 11.0 equivalents) was added dropwise at -78°C. The resulting mixture was stirred for 10 minutes and then warmed to -10°C for 10 minutes. The mixture was cooled to -78°C, and a solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole (307.67 mg, 2.05 mmol) 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 a saturated NH4Cl solution and extracted with Â(3 × 20 mL). The combined organic solution was dried with Na2SO4 and evaporated under vacuum to obtain 0.15 g of crude product, which was purified using preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (20.1 mg, 38.22 μmol, yield 21%). 24 H 24 MS calculation value for ClF4N5O2: 525.2; Measured value: 526.2 [M+1] + ; 1H 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

change

[0310] 4-(5-(3-chloro-1-methyl-1H-pyrazole-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), n-butyllithium (1.06 mmol, 430.0 μl, 2.5 M in hexane, 4.0 equivalents) was added dropwise at -78°C, and the resulting mixture was stirred for 10 minutes. The temperature of the reaction mixture 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 under vacuum to obtain the crude product, which was purified using preparative HPLC to obtain 4-(5-(3-chloro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (2.2 mg, purity 95.0%, 4.24 μmol, yield 1.6%). 23 H 24 MS calculation value for Cl2FN5O2: 491.1; Measured value: 493.0 [M+2] + ; 1H 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

change

[0312] 4-(5-(3-chloro-1-methyl-1H-pyrazole-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), n-butyllithium (109.0 mg, 1.7 mmol, 680.0 μl, 8.0 equivalents) was added dropwise at -78°C, and the mixture was stirred for 10 minutes. The temperature of the reaction mixture was raised to -60°C and stirred for 1 hour. Next, the mixture was cooled to -78°C and added dropwise to 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). The reaction mixture was stirred at -78°C for 15 minutes. The resulting mixture was warmed to room temperature and quenched with saturated ammonium chloride. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product, which was purified using preparative HPLC to obtain 4-(5-(3-chloro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (2.8 mg, purity 97.8%, 5.33 μmol, yield 2.5%). 27 H 33 MS calculation value for ClFN5O2: 513.2; Measured value: 512.0 [MH] - ; 1H 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-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole. A mixture of 1,4-dimethyl-1H-pyrazole-3-amine (2.1 g, 18.9 mmol), hexane-2,5-dione (2.22 mL, 18.9 mmol), and catalyst 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 obtain 3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole.

[0315] Intermediate 27 [ka]

[0316] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of 3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole (400 mg, 2.1 mmol) in THF (8 mL), n-BuLi (0.85 mL, 2.5 M, 2.1 mmol) was added under argon at -78 °C. The mixture was stirred at -50 °C for 2.5 hours. To the resulting mixture, 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) was added 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 ELISA (10 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the crude compound (420 mg). This was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide as a single diastereomer (11 mg, yield 9%).

[0317] Example 75 [ka]

[0318] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (11 mg, 0.02 mmol) in EtOH (1 mL), hydroxylamine hydrochloride (270 mg, 3.9 mmol) and KOH solution (4.7 mL, 4.5% in 1:1 EtOH:H2O, 3.8 mmol) were added. The resulting mixture was refluxed for 2 days. Then, additional hydroxylamine hydrochloride (270 mg, 3.9 mmol) and triethylamine (0.528 mL, 3.85 mmol) were added, and the resulting mixture was refluxed for 2 days. The final step was repeated. EtOH was evaporated from the cooled reaction mixture, the product was extracted with RINKAN, washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the crude compound, which was purified by preparative HPLC to obtain 4-(5-(3-amino-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide (2.7 mg, yield 28%). MS calculation value for C24H28ClFN6O2: 486.2; measured value: 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-pyrrole-1-yl)-1-ethyl-1H-pyrazole. The title compound was synthesized according to the procedure described for 3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole.

[0321] Intermediate 29 [ka]

[0322] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrole-1-yl)-1-ethyl-1H-pyrazole-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-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (25 mg, purity 95%, yield 22%). 30 H 34 MS calculation value for ClFN6O2: 564.2; Measured value: 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-pyrazole-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-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide. MS calculation value for C24H28ClFN6O2: 486.2; measured value: 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-pyrazole-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-pyrazole-5-yl)-5-hydroxyoctahydropentalen-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazole-5-carboxamide.25 H 30 MS calculation value for ClFN6O2: 500.2; Measured value: 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-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. (R)-1-(1-methyl-1H-pyrazole-3-yl)ethanol (268.91 mg, 2.13 mmol, 10.0 equivalents) was dissolved in anhydrous THF (10 mL) to which n-butyllithium (2.5 M in n-hexane, 4.26 mmol, 1.71 mL, 20.0 equivalents) was added dropwise at -78°C. The resulting mixture was stirred for 30 minutes and then warmed to -30°C for 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 a cooled (-78°C) reaction mixture. The resulting mixture was stirred at -78°C for 1 hour, and then gradually warmed to room temperature. After 12 hours, the mixture was poured into saturated NH4Cl and extracted with ELISA (3 × 10 mL). The combined organic solution was dried over Na2SO4 and evaporated under vacuum to obtain 0.35 g of crude product, which was purified using preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (9.4 mg, 18.73 μmol, yield 8.8%). 25 H 29 MS calculation value for ClFN5O3: 501.2; Measured value: 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] (注:这里的

化

[0330] 2,2,2-trifluoro-1-(1-methyl-1H-pyrazole-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 equivalents) in THF (20 mL), a solution of TBAF (1 M in THF, 908.24 μmol, 0.91 mL, 0.1 equivalents) in THF was added dropwise at -20°C. The reaction mixture was stirred at 0°C for 30 minutes, then gradually warmed to room temperature. After 12 hours, an additional TBAF (1 M in THF, 5.0 mL) was added, the mixture was poured into water, and extracted with RINKAN (3 × 20 mL). The combined organic solution was dried over Na2SO4 and evaporated under vacuum to obtain 2,2,2-trifluoro-1-(1-methyl-1H-pyrazole-3-yl)ethanol as an oily substance (1.4 g, purity 95.0%, 7.38 mmol, yield 81%). The crude product was used directly without any further purification. MS calculation value for C6H7F3N2O: 180.1; measured value: 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-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. n-butyllithium (2.5 M, 3.2 mmol, 1.28 mL, 20.0 equivalents in n-hexane) was added dropwise at -78°C to a solution of 2,2,2-trifluoro-1-(1-methyl-1H-pyrazole-3-yl)ethanol (288.36 mg, 1.6 mmol, 10.0 equivalents) in anhydrous THF (10 mL). The resulting mixture was stirred for 30 minutes and then warmed to -20°C for 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 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and extracted with ELISA (3 × 10 mL). The combined organic solution was dried with Na2SO4 and evaporated under vacuum to obtain 0.2 g of crude product, which was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (6.5 mg, 11.69 μmol, yield 7.3%). 24 H 24 MS calculation value for ClF4N5O3: 541.2; Measured value: 542.2 [M+1] + ; 1H 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 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-necked flask fitted with a thermometer and dropping funnel. Triduteriomethyliodide (231.27 mg, 1.6 mmol, 100.0 μl, 10.0 equivalents) was added to the magnesium suspension in diethyl ether (2 mL) via a dropping funnel, and small iodine crystals were added. The magnesium suspension was briefly warmed, and then the 1,1,1-triduteriomethyliodide solution was added dropwise to the flask. After the addition was complete, the mixture was warmed under 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) was added dropwise to the reaction mixture in THF (1.5 mL) and allowed to rise to room temperature overnight. The mixture was separated into aqueous ammonium chloride solution (20 mL) and MTBE (50 mL) and extracted with ethyl acetate. The combined organic solution was dried over Na2SO4 and evaporated under vacuum to obtain 0.075 g of crude product, which was purified by preparative HPLC to obtain 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, yield 24%). 20 H 20 MS calculation value for D3ClFN3O2: 394.2; Measured value: 395.2 [M+1] + ; 1H 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 using the corresponding starting materials according to the previously provided procedure. [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-pyrazole-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide:4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (5.8 g, 25.0 mmol) was dissolved in dry Et2O (65 mL), to which t-BuLi (1.3 M, 19.5 mL, 25.0 mmol) was added dropwise, and the mixture was stirred at -78°C in an N2 atmosphere for 5 minutes. Next, 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 under vacuum to obtain the crude product, which was purified by column chromatography to obtain a white solid, N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (600.0 mg, 46%), as a single diastereomer. 24 H 24 MS calculation value for ClF4N5O2: 525.2; Measured value: 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-pyrazole-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-pyrazole-4-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (740.0 mg, 1.4 mmol) in dioxane / H2O (45 mL, v / v=2:1), Zn(CN)2 (1.7 g, 14.0 mmol), t-BuXPhos (300.0 mg, 0.7 mmol), and a third-generation t-BuXPhos pre-catalyst (560.0 mg, 0.7 mmol) were added. The reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, washed with methanol, and concentrated to obtain a crude product. This was purified by column chromatography and reverse-phase chromatography to obtain N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-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 calculation value for F4N6O2: 516.2; Measured value: 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 under N2 conditions 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). The mixture was stirred overnight at 85 °C. It was then cooled, filtered, washed with EA, and the organic layer was concentrated under vacuum. The residue was purified by silica gel chromatography using 1-5% MeOH / DCM (v / v) to obtain N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydropentalen-2-yl)-1H-imidazole-5-carboxamide (4g, 68%) as a yellow solid. TLC: 5% EtOH / DCM (Rf: 0.5); C 20 H 19 MS calculation value for FN4O2: 366.1; Measured value: 367.1 [M+1] + .

[0342] Synthesis of Examples 116-222. Examples 116-222 in Table 7 were synthesized using the corresponding starting materials according to the previously provided procedure. [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 against 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), 1×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). Next, tetracycline-free treated medium (15 mL of DMEM / F12 (1:1), 1× Pen / Strep, containing 2% FBS, approved Tet-system (Clontech, catalog number: 631106)) was added to the mix and transferred to a 50 mL conical tube (Falcon, catalog number: 21008-918), where it was rotated at 1300 rpm for 5 minutes. The pelleted cells were then resuspended / washed twice with 50 mL of 1× DPBS (Invitrogen, catalog number: 14190-136) and twice with 50 mL of treated medium. HepAD38 cells were then resuspended in 10 mL of treated medium, placed in a syringe, and counted. 50,000 cells / well were seeded into the wells of a 96-well transparent-bottom TC plate (Corning, catalog number: 3904) in 180 μL of treatment medium. 10% DMSO (Sigma, catalog number: D4540) was added as a control, or 20 μL of a 10× solution of the test compound in 10% DMSO in the treatment medium was added to a final compound concentration starting at 10 μM. The plates were incubated in a 5% CO2 incubator at 37°C for 5 days.

[0346] Next, viral load production was assayed by quantitative PCR (qPCR) of the HBV core sequence. A PCR reaction mixture was prepared containing the forward primer HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3' (IDT DNA), the reverse primer HBV-r 5'-AAGGAAAGAAGTCAGAAGGCAAAA-3' (IDT DNA), Fluorescent TaqMan® Probes HBV-probe5'-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). 4 μL of supernatant was added to 16 μL of reaction mixture in a qPCR plate (Applied Biosystems, catalog number: 4309849), sealed with film (Applied Biosystems, catalog number: 4311971), centrifuged for several seconds, and then subjected to 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 10 seconds at 95°C and 20 seconds at 60°C. Viral load was quantified against a known HBV DNA standard using VIIA® 7 software. The viral load in the supernatant from wells containing treated cells was compared to the viral load in the supernatant from DMSO control wells (≧3 (per plate)). A modified CellTiter-Glo Luminescent Cell Viability Assay (Promega, catalog number: G7573) was used to perform the cell viability assay. An appropriate amount of CellTiter-Glo(CTG) 1×DPBS was mixed in a 1:1 ratio, and 100 μL of the mixture was added to each well. Subsequently, all supernatant in each well was completely removed without contact with the cell surface.The plates were incubated on an orbital shaker at room temperature for 10 minutes, and then read using a plate reader (TECAN M1000 or Envision). EC was performed via curve fitting of a 4-parameter nonlinear logistic regression model (GraphPad Prism or Dotmatics). 50 or CC 50 The value was calculated. CC 50 All values ​​were >10 μM.

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

[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-pyrazole-4-carboxamide. 5-amino-N-(3-chloro-4-fluorophenyl)-3-(hexahydro-1'H-spiro[oxiran-2,2'-pentalen]-5'-yl)-1-methyl-1H-pyrazole-4-carboxamide (200 mg, 0.495 mmol) was dissolved in THF / H2O (6 mL / 2 mL) and NaSMe (138.6 mg, 1.98 mmol) was added. The mixture was stirred overnight at room temperature. After removing the solvent, the crude product was purified by silica gel column chromatography using 3:1 (v / v) petroleum ether / ethyl acetate to obtain 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 value: 452.1, Measured value: 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), m-CPBA (114.8 mg, 0.66 mmol) was added. The mixture was stirred overnight at room temperature. After removing the solvent, the crude material was purified by silica gel column chromatography using 3:1 (v / v) DCM / MeOH to obtain AIA-227 (40 mg, 37.3%) as a white solid. MS (m / z): Calculated: 484.1, Measured: 484.3 [M+1] + AIA-227 was separated by SFC to obtain 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: 11H 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] Synthesis of an alternative to 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), n-BuLi (327.5 mL, 818.7 mmol, 2.5 M) was added dropwise at -78 °C. The resulting solution was warmed to -20 °C and stirred for 1 hour. The reaction mixture 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 hours. The mixture was warmed to room temperature and stirred for a further 4 hours. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride (200 mL). The solvent was removed, followed by dilution with water, extraction with ethyl acetate (3 × 200 mL), drying over Na₂SO₄, filtration, and concentration to obtain the crude product. The crude product was purified by column chromatography using 0-5% (v / v) methanol in DCM and basic preparative HPLC to obtain 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 value: 484.1, MS measured value: 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] Twenty days after volatilization, crystals of compound AIA-227-2, measuring 0.08 × 0.10 × 0.20 mm, were obtained from EtOH and used for X-ray diffraction data acquisition. Using CuKα radiation in ω / φ scan mode, data were collected at room temperature using a Bruker SMART CCD area-detector diffractometer. 10,846 reflections were collected, of which 3,754 were unique (Rint = 0.0507).

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

[0358] The structure was elucidated using a direct method, and all non-H atoms were extracted using the full matrix least squares method using the SHELXTL program. 2 The analysis was refined. All H atoms were placed in geometrically ideal positions and constrained to rest on their parent atoms. Using a multi-scan absorption correction method, the maximum and minimum transmission parameters were 0.7531 and 0.6017, respectively. The final R, wR2, and GOF were 0.0457, 0.1293, and 1.024, respectively.

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

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

[0361] Embedding by reference All publications and patent documents referred to herein, including those listed below, are incorporated herein by reference for any purpose as if each individual publication or patent document were incorporated specifically by reference individually. In the event of any conflict, this application shall prevail, including any definitions herein.

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

[0363] Unless otherwise specified, all numerical values ​​used herein and in the claims, such as amounts of components, reaction conditions, etc., should be understood in all cases to be modified by the term "approximately." Accordingly, the numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained by this disclosure, unless otherwise indicated. In one embodiment, for example, the following items are provided. (Item 1) Compound of formula I [ka] or a pharmaceutically acceptable salt thereof [in the formula, L is C 1~4 Alkylene or Halo C 1~4 It is alkylene, L 1 and L 2 Independently, combined, 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 CR 4 R 8 And, X 4 and X 6 They are independently either 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, Halo C 1~6 Alkyl and C 3~6 Each element is independently selected from the group consisting of monocycloalkyls, R d is hydrogen, OH, C 1~6 Alkyl or C 1~6 It is an alkoxy, R x1 is hydrogen, C 1~4 Alkyl, C 1~4 Alkenil, C 1~4 Alkinil, Halo C 1~4 Alkyl, or C 3~6 It is monocycloalkyl, or R x1 and R 2 They come together, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 CH 2 O- -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 -NH- -CH 2 NHCH 2 -, -CH 2 CH 2 CH 2 NH- or -CH 2 CH 2 NHCH 2 -Forms a group, R 0a These are hydrogen, halogen, OH, CN, NO 2 、R a R b N-, C 1~4 Alkyl and Halo C 1~4 Each element is independently selected from the group consisting of alkyl groups, R 4a and R 6a These are, independently, hydrogen or C 1~4 It is alkyl, R 0 、R 6 and R 11 These are hydrogen, halogen, OH, CN, NO 2 , oxo, R d N=, hydrazino, formyl, azide, silyl, siloxy, HOC(O)-, R a R b N-, R a R b NS(O) t -、C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinil, Halo C 1~6 Alkyl, hydroxy C 1~6 Alkyl-, R aR 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, Halo C 1~6 Alkoxy, Hydroxy C 1~6 Alkoxy-, R a R b NC 1~6 Alkoxy-, C 1~6 Alkoxy C 1~6 Alkyl-, Halo C 1~6 Alkoxy C 1~6 Alkyl-, R a R b NC(O)-, C 1~6 Alkyl C(O)-, C 1~6 Alkoxy C(O)-, C 1~6 Alkyl C(O)O-, C 1~6 Alkyl S(O) q -、C 1~6 Alkyl S(O) t NR c -、C 1~6 Alkyl S(O) t C 1~6 Alkyl-, C 1~6 Alkyl S(O) t NR a C 1~6 Alkyl-, C3~6 Cycloalkyl S(O) t C 1~6 Alkyl-, C 1~6 Alkyl C(O)C 1~6 Alkyl-, and C 1~6 Alkyl C(O)OC 1~6 Each element is independently selected from the group consisting of alkyl-, R 1 is a phenyl or a 5-6 member monocyclic heteroaryl, wherein the phenyl or 5-6 member monocyclic heteroaryl is 1, 2, or 3 independently selected R 11 It is replaced as needed in the base, R 2 and R 8 These are hydrogen, halo, CN, OH, and R. a R b N, C 1~4 Alkyl, Halo C 1~4 Alkyl, C 3~5 Monocycloalkyl, C 1~4 Alkoxy and Halo C 1~4 Independently selected from the group consisting of alkoxys, R 3 teeth

change

change

change

change

change

change

Claims

1. Compound of formula I 【Chemistry 144】 or a pharmaceutically acceptable salt thereof [in the formula, L is C １～４ Alkylene or Halo C １～４ It is alkylene, L １ is a bond, 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 NR ｘ１ And, X ３ CR ４ R ８ And, R ａ , R ｂ and R ｃ is hydrogen, C １～６ Alkyl, Halo C １～６ Alkyl and C ３～６ Each element is independently selected from the group consisting of monocycloalkyls, R ｄ is hydrogen, OH, C １～６ Alkyl or C １～６ It is an alkoxy, R ｘ１ is hydrogen, C １～４ Alkyl, C １～４ Alkenil, C １～４ Alkinil, Halo C １～４ Alkyl, or C ３～６ It is monocycloalkyl, or R ｘ１ and R ２ They come together, -CH ２ CH ２ CH ２ -ien-CH ２ CH ２ CH ２ CH ２ -ien-CH ２ CH ２ O-, -CH ２ OCH ２ -ien-CH ２ CH ２ CH ２ O- -CH ２ CH ２ OCH ２ -ien-CH ２ CH ２ -NH- -CH ２ NHCH ２ -ien-CH ２ CH ２ CH ２ NH- or -CH ２ CH ２ NHCH ２ - Forms a group, R ０ａ These are hydrogen, halogen, OH, CN, NO ２ , R ａ R ｂ N-, C １～４ Alkyl and Halo C １～４ Each element is independently selected from the group consisting of alkyl groups, R ６ａ is hydrogen or C １～４ It is alkyl, R ０ 、R ６ and R １１ are hydrogen, halogen, OH, CN, NO ２ , oxo, R ｄ N=, hydrazino, formyl, azido, silyl, siloxy, HOOC(=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, halo C １～６ alkyl, hydroxy C １～６ alkyl-, R ａ R ｂ NC １～６ alkyl-, HOOC(=O)C １～６ alkyl-, R ａ R ｂ NC １～６ alkylNR ｃ -, C １～６ alkylNR ａ C １～６ alkylNR ｃ -, C １～６ alkoxy, halo C １～６ alkoxy, hydroxy C １～６ alkoxy-, R ａ R ｂ NC １～６ alkoxy-, C １～６ alkoxy C １～６ alkyl-, halo C s １～６ alkoxy C １～６ alkyl-, R ａ s R ｂ NC(=O)-, C １～６ alkylC(=O)-, C １～６ alkoxyC(=O)-, C １～６ alkylC(=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 Cycloalkyl S(O) ｔ C １～６ Alkyl-, C １～６ Alkyl C(O)C １～６ Alkyl- and C １～６ Alkyl C(O)OC １～６ Each element is independently selected from the group consisting of alkyl groups, R １ is a phenyl or a 5-6 member monocyclic heteroaryl, wherein the phenyl or 5-6 member monocyclic heteroaryl has 1, 2, or 3 independently selected R １１ It is replaced as needed in the base, R ２ is hydrogen, halo, CN, OH, R ａ R ｂ N, C １～４ Alkyl, Halo C １～４ Alkyl, C ３～５ Monocycloalkyl, C １～４ Alkoxy and Halo C １～４ Selected from the group consisting of alkoxys, R8 is selected from the group consisting of hydrogen, halo, CN, OH, R a R b N, C1-4 alkyl, halo C1-4 alkyl, C3-5 monocycloalkyl, C1-6 alkoxy, and halo C1-4 alkoxy. R ３ The basis of the following equation 【Chemistry 145】 And, R ４ R ５ -L １ -, R ６ or R ９ And, R ５ The basis of the following equation 【Chemistry 146】 And, R ９ R １４ S(O) ｑ -L-, R １４ S(O) ｑ NH-L-, or R １４ It is C(O)NH-L-, R １４ R ａ R ｂ N-, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 from 0, 1, and 2 each time they appear.

2. R ｘ１ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

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

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

5. R ２ A compound according to any one of claims 1 to 4, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

6. R １ However, the basis of the following equation 【Chemistry 147】 And, R １１ However, halogen, CN, C １～６ Alkyl and Halo C １～６ Each element is independently selected from the group consisting of alkyl groups, A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein z1 is 0, 1, 2, or 3.

7. Each time it appears, R １１ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of CN, F, Cl, Br, and I.

8. R １ However, the basis of the following equation 【Chemistry 148】 The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. R １ However, the basis of the following equation 【Chemistry 149】 The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

10. R ３ However, the basis of the following equation [Chemical 150] The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R ４ R ６ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ４ R ５ -L １ - The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

13. L １ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein the bond is a linkage.

14. R ４ R ９ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

15. R ８ However, hydrogen, OH or C １～６ A compound according to any one of claims 1 to 14, which is an alkoxy, or a pharmaceutically acceptable salt thereof.

16. R ８ The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein the OH group is OH.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A composition for treating hepatitis B (HBV) infection in subjects requiring treatment of HBV infection, comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 17 for treating hepatitis B (HBV) infection in subjects who require treatment for HBV infection.

20. The compound shown below 【Chemistry 152】 or a pharmaceutically acceptable salt thereof.

21. The compound shown below 【Chemistry 151】 or a pharmaceutically acceptable salt thereof.

22. Below formula 【Chemistry 153】 Diastereomers of the compound or pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition comprising a compound according to any one of claims 20, 21, and 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. A composition for treating hepatitis B (HBV) infection in subjects requiring treatment for HBV infection, comprising a compound according to any one of claims 20, 21, and 22, or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition according to claim 23 for treating HBV infection in subjects who require treatment for hepatitis B (HBV) infection.

Images