process

Abstract

The present disclosure generally relates to methods for the synthesis of compounds useful as modulators of Hepatitis B virus core protein assembly, as well as novel synthetic intermediates. The methods of the present disclosure can be used to produce compounds that can have dimer, multimer, and allosteric effector properties against Hepatitis B virus (HBV) core protein (Cp), a protein that exists as the protein shell of the HBV core. As an example, a process for the preparation of a compound that can be useful for treating viral infections, such as Hepatitis B, is provided herein.

Description

[Technical field]

[0001] The present disclosure generally relates to methods for the synthesis of compounds useful as modulators of Hepatitis B virus core protein assembly, as well as novel synthetic intermediates. The methods of the present disclosure can be used to produce compounds that can have dimer, multimer, and allosteric effector properties against Hepatitis B virus (HBV) core protein (Cp), a protein that exists as the protein shell of the HBV core. As an example, a process for the preparation of a compound that can be useful for treating viral infections, such as Hepatitis B, is provided herein. [Background technology]

[0002] Hepatitis B (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of cirrhosis and liver cancer (hepatocellular carcinoma). Approximately 2 billion people worldwide 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 through body fluids (mother-to-child, through sexual intercourse, and through blood products). Children born to HBV-positive mothers may also be infected unless they have been vaccinated at birth.

[0003] Hepatitis virus particles consist of a lipid envelope surrounding a viral core, covered with a surface protein (HBsAg). The core is composed of a protein shell, or capsid, made of 120 core protein (Cp) dimers, which contains the incomplete double-stranded DNA (rcDNA) viral genome as well as viral and host proteins. In infected cells, the genome exists as a completely closed circular double-stranded DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNA and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA) and viral polymerase (P). After assembly, P reverse transcribes the pgRNA into rcDNA within the capsid, generating a viral core filled with DNA.

[0004] Currently, chronic HBV is primarily treated with nucleoside(t)analogues (e.g., entecavir), which suppress the virus while the patient is on treatment, but do not clear the infection even after years of treatment. Once started on nucleoside(t)analogues, the majority of patients must continue taking them, risking a life-threatening immune response due to viral rebound. Furthermore, nucleoside therapy can lead to the emergence of antiviral drug resistance.

[0005] The only FDA-approved alternative to nucleoside(t) analogues is treatment with interferon alpha or pegylated interferon alpha. Unfortunately, the adverse event rate and profile of interferon alpha is poorly tolerated, and many patients fail to complete treatment. Furthermore, only a small proportion of patients are considered suitable for interferon therapy, and only a small proportion may demonstrate a sustained clinical response to interferon therapy. As a result, interferon-based therapies are used in only a small proportion of all diagnosed patients who choose treatment.

[0006] Therefore, current HBV treatments vary from symptomatic to watchful waiting. Nucleotide analogues suppress viral production and treat symptoms, but the infection remains. Interferon-α has severe side effects and is poorly tolerated among patients, making it a successful limited treatment strategy in only a small minority of patients. There is a clear ongoing need for more effective treatments for HBV infection.

[0007] The present disclosure relates to alternative and novel methods for the synthesis of compounds disclosed in WO2021 / 216656 (PCT / US2021 / 028323), the entire contents of which are incorporated herein by reference. Summary of the Invention

[0008] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: [ka] Forming a vinyl triflate (compound 2) [ka] Forming a vinylboronic ester (compound 3) [ka] Alkynylation of compound 3 to form compound 3.1 [ka] Formation of Hydroxypyrazole (Compound 3.2) [ka] Alkylation of compound 3.2 to form compound 3.3 [ka] Cross-coupling of compound 3.3 to form vinyl imidazole (compound 3.4) [ka] Hydrogenating compound 3.4 to form compound I or a salt thereof. [ka]

[0009] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: [ka] Converting compound 3.4 to compound I or a salt thereof (e.g., by hydrogenation). [ka]

[0010] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3.3 to compound 3.4; and ii. Converting compound 3.4 to compound I or a salt thereof [ka]

[0011] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3.2 to compound 3.3; ii. converting compound 3.3 to compound 3.4; and iii. Converting compound 3.4 to compound I or a salt thereof [ka]

[0012] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3.1 to compound 3.2; ii. converting compound 3.2 to compound 3.3; iii. Converting compound 3.3 to compound 3.4; and iv. Converting compound 3.4 to compound I or a salt thereof [ka]

[0013] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3 into compound 3.1; ii. converting compound 3.1 to compound 3.2; iii. Converting compound 3.2 to compound 3.3; iv. converting compound 3.3 to compound 3.4; and v. Converting compound 3.4 to compound I or a salt thereof [ka]

[0014] In one embodiment, compound I is a mixture of diastereomers.In one embodiment, compound I is stereochemically pure.

[0015] In one embodiment, compound I is a diastereomeric compound I(a) or a salt thereof. [ka]

[0016] In one embodiment, intermediate compound 3.1 is provided. [ka]

[0017] In one embodiment, intermediate compound 3.1a is provided. [ka]

[0018] In one embodiment, intermediate compound 3.2 is provided. [ka]

[0019] In one embodiment, intermediate compound 3.2a is provided. [ka]

[0020] In one embodiment, intermediate compound 3.3 is provided. [ka]

[0021] In one embodiment, intermediate compound 3.3a is provided. [ka]

[0022] In one embodiment, intermediate compound 3.4 is provided. [ka]

[0023] In one embodiment, intermediate compound 3.4a is provided. [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The features and other details of the present disclosure will be described in more detail.Before further description of the present disclosure, the terms used in this specification, examples and appended claims are summarized here.These definitions should be interpreted as understood by those skilled in the art in light of the remaining parts of this disclosure.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0025] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0026] As used herein, "Compound I" refers to N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide: [ka] Refers to...

[0027] As used herein, "compound I(a)" refers to N-(3-chloro-4-fluorophenyl)-4-((2s,3aR,5r,6aS)-5-hydroxy-5(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide: [ka] Refers to...

[0028] Unless the context requires otherwise, throughout this specification and claims, words such as "comprise" and "comprising" are to be interpreted in an open and inclusive sense, words such as "a" and "an" are to be construed to mean at least one, and not limited to just one, and the term "about" is to be interpreted to mean plus or minus 10%. Terms not specifically defined herein are to be given the meaning given to them by one of ordinary skill in the art in light of this disclosure and the context.

[0029] In certain cases, the depicted substituents may contribute to optical or stereoisomerism. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." Single diastereoisomeric compounds may form an aspect of the present disclosure.

[0030] When a compound has an asymmetric center, for example when it is bonded to four different groups, a set of enantiomers can result. Enantiomers can be characterized by the absolute configuration of the asymmetric center and are determined by the Cahn and Prelog rules (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (Errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed. Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: Chiral compounds can exist as either enantiomer or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0031] The compounds of the present disclosure may exist as stereoisomers. The term "stereoisomers" as used herein consists of all enantiomers or diastereomers. As previously mentioned, these compounds may be represented by the symbols "(+)", "(-)", "R", or "S", depending on the arrangement of the substituents around the asymmetric carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Although mixtures of enantiomers or diastereomers may be represented in the nomenclature as "(±)", those skilled in the art will recognize that the structure may imply chiral centers.

[0032] The compounds of the present disclosure may contain one or more double bonds and therefore may exist as geometric isomers resulting from the configuration of substituents around a carbon-carbon double bond. [ka] The symbol denotes a bond that may be a single bond, a double bond, or a triple bond, as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise noted, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be designated as "cis" or "trans", with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond.

[0033] The compounds of the present disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers due to the arrangement of the substituents around the ring. The arrangement of the substituents around the carbocyclic or heterocyclic rings is designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise noted, structures depicting carbocyclic or heterocyclic rings encompass both the "Z" and "E" isomers. The substituents around the carbocyclic or heterocyclic rings may also be referred to as "cis" or "trans", with the term "cis" referring to the substituents on the same side of the ring plane and the term "trans" referring to the substituents on opposite sides of the ring plane. Mixtures of compounds in which the substituents are arranged on both the same and opposite sides of the ring plane are designated as "cis / trans".

[0034] Each enantiomer and diastereomer of the compounds of the present disclosure may be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. Examples of these resolution methods include (1) coupling of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers by a chiral liquid chromatography column, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved 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 is a chemical or enzymatic reaction in which a single reactant forms a mixture of unequal stereoisomers during the generation of a new stereocenter or during the transformation of an existing stereocenter, and is well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0035] The terms "individual", "patient" or "subject" are used interchangeably and include any animal, such as a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human. The compounds or pharmaceutical compositions of the present disclosure can be administered to a mammal, such as a human, but also to other mammals, such as animals in need of veterinary treatment, for example, farm animals (e.g., dogs, cats, and the like), livestock (e.g., cow, sheep, pig, horse, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated by the method of the present disclosure is preferably a mammal for which treatment of HBV infection is desired.

[0036] The term "modulation" includes antagonism (eg, inhibition), agonism, partial antagonism, and / or partial agonism.

[0037] The term "pharmaceutical acceptable" includes molecular entities and compositions that do not produce adverse allergic or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and overall safety and purity standards as required by FDA Office of Biologics standards.

[0038] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any solvent, dispersion medium, coating, isotonic and absorption delaying agent, filler, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional, or enhancing therapeutic functions.

[0039] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0040] The term "salt" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a variety of salts with various inorganic and organic acids. Acids which may be used to prepare acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e., salts with pharmacologically acceptable anions, such as, but not limited to, maleate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds contained in the present composition that are acidic in nature can form base salts with various cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present composition that contain basic or acidic moieties can also form salts with various amino acids. Compounds of the present 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, zwitterion, or base salt.

[0041] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount of a compound of interest that elicits a biological or medical response in a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve a desired therapeutic and / or prophylactic effect. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0042] The term "treat" includes any effect, such as amelioration, reduction, regulation, or elimination, via interference with HBV core protein assembly that results in the improvement of disease. "Interference" includes inhibition of HBV viral assembly and infection. The compounds disclosed herein may exist in solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like, and both solvated and unsolvated forms are intended to be encompassed by the present disclosure. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0043] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to the compounds described herein except that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36Cl. For example, compounds of the present disclosure may have H atoms replaced with one or more deuterium atoms.

[0044] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavy isotopes, such as H, may confer some therapeutic advantage due to increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure may generally be prepared following procedures similar to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0045] The term "prodrug" refers to a compound that is converted in vivo to produce a compound of the present disclosure or a pharma- ceutically acceptable salt, hydrate, or solvate of a compound of the present disclosure. The conversion can occur at various locations (e.g., in the intestinal lumen or during passage through the intestinal tract, blood, or liver) and by various mechanisms (e.g., esterase, amidase, phosphatase, oxidative and / or reductive metabolism, etc.). Prodrugs are well known in the art (see, for example, Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).

[0046] In certain embodiments of the present disclosure, the compounds disclosed herein are "stereochemically pure". A stereochemically pure compound has a level of stereochemical purity that would be recognized as "pure" by those skilled in the art. Of course, this level of purity may be less than 100%. In certain embodiments, "stereochemically pure" designates a compound that is substantially free of other isomers, i.e., at least about 85% or more free. In certain embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% free of other isomers.

[0047] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. The term "stereoisomers" as used herein consists of all enantiomers or diastereomers. These compounds may be designated with the symbols "(+)", "(-)", "R", or "S" depending on the arrangement of the substituents around the asymmetric carbon atom, but one of skill in the art will recognize that the structure may imply a chiral center. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated with "(±)" in the nomenclature, but one of skill in the art will recognize that the structure may imply a chiral center.

[0048] In one embodiment, compound I is a mixture of diastereomers. In one embodiment, compound I(a) is formed as a predominant stereoisomer according to the route described herein. The term "stereochemically pure" with respect to compound I(a) means that compound I(a) is dominated by one diastereomer, for example, the other diastereomer (e.g., compounds I(b), I(c), and / or I(d)) is present at less than about 20% by weight (e.g., less than about 15%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5% by weight).

[0049] In one embodiment, compound I is substantially compound I(a), e.g., compound I comprises compound I(a) and less than 10% by HPLC area of ​​other diastereoisomers (compounds I(b), I(c), and I(d)). In one embodiment, compound I comprises compound I(a) and less than 5% by HPLC area (e.g., less than 3%, less than 2%, or less than 1%) of other diastereoisomers.

[0050] Suitably, compound I consists essentially of a single diastereomer. Suitably, compound I consists of a single diastereomer. In one embodiment, the single diastereomer is compound I(a) or a salt thereof. In one embodiment, compound I(a) or a salt thereof is stereochemically pure.

[0051] At various places in this specification, values ​​are disclosed in groups or ranges. All individual subcombinations of the members of such groups and ranges, and all combinations of the various endpoints of such groups or ranges, are specifically intended to be included in the description. For example, integers in the range of 0 to 40 are specifically intended to disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, respectively, and integers in the range of 1 to 20 are specifically intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, respectively.

[0052] The use of any and all examples or exemplary language herein, such as "such as," "including," or "for example," is intended merely to better explain the present teachings and does not pose a limitation on the scope of the invention unless otherwise stated in the claims.

[0053] synthesis In general, the compounds of the invention may be prepared, isolated, or obtained by any method apparent to one of ordinary skill in the art. Representative methods of preparation are illustrated by the following schemes and descriptions.

[0054] Example 55 of WO2021 / 216656 (PCT / US2021 / 028323), which is incorporated herein by reference, discloses Compound I: N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide: [ka] One embodiment for preparing the compound is provided.

[0055] MeMgBr (3M in DEE, 0.59 mL, 1.78 mmol) was added slowly to a stirred solution of ethyl 2-((5-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxy-octahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)acetate (0.5 g, 0.89 mmol) in dry THF (5 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by CombiFlash® column chromatography followed by prep. HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (0.501 g, 61%) as an off-white solid. TLC: 5% MeOH (R f : 0.4); 1H 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. MS C 27 H 33 Calculated for ClFN5O4: 545.2; Found: 546.3 [M+1] +

[0056] The product of Example 55 is sometimes referred to herein as Compound I: [ka] , N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide (Compound I). Different chemical names may be given if alternative naming conventions are followed.

[0057] As will be appreciated by those skilled in the art, compound I is a mixture of diastereomers. Thus, stereoisomerically enriched or stereoisomerically purified compounds may form an aspect of the present disclosure, as encompassed by the phrase "stereochemically pure" as used above. Diastereomers of compound I include: [ka] Includes:

[0058] As described herein, the present disclosure relates to alternative and novel synthetic methods for preparing compounds I, and each of Ia, Ib, Ic, and Id.

[0059] Suitably, the diastereomer of compound I is compound I(a).

[0060] Synthesis method Formation of Compound II [ka] Compound II, where R1 is a suitable leaving group such as triflate, mesylate, or tosylate, may be formed by reacting compound 1 (tetrahydropentalene-2,5(1H,3H)-dione) with a suitable strong base (such as butyllithium or lithium hexamethyldisilazane) followed by the addition of a suitable leaving group reagent (such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, or toluenesulfonic anhydride). Suitably, R1 is triflate (compound 2).

[0061] Formation of Compound III [ka] Compound III, where each R2 is independently hydrogen, alkyl, or phenyl, or both combine to form a cyclic boronic ester, such as a pinacol boronate, neopentyl, or catechol ester, may be formed by reacting compound II with a suitable boron reagent, such as bis(pinacolato)diboron, in the presence of a palladium catalyst, such as Pd(dppf)Cl2, and a suitable base, such as potassium carbonate. Suitably, both R2 combine to form a pinacol boronate ester (compound 3).

[0062] Formation of Compound IV [ka] Compound IV (wherein R3 is C 1-4 alkyl (such as methyl or ethyl) to form compound III, 1-4 It may be formed by reaction with an organometallic formed from the reaction of an alkylpropiolate with a suitable strong base (such as butyllithium or lithium hexamethyldisilazane). Suitably, both R2 in compound IV are linked to form a boronic acid pinacol ester and R3 is methyl (compound 3.1).

[0063] Formation of Compound V [ka] Compound V may be formed by reacting compound IV with methylhydrazine or a salt of methylhydrazine (such as methylhydrazine sulfate) in a suitable solvent (such as toluene) with heating (such as >60° C., >70° C., >80° C., or about 90° C.). If a salt of methylhydrazine is used, a suitable base (such as triethylamine or DIPEA) is also required in the reaction to decompose the salt. Suitably, both R2 in compound V combine to form a boronic acid pinacol ester (compound 3.2).

[0064] Formation of Compound VI [ka] Compound VI may be formed by reacting compound V with a suitable base (such as potassium carbonate) followed by the addition of a suitable alkylating agent (such as isobutylene oxide). Suitably, both R2 in compound VI are linked to form a boronic acid pinacol ester (compound 3.3).

[0065] Formation of compound 3.4 [ka] Compound 3.4 may be formed by a cross-coupling reaction between compound VI and compound VII, where R4 is a suitable leaving group (such as bromo, iodo, or triflate). The cross-coupling reaction proceeds in the presence of a suitable base (such as potassium carbonate, cesium carbonate of potassium acetate, etc.) and a suitable palladium catalyst (such as Pd(PPh3)4, Pd(dppf)Cl2, or cataCXium® A Pd G3 - mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)), in a suitable solvent (such as dioxane, DMA, NMP, and / or water), and with heating (such as >50°C, >60°C, >70°C, or at about 80°C).

[0066] Compound VII may be synthesized by reaction of 3-chloro-4-fluoroaniline with the appropriate imidazole acid using standard amide coupling methods (eg, via HATU, EDCI, T3P coupling reagents or acid chlorides).

[0067] Formation of Compound I [ka] Compound I may be formed by hydrogenating compound 3.4 over a suitable supported metal catalyst (such as palladium on carbon or platinum on carbon) in a suitable solvent (such as ethanol, acetonitrile, ethyl acetate, acetone, or THF). The reaction is typically carried out at -5 to 30°C, such as about -5 to 0°C.

[0068] In one embodiment, a method for synthesizing compound I or a salt thereof is provided, comprising converting compound 3.4 to compound I or a salt thereof (eg, by hydrogenation). [ka]

[0069] In one embodiment, there is provided a method for the synthesis of compound Ia or a salt thereof comprising converting compound 3.4a to compound Ia or a salt thereof (eg, by hydrogenation). [ka]

[0070] In the hydrogenation reaction, suitably the catalyst is palladium on carbon (such as 10% palladium on carbon) and suitably the solvent is THF.

[0071] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound VI to compound 3.4a; and ii. Converting compound 3.4a to compound Ia or a salt thereof [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both are joined to form a cyclic boronic ester (such as a pinacol, neopentyl, or catechol boronic ester).

[0072] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3.3 to compound 3.4; and ii. Converting compound 3.4 to compound I or a salt thereof [ka]

[0073] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 3.3a to compound 3.4a; and ii. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0074] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound V to compound VI; ii. converting compound VI to compound 3.4a; and iii. Converting compound 3.4a to compound Ia or a salt thereof [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both are joined to form a cyclic boronic ester (such as a pinacol, neopentyl, or catechol boronic ester).

[0075] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3.2 to compound 3.3; ii. converting compound 3.3 to compound 3.4; and iii. Converting compound 3.4 to compound I or a salt thereof [ka]

[0076] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 3.2a to compound 3.3a; ii. Converting compound 3.3a to compound 3.4a; and iii. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0077] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound IV to compound V; ii. converting compound V to compound VI; iii. converting compound VI to compound 3.4a; and iv. Converting compound 3.4a to compound Ia or a salt thereof [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both are joined to form a cyclic boronic ester (e.g., pinacol, neopentyl, or catechol boronic ester); R3 is C 1-4 alkyl (e.g., methyl or ethyl)]

[0078] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3.1 to compound 3.2; ii. converting compound 3.2 to compound 3.3; iii. Converting compound 3.3 to compound 3.4; and iv. Converting compound 3.4 to compound I or a salt thereof [ka]

[0079] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 3.1a to compound 3.2a; ii. converting compound 3.2a to compound 3.3a; iii. Converting compound 3.3a to compound 3.4a; and iv. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0080] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound III to compound IV; ii. converting compound IV to compound V; iii. converting compound V to compound VI; iv. converting compound VI to compound 3.4a; and v. Converting compound 3.4a to compound Ia or a salt thereof [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both are joined to form a cyclic boronic ester (e.g., pinacol, neopentyl, or catechol boronic ester); R3 is C 1-4 alkyl (e.g., methyl or ethyl)]

[0081] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 3 into compound 3.1; ii. converting compound 3.1 to compound 3.2; iii. Converting compound 3.2 to compound 3.3; iv. converting compound 3.3 to compound 3.4; and v. Converting compound 3.4 to compound I or a salt thereof [ka]

[0082] In one embodiment, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 3a to compound 3.1a; ii. converting compound 3.1a to compound 3.2a; iii. Converting compound 3.2a to compound 3.3a; iv. Converting compound 3.3a to compound 3.4a; and v. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0083] Alternative Route to Intermediate Compound 3.4 [ka] The alternative route described above intersects with the process described herein at either compound V or compound 3.4. Examples 4-6 below are embodiments of this alternative route starting from compound 1 (tetrahydropentalene-2,5(1H,3H)-dione).

[0084] Compound VIII (wherein R5 is C 1-4 The compound 1 is reacted with a suitable strong base (such as butyllithium or lithium hexamethyldisilazane) followed by the synthesis of XP(O)(OR5)2 (where R5 is C 1-4 X is an appropriate leaving group such as chloro or bromo) may be added to compound VIII. Suitably, R5 in compound VIII are both phenyl (compound 12) or R5 are both ethyl (compound 12.1).

[0085] Compound IX (wherein R3 is C 1-4 alkyl (such as methyl or ethyl) to form compound VIII, 1-4It may be formed by reaction with an organometallic formed from the reaction of an alkylpropiolate with a suitable strong base (such as butyllithium or lithium hexamethyldisilazane). Suitably, R5 in compound IX are both phenyl and R3 is methyl (compound 13).

[0086] Compound X may be formed by reacting compound IX with methylhydrazine or a salt of methylhydrazine (such as methylhydrazine sulfate) in a suitable solvent (such as toluene) with heating (such as >50° C., >60° C., >70° C., or about 80° C.). If a salt of methylhydrazine is used, a suitable base (such as triethylamine or DIPEA) is also required in the reaction to decompose the salt. Suitably, both R5 in compound X are phenyl (compound 14).

[0087] Compound V, where each R2 is independently hydrogen, alkyl, or phenyl, or both are combined to form a cyclic boronic ester, such as a pinacol boronate, neopentyl, or catechol ester, may be formed by reacting compound X with a suitable boron reagent, such as bis(pinacolato)diboron, in the presence of a palladium catalyst, such as Pd(XPhos)allylCl, and a suitable base, such as potassium pivalate. Suitably, both R2 in compound V combine to form a pinacol boronate ester (compound 3.2). Compound V may then be converted to compound VI, which may be converted to compound 3.4 by the methods described above.

[0088] Compound XI may be formed by reacting compound X with a suitable base (such as potassium carbonate) followed by the addition of a suitable alkylating agent (such as chloroacetone). Suitably, both R2 in compound XI are phenyl (compound 15).

[0089] Compound XII, where each R2 is independently hydrogen, alkyl, or phenyl, or both combine to form a cyclic boronic ester, such as a pinacol boronate, neopentyl, or catechol ester, may be formed by reacting compound XI with a suitable boron reagent, such as bis(pinacolato)diboron, in the presence of a palladium catalyst, such as Pd(XPhos)allylCl, and a suitable base, such as potassium pivalate. Suitably, both R2 in compound XII combine to form a pinacol boronate ester (compound 16).

[0090] Compound 17 may be formed by a cross-coupling reaction between compound XII and compound VII, where R4 is a suitable leaving group (such as bromo, iodo, or triflate). The cross-coupling reaction proceeds in the presence of a suitable base (such as potassium carbonate, cesium carbonate of potassium acetate, etc.) and a suitable palladium catalyst (such as Pd(PPh3)4, Pd(dppf)Cl2, or cataCXium® A Pd G3 - mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)), in a suitable solvent (such as dioxane, DMA, NMP, and / or water), and with heating (such as >50°C, >60°C, >70°C, or at about 80°C).

[0091] Compound 3.4 may be formed by reacting compound 17 with a suitable methyl anion species, such as methylmagnesium bromide, in a suitable solvent, such as THF.

[0092] In one embodiment of the present disclosure, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 17 to compound 3.4a; and ii. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0093] One embodiment of the present disclosure is a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 16 to compound 17; ii. converting compound 17 to compound 3.4a; and iii. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0094] One embodiment of the present disclosure is a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 15 to compound 16; ii. converting compound 16 to compound 17; iii. Converting compound 17 to compound 3.4a; and iv. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0095] One embodiment of the present disclosure is a method for synthesizing Compound I or a salt thereof, comprising the steps of: i. converting compound 14 to compound 15; ii. converting compound 15 to compound 16; iii. converting compound 16 to compound 17; iv. converting compound 17 to compound 3.4a; and v. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0096] In one embodiment of the present disclosure, there is provided a method for synthesizing compound Ia or a salt thereof, comprising the steps of: i. converting compound 14 to compound 3.2a; ii. converting compound 3.2a to compound 3.3a; iii. Converting compound 3.3a to compound 3.4a; and iv. Converting compound 3.4a to compound Ia or a salt thereof [ka]

[0097] In one embodiment of the present disclosure, a method for synthesizing compound 14 is provided, comprising converting compound 13 to compound 14. [ka]

[0098] In one embodiment, a method for synthesizing compound 14 is provided, comprising the steps of: i. converting compound 12 to compound 13; and ii. Converting compound 13 to compound 14 [ka]

[0099] In one embodiment, a method for synthesizing compound 14 is provided, comprising the steps of: i. converting compound 1 into compound 12; ii. converting compound 12 into compound 13; and iii. Converting compound 13 to compound 14 [ka]

[0100] Intermediates In another aspect, the present invention relates to intermediates useful in the preparation of compound I.

[0101] In one embodiment of this aspect, intermediate compound II is provided. [ka] wherein R1 is chloro, bromo, iodo, triflate, mesylate, or tosylate.

[0102] In one embodiment, intermediate compound III is provided. [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both R2 are joined to form a cyclic boronic ester.

[0103] In one embodiment, intermediate compound IV is provided. [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both R2 are joined to form a cyclic boronic ester; and R3 is C 1-4 is alkyl] In one embodiment, both R2 are linked to form a cyclic boronic acid ester and R3 is methyl. In one embodiment, both R2 are linked to form a boronic acid pinacol ester and R3 is methyl. Suitably, compound IV is methyl 3-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl)propiolate.

[0104] In one embodiment, compound 3.1 or compound 3.1a is provided. [ka]

[0105] In one embodiment, intermediate compound V is provided. [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both R2 are joined to form a cyclic boronic ester. In one embodiment, both R2 are linked to form a cyclic boronic acid ester. In one embodiment, both R2 are linked to form a boronic acid pinacol ester. Suitably, compound V is 5-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-ol.

[0106] In one embodiment, compound 3.2 or compound 3.2a is provided. [ka]

[0107] In one embodiment, intermediate compound VI is provided. [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both R2 are joined to form a cyclic boronic ester. In one embodiment, both R2 are linked to form a cyclic boronic acid ester. In one embodiment, both R2 are linked to form a boronic acid pinacol ester. Suitably, compound VI is 2-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-ol.

[0108] In one embodiment, compound 3.3, or compound 3.3a, is provided. [ka]

[0109] In one embodiment, intermediate compound 3.4 is provided. [ka]

[0110] Compound 3.4 is N-(4-chloro-3-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide.

[0111] In one embodiment, intermediate compound 3.4a is provided. [ka]

[0112] Compound 3.4a is N-(3-chloro-4-fluorophenyl)-4-((3aS,5S,6aR)-5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide.

[0113] In one embodiment, intermediate compound VIII is provided. [ka] [Wherein, R5 is C 1-4 alkyl or phenyl] In one embodiment, R5 is ethyl or phenyl. In one embodiment, R5 is phenyl. Suitably, compound VIII is 5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl diphenyl phosphate.

[0114] In one embodiment, intermediate compound IX is provided. [ka] [Wherein, R5 is C 1-4 alkyl or phenyl; R3 is C 1-4 is alkyl] In one embodiment, R5 is ethyl or phenyl and R3 is methyl or ethyl. In one embodiment, R5 is phenyl and R3 is methyl. Suitably, compound IX is methyl 3-(5-((diphenoxyphosphoryl)oxy)-2-hydroxy-1,2,3,3a,4,6a-hexahydropentalen-2-yl)propiolate.

[0115] In one embodiment, an intermediate compound X is provided. [ka] [Wherein, R5 is C1-4 alkyl or phenyl] In one embodiment, R5 is ethyl or phenyl. In one embodiment, R5 is phenyl. Suitably, compound X is 5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl diphenyl phosphate.

[0116] In one embodiment, intermediate compound XI is provided. [ka] [Wherein, R5 is C 1-4 alkyl or phenyl] In one embodiment, R5 is ethyl or phenyl. In one embodiment, R5 is phenyl. Suitably, compound XI is 5-hydroxy-5-(1-methyl-3-(2-oxopropoxy)-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl diphenyl phosphate.

[0117] In one embodiment, intermediate compound XII is provided. [ka] wherein each R2 is independently hydrogen, alkyl, or phenyl, or both are joined to form a cyclic boronic ester. In one embodiment, R2 are both linked to form a cyclic pinacol, neopentyl, or catechol ester of boronate. In one embodiment, R2 are both linked to form a cyclic pinacol ester of boronate. Suitably, compound XII is 1-((5-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propan-2-one.

[0118] In one embodiment, intermediate compound 17 is provided. [ka]

[0119] Compound 17 is N-(4-chloro-3-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2-oxopropoxy)-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide. EXAMPLES

[0120] As previously mentioned, the present disclosure relates to alternative and novel methods for the synthesis of compounds disclosed in PCT / US2021 / 028323 (PCT'323), which is incorporated by reference in its entirety.

[0121] One route to compound I uses the guidance of PCT '323 as a template. [ka]

[0122] As shown in Scheme 1, one route provides for the introduction of a starting material designated compound 3b (N-(4-chloro-3-fluorophenyl)-4-bromo-1-methyl-1H-imidazole-5-carboxamide) early in the overall route, i.e., the third step in the process.

[0123] The present disclosure includes an alternative route that delays the introduction of starting material compound 3b until later in the synthetic scheme, thereby saving costs and reducing waste.

[0124] Thus, one embodiment of the present disclosure provides the following route, as shown in Scheme 2: [ka]

[0125] As shown in Scheme 2, compound 3b starting material is introduced just prior to step 6 of this embodiment of the present disclosure, the penultimate step in producing product compound I.

[0126] Detailed synthesis Example 1 One embodiment of the present disclosure provides the synthesis of compound I following the route shown in Scheme 2.

[0127] Step a) Formation of Compound 2 [ka] Tetrahydropentalene-2,5(1H,3H)-dione-compound 1 is dissolved in THF and cooled to -78°C. Lithium hexamethyldisilazane is added to the solution followed by trifluoromethanesulfonic anhydride. The mixture is stirred at -78°C until the reaction is complete. The mixture is quenched with water. The process temperature is raised to approximately 0°C followed by concentration. The concentrated solution is diluted with ethyl acetate and the diluted solution is concentrated. The concentrated solution is washed with aqueous sodium chloride. The organic layer is concentrated. The crude is taken up in heptane and purified by silica gel chromatography.

[0128] Step b) Formation of compound 3 [ka] Compound 2 is dissolved in a mixture of dimethoxyethane and water. Potassium carbonate is added to the vinyl triflate solution followed by the palladium catalyst. The process temperature is increased to approximately 80° C. and stirred at that temperature until the reaction is complete. The process temperature is reduced to approximately 40° C. and the mixture is concentrated. 2-Methyltetrahydrofuran and water are added to the mixture. The layers are separated, the organic layer is diluted with heptane and the solution is filtered through silica gel. The filtrate is concentrated and the remaining crude is diluted with ethyl acetate and stirred at approximately 0° C. until the pure product precipitates from the solution. The product is collected by filtration.

[0129] Step c) Formation of compound 3.1 [ka] Methyl propiolate is dissolved in THF and cooled to -78°C. Compound 3 is added to the cooled alkyne solution in THF. The reaction mixture is stirred at -78°C until the reaction is complete. The mixture is quenched with aqueous ammonium chloride and the mixture is extracted with ethyl acetate. The organic layer is concentrated to dryness and the crude product is purified by silica gel chromatography. The crude product is purified by silica gel chromatography.

[0130] Step d) Formation of compound 3.2 [ka] Methylhydrazine sulfate is suspended in toluene. Triethylamine is added to the suspension and the mixture is stirred for a short time. Compound 3.1 is added. The process temperature is increased to approximately 90° C. and the reaction is stirred at that temperature until the reaction is complete. The reaction mixture is cooled to ambient temperature and quenched with water. The crude product is collected by filtration. The crude product is then taken up in isopropanol and stirred at ambient temperature. The purified product is collected by filtration.

[0131] Step e) Formation of compound 3.3 [ka] Compound 3.2 is dissolved in a mixture of dimethylacetamide / water. Potassium carbonate is added to the solution followed by isobutylene oxide. The process temperature is increased to 75° C. and the reaction is stirred at that temperature until the reaction is complete. The reaction mixture is filtered. The filtrate is diluted with ethyl acetate and the solution is concentrated to a reduced volume. The dilution / concentration sequence is repeated and the remaining solution is used directly in the next step. Alternatively, the crude material may be purified by silica gel chromatography.

[0132] Step f) Formation of compound 3.4 [ka] The compound 3.3 solution is diluted with a mixture of dioxane / water. Potassium carbonate is added to the vinyl boronate solution, followed by the palladium catalyst. The process temperature is raised to approximately 80° C., and the mixture is stirred at that temperature until the reaction is complete. The mixture is cooled to ambient temperature, followed by filtration. The filtrate is concentrated. The crude is diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, followed by concentration. The crude is purified by silica gel chromatography.

[0133] Step g) Formation of Compound I [ka] Compound 3.4 is dissolved in THF. 10% palladium on carbon is added to the solution. The mixture is exposed to a hydrogen atmosphere. The mixture is stirred at ambient temperature and pressure until the reaction is complete. The mixture is filtered through Celite. The filtrate is concentrated to a minimum volume and then diluted with ethyl acetate. The diluted solution is concentrated to a minimum volume and stirred at ambient temperature. The precipitated product (Compound I) is collected by filtration.

[0134] Example 2 One embodiment of the present disclosure provides the synthesis of compound I below based on the route shown in Scheme 2.

[0135] Step a) Formation of Compound 2 Tetrahydropentalene-2,5(1H,3H)-dione-compound 1 (1 g, 7.24 mmol) was dissolved in THF (15 ml, 15 Vol) and cooled to -78°C. Lithium hexamethyldisilazane (1M THF, 6.15 mL, 6.15 mmol, 0.85 Eq) was added to the solution followed by trifluoromethanesulfonic anhydride (1.35 mL, 7.96 mmol, 1.1 Eq). The mixture was stirred at -78°C until the reaction was complete. The mixture was quenched with water (2 ml, 2 Vol). The process temperature was raised to approximately 0°C and stirred for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate (15 ml, 15 Vol) and saturated NaHCO3 (15 ml, 15 Vol). The layers were separated and the organic layer was washed with saturated brine (20 ml, 20 Vol). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give a gum. The crude material was purified by silica gel chromatography (40 g cartridge) using a gradient of cyclohexane / ethyl acetate (1 / 0 to 1 / 1 over 12 CV) to give 5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate-compound 2 as a pale yellow oil (857 mg, 52% yield). 1 H NMR (400 MHz, MeOD, ppm) δ 5.72 (q, J = 2.1 Hz, 1H), 3.58-3.49 (m, 1H), 3.18-3.08 (m, 1H), 3.04 (ddt, J = 16 / 8.1 / 2.6 Hz, 1H), 2.67-2.48 (m, 2H), 2.47-2.39 (m, 1H), 2.30-2.21 (m, 1H), 2.11 (dd, J = 19 / 7.2 Hz, 1H)

[0136] Step b) Formation of compound 3 Compound 2 (750 mg, 2.78 mmol, 1 Eq) was dissolved in a mixture of dimethoxyethane (7.5 mL, 10 Vol) and bis(pinacolato)diboron (773 mg, 3.04 mmol, 1.1 Eq) at room temperature. Potassium carbonate (840 mg, 8.41 mmol, 3 Eq) was added to the compound 2 solution, followed by Pd(dppf)Cl2 (8.2 mg, 0.011 mmol, 0.004 Eq). The process temperature was increased to approximately 80°C and stirred at that temperature until the reaction was complete. The process temperature was reduced to room temperature and the mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to approximately 1 Vol, n-heptane (1.5 mL, 2 Vol) was added, and the mixture was concentrated under reduced pressure to a minimum volume. Addition / concentration of n-heptane was repeated, then the crude material was dissolved in n-heptane (750 mL, 1 Vol) and purified by silica gel chromatography using a gradient of n-heptane / ethyl acetate (1 / 0 to 10 / 1 over 8 CV). Fractions containing the pure product were combined, concentrated in vacuo to a minimum volume, and precipitated by stirring in n-heptane (100 mL, 0.2 Vol) at 0-10 °C for 1-2 h. The product was isolated by filtration to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydropentalen-2(1H)-one-compound 3 as an off-white solid (581 mg, 84% yield). 1 H NMR (400 MHz, DMSO) δ 6.27 (q, J = 2.1 Hz, 1H), 3.45 - 3.37 (m, 1H), 2.92 (dqd, J = 9.8, 7.5, 2.2 Hz, 1H), 2.64 (ddt, J = 16.4, 5.1, 2.7 Hz, 1H), 2.48 - 2.39 (m, 2H), 2.27 - 2.10 (m, 2H), 1.81 (ddd, J = 19.0, 6.7, 1.9 Hz, 1H), 1.20 (s, 12H)

[0137] Step c) Formation of compound 3.1 Methyl propiolate (281 μL, 4 Eq, 3.22 mmol) was dissolved in THF (3 ml, 15 Vol) and cooled to -78°C. n-BuLi (2.5M in hexanes, 1.29 mL, 4 Eq, 3.22 mmol) was added dropwise to the solution and the reaction mixture was stirred for 1 h. To the cooled alkyne solution was added compound 3 (200 mg, 1 Eq, 806 μmol) in THF (1 ml, 5 Vol). The reaction mixture was stirred at -78°C until the reaction was complete. The mixture was quenched with aqueous ammonium chloride (0.6 ml, 3 Vol) and the mixture was extracted with ethyl acetate (2 x 2 ml, 10 Vol). The organic layer was concentrated to dryness under reduced pressure and the crude material was purified by silica gel chromatography (0-30% ethyl acetate in cyclohexane, 12 CV, 20 g) to give methyl 3-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl) propiolate - compound 3.1 (182 mg, 68% yield) as a pale yellow oil. 1 H NMR (400 MHz, MeOD) δ ppm: 6.33 (q, J = 2.2 Hz, 1H), 3.74 (s, 3H), 3.38-3.31 (m, 1H), 2.93-2.83 (m, 1H), 2.68 (dtt, J = 16.8, 9.3, 2.3 Hz, 1H), 2.38-2.24 (m, 3H), 1.77-1.63 (m, 2H), 1.25 (s, 12H)

[0138] Step d) Formation of compound 3.2 Methylhydrazine sulfate (775 mg, 3 Eq, 5.37 mmol) was suspended in toluene (6 mL, 10 Vol). Triethylamine (749 μL, 3 Eq, 5.37 mmol) was added to the suspension and the mixture was stirred at 20-30° C. for 30-60 min. Compound 3.1 (595 mg, 1 Eq, 1.79 mmol) was added and the process temperature was increased to approximately 90° C. and the reaction was stirred at that temperature until the reaction was complete. The reaction mixture was cooled to ambient temperature and quenched with water (6 mL, 10 Vol). The crude product was collected by filtration. The crude product was then taken up in isopropanol (1.2 mL, 2 Vol) and stirred at ambient temperature for 10-12 h. The purified product was collected by filtration to give 5-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-ol-compound 3.2 (299 mg, 48% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.31 (s, 1H), 5.11 (s, 1H), 3.65 (s, 3H), 3.14 (br s, 1H), 2.60 - 2.52 (m, 2H), 2.34 - 2.17 (m, 3H), 1.67 (ddd, J = 24.7, 13.0, 6.8 Hz, 2H), 1.20 (s, 12H)

[0139] Step e) Formation of compound 3.3 Compound 3.2 (500 mg, 1 Eq, 1.44 mmol) was dissolved in a mixture of dimethylacetamide / water (10:1 ratio, 5.5 mL, 11 Vol). Potassium carbonate (499 mg, 2.5 Eq, 3.61 mmol) was added to the solution, followed by isobutylene oxide (521 mg, 5 Eq, 7.22 mmol). The process temperature was increased to 75° C. and the reaction was stirred at that temperature until the reaction was complete. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (2.5 mL, 5 Vol), and the solution was concentrated under reduced pressure to approximately 11 Vol. The dilution / concentration sequence was repeated, and the resulting solution of compound 3.3 was used directly in the next step (approximately 0.26 M concentration).

[0140] Step f) Formation of compound 3.4 The compound 3.3 solution from the previous step (approximately 5.5 ml, 1 Eq, 1.44 mmol) was diluted with a mixture of dioxane / water (5:1 ratio, 6 mL, 12 Vol). 4-Bromo-N-(4-chloro-3-fluorophenyl)-1-methyl-1H imidazole-5-carboxamide-compound 3b (528 mg, 1.1 Eq, 1.59 mmol) and potassium carbonate (499 mg, 2.5 Eq, 3.61 mmol) were added to the solution, followed by palladium catalyst (cataCXium® A Pd G3, 26 mg, 0.025 Eq, 0.036 mmol). The process temperature was raised to approximately 80° C., and the mixture was stirred at that temperature until the reaction was complete. The mixture was cooled to ambient temperature and then filtered. The filtrate was concentrated under reduced pressure to approximately 13 Vol. The crude was diluted with water (5 mL, 10 Vol) and extracted with ethyl acetate (3 x 3 mL / 6 Vol). The organic layer was washed with saturated brine (3 x 5 mL / 10 Vol) and then concentrated under reduced pressure to approximately 1 Vol. The crude was purified by silica gel chromatography to give N-(4-chloro-3-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide-compound 3.4 as a white solid (385 mg, 49% yield over two steps). 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.01 (dd, J = 6.8, 2.5 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.55 (m, 1H), 7.42 (t, J = 9.1 Hz, 1H), 6.01 (d, J = 2.2 Hz, 1H), 5.56 (s, 1H), 5.26 (s, 1H), 4.52 (s, 1H), 3.73 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.19 (d, J = 8.2 Hz, 1H), 2.85 (dd, J = 16.1, 9.2 Hz, 1H), 2.62 (t, J = 8.5 Hz, 1H), 2.44 (br s, 1H), 2.37 - 2.24 (m, 2H), 1.72 (td, J = 13.0, 7.5 Hz, 2H), 1.13 (s, 6H)

[0141] Step g) Formation of Compound I Compound 3.4 (250 mg, 0.46 mmol, 1 Eq) was dissolved in THF (5 mL, 20 Vol). To this solution was added 10% palladium on carbon (0.1 w / w, 25 mg, 0.01 Eq). The mixture was exposed to a hydrogen atmosphere. The mixture was stirred at ambient temperature and pressure until the reaction was complete. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to a minimum volume and then diluted with ethyl acetate (1.25 mL, 5V). The diluted solution was concentrated under reduced pressure to approximately 2 Vol and stirred at ambient temperature for 2-4 h. The precipitated product was collected by filtration to give compound I as an off-white solid (213 mg, 85% yield). 1H 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. MS C 27 H 33 Calculated for ClFN5O4: 545.2; Found: 546.3 [M+1] +

[0142] Example 3 The synthesis of compound I was further carried out according to the route shown in Scheme 3. After isolation and purification of compound I, the stereochemistry of compound I was confirmed by single crystal X-ray diffraction to be compound I(a): [ka] It was decided as follows. [ka]

[0143] The process described in Example 2 was modified as follows:

[0144] Example 3A - Shortening of steps c) and d) to produce compound 3.2 [ka] [ka]

[0145] Methyl propiolate (13.55 g, 4 Eq, 0.161 mol) was dissolved in THF (400 ml, 40 Vol) and combined with n-BuLi (1.6 M in THF, 106 mL, 4.2 Eq, 0.169 mol) at -85 °C in a stainless steel flow reactor (13 mL Φ6, Rt = 1.0 min). The product from the flow reactor was added continuously to a standard batch reactor containing a solution of compound 3 (10.0 g, 1 Eq, 0.040 mol) in THF (100 ml, 10 Vol) at -85 °C. After the addition of the methyl propiolate / n-BuLi solution was complete, the reaction mixture was stirred for 2 h at -85 °C. The reaction mixture was warmed to -60 °C and the pH was adjusted to 6-8 by adding a solution of acetic acid in THF (1:3 v / v acetic acid / THF). The quenched reaction mixture was warmed to ambient temperature, washed with water (50 ml, 5 Vol), separated and the organic phase concentrated in vacuo to 1-2 Vol. Toluene (50 mL, 5 Vol) was added and the mixture concentrated in vacuo to 1-2 Vol and the toluene addition / concentration step was repeated. Toluene (150 ml, 15 Vol) was added and the amount of compound 3.1 assayed by HPLC (87% assay yield) and the crude material in toluene (approximately 0.23M) was used directly in the next step.

[0146] Methylhydrazine sulfate (15.16 g, 3 Eq, 0.105 mol) and triethylamine (14.66 mL, 3 Eq, 0.105 mol) were added to a solution of compound 3.1 (150 mL, 1 Eq, 0.035 mol) in toluene. The process temperature was raised to approximately 90° C. and the reaction was stirred at that temperature until the reaction was complete. The reaction mixture was cooled to ambient temperature and quenched with water (116 mL, 10 Vol). The crude product was collected by filtration. The crude product was then taken up in isopropanol (23.3 mL, 2 Vol) and stirred at ambient temperature for 10-12 h. The purified product was collected by filtration to give compound 3.2 (6.84 g, 49% yield over two steps) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.31 (s, 1H), 5.11 (s, 1H), 3.65 (s, 3H), 3.14 (br s, 1H), 2.60 - 2.52 (m, 2H), 2.34 - 2.17 (m, 3H), 1.67 (ddd, J = 24.7, 13.0, 6.8 Hz, 2H), 1.20 (s, 12H)

[0147] Example 3B - Shortening of steps e) and f) with the crystallization procedure of compound 3.4 [ka]

[0148] Compound 3.2 (10.0 g, 1 Eq, 28.8 mmol) was dissolved in a mixture of dimethylacetamide / water (10:1 ratio, 110 mL, 11 Vol). Potassium carbonate (9.98 g, 2.5 Eq, 72 mmol) was added to the solution, followed by isobutylene oxide (10.4 g, 5 Eq, 144 mmol). The process temperature was raised to 75° C. and the reaction was stirred at that temperature until the reaction was complete. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (50 mL, 5 Vol), and the solution was concentrated under reduced pressure to approximately 11 Vol. The dilution / concentration sequence was repeated, and the resulting solution of compound 3.3 (approximately 0.26 M concentration) was used directly in the next step.

[0149] The compound 3.3 solution from the previous step (approximately 110 ml, 1 Eq, 28.8 mmol) was diluted with a mixture of dioxane / water (5:1 ratio, 120 mL, 12 Vol). To this solution was added 4-bromo-N-(4-chloro-3-fluorophenyl)-1-methyl-1H imidazole-5-carboxamide (10.56 g, 1.1 Eq, 31.8 mmol) and potassium carbonate (9.98 g, 2.5 Eq, 72 mmol), followed by palladium catalyst (cataCXium® A Pd G3, 516 mg, 0.025 Eq, 0.72 mmol). The process temperature was raised to approximately 80° C., and the mixture was stirred at that temperature until the reaction was complete. The mixture was cooled to ambient temperature and then filtered. The filtrate was concentrated under reduced pressure to approximately 13 Vol. The crude was diluted with water (100 mL, 10 Vol) and extracted with ethyl acetate (3 x 60 mL / 6 Vol). The combined organic layers were washed with saturated brine (3 x 60 mL / 6 Vol) and then concentrated under reduced pressure to approximately 1 Vol. THF (70 mL, 7 Vol) was added to the crude, the temperature was raised to 55°C, and the mixture was stirred until complete dissolution. The resulting pale yellow solution was filtered through a 0.45 μM membrane and concentrated under reduced pressure at 55°C to approximately 3 Vol to give a cloudy solution. EtOH (90 mL, 9 Vol) was added to the mixture with stirring over 30 min to give a suspension and the process temperature was reduced to 20°C at a rate of 5°C per hour. The mixture was stirred at 20°C for 12 h and isolated by filtration. The filter cake was washed with EtOH (2 x 20 mL / 2 Vol) and then dried in a vacuum oven at 50°C for 24 h. 11H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.01 (dd, J = 6.8, 2.5 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.55 (m, 1H), 7.42 (t, J = 9.1 Hz, 1H), 6.01 (d, J = 2.2 Hz, 1H), 5.56 (s, 1H), 5.26 (s, 1H), 4.52 (s, 1H), 3.73 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.19 (d, J = 8.2 Hz, 1H), 2.85 (dd, J = 16.1, 9.2 Hz, 1H), 2.62 (t, J = 8.5 Hz, 1H), 2.44 (br s, 1H), 2.37 - 2.24 (m, 2H), 1.72 (td, J = 13.0, 7.5 Hz, 2H), 1.13 (s, 6H)

[0150] Example 3C - Purification and recrystallization of Compound I

Chem.

[0151] Example 4 - Alternative Route to Compound 3.2 [ka]

[0152] Step a) Formation of compound 12 [ka] A solution of tetrahydropentalene-2,5(1H,3H)-dione-compound 1 (10.0 g, 1 Eq, 72.4 mmol) in dry THF (150 mL, 15 vol) under N2 was cooled to -78 °C. LiHMDS (61.5 mL, 1 molar in THF, 0.85 Eq, 61.5 mmol) was added dropwise over 25 min and stirred for 20 min. Diphenylphosphoryl chloride (16.5 mL, 1.1 Eq, 79.6 mmol) was added dropwise to the solution over 15 min and the reaction mixture was stirred at -78 °C for 4 h. 20 mL of water was added and the reaction mixture was stirred for 5 min. The dry ice bath was removed and the reaction mixture was stirred for 25 min. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0–50% ethyl acetate in cyclohexane, 10 CV, 330 g) to give 5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl diphenylphosphate-compound 12 (16.1 g, 43.5 mmol, 71%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.52 - 7.40 (m, 4H), 7.35 - 7.20 (m, 6H), 5.36 (p, J = 1.9 Hz, 1H), 3.39 (dtd, J = 9.7, 5.3, 2.8 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.85 (ddq, J = 16.1, 8.1, 2.4 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.46-2.36 (m, 1H), 2.23 (dt, J = 15.9, 2.1 Hz, 1H), 2.12 (dt, J = 18.7, 2.4 Hz, 1H), 1.93 (ddd, J = 18.9, 6.8, 1.9 Hz, 1H)

[0153] Step b) Formation of compound 13 [ka] A solution of methyl propiolate (3.43 mL, 2.5 Eq, 39.8 mmol) in dry THF (89 ml, 15 vol) was cooled to -78°C. LiHMDS (31.9 mL, 1 molar in THF, 2 Eq, 31.9 mmol) was added dropwise and the reaction mixture was stirred for 1 h. A solution of compound 12 (5.90 g, 1 Eq, 15.9 mmol) in dry THF (30 ml, 5 vol) was added dropwise and the reaction was stirred for 90 min. The reaction mixture was quenched with 4 mL of acetic acid and allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, saturated brine and dried over Na2SO4. The residue was purified by flash column chromatography (0–30% ethyl acetate in cyclohexane, 120 g) to give methyl 3-(5-((diphenoxyphosphoryl)oxy)-2-hydroxy-1,2,3,3a,4,6a-hexahydropentalen-2-yl)propiolate-compound 13 (6.13 g, 13.5 mmol, 85%) as a yellow oil that solidified over time. 1 H NMR (300 MHz, DMSO) δ 7.51 - 7.38 (m, 4H), 7.35 - 7.17 (m, 6H), 5.90 (s, 1H), 5.35 (p, J = 1.9 Hz, 1H), 3.71 (s, 3H), 3.19 (s, 1H), 2.86 - 2.61 (m, 2H), 2.38 - 2.26 (m, 1H), 2.17 (dt, J = 13.0, 8.4 Hz, 2H), 1.75 (ddd, J = 15.8, 12.9, 5.6 Hz, 2H)

[0154] Step c) Formation of compound 14 [ka] To a solution of methylhydrazine sulfate (5.84 g, 3 Eq, 40.5 mmol) in dry toluene (73 mL, 12 vol) was added triethylamine (5.64 mL, 3 Eq, 40.5 mmol) at room temperature. The reaction mixture was stirred for 1 h under N2. A solution of compound 13 (6.13 g, 1 Eq, 13.5 mmol) in dry toluene (30 mL, 5 vol) was added over 15 min and the reaction mixture was stirred at 70° C. for 72 h. The reaction mixture was heated at 80° C. and continued to stir for 16 h. The reaction mixture was allowed to reach room temperature and quenched with acetone (1.98 mL, 2 Eq, 27.0 mmol) and continued to stir for 30 min. The reaction mixture was diluted with DCM (300 mL) and water (200 mL) was added. The reaction mixture was filtered to give 5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl diphenylphosphate-compound 14 (2.84 g, 6.06 mmol, 45%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 7.50 - 7.40 (m, 4H), 7.34 - 7.23 (m, 6H), 5.38 (p, J = 1.9 Hz, 1H), 5.31 (s, 1H), 5.27 (s, 1H), 3.68 (s, 3H), 3.11 (d, J = 9.1 Hz, 1H), 2.75 - 2.58 (m, 2H), 2.41 - 2.31 (m, 1H), 2.24 (td, J = 12.9, 8.7 Hz, 2H), 1.78 (ddd, J = 21.3, 12.9, 6.0Hz, 2H)

[0155] Step d) Formation of compound 3.2 [ka] Potassium pivalate (89 mg, 2.2 Eq, 634 μmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (2.75 mg, 0.02 Eq, 5.76 μmol), compound 14 (135 mg, 1 Eq, 288 μmol), and bis(pinacolato)diboron (88 mg, 1.2 Eq, 346 μmol) were weighed into a flask and evaporated once from toluene (5 ml). After evaporation of the toluene, the rotary evaporator was also flushed with nitrogen. The residue was dissolved in dry isopropyl acetate (0.5 mL, 10 vol) and purged with N2. Pd(XPhos)allylCl (3.80 mg, 0.02 Eq, 5.76 μmol) was added under a stream of nitrogen. The system was again evacuated and filled with N2 and heated to 95 °C for 3 h. The reaction mixture was allowed to warm to room temperature, filtered, and washed with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution and saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-100% ethyl acetate in cyclohexane, 12 g) to give 5-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-ol - Compound 3.2 (80 mg, 231 μmol, 80%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.31 (s, 1H), 5.11 (s, 1H), 3.65 (s, 3H), 3.14 (br s, 1H), 2.60 - 2.52 (m, 2H), 2.34 - 2.17 (m, 3H), 1.67 (ddd, J = 24.7, 13.0, 6.8 Hz, 2H), 1.20 (s, 12H)

[0156] The route from compound 1 to compound 3.2 described in Example 4 is a four-step route with an overall yield of 21.7%. This compares favorably with the four-step route from compound 1 to compound 3.2 described in Example 2, which has an overall yield of 14.3%. In particular, the desymmetrization of the diketone (compound 1) to vinyl diphenyl phosphate (compound 12) proceeded in a much higher yield (71%) than the conversion of the corresponding diketone to vinyl triflate (compound 2; 52%), and the amount of methyl propiolate organometallic species required for the formation of compound 13 was reduced to 2 equivalents compared to the 4 equivalents used in the formation of compound 3.1.

[0157] Example 5 - Formation of Compound 12.1 [ka] A solution of tetrahydropentalene-2,5(1H,3H)-dione-compound 1 (500 mg, 1 Eq, 3.62 mmol) in dry THF (7.5 mL, 15 vol) under N2 was cooled to -78 °C. LiHMDS (3.08 mL, 1 molar in THF, 0.85 Eq, 3.08 mmol) was added dropwise over 4 min and stirred for 20 min. Diethyl phosphoryl chloride (576 μL, 1.1 Eq, 3.98 mmol) was added dropwise to the solution over 7 min and the reaction mixture was stirred at -78 °C for 4 h. 1 mL of water was added and the reaction mixture was stirred for 5 min. The dry ice bath was removed and the reaction mixture was stirred for 25 min. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-75% ethyl acetate in cyclohexane, 40 g) to give diethyl (5-oxo-1,3a,4,5,6,6a-hexahydropentalen-2-yl) phosphate-compound 12.1 (570 mg, 2.08 mmol, 68%) as a pale yellow oil. 11H NMR (400 MHz, DMSO) δ 5.17 (p, J = 1.9 Hz, 1H), 4.08 (ddt, J = 8.5, 7.8, 6.8 Hz, 4H), 3.36 (dtd, J = 9.7, 5.1, 2.5 Hz, 1H), 2.99 - 2.88 (m, 1H), 2.81 (ddq, J = 16.1, 8.1, 2.3 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.44 (ddd, J = 18.6, 9.4, 1.8 Hz, 1H), 2.21 (dt, J = 16.1, 2.1 Hz, 1H), 2.10 (dt, J = 18.5, 2.5 Hz, 1H), 1.95 (ddd, J = 18.9, 6.5, 1.6 Hz, 1H), 1.25 (tt, J = 7.1, 1.0 Hz, 6H)

[0158] Example 6 - Synthesis of Compound 3.4 from Compound 14

Chem.

[0159] Step a) Formation of compound 15

Chem.

[0160] Step b) Formation of compound 16 [ka] Potassium pivalate (374 mg, 2.2 Eq, 2.66 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (11.5 mg, 0.02 Eq, 24.2 μmol), compound 15 (730 mg, 87% Wt, 1 Eq, 1.21 mmol), and bis(pinacolato)diboron (369 mg, 1.2 Eq, 1.45 mmol) were weighed into a flask and evaporated once from toluene (10 ml). After evaporation of the toluene, the rotary evaporator was also flushed with nitrogen. The residue was dissolved in dry isopropyl acetate (7.3 mL, 10 vol) and purged with N2. Pd(XPhos)allylCl (16.0 mg, 0.02 Eq, 24.2 μmol) was added under a stream of nitrogen. The microwave vial was again purged with N2 and heated to 95 °C for 2.5 h. The reaction mixture was allowed to warm to room temperature, filtered, and washed with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution and saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in ethyl acetate and the filtrate was washed on a silica pad with ethyl acetate. The filtrate was concentrated in vacuo to give 1-((5-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,3a,4,6a-hexahydropentalen-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propan-2-one-compound 16 (580 mg, 0.97 mmol, 80%, 67% purity) as an oil. 1 H NMR (400 MHz, MeOD) δ 6.39 (m, 1H), 5.65 (s, 1H), 4.69 (s, 2H), 3.80 (s, 3H), 3.28 - 3.22 (m, 1H), 2.73 - 2.62 (m, 2H), 2.50 - 2.30 (m, 3H), 2.17 (s, 3H), 1.86 - 1.71 (m, 2H), 1.26 (s, 12H)

[0161] Step c) Formation of compound 17 [ka] Compound 16 (290 mg, 67% Wt, 1 Eq, 483 μmol) was dissolved in a mixture of DMAc (2 mL, 10 vol), 1,4-dioxane (2 mL, 10 vol), and water (0.8 mL, 4 vol). N-(4-chloro-3-fluorophenyl)-4-iodo-1-methyl-1H-imidazole-5-carboxamide (192 mg, 1.05 Eq, 507 μmol), potassium carbonate (167 mg, 2.5 Eq, 1.21 mmol), and cataCXium® A Pd G3 (8.79 mg, 0.025 Eq, 12.1 μmol) were added and the reaction mixture was degassed with sonication for 5 min. The reaction mixture was placed in a preheated heating block and kept stirring at 80° C. for 40 h. The reaction was quenched with saturated NH4Cl solution, extracted twice with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (0-10% MeOH in CHCl) to give N-(4-chloro-3-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2-oxopropoxy)-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide-compound 17 (77 mg, 0.15 mmol, 30%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.01 (m, 1H), 7.70 (s, 1H), 7.58 (ddd, J = 9.1, 4.4, 2.4 Hz, 1H), 7.42 (t, J = 9.1 Hz, 1H), 6.01 (d, J = 2.2 Hz, 1H), 5.61 (s, 1H), 5.31 (s, 1H), 4.67 (s, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.123-3.13 (m, 1H), 2.85 (dd, J = 16.2, 9.1 Hz, 1H), 2.64-2.57 (m, 1H), 2.47-2.43 (m, 1H), 2.37 - 2.24 (m, 2H), 2.08 (s, 3H), 1.72 (td, J = 12.9, 7.6 Hz, 2H)

[0162] Step d) Formation of compound 3.4 [ka] A solution of 3M methylmagnesium bromide in diethyl ether (212 μL, 4 Eq, 636 μmol) was added to a solution of compound 17 (84.0 mg, 1 Eq, 159 μmol) in dry THF (2 mL) at 0° C. The reaction mixture was stirred for 1 h, then quenched with saturated NH4Cl solution, extracted twice with ethyl acetate, dried over Na2SO4, and concentrated in vacuo to give N-(4-chloro-3-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-1-methyl-1H-imidazole-5-carboxamide-compound 3.4 (85 mg, 0.16 mmol, 98%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.01 (dd, J = 6.8, 2.5 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.55 (m, 1H), 7.42 (t, J = 9.1 Hz, 1H), 6.01 (d, J = 2.2 Hz, 1H), 5.56 (s, 1H), 5.26 (s, 1H), 4.52 (s, 1H), 3.73 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.19 (d, J = 8.2 Hz, 1H), 2.85 (dd, J = 16.1, 9.2 Hz, 1H), 2.62 (t, J = 8.5 Hz, 1H), 2.44 (br s, 1H), 2.37 - 2.24 (m, 2H), 1.72 (td, J = 13.0, 7.5 Hz, 2H), 1.13 (s, 6H)

[0163] All publications, patents, and patent applications cited herein are hereby incorporated by reference for the teachings in which such citations are used.

[0164] The test compounds in the experiments described herein were used in free or salt form.

[0165] The particular response observed may vary depending on the particular active compound selected, or whether a carrier is present, as well as the type of formulation and method of administration utilized, and such variations or differences in expected results are contemplated in accordance with the practice of the present invention.

[0166] Although specific embodiments of the present invention are explained and described in detail herein, the present invention is not limited thereto. The above detailed description is provided as an example of the present invention and should not be construed as constituting a limitation of the present invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims.

[0167] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations and may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A method for synthesizing Compound I or a salt thereof, comprising converting Compound 3.4 to Compound I or a salt thereof. 【Chemistry 1】

2. 10. The method of claim 1 further comprising converting compound 3.3 to compound 3.

4. 【Chemistry 2】

3. 3. The method of claim 2, further comprising converting compound 3.2 to compound 3.

3. 【Transformation 3】

4. 4. The method of claim 3, further comprising converting compound 3.1 to compound 3.

2. 【Chemistry 4】

5. 5. The method of claim 4, further comprising converting compound 3 to compound 3.

1. 【Transformation 5】

6. 6. The method of claim 5, further comprising converting compound 2 to compound 3. 【Transformation 6】

7. 7. The method of claim 6, further comprising converting compound 1 to compound 2. 【Transformation 7】

8. A method for synthesizing compound Ia or a salt thereof, comprising converting compound 3.4a to compound Ia or a salt thereof. 【Transformation 8】

9. 9. The method of claim 8, further comprising converting compound 3.3a to compound 3.4a. 【Chemistry 9】

10. 10. The method of claim 9, further comprising converting compound 3.2a to compound 3.3a. 【Chemistry 10】

11. 11. The method of claim 10, further comprising converting compound 3.1a to compound 3.2a. 【Chemistry 11】

12. 12. The method of claim 11, further comprising converting compound 3a to compound 3.1a. 【Chemistry 12】

13. 13. The method of claim 12, further comprising converting compound 2a to compound 3a. 【Chemistry 13】

14. 14. The method of claim 13, further comprising converting compound 1a to compound 2a. 【Chemistry 14】

15. Compound I or a salt thereof obtained or obtainable by the method according to any one of claims 1 to 7.

16. 16. Compound I according to claim 15, which is substantially compound I(a), or a salt thereof.

17. 17. Compound I or a salt thereof according to claim 16, comprising compound I(a) and less than 10% (e.g., less than 5%, less than 2%, or less than 1%) of other stereoisomers by HPLC area.

18. Compound Ia or a salt thereof obtained or obtainable by a method according to any one of claims 8 to 14.

19. 19. Compound Ia or a salt thereof according to claim 18, which is stereochemically pure.

20. Compound 3.4 or Compound 3.4a, or a salt thereof. 【Chemistry 15】

21. Compound VIII: 【Chemistry 16】 [In the formula, R ５ is C １－４ alkyl or phenyl.

22. A compound selected from the following or a salt thereof: 【Chemistry 17】 [In the formula, R ２ are each independently hydrogen, alkyl, or phenyl, or both R ２ is bonded to form a cyclic boronic ester; R ３ is C １－４ alkyl; R ５ is C １－４ alkyl or phenyl.

23. Both R ２ is linked to form a boronic acid pinacol ester.

24. R ３ 23. The compound of claim 22, wherein is methyl or ethyl.

25. R ５ The compound according to any one of claims 21 to 24, wherein is phenyl.

26. Use of a compound according to any one of claims 20 to 24 for preparing compound I or compound Ia.

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