Synthesis of substituted 1-aryl-1'-heteroaryl and 1,1'-biheteroaryl compounds and their analogues

Abstract

The present disclosure includes synthetic methods for preparing certain substituted 1-aryl-1′-heteroaryl and 1,1′-biheteroaryl compounds, particularly the compound 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one, which may be used to treat, ameliorate, and / or prevent hepatitis B virus (HBV) infection in a patient. TIFF2025526864000077.tif18128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63,398,452, filed August 16, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus belonging to the Hepadnaviridae family. HBV infection is one of the most prevalent diseases worldwide and is listed as a high-priority area of concern by the National Institute of Allergy and Infectious Diseases (NIAID). While most people recover from infection after acute symptoms, approximately 30% of cases become chronic. It is estimated that 350–400 million people worldwide have chronic hepatitis B, resulting in 500,000–1 million deaths annually, primarily due to the development of hepatocellular carcinoma, cirrhosis, and / or other complications.

[0003] The number of medications currently approved for the management of chronic hepatitis B is limited, including two formulations of alpha-interferon (standard and pegylated) and five nucleoside / nucleotide analogs that inhibit HBV DNA polymerase (lamivudine, adefovir, entecavir, telbivudine, and tenofovir). Currently, first-line treatment options are entecavir, tenofovir, and / or pegylated interferon alfa-2a. However, with pegylated interferon alfa-2a, only one-third of treated patients achieve desirable serological outcomes and are often associated with severe side effects. While entecavir and tenofovir are potent HBV inhibitors, they require long-term or even lifelong administration to continuously suppress HBV replication, and the emergence of drug-resistant virus may ultimately render them ineffective. Therefore, there is an urgent need for the introduction of novel, safe, and effective treatments for chronic hepatitis B.

[0004] Hepatitis D virus (HDV) is a small, circular, enveloped RNA virus that can only replicate in the presence of HBV. In particular, HDV requires HBV surface antigen proteins for replication. Infection with both HBV and HDV results in more severe complications than infection with HBV alone. These complications include a higher likelihood of experiencing liver failure in acute infection and rapid progression to cirrhosis and a higher risk of developing liver cancer in chronic infection. In combination with hepatitis B virus, hepatitis D is the most lethal of all hepatitis infections. HDV transmission is similar to that of HBV. Infection is primarily limited to individuals at high risk for HBV infection, particularly injection drug users and those receiving clotting factor concentrates.

[0005] Currently, there is no effective antiviral therapy available for the treatment of acute or chronic hepatitis D. Interferon-alpha, administered weekly for 12 to 18 months, is the only approved treatment for hepatitis D. Response to this therapy is limited, with serum HDV RNA becoming undetectable after 6 months of treatment in only about one-quarter of patients.

[0006] Thus, there is a need in the art for novel compounds and / or compositions that can be used to treat, ameliorate, and / or prevent HBV infection in a subject. In certain embodiments, the compounds can be used in patients infected with HBV, patients at risk of HBV infection, and / or patients infected with drug-resistant HBV. In another embodiment, the HBV-infected subject is further infected with HDV. There is a further need in the art to identify scalable synthetic schemes that allow for the preparation of large batches of such compounds. The present disclosure addresses this need. Summary of the Invention

[0007] overview The present disclosure provides 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one (K): A method for preparing TIFF2025526864000002.tif18128 or a salt or solvate thereof is provided. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of the Invention The present disclosure relates, in certain aspects, to the discovery of a scalable synthetic route that allows for the reproducible multigram synthesis of certain substituted 1-aryl-1′-heteroaryl and substituted 1,1′-biheteroaryl compounds useful for treating, ameliorating, and / or preventing hepatitis B virus (HBV) and / or hepatitis D virus (HDV) infection and related conditions in subjects.

[0009] The disclosures of PCT International Patent Application No. PCT / IB2022 / 052782, filed March 25, 2022, U.S. Provisional Application No. 63 / 167,440, filed March 29, 2021, and U.S. Provisional Application No. 63 / 291,666, filed December 20, 2021, are incorporated by reference herein in their entireties.

[0010] definition As used herein, each of the following terms has the meaning associated with it in this section. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmacology, separation science, and organic chemistry are those well known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is not important so long as the present teachings remain operable. Section headings, however used, are intended to aid in the reading of the document and are not to be construed as limiting, and information related to a section heading may be found within or outside of that particular section. All publications, patents, and patent documents mentioned herein are incorporated by reference in their entirety, as if individually incorporated by reference.

[0011] When an application states that an element or component is included in and / or selected from a list of described elements or components, it should be understood that the element or component can be any one of the described elements or components, or can be selected from a group consisting of two or more of the described elements or components.

[0012] In the methods described herein, acts may be performed in any order unless a temporal or operational order is expressly recited. Furthermore, specified acts may be performed simultaneously unless the claim language expressly recites them as being performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in a single operation, and the resulting process would be encompassed within the process language of the claim.

[0013] As used herein, the terms "a," "an," or "the" are used to include one or more, unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise indicated. The phrases "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B."

[0014] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, "about" when referring to a measurable value, such as an amount, duration, or the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, which variations are still adequate to practice the disclosed methods.

[0015] As used herein, the term "alkenyl," employed alone or in combination with other terms, means, unless otherwise specified, a stable mono- or di-unsaturated, straight- or branched-chain hydrocarbon group having the specified number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. An example of a functional group representing an alkene is -CH-CH=CH.

[0016] As used herein, unless otherwise specified, the term "alkoxy," employed alone or in combination with another term, means an alkyl group, as defined elsewhere herein, having the specified number of carbon atoms, connected to the remainder of the molecule through an oxygen atom, e.g., methoxy, ethoxy, 1-propoxy, 2-propoxy (or isopropoxy) and higher homologs and isomers. Specific examples are (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy.

[0017] As used herein, the term "alkyl," by itself or as part of another substituent, means an alkyl group having the specified number of carbon atoms (i.e., C1 to C6), unless otherwise stated. 10 means a straight or branched chain hydrocarbon having 1 to 10 carbon atoms, including straight, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. A specific embodiment is (C1-C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0018] As used herein, the term "alkynyl," employed alone or in combination with another term, means, unless otherwise specified, a stable straight or branched chain hydrocarbon group with a carbon-carbon triple bond and the specified number of carbon atoms. Non-limiting examples include ethynyl and propynyl and higher homologs and isomers. The term "propargyl" refers to a group exemplified by -CH-C≡CH. The term "homopropargyl" refers to a group exemplified by -CHCH-C≡CH.

[0019] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring with one or more polyunsaturated rings that have aromatic properties, i.e., have (4n+2) delocalized π (pi) electrons, where "n" is an integer.

[0020] As used herein, the term "aryl," employed alone or in combination with another term, means, unless otherwise specified, a carbocyclic aromatic system containing one or more rings (typically 1, 2, or 3 rings), where such rings may be attached together in a pendant manner, as in biphenyl, or may be fused, as in naphthalene. Examples include phenyl, anthracyl, and naphthyl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbocyclic rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, or indanyl), which may have one or more carbon atoms of the aromatic and / or saturated or partially saturated rings substituted.

[0021] As used herein, the term "aryl-(C1-C6)alkyl" refers to a functional group in which an alkylene chain of one to six carbons is attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl (or benzyl). Specific examples are aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C6)alkyl" refers to an aryl-(C1-C6)alkyl functional group in which the aryl group is substituted. Specific example is substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C6)alkyl" refers to a functional group in which an alkylene chain of one to three carbons is attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. Specific example is heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C6)alkyl" refers to a heteroaryl-(C1-C6)alkyl functional group in which the heteroaryl group is substituted. Specific example is substituted heteroaryl-(CH2)-.

[0022] As used herein, the term "cycloalkyl," by itself or as part of another substituent, refers to a cyclic chain hydrocarbon having the specified number of carbon atoms (i.e., C3-C6 refers to a cyclic group containing a ring group of 3 to 6 carbon atoms), unless otherwise specified, and includes straight-chain, branched-chain, or cyclic substituents. Examples of (C3-C6)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl ring may be optionally substituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0023] As used herein, a "disease" is a state of health in a subject in which the subject is unable to maintain homeostasis and in which the subject's health continues to deteriorate if the disease is not improved.

[0024] As used herein, a "disorder" in a subject is a health condition in which the subject is able to maintain homeostasis, but in which the subject's health condition is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the subject's health condition.

[0025] As used herein, the term "halide" refers to a negatively charged halogen atom. The halide anion is fluoride (F - ), chloride (Cl - ), bromide (Br - ), iodide (I - )

[0026] As used herein, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0027] As used herein, the term "heteroalkenyl," by itself or in combination with other terms, refers to a stable, straight- or branched-chain, mono- or di-unsaturated hydrocarbon group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, unless otherwise specified, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. Up to two heteroatoms may be arranged consecutively. Examples include -CH=CH-O-CH, -CH=CH-CH-OH, -CH-CH=N-OCH, -CH=CH-N(CH)-CH, and -CH-CH=CH-CH-SH.

[0028] As used herein, the term "heteroalkyl," by itself or in combination with other terms, refers to a stable, straight- or branched-chain alkyl group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, unless otherwise specified, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, or at the bond to the most distal carbon atom in the heteroalkyl group. Examples include -OCHCHCH, -CHCHCHOH, -CHCHNHCH, -CHSCHCH, and -CHCHS(=O)CH. Up to two heteroatoms may be consecutive, such as, for example, -CHNH-OCH or -CHCHSSCH.

[0029] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. Polycyclic heteroaryls may contain one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0030] As used herein, the terms "heterocycle" or "heterocyclyl" or "heterocyclic," by themselves or as part of another substituent, refer to a stable, unsubstituted or substituted, monocyclic or polycyclic heterocyclic ring system containing carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, unless otherwise specified, where the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heterocyclic ring system may be attached to any heteroatom or carbon atom that results in a stable structure, unless otherwise specified. The heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is heteroaryl.

[0031] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepine, and hexamethylene oxide.

[0032] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0033] Examples of polycyclic heterocycles include indolyl (including, but not limited to, 2-, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (including, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, and benzofuryl. (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl, and quinolizidinyl.

[0034] The heterocyclyl and heteroaryl moieties listed above are intended to be representative and non-limiting.

[0035] As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful within the disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

[0036] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of a compound useful within the disclosure and that is relatively non-toxic, i.e., the substance may be administered to a subject without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0037] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the disclosure within or to a patient so that the compound may perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not harmful to the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyhydric alcohols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the disclosure and are physiologically acceptable to the subject. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include pharmaceutically acceptable salts of compounds useful within the disclosure.Other additional ingredients that may be included in pharmaceutical compositions used in the practice of the disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0038] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids and / or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates), and clathrates thereof.

[0039] As used herein, a "pharmaceutically effective amount," "therapeutically effective amount," or "effective amount" of a compound is the amount of the compound sufficient to provide a beneficial effect to the subject to which the compound is administered.

[0040] As used herein, the terms "prevent," "preventing," or "prevention" refer to avoiding or delaying the onset of symptoms associated with a disease or condition in a subject who has not developed such symptoms at the time administration of an agent or compound is initiated. Disease, condition, and disorder are used interchangeably herein.

[0041] As used herein, the terms "specifically bind" or "specifically binds" mean that a first molecule binds preferentially to, but not necessarily exclusively to, a second molecule (e.g., a particular receptor or enzyme).

[0042] As used herein, the terms "subject," "individual," and "patient" may be used interchangeably and may refer to a human or non-human mammal or bird. Non-human mammals include livestock and pets, such as mammals such as sheep, cows, pigs, dogs, cats, and mice. In certain embodiments, the subject is a human.

[0043] As used herein, the term "substituted" refers to an atom or group of atoms replacing a hydrogen as a substituent attached to another group.

[0044] As used herein, the terms "substituted alkyl," "substituted cycloalkyl," "substituted alkenyl," or "substituted alkynyl" include any of the following: halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH, -NH(C-C alkyl), -N(C-C alkyl), 1-methyl-imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, -C(=O)O(C-C)alkyl, trifluoromethyl, -C≡N, -C(=O)NH, -C(=O)NH(C-C)alkyl, -C(=O)N((C-C)alkyl) " refers to alkyl, cycloalkyl, alkenyl, or alkynyl, as defined elsewhere herein, substituted by one, two, or three substituents independently selected from the group consisting of -NH(C1-C6 alkyl), -SON(C1-C6 alkyl), -SON(C1-C6 alkyl), -C(=NH)NH, and -NO, and in certain embodiments, containing one or two substituents independently selected from halogen, -OH, alkoxy, -NH, trifluoromethyl, -N(CH3)2, and -C(=O)OH, and in certain embodiments, independently selected from halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0045] For aryl, aryl-(C1-C3)alkyl, and heterocyclyl groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the number of substituents varies from 1 to 4. In other embodiments, the number of substituents varies from 1 to 3. In still other embodiments, the number of substituents varies from 1 to 2. In still other embodiments, the substituents are independently selected from the group consisting of C1-C6 alkyl, —OH, C1-C6 alkoxy, halogen, amino, acetamido, and nitro. As used herein, when a substituent is an alkyl or alkoxy group, the carbon chain can be branched, straight, or cyclic.

[0046] Unless otherwise specified, when two substituents taken together form a ring having the specified number of ring atoms (e.g., R 2 and R 3 together with the nitrogen to which they are attached to form a ring having 3 to 7 ring members, the ring can contain carbon atoms and, optionally, one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring can be saturated or partially saturated, or substituted.

[0047] When a term, or any of its prefix roots, appears in a name of a substituent, the name is interpreted as including the limitations provided herein. For example, when the term "alkyl" or "aryl" or any of its prefix roots appears in a name of a substituent (e.g., arylalkyl, alkylamino), the name is interpreted as including the limitations given elsewhere in this specification for "alkyl" and "aryl," respectively.

[0048] In certain embodiments, substituents of compounds are disclosed in groups or in ranges. The description is specifically intended to include every individual subcombination of the members of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0049] The terms "treat," "treating," and "treatment," as used herein, mean reducing the frequency or severity with which a subject experiences symptoms of a disease or condition by administering an agent or compound to the subject.

[0050] Specific abbreviations used herein are as follows: cccDNA, covalently closed circular DNA; DMSO, dimethyl sulfoxide; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HDV, hepatitis D virus; HPLC, high pressure liquid chromatography; LCMS, liquid chromatography mass spectrometry; NMR, nuclear magnetic resonance; pg RNA, pregenomic RNA; RT, retention time; sAg, surface antigen; TLC, thin layer chromatography.

[0051] Ranges: Throughout this disclosure, various aspects of the present disclosure may be expressed in range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values within that range. For example, description of a range such as 1 to 6 should be considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, and 3 to 6, as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. For example, the range "about 0.1% to about 5%" or "about 0.1% to 5%" should be considered to include not only about 0.1% to about 5%, but also individual values (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the stated range. Unless otherwise specified, the expression "about X to Y" has the same meaning as "about X to about Y." Similarly, the expression "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified. This applies regardless of the breadth of the range.

[0052] synthesis The present disclosure further provides methods for preparing specific compounds of the present disclosure.The compounds of the present teachings can be prepared by following the procedures outlined herein and employing standard synthetic methods and procedures known to those skilled in the art from commercially available starting materials, compounds known in the literature, or easily prepared intermediates.Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field.

[0053] Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions may also be used unless otherwise specified. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein.

[0054] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0055] Preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0056] The reaction or process described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents typically do not substantially react with reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., the temperature can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.A suitable solvent for a specific reaction step can be selected according to the specific reaction step.

[0057] The present disclosure provides 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one, also known as compound (K): TIFF2025526864000003.tif18128 or a salt, solvate, prodrug, isotopically labeled derivative, and / or tautomer thereof, and methods for preparing any mixture thereof.

[0058] In certain embodiments, compounds of formula (K), or salts, solvates, prodrugs, isotopically labeled derivatives, and / or tautomers thereof, may be prepared according to the non-limiting synthetic schemes outlined in Schemes 1-3, 1 is independently selected at each occurrence from the group consisting of Br and I; Z 2 is selected from the group consisting of Cl, Br, or I; R is selected from the group consisting of H, C1-C6 alkyl, and C3-C8 cycloalkyl; and any two R groups together with the atoms to which they are attached may form a C3-C4 heterocycloalkyl.

[0059] Commercially available 1-Z 1 -2-chloro-3-Z 1Benzene (A) can be converted to a boronic ester or boronic acid (B) by reaction of (A) with a suitable organomagnesium halide, including, but not limited to, iPrMg·LiCl (i.e., turbo Grignard), in the presence of a suitable solvent, including, but not limited to, 2-methyltetrahydrofuran (MeTHF), at a suitable temperature, including, but not limited to, about −25° C. to −10° C., to provide an organomagnesium intermediate, which can be converted to a boronic ester or boronic acid (B) by reaction with a borate, including, but not limited to, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, at a suitable temperature, including, but not limited to, about −20° C. to −10° C. In certain embodiments, borate (B) can be converted to compound (D) without purification, for example, using solution compound (B) generated in situ, as described herein. In other embodiments, compound (B) can be isolated and / or purified.

[0060] Compound (D) can be prepared by the reaction of compound (B) with heteroaryl halide (C) under suitable reaction conditions, including, but not limited to, a temperature of about 50° C. to about 60° C., in the presence of a suitable palladium catalyst, including, but not limited to, Pd(PPh3)4, a suitable base, including, but not limited to, K2CO3, and a suitable solvent, including, but not limited to, a mixture of MeTHF and water. Thus, in certain embodiments, compound (D) can be prepared from compound (A) without purification of the intermediate.

[0061] Compound (F) can be prepared by the reaction of an aromatic halide (D) with a boronic ester or boronic acid (E) under suitable conditions, including, but not limited to, having a temperature of about 65° C. to about 70° C., in the presence of a suitable palladium catalyst, including, but not limited to, Pd(amphos)Cl (i.e., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)), a suitable base, including, but not limited to, KHPO, and a suitable solvent, including, but not limited to, a mixture of MeTHF, water, and dimethylacetamide (DMAc). TIFF2025526864000004.tif83140

[0062] In certain embodiments, compound (F) may be prepared in an alternative sequence as provided in Scheme 2.

[0063] Compound (D') can be prepared by reacting compound (D) with a suitable boronating reagent, including, but not limited to, bis(pinacolato)diboron (i.e., B2Pin2), under suitable reaction conditions, including, but not limited to, a temperature of about 90°C to about 100°C, in the presence of a suitable palladium catalyst, including, but not limited to, Pd(dppf)Cl·CH2Cl2, a suitable base, including, but not limited to, KOAc, and a suitable solvent, including, but not limited to, a mixture of dimethylformamide (DMF) and toluene.

[0064] Compound (F) can be prepared by the reaction of (D') with (E') under suitable reaction conditions, including, but not limited to, having a temperature of about 55°C, in the presence of a suitable palladium catalyst, including, but not limited to, Pd(dppf)Cl·CH2Cl2, a suitable base, including, but not limited to, K2CO3, and a suitable solvent, including, but not limited to, a mixture of MeTHF and water. TIFF2025526864000005.tif72130

[0065] Compound (H) can be prepared by reacting compound (G) with a suitable boronating reagent, including, but not limited to, bis(pinacolato)diboron (i.e., B2Pin2), under suitable reaction conditions, including, but not limited to, a temperature of about 80°C to about 90°C, in the presence of a suitable palladium catalyst, including, but not limited to, Pd(dppf)Cl·CH2Cl2, a suitable base, including, but not limited to, KOAc, and a suitable solvent, including, but not limited to, a mixture of dimethylformamide (DMF) and toluene.

[0066] Compound (I) can be prepared by the reaction of compound (H) with compound (F) under suitable reaction conditions, including, but not limited to, a temperature of about 65° C. to about 75° C., in the presence of a suitable palladium catalyst, including, but not limited to, Pd(PPh3)4, a suitable base, including, but not limited to, K2CO3, and a suitable solvent, including, but not limited to, a mixture of MeTHF, DMF, and water.

[0067] Compound (K) may be prepared by the reaction of compound (I) with compound (J) in the presence of a suitable reducing agent, including but not limited to NaBH(OAc)3, a suitable base, including but not limited to NaOMe and i-Pr2NEt, and a suitable solvent, including but not limited to a mixture of DCM and methanol, MeOH, and / or a mixture of MeOH and MeTHF. TIFF2025526864000006.tif107149

[0068] It is understood that the reactions or processes described herein for preparing 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one (K) are not limited to the embodiments depicted in Schemes 1-3.

[0069] In one aspect, the present disclosure provides a compound comprising 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one (K): TIFF2025526864000007.tif18128 or a salt or solvate thereof, The method is: 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (I): TIFF2025526864000008.tif18128 and 2,6-diazaspiro[3.4]octan-7-one (J): TIFF2025526864000009.tif12128 in the presence of a reducing agent and a base to generate a first reaction system containing (K).

[0070] In certain embodiments, the reducing agent comprises NaBH(OAc) 3 .

[0071] In certain embodiments, the base comprises NaOMe. In certain embodiments, the base comprises i-PrNEt2.

[0072] In certain embodiments, (J) is a salt of 2,6-diazaspiro[3.4]octan-7-one. In certain embodiments, (J) is 2,6-diazaspiro[3.4]octan-7-one hydrochloride. In certain embodiments, (J) is 2,6-diazaspiro[3.4]octan-7-one hydrobromide. In certain embodiments, (J) is 2,6-diazaspiro[3.4]octan-7-one trifluoroacetate. In certain embodiments, (J) is 2,6-diazaspiro[3.4]octan-7-one mesylate. In certain embodiments, (J) is 2,6-diazaspiro[3.4]octan-7-one tosylate.

[0073] In certain embodiments, the reaction of (I) with (J) is carried out in the presence of a solvent.

[0074] In certain embodiments, the solvent is a mixture comprising dichloromethane (DCM) and methanol (MeOH). In certain embodiments, the solvent is a mixture comprising 2-methyltetrahydrofuran (MeTHF) and MeOH. In certain embodiments, the solvent comprises tetrahydrofuran (THF). In certain embodiments, the solvent comprises dimethylformamide (DMF). In certain embodiments, the solvent comprises dimethylacetamide (DMAc). In certain embodiments, the solvent comprises a mixture of any of DCM, MeOH, MeTHF, THF, DMF, and DMAc.

[0075] In certain embodiments, the purification of (K) comprises: (a) adding water to a first reaction system containing (K) to produce a two-phase solution; (b) separating the biphasic solution to obtain a first aqueous phase and a first organic phase; (c) adding an organic solvent to the first aqueous solution to obtain a second two-phase solution; (d) basifying the second biphasic solution to a pH of 8 to 11 to obtain a basified biphasic solution; and (e) separating the basified biphasic solution to obtain a second aqueous phase and a second organic phase comprising (K). Includes:

[0076] In certain embodiments, the purification of (K) comprises: (a) adding water to a first reaction system containing (K) to produce a two-phase solution; (b) separating the biphasic solution to obtain a first aqueous phase and a first organic phase; (c) adding an organic solvent to the first aqueous solution to obtain a second two-phase solution; (d) adjusting the pH of the second biphasic solution to between 8 and 11 to obtain a basified biphasic solution; (e) separating the basified biphasic solution to obtain a second aqueous phase and a second organic phase; (f) combining the first organic phase and the second organic phase to obtain a third organic phase; (g) adding water to the third organic phase to obtain a biphasic solution; and (h) separating the third biphasic solution to obtain a third aqueous phase and a final organic phase comprising (K). Includes:

[0077] In certain embodiments, the biphasic solution is agitated. In certain embodiments, the biphasic solution is agitated for about 20 minutes.

[0078] In certain embodiments, the organic solvent comprises dichloromethane.

[0079] In certain embodiments, the basifying comprises adding a base selected from the group consisting of NaOH, KOH, LiOH, NaHCO3, K2CO3, CaCO3, Na2CO3, and K3PO4. In certain embodiments, the NaOH is 3N NaOH.

[0080] In certain embodiments, the purification of (K) comprises: (a) providing crude (K) in a solvent comprising 2-propanol to provide a dilute crude solution of (K); the diluted crude solution of (K) has a concentration of about 110 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (K) to obtain a concentrated crude solution of (K), the concentrated crude solution of (K) has a concentration of about 220 g / L to about 280 g / L; and (c) cooling the concentrated (K) crude solution to a temperature of about 20°C to provide a purified (K) slurry; and (d) filtering the purified (K) slurry to obtain (K). Includes:

[0081] In certain embodiments, the purification of (K) comprises: (a) providing crude (K) in a solvent comprising 2-propanol to provide a dilute crude solution of (K); the diluted crude solution of (K) has a concentration of about 110 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (K) to obtain a concentrated crude solution of (K), The concentrated crude solution of (K) has a concentration of about 220 g / L to about 280 g / L, wherein the at least partial evaporation optionally comprises heating the dilute crude solution of (K) to a temperature of about 40° C. to 50° C., optionally for about 2 hours; (c) adding seed crystals of (K) in an amount of about 0.1% to 1.0% w / w of the crude (K) to obtain a crude (K) slurry; (d) heating the crude (K) slurry at a temperature of about 50°C to obtain a heated crude (K) slurry; (e) cooling the heated crude (K) slurry to a temperature of about 20°C to obtain a cooled crude (K) slurry; cooling the heated crude (K) slurry for about 10 hours; (f) stirring the cooled crude (K) slurry at a temperature of about 20° C. for about 4 hours to obtain a refined (K) slurry; stirring the cooled crude (K) for 4 hours; (g) filtering the purified (K) slurry to obtain (K). Includes:

[0082] In certain embodiments, the purification of (K) comprises: (a) providing crude (K) in a solvent comprising MeOH to provide a crude solution of (K); the crude solution of (K) has a concentration of about 200 g / L to about 300 g / L; (b) heating the crude solution of (K) to a temperature of about 50°C to obtain a hot crude solution of (K); (c) cooling the hot crude solution of (K) to a temperature of about 20°C to obtain a cooled (K) slurry; (d) adding a solvent comprising methyl tert-butyl ether (MTBE) to the cooled (K) slurry to obtain a purified (K) slurry; and (e) filtering the refined (K) slurry to obtain (K). Includes:

[0083] In certain embodiments, the purification of (K) comprises: (a) adding an aqueous solution of NaCl to a first reaction system containing (K) to produce a two-phase solution; (b) separating the biphasic solution to obtain a first aqueous phase and a first organic phase; (c) washing the first aqueous phase one or more times with one or more organic solvents to obtain a washed aqueous phase, the one or more organic solvents optionally comprising MeTHF and / or MEK; (d) adding an organic solvent to the washed aqueous phase to obtain a second two-phase solution; the organic solvent optionally comprises MEK; (e) basifying the second two-phase solution to a pH of about 9.5 to 10.5 to obtain a basified second two-phase solution; the second two-phase solution is optionally basified with an aqueous solution; the aqueous solution optionally comprises at least one selected from the group consisting of Na2CO3, NaOH, KOH, LiOH, K2CO3, CaCO3, Na2CO3, and K3PO4; (f) separating the basified second biphasic solution to obtain a second aqueous phase and a second organic phase; the second aqueous phase is optionally washed with an organic solvent to obtain a third organic phase that is combined with the second organic phase; The second organic phase is optionally washed with an aqueous solution of NaCl, the second organic phase is optionally filtered through Celite; (g) at least partially evaporating the second organic phase and adding MeOH one or more times to obtain a solution of crude (K) having a concentration of about 200 g / L to about 300 g / L; (h) heating the crude solution of (K) to a temperature of about 50° C. to obtain a hot crude solution of (K), The hot crude solution of (K) is stirred arbitrarily for about 3 hours, seed crystals of (K) are optionally added to the hot crude solution of (K); (i) cooling the hot crude solution of (K) to a temperature of about 20°C to obtain a cooled crude solution of (K), cooling for about 4 hours; (j) adding methyl tert-butyl ether (MTBE) to the cooled solution of (K) to obtain a crude slurry of (K); and (k) filtering the crude slurry of (K) to obtain (K); (K) is optionally washed with a mixture containing MeOH / MTBE; (K) is optionally vacuum dried for at least 24 hours. Includes:

[0084] In certain embodiments, 2-methoxy-4-(B(OR 1a)(OR 1b ))-Benzaldehyde (H): TIFF2025526864000010.tif23128 and 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (F): TIFF2025526864000011.tif18128 in the presence of a palladium catalyst and a base to prepare (I), In the formula, each R 1a and R 1b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 1a and R 1b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl.

[0085] In certain embodiments, the palladium catalyst comprises Pd(PPh3)4.

[0086] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0087] In certain embodiments, the base comprises K2CO3.

[0088] In certain embodiments, the reaction of (H) with (F) is carried out in the presence of a solvent.

[0089] In certain embodiments, the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF), dimethylformamide (DMF), and water.

[0090] In certain embodiments, the reaction of (H) with (F) is carried out at a temperature of about 65°C to about 70°C.

[0091] In certain embodiments, purifying (I) comprises adding N-acetylcysteine to the reaction of (H) with (F). In certain embodiments, the N-acetylcysteine is added as a solution. In certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt% N-acetylcysteine.

[0092] In certain embodiments, 4-Z 2 -2-Methoxybenzaldehyde (G): TIFF2025526864000012.tif18128, wherein Z 2 is selected from the group consisting of Cl, Br, and I; (G) (H) is prepared by reacting (H) with a boronating reagent in the presence of a palladium catalyst and a base.

[0093] In certain embodiments, (G) is 4-bromo-2-methoxybenzaldehyde. In certain embodiments, (G) is 4-chloro-2-methoxybenzaldehyde. In certain embodiments, (G) is 4-iodo-2-methoxybenzaldehyde.

[0094] In certain embodiments, the boronating reagent is bis(pinacolato)diboron.

[0095] In certain embodiments, the palladium catalyst comprises Pd(dppf)Cl 2 .

[0096] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5.0 mol %.

[0097] In certain embodiments, the base comprises KOAc.

[0098] In certain embodiments, the reaction of (G) with a boronating reagent is carried out in the presence of a solvent.

[0099] In certain embodiments, the solvent comprises dimethylformamide (DMF) and / or toluene.

[0100] In certain embodiments, the reaction of (G) with a boronating reagent is carried out at a temperature of about 80°C to about 90°C.

[0101] In certain embodiments, the purification of (H) comprises (a) adding N-acetylcysteine to the reaction of (G) with a boronating reagent; and (b) adding activated carbon to the reaction of (G) with a boronating reagent. It includes at least one of the following:

[0102] In certain embodiments, the N-acetylcysteine is added as a solution, hi certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt% N-acetylcysteine.

[0103] In certain embodiments, the purification of (H) comprises: (a) providing crude (H) in a solvent comprising 2-propanol to provide a dilute crude solution of (H); (H) the diluted crude solution has a concentration of about 390 g / L to about 430 g / L; (b) at least partially evaporating the diluted crude solution of (H) to obtain a concentrated crude solution of (H), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (H) to a temperature of about 50° C. and optionally further maintaining that temperature for about 1.5 hours; (c) cooling the concentrated crude (H) solution to a temperature of about 6° C. to obtain a purified (H) slurry, wherein the cooling step is optionally carried out for about 3 hours; and (d) filtering the refined (H) slurry to obtain (H). Includes:

[0104] In certain embodiments, 6-(3-Z 1 -2-chlorophenyl)-2-methoxynicotinaldehyde (D): TIFF2025526864000013.tif18128, wherein Z 1is selected from the group consisting of Br and I; (D) and 2,3-dichloro-4-(B(OR 2a )(OR 2b ))-Pyridine (E): TIFF2025526864000014.tif17128 in the presence of a palladium catalyst and a base to prepare (F); In the formula, each R 2a and R 2b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 2a and R 2b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl.

[0105] In certain embodiments, (D) is 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. In certain embodiments, (D) is 6-(3-iodo-2-chlorophenyl)-2-methoxynicotinaldehyde.

[0106] In certain embodiments, R 2a is H. In certain embodiments, R 2b is H.

[0107] In certain embodiments, the palladium catalyst comprises Pd(amphos)Cl 2 .

[0108] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0109] In certain embodiments, the base comprises K2HPO4.

[0110] In certain embodiments, the reaction of (D) with (E) comprises adding (E) to a reaction vessel containing (D), where (E) is optionally added to the vessel containing (D) over a period of about 3.5 hours.

[0111] In certain embodiments, the reaction of (D) with (E) is carried out in the presence of a solvent.

[0112] In certain embodiments, the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF), dimethylacetamide (DMAc), and / or water.

[0113] In certain embodiments, the reaction of (D) with (E) is carried out at a temperature of about 65°C to about 70°C.

[0114] In certain embodiments, purifying (F) comprises adding N-acetylcysteine to the reaction of (D) and (E). In certain embodiments, the N-acetylcysteine is added as a solution. In certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt% N-acetylcysteine.

[0115] In certain embodiments, the purification of (F) comprises: (a) providing crude (F) in a solvent comprising 2-propanol to provide a dilute crude solution of (F); (F) the diluted crude solution has a concentration of about 100 g / L to about 150 g / L; (b) at least partially evaporating the diluted crude solution of (F) to obtain a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (F) to a temperature of about 40°C to about 55°C, and optionally maintaining that temperature for about an additional hour; (c) cooling the concentrated crude (F) solution to a temperature of about 20 to about 25° C. to obtain a crude (F) slurry, wherein the cooling step is optionally carried out over a period of about 3 hours; and (d) filtering the crude (F) slurry to obtain (F), wherein the filtering step optionally further comprises washing with 2-propanol. Includes:

[0116] In certain embodiments, the purification of (F) comprises: (e) feeding the solution of (F) obtained by carrying out steps (a) to (d) described elsewhere herein into a solvent containing 2-propanol to obtain a diluted first crop solution, (F) The diluted first crop solution has a concentration of about 100 g / L to about 150 g / L; A diluted first crop solution is obtained by dissolving (F) (i.e., first crop (F)) obtained by carrying out steps (a) to (d) described elsewhere herein in 2-methyltetrahydrofuran and solvent-exchanging with 2-propanol; (f) at least partially evaporating the diluted first crop solution of (F) to obtain a concentrated first crop solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted first crop solution of (F) to a temperature of about 40° C. to about 55° C., and wherein the heating is optionally maintained for about 1 hour; (g) cooling the concentrated first crop solution of (F) to obtain a first crop (F) slurry, wherein the cooling optionally comprises decreasing the temperature to a temperature of about 20°C to about 25°C, and the cooling is optionally carried out for about 1 hour; and (h) filtering the first crop (F) slurry to obtain a second crop (F) (i.e., purified (F) or (F)), wherein the filtering step optionally further comprises washing with a solvent comprising 2-propanol. Further includes:

[0117] In certain embodiments, 6-(2-chloro-3-(B(OR 3a )(OR 3b ))phenyl)-2-methoxynicotinaldehyde (D'): TIFF2025526864000015.tif18128 and 2,3-dichloro-4-Z 1 -pyridine (E'): TIFF2025526864000016.tif17128, wherein Z 1 is selected from the group consisting of Br and I; (E') in the presence of a palladium catalyst and a base to prepare (F), In the formula, each R 3a and R 3b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 3a and R 3b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl.

[0118] In certain embodiments, (E') is 2,3-dichloro-4-iodopyridine. In certain embodiments, (E') is 2,3-dichloro-4-bromopyridine.

[0119] In certain embodiments, (D') is 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde.

[0120] In certain embodiments, the palladium catalyst comprises Pd(dppf)Cl 2 .

[0121] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0122] In certain embodiments, the base comprises K2CO3.

[0123] In certain embodiments, the reaction of (D') with (E') is carried out in the presence of a solvent.

[0124] In certain embodiments, the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

[0125] In certain embodiments, the reaction of (D') with (E') is carried out at a temperature of about 55°C.

[0126] In certain embodiments, purifying (F) comprises adding N-acetylcysteine to the reaction of (D') with (E'). In certain embodiments, the N-acetylcysteine is added as a solution. In certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt% N-acetylcysteine.

[0127] In certain embodiments, the purification of (F) comprises: (a) providing crude (F) in 2-propanol to provide a dilute crude solution of (F), (F) the diluted crude solution has a concentration of about 100 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (F) to obtain a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (F) to a temperature of about 50°C to about 55°C, and optionally maintaining that temperature for about an additional hour; (c) cooling the concentrated crude (F) solution to a temperature of about 20°C to about 25°C to obtain a purified (F) slurry; and (d) filtering the refined (F) slurry to obtain (F). Includes:

[0128] In certain embodiments, (D): TIFF2025526864000017.tif18128, wherein Z 1 is selected from the group consisting of Br and I; (D) (D') is prepared by reacting (D') with a boronating reagent in the presence of a palladium catalyst and a base.

[0129] In certain embodiments, (D) is 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. In certain embodiments, (D) is 6-(3-iodo-2-chlorophenyl)-2-methoxynicotinaldehyde.

[0130] In certain embodiments, the boronating reagent comprises bis(pinacolato)diboron.

[0131] In certain embodiments, the palladium catalyst comprises Pd(dppf)Cl 2 .

[0132] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 7 mol %.

[0133] In certain embodiments, the base comprises KOAc.

[0134] In certain embodiments, the reaction of (D) with a boronating reagent is carried out in the presence of a solvent.

[0135] In certain embodiments, the solvent comprises at least one of dimethylformamide (DMF) and / or toluene.

[0136] In certain embodiments, the reaction of (D) with a boronating reagent is carried out at a temperature of about 90°C to about 100°C.

[0137] In certain embodiments, the purification of (D') comprises: (a) adding N-acetylcysteine to the reaction of (D) with a boronating reagent; and (b) adding activated carbon to the reaction of (D) with a boronating reagent; It includes at least one of the following:

[0138] In certain embodiments, the N-acetylcysteine is added as a solution, hi certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt% N-acetylcysteine.

[0139] In certain embodiments, the purification of (D') comprises: (a) providing crude (D') in a solvent comprising 2-propanol to provide a crude solution of (D'); the crude solution of (D') has a concentration of about 140 g / L to about 180 g / L; (c) cooling the crude solution of (D') to a temperature of about 0°C to about 5°C to obtain a purified (D') slurry; and (d) filtering the refined (D') slurry to obtain (D'). Includes:

[0140] In certain embodiments, 1-(B(OR 4a )(OR 4b ))-2-chloro-3-Z 1 -Benzene (B): TIFF2025526864000018.tif17128 and 6-Z 2 -2-Methoxynicotinaldehyde (C): TIFF2025526864000019.tif13128 in the presence of a palladium catalyst and a base to prepare (D); In the formula, Z 1 is selected from the group consisting of Br and I; In the formula, Z 2 is selected from the group consisting of Cl, Br, and I; In the formula, each R 4a and R 4b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 4a and R 4b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl.

[0141] In certain embodiments, (B) is 2-(3-bromo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In certain embodiments, (B) is 2-(3-iodo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0142] In certain embodiments, the palladium catalyst comprises Pd(PPh3)4.

[0143] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0144] In certain embodiments, the base comprises K2CO3.

[0145] In certain embodiments, the reaction of (B) with (C) is carried out in the presence of a solvent.

[0146] In certain embodiments, the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF) and / or water.

[0147] In certain embodiments, the reaction of (B) with (C) is carried out at a temperature of about 50°C to about 60°C.

[0148] In certain embodiments, purifying (D) comprises adding N-acetylcysteine to the reaction of (B) and (C). In certain embodiments, the N-acetylcysteine is added as a solution. In certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt% N-acetylcysteine.

[0149] In certain embodiments, the purification of (D) comprises: (a) providing crude (D) in a solvent comprising 2-propanol to provide a diluted crude solution of (D); (D) the diluted crude solution has a concentration of about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to obtain a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (D) to a temperature of about 50°C to about 55°C, and optionally maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (D) solution to a temperature of about 20° C. to about 25° C. to obtain a purified (D) slurry; and (d) filtering the refined (D) slurry to obtain (D). Includes:

[0150] In certain embodiments, (a) To form an arylmagnesium intermediate, 1-Z 1-2-chloro-3-Z 1 -Benzene (A): TIFF2025526864000020.tif17128, wherein Z 1 is independently selected at each occurrence from the group consisting of Br and I; with an organomagnesium halide; and (b) reacting the arylmagnesium intermediate with a borate (B) is prepared by

[0151] In certain embodiments, (A) is 1,3-dibromo-2-chlorobenzene. In certain embodiments, (A) is 1,3-diiodo-2-chlorobenzene. In certain embodiments, (A) is 1-iodo-2-chloro-3-bromobenzene.

[0152] In certain embodiments, the borate is: TIFF2025526864000021.tif10128, In the formula, each R 5a , R 5b , and R 5c are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; R 5a , R 5b , and R 5c Any two selected from the group consisting of may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl.

[0153] In a particular embodiment, the borate is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0154] In certain embodiments, the organomagnesium halide comprises i-PrMgCl, which is optionally a solution comprising i-PrMgCl complexed with LiCl (ie, an i-PrMgCl·LiCl solution).

[0155] In certain embodiments, the reaction of (A) with the organomagnesium halide is carried out in a solvent.

[0156] In certain embodiments, the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0157] In certain embodiments, the reaction of (A) with the organomagnesium halide is carried out at a temperature of about -25°C to about -15°C.

[0158] In certain embodiments, the reaction of the arylmagnesium intermediate with the borate is carried out at a temperature of about -18°C to about -15°C, and the reaction is subsequently optionally warmed to a temperature of about 2°C.

[0159] In certain embodiments, (a) To form an arylmagnesium intermediate, 1-Z 1 -2-chloro-3-Z 1 -Benzene (A): TIFF2025526864000022.tif17128, wherein Z 1 is independently selected at each occurrence from the group consisting of Br and I; with an organomagnesium halide; (b) reacting the aryl magnesium intermediate with a borate to provide a boronic ester intermediate; and (c) a boronic ester intermediate; 6-Z 2 -2-Methoxynicotinaldehyde (C): TIFF2025526864000023.tif13128, wherein Z 2 is selected from the group consisting of Cl, Br, and I; (C) in the presence of a palladium catalyst and a base. (D) is prepared by

[0160] In certain embodiments, the organomagnesium halide comprises i-PrMgCl, which is optionally a solution comprising i-PrMgCl complexed with LiCl (ie, an i-PrMgCl·LiCl solution).

[0161] In certain embodiments, the reaction of (A) with the organomagnesium halide is carried out in a solvent.

[0162] In certain embodiments, the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0163] In certain embodiments, the reaction of (A) with the organomagnesium halide is carried out at a temperature of about -25°C to about -15°C.

[0164] In certain embodiments, the reaction of the arylmagnesium intermediate with the borate is carried out at a temperature of about -18°C to about -15°C, and the reaction is subsequently optionally warmed to a temperature of about 2°C.

[0165] In certain embodiments, (C) is 6-chloro-2-methoxynicotinaldehyde. In certain embodiments, (C) is 6-bromo-2-methoxynicotinaldehyde. In certain embodiments, (C) is 6-iodo-2-methoxynicotinaldehyde.

[0166] In certain embodiments, the borate is: TIFF2025526864000024.tif10128, In the formula, each R 5a , R 5b , and R 5c are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 5a , R 5b , and R 5c Any two selected from the group consisting of may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl.

[0167] In a particular embodiment, the borate is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0168] In certain embodiments, the palladium catalyst comprises Pd(PPh3)4.

[0169] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0170] In certain embodiments, the base comprises K2CO3.

[0171] In certain embodiments, the reaction of the boronic ester intermediate with (C) is carried out in the presence of a solvent.

[0172] In certain embodiments, the solvent comprises at least one selected from the group consisting of 2-methyltetrahydrofuran (MeTHF) and water.

[0173] In certain embodiments, the reaction of the boronic ester intermediate with (C) is carried out at a temperature of about 50°C to about 60°C.

[0174] In certain embodiments, purifying (D) comprises adding N-acetylcysteine to the reaction of (C) with the boronate ester intermediate. In certain embodiments, the N-acetylcysteine is added as a solution. In certain embodiments, the N-acetylcysteine solution is about 1, 2, 3, 4, or 5 wt % N-acetylcysteine.

[0175] In certain embodiments, the purification of (D) comprises: (a) providing crude (D) in a solvent comprising 2-propanol to provide a diluted crude solution of (D); (D) the diluted crude solution has a concentration of about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to obtain a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (D) to a temperature of about 50°C to about 55°C, and optionally maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (D) solution to a temperature of about 20° C. to about 25° C. to obtain a purified (D) slurry; and (d) filtering the refined (D) slurry to obtain (D). Includes:

[0176] The disclosed compounds may have one or more stereocenters, and each stereocenter may independently exist in either the (R)- or (S)-configuration. In certain embodiments, the compounds described herein exist in optically active or racemic form. The compounds described herein include racemic, optically active, regioisomeric, and stereoisomeric forms, or combinations thereof, that possess the therapeutically useful properties described herein. Preparation of optically active forms can be accomplished in any suitable manner, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. Compounds represented herein by racemic formulas further represent either of the two enantiomers or any mixture thereof, or, if two or more chiral centers are present, all diastereomers or any mixture thereof.

[0177] In certain embodiments, the disclosed compounds exist as tautomers, and all tautomers are included within the scope of the compounds provided herein.

[0178] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include:2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 This includes, but is not limited to, S. In certain embodiments, substitution with heavier isotopes, such as deuterium, results in greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or process, using an appropriate isotopically labeled reagent in place of an otherwise non-labeled reagent.

[0179] In certain aspects, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0180] In all embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed disclosure. The disclosed compounds may contain any of the substituents or combinations of substituents provided herein.

[0181] salt The compounds described herein may form salts with acids or bases, and such salts are also included in the present disclosure. The term "salt" encompasses addition salts of free acids or bases useful in the disclosed methods. The term "pharmaceutically acceptable salt" refers to a salt that has a toxicity profile within a range that makes it useful in pharmaceutical applications. In certain embodiments, the salt is a pharmaceutically acceptable salt. Pharmaceutically unacceptable salts may still have properties such as high crystallinity, and may be useful in implementing the present disclosure, for example, in the process of synthesizing, purifying, or formulating compounds useful within the disclosed methods.

[0182] Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, aromatic fatty acid, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, and mandelic acid. , embonic acid (i.e., pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, sulfanilic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, galacturonic acid, glycerophosphonic acid, and saccharin (e.g., saccharinate, saccharate). The salts may contain less than, one molar equivalent, or more than one molar equivalent of acid or base relative to any of the disclosed compounds.

[0183] Suitable pharmaceutically acceptable base addition salts of the disclosed compounds include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts, such as calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (i.e., N-methylglucamine), and procaine. All of these salts may be prepared from the corresponding compound, for example, by reacting the appropriate acid or base with the compound.

[0184] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and encompassed by the claims appended hereto. For example, it should be understood that varying reaction conditions, including but not limited to reaction time, reaction scale / amount, and experimental reagents, such as solvents, catalysts, pressure, ambient conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, is within the scope of this application.

[0185] Where values and ranges are provided herein, it should be understood that the descriptions in range format are merely for convenience and brevity and should not be construed as inflexible limitations on the scope of the disclosure. Accordingly, all values and ranges encompassed within these values and ranges are intended to be encompassed within the scope of the present disclosure. Also, all values falling within these ranges, as well as the upper or lower limits of a range of values, are contemplated by this application. The description of a range should be considered to specifically disclose all possible subranges, individual numerical values within that range, and, where appropriate, partial integers of numerical values within the range. For example, the description of a range such as 1 to 6 should be considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0186] The examples provided herein illustrate aspects of the present disclosure. However, they do not limit the teachings or disclosure of the present disclosure described herein in any way. The examples herein are provided for illustrative purposes only, and the disclosure is not limited to these examples, but rather encompasses all variations that become apparent as a result of the teachings provided herein. [Example]

[0187] The disclosure will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure is not limited to these examples, but rather encompasses all variations that become apparent as a result of the teachings provided herein.

[0188] Step 1 - Synthesis of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde TIFF2025526864000025.tif17128

[0189] (a) Synthesis of 2-(3-bromo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A 30 L reactor was charged with MeTHF (2.6 L) and i-PrMgCl·LiCl (2.64 L, 3.4 mol, 1.3 M in THF) under a nitrogen atmosphere. The resulting solution was cooled to a temperature of approximately -25°C to -15°C (e.g., -24°C). In a separate 3 L reactor, a solution of compound A (675.5 g, 2.5 mol) in MeTHF (1.06 L) was prepared at a temperature of approximately 8°C to 25°C under a nitrogen atmosphere. Using an addition funnel, the compound A solution was added to the i-PrMgCl·LiCl solution over approximately 40 minutes, maintaining the internal temperature at approximately -25°C to -15°C. The resulting mixture was stirred for 45 minutes at a temperature of approximately -20°C to -18°C. Next, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (593.4 g, 3.2 mol, i.e., i-PrBPin) was slowly added to the reaction mixture over approximately 40 minutes using an addition funnel, while maintaining the internal temperature at approximately -18°C to -15°C. The resulting mixture was stirred for 30 minutes at a temperature of approximately -17°C to -15°C. The reaction mixture was then warmed to approximately 2°C over approximately 30 minutes and stirred at this temperature for at least 2 hours until the reaction was complete. Completion of the reaction was determined by HPLC and was considered complete when 0.5% or less of Compound A remained. The reaction solution was diluted with MeTHF (4.3 L), and water (4.3 L) was slowly charged over 30 minutes, while maintaining the internal temperature at approximately 8°C to 15°C. The pH of the aqueous layer was adjusted to 6.5 by adding an aqueous solution of HCl (1.16 L, 3N). The mixture was stirred for 30 minutes, and then the layers were separated. The organic layer was washed with 5 wt.% NH4Cl (3.7 L), 10 wt.% NaCl (3.7 L), dried over MgSO4 (530 g), and filtered. The filtrate containing compound B was evaporated to approximately 4.2 L and used in the next reaction without purification.

[0190] (b) Synthesis of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde To a 5 L reactor was added K2CO3 (1.02 kg, 7.4 mol) and water (1.7 L), and the mixture was stirred to dissolve the solids. The atmosphere was evacuated and backfilled with nitrogen gas three times, and then the solution was sparged with nitrogen gas for approximately 1.5 hours. A separate 30 L reactor was charged with MeTHF (4.8 L) and compound C (530 g, 2.4 mol) and stirred under nitrogen to obtain a clear solution. A solution of compound B, prepared as described elsewhere herein, was then added to the solution of compound C. The vessel containing the resulting reaction mixture was evacuated and backfilled with nitrogen gas three times, and then the reaction mixture was sparged with nitrogen gas for approximately 45 minutes. The K2CO3 solution was transferred to the reaction mixture, which was sparged with nitrogen for approximately 10 minutes. Next, Pd(PPh3)4 (56.7 g, 0.05 mol) was charged, and the resulting mixture was sparged with nitrogen for approximately 45 minutes. The reaction mixture was heated to 55°C and stirred at this temperature for at least 8 hours until the reaction was complete. Completion of the reaction was determined by HPLC and was considered complete when 2.0% or less of Compound C remained. Upon completion, MeTHF (5.3 L) was slowly added to the reaction while maintaining the internal temperature at approximately 45°C to 55°C. Next, a 2 wt. % solution of N-acetylcysteine (4.2 L) was slowly charged to the reaction mixture while maintaining the internal temperature at approximately 42°C to 48°C. The contents were stirred at this temperature for approximately 1.5 hours, allowing the layers to separate. The layers were separated, and the organic layer was washed twice with water (4.2 L and 2.1 L) at a temperature of approximately 42°C to 45°C. The organic layer was evaporated to a volume of about 2.6 L and diluted with MeTHF to a volume of about 3.7 L. The resulting slurry was subjected to a thermal cycle in which the temperature was raised to about 50° C., cooled to about 18° C. with stirring, and then stirred at a temperature of about 18° C. for about 1.5 hours. The solid was filtered, washed with a mixture of MeTHF / n-heptane (1:1, 1.6 L), and dried at a temperature below 50° C. for about 8 hours to provide the title compound (690 g, 86% yield) as an off-white to gray solid. TIFF2025526864000028.tif19145

[0191] Step 2 - Synthesis of 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde TIFF2025526864000029.tif31147 A 10 L reactor was charged with compound D (240 g, 0.73 mol) and MeTHF (4.2 L), and the mixture was stirred to dissolve the solids. The reactor was evacuated and filled with nitrogen gas twice, and then nitrogen gas was bubbled through the solution for approximately 0.5 hours. A separate 2 L reactor was charged with K2HPO4 (256 g, 1.5 mol) and water (840 mL), and the mixture was stirred to dissolve the solids. The reactor was evacuated and filled with nitrogen gas twice, and then nitrogen gas was bubbled through the solution for approximately 1 hour. The K2HPO4 solution was then transferred to a 10 L reactor under a nitrogen atmosphere. Pd(amphos)Cl2 (10.4 g, 14.7 mmol) was charged to the reaction mixture, and then nitrogen gas was bubbled through the solution for approximately 0.5 hours. The reaction mixture was heated to a temperature of approximately 65°C to 70°C. A separate reactor was charged with compound E (155.2 g, 0.81 mol), 2-MeTHF (600 mL), and DMAc (600 mL), and the mixture was stirred to dissolve the solids. The reactor containing the compound E solution was evacuated and filled with nitrogen twice, and then nitrogen gas was bubbled through the solution for approximately 0.5 hours. The degassed solution of compound E was slowly transferred to the 10 L reaction mixture over approximately 3.5 hours, while maintaining the internal temperature at approximately 65°C to 70°C. The mixture was stirred at this temperature for approximately 1 hour. Additional compound E (7.0 g, 36.5 mmol) was added to the reaction mixture, and heating was continued for 1 hour or more until the reaction was complete. Completion of the reaction can be determined by HPLC and is considered complete when 2.5% or less of compound D remains. In certain embodiments, additional compound E may be added to drive the reaction to completion. Next, 2-MeTHF (2.4 L) was charged to the reaction mixture, and the contents were then adjusted to a temperature of approximately 25°C to 30°C. A 4 wt.% N-acetylcysteine solution (2.4 L) was charged to the reaction mixture and stirred for approximately 20 minutes at a temperature of approximately 20°C to 30°C. The layers were separated, and the organic layer was washed sequentially with 10 wt.% NaCl solution (2.4 L), 5 wt.% Na2CO3 solution (2.4 L), and water (2.4 L), then dried over Na2SO4 and filtered. The filtrate was evaporated at a temperature of approximately 40°C to 55°C, and the solvent was exchanged with 2-propanol (2 x 2.4 L) to give a final volume of 1.8 L.The solution was stirred at a temperature of about 40°C to 55°C for 1 hour, then cooled to a temperature of about 20°C to 25°C and stirred for an additional hour. The solid was filtered, washed with 2-propanol (720 mL), and dried at a temperature below 50°C to give a crude product (241 g).

[0192] The crude product was redissolved in MeTHF (4.5 L), evaporated at approximately 40-55°C, and solvent-swapped with 2-propanol (2 x 2.4 L) to a final volume of 1.8 L. The solution was stirred at approximately 40-55°C for 1 hour, then cooled to approximately 20-25°C and stirred for an additional hour. The resulting solid was filtered, washed with 2-propanol (720 mL), and dried at temperatures below 50°C to afford the title compound as an off-white solid (213 g, 74% yield). TIFF2025526864000030.tif19147

[0193] Step 2' - Synthesis of 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde TIFF2025526864000031.tif36137 Compound D (17.0 g, 52.0 mmol), bis(pinacolato)diboron (15.9 g, 62.5 mmol), toluene (170 mL), and DMF (102 mL) were added to a 500 mL reactor. The mixture was degassed by bubbling nitrogen gas through the solution for approximately 15 minutes while stirring. Potassium acetate (15.3 g, 156.2 mmol) and Pd(dppf)Cl2·CHCl2 (2.12 g, 2.6 mmol) were added to the solution, and the mixture was degassed by bubbling nitrogen gas through the solution for approximately 15 minutes. The reaction solution was heated to approximately 95°C–100°C and stirred at this temperature for at least 4 hours until the reaction was complete. Completion of the reaction was determined by HPLC and was considered complete when less than 1% compound D remained. The reaction mixture was adjusted to a temperature of approximately 50°C, and then a 5 wt.% solution of N-acetylcysteine (170 mL) was added. The reaction mixture was cooled to a temperature of approximately 20°C to 30°C, stirred for 1 hour, and the layers were allowed to separate. The layers were separated, and the organic layer was washed with 10 wt.% NaCl (2 × 170 mL). Activated carbon (8.5 g) was added to the organic layer, and the mixture was stirred for approximately 1.5 hours. The suspension was filtered through Celite. The filtrate was evaporated and solvent-swapped with 2-propanol (3 × 85 mL). The volume was adjusted to approximately 90 mL, and the solution was stirred for 1 hour at a temperature of approximately 20°C to 25°C. The resulting suspension was cooled to a temperature of approximately 0°C to 5°C and stirred for 1 hour. The resulting solid was filtered, washed with cold 2-propanol (35 mL), and dried at a temperature below 50°C to give the title compound as a brown solid (14.5 g, 76% yield). TIFF2025526864000032.tif25145

[0194] Step 2'' - Synthesis of 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde TIFF2025526864000033.tif36148 A 1-L reactor was charged with MeTHF (225 mL) and water (49.5 mL) and degassed by bubbling nitrogen gas through the solution for approximately 15 minutes. Compound E' (11.0 g, 40.1 mmol) and K2CO3 (16.6 g, 120.4 mmol) were added, and the mixture was stirred and degassed by bubbling nitrogen gas through the solution for approximately 15 minutes. Pd(dppf)Cl2·CHCl2 (1.3 g, 1.6 mmol) was added, and the mixture was stirred and degassed by bubbling nitrogen gas through the solution for approximately 15 minutes. The reaction mixture was heated to approximately 55 °C, at which point the solution became clear and colorless. Compound D' (15.0 g, 40.1 mmol) and MeTHF (75 mL) were added to a separate 250 mL reactor and degassed by bubbling nitrogen gas through the solution with stirring for approximately 15 minutes. Next, the solution of compound D' was slowly added to the 1 L reactor over approximately 1.5 hours while maintaining the reaction temperature at approximately 50-60°C. The reaction mixture was stirred at 55°C for at least 12 hours until the reaction was complete. Completion of the reaction was determined by HPLC and was considered complete when 2.0% or less of compound E' remained. The reaction mixture was adjusted to a temperature of approximately 50°C, and 150 mL of a 5 wt.% N-acetylcysteine solution was added. The reaction mixture was cooled and stirred at a temperature of approximately 20-30°C for approximately 1 hour. MeTHF (150 mL) and 75 mL of 5 wt.% NaCl were added to the reaction mixture. The mixture was stirred for 5 minutes, then the layers were separated and the aqueous layer was separated. The organic layer was washed with 75 mL of 10 wt.% NaCl, dried over MgSO4, and filtered. The filtrate was evaporated to a volume of approximately 45 mL and solvent-swapped with 2-propanol (2 x 120 mL). Additional 2-propanol (75 mL) was then added, and the solvent was evaporated until the total volume of the solution was approximately 105 mL. The resulting suspension was heated to a temperature of approximately 50-55°C and maintained at this temperature for approximately 1 hour. The solution was then cooled to a temperature of approximately 20-25°C and stirred for 1 hour. The resulting solid was filtered, washed with 2-propanol (30 mL), and dried at temperatures below 55°C to afford the title compound as a light brown solid (12.5 g, 79% yield).

[0195] Step 3 - Synthesis of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde A 15 L reactor was charged with compound G (470.0 g, 2.2 mol), bis(pinacolato)diboron (666.0 g, 2.6 mol), potassium acetate (321.7 g, 3.3 mol), toluene (4.7 L), and DMF (2.8 L). The resulting suspension was evacuated and refilled with nitrogen gas three times, followed by a nitrogen sparge for approximately 1 hour. Next, Pd(dppf)Cl2 (48.0 g, 65.6 mmol) was added, and nitrogen was sparged through the mixture for approximately 30 minutes. The reaction mixture was heated to approximately 85 °C and stirred for 7 hours or more until the reaction was complete as determined by HPLC. Completion of the reaction was determined by HPLC and was considered complete when 1.0% or less of compound G remained. The reaction mixture was cooled to 27°C, then a solution of N-acetylcysteine (4.7 L, 5 wt%) was added while maintaining an internal temperature of approximately 23°C to 31°C and stirred for 1 hour. The phases were then separated, and 5 wt% NaCl (4.7 L) was added to the organic layer. The mixture was agitated and filtered through Celite. The filtrate was allowed to settle, the phases were separated, and the organic layer was washed with 5 wt% NaCl (4.7 L). Activated carbon (235.0 g) was added to the organic layer, and the mixture was agitated for 1.5 hours and then filtered through Celite. The filtrate was evaporated to a volume of approximately 1 L and solvent-switched into 2-propanol (2 x 4.7 L) to obtain a solution volume of approximately 1.2 L. The solution was heated to a temperature of approximately 50°C, maintained at this temperature for approximately 1.5 hours, and then slowly cooled to a temperature of approximately 6°C over approximately 3 hours and stirred at this temperature for approximately 1.5 hours. The resulting solid was filtered, washed with 2-propanol (2 x 0.45 L), and dried at a temperature below 50°C for 12 hours to give the title compound as a light brown solid (492.0 g, 86% yield). TIFF2025526864000035.tif19135

[0196] Step 4 - Synthesis of 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde TIFF2025526864000036.tif34155 K2CO3 (526.6 g, 3.8 mol) and water (2.0 L) were added to a 5 L reactor and the mixture was swirled to facilitate dissolution of the solids. The solution was evacuated and backfilled with nitrogen gas four times, followed by bubbling nitrogen gas through the solution for approximately 2 hours to degas the solution. To a separate 30 L reactor, MeTHF (7.5 L), DMF (2.0 L), compound F (500.0 g, 1.27 mol), and compound H (349.6 g, 1.33 mol) were added and the mixture was swirled to facilitate dissolution of the solids. The solution was evacuated and backfilled with nitrogen gas four times, followed by bubbling nitrogen gas through the solution for approximately 1 hour to degas the solution. Next, K2CO3 solution was added followed by Pd(PPh3)4 (44.0 g, 0.04 mol), and the resulting mixture was sparged with nitrogen for approximately 1 hour. The reaction mixture was heated to approximately 65-70°C and stirred at this temperature for at least 3 hours until the reaction was complete. Completion of the reaction was determined by HPLC and was considered complete when the remaining compound F was 1.0% or less. The reaction mixture was adjusted to a temperature of approximately 60°C, and then a 5 wt.% N-acetylcysteine solution (5.0 L) was slowly added over approximately 40 minutes. The reaction mixture was cooled to a temperature of approximately 22°C over approximately 1.5 hours and stirred at this temperature for 1.5 hours. The resulting solid was filtered, washed with water (7.5 L), and then with EtOH (2.5 L). The wet cake was dried at approximately 50°C to afford the title compound as a tan solid (581 g, 92% yield). TIFF2025526864000037.tif30145

[0197] Step 5 - Synthesis of 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one Compound J (332.3 g, 2.04 mol), CHCl (13.4 L), and MeOH (2.9 L) were added to a 50 L reactor and the mixture was stirred. NaOMe (110 g, 2.04 mol, 25 wt.% solution in MeOH) was then added, and the resulting slurry was stirred for 30 minutes at a temperature of approximately 15-20°C. Compound I (420.0 g, 0.851 mol) was added, and the mixture was stirred for 1 hour at a temperature of approximately 22-28°C. The slurry was cooled to a temperature of approximately 18°C, and NaBH(OAc) (1.08 kg, 5.1 mol) was added in portions (i.e., in three portions, approximately 20 minutes apart). The reaction mixture was stirred for at least 1 hour until the reaction was deemed complete. Completion of the reaction was determined by HPLC and was considered complete when 1.0% or less of Compound I remained. Water (8.4 L) was added to the reaction mixture, and the resulting clear, biphasic mixture was agitated for approximately 20 minutes at a temperature of approximately 20°C to 25°C. The layers were allowed to settle and separated. The aqueous layer was washed with CHCl (6.3 L). CHCl (8.4 L) was added to the aqueous phase, and the pH of the aqueous layer was adjusted to pH 8-9 using 3N aqueous NaOH (3.2 L). The resulting mixture was agitated for 20 minutes, and then the phases were separated. The aqueous layer was further extracted with CHCl (2.1 L), and the combined organic layers were washed with water (4.2 L). The aqueous layer was extracted again with CHCl (2.1 L), and the combined organic layers were filtered through a pad of NaSO. The filtered solution was concentrated in vacuo and solvent exchanged with 2-propanol (2 × 2.1 L) at a temperature of approximately 40°C to 50°C. The final volume of the solution was adjusted to a volume of about 2.1 L. The solution was seeded with compound K (2.1 g) to obtain a fine slurry, which was stirred at a temperature of about 50° C. for about 2 hours and then gradually cooled to a temperature of about 20° C. over a period of about 10 hours. The resulting viscous slurry was stirred at the same temperature (i.e., about 20° C.) for about 4 hours. The solid was filtered and washed with 2-propanol (840 mL). The wet cake was dried in vacuo at 55° C. for not less than 24 hours to afford the title compound as a white to off-white solid (533 g, 88% yield). TIFF2025526864000039.tif32153

[0198] In certain embodiments, the recrystallization described herein utilizes seed crystals of Compound K to promote the recrystallization. In certain embodiments, seed crystals of Compound K are prepared as described in step 5, except that the recrystallization is not promoted by the addition of seed crystals.

[0199] Step 5' - Synthesis of 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one Compound J (553.8 g, 3.40 mol), MeTHF (21 L), and MeOH (7 L) were added to a 50 L reactor and the mixture was stirred. DIPEA (458.5 g, 3.5 mol) was added, and the resulting slurry was stirred at approximately 15-20°C for 1 hour. Compound I (700.0 g, 1.42 mol) was added, and the mixture was stirred at approximately 33-35°C for 1.5 hours. The slurry was cooled to approximately 15-20°C, and NaBH(OAc)3 (1.8 kg, 8.5 mol) was added in portions (i.e., in four portions, approximately 20 minutes apart). The reaction mixture was warmed to 20-25°C and stirred for at least 1 hour until the reaction was complete. The reaction was determined to be complete by HPLC and was considered complete when 1.0% or less of Compound I remained. 10% NaCl (9 L) was added to the reaction mixture, and the resulting clear, biphasic mixture was agitated for approximately 20 minutes at a temperature of approximately 20°C to 25°C. The layers were allowed to settle and separated. The organic layer was extracted with 10% NaCl (3.5 L). The combined aqueous layers were washed sequentially with MeTHF (3.5 L) and MEK (2 × 7 L). MEK (14 L) was added to the aqueous phase, and the pH of the aqueous layer was adjusted to pH 9.5–10.5 using 20 wt% aqueous Na2CO3 (9 L). The resulting mixture was agitated for 20 minutes, and then the phases were separated. The aqueous layer was further extracted with MEK (2 × 9 L). The combined organic layers were washed with 24 wt% NaCl (7 L). The organic layer was filtered through a pad of Na2SO4. The filtered solution was diluted with MeOH (3.5 L), concentrated in vacuo, and solvent-swapped with MeOH (17 L) in three portions at approximately 40°C to 50°C. The final volume of the solution was adjusted to approximately 3.5 L. The solution was stirred at 48°C to 50°C and seeded with compound K (3.5 g) to obtain a fine slurry, which was stirred at approximately 50°C for approximately 3 hours and then gradually cooled to approximately 20°C over approximately 4 hours. The resulting viscous slurry was stirred at the same temperature (i.e., approximately 20°C) for approximately 10 hours. MTBE (7 L) was charged, and the slurry was stirred for 4 hours. The solid was filtered and washed with 30% MeOH / MTBE (2 x 1.4 L). The wet cake was dried in vacuo at 65°C for at least 24 hours to give the title compound as a white to off-white solid (760 g, 74% yield).

[0200] In certain embodiments, compound K obtained by the methods described herein may contain higher concentrations of residual MTBE. Excess MTBE can be reduced by preparing a hot MeOH slurry of the isolated material, cooling the slurry to ambient temperature, filtering, washing with MeOH, and drying. In certain embodiments, the recrystallization methods described herein utilize a solvent other than MTBE as the anti-solvent.

[0201] Numbered aspects The following exemplary aspects are provided, the numbering of which should not be construed as indicating order of importance.

[0202] Aspect 1 provides the following: below: 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one (K): To generate the first reaction system containing TIFF2025526864000041.tif18128, 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (I): TIFF2025526864000042.tif18128 and 2,6-diazaspiro[3.4]octan-7-one (J): reacting TIFF2025526864000043.tif12128 in the presence of a reducing agent and a base A method for preparing (K) or a salt or solvate thereof, comprising:

[0203] Aspect 2 provides the following: The method of embodiment 1, wherein the reducing agent is NaBH(OAc)3.

[0204] Aspect 3 provides the following: 3. The method of embodiment 1 or 2, wherein the base comprises NaOMe or i-PrNEt2.

[0205] Aspect 4 provides the following: 4. The method of any one of aspects 1 to 3, wherein (J) is selected from the group consisting of 2,6-diazaspiro[3.4]octan-7-one hydrochloride, 2,6-diazaspiro[3.4]octan-7-one hydrobromide, 2,6-diazaspiro[3.4]octan-7-one trifluoroacetate, 2,6-diazaspiro[3.4]octan-7-one mesylate, and 2,6-diazaspiro[3.4]octan-7-one tosylate.

[0206] Aspect 5 provides the following: A method according to any one of aspects 1 to 4, wherein the reaction of (I) with (J) is carried out in the presence of a solvent.

[0207] Aspect 6 provides the following: 6. The method of embodiment 5, wherein the solvent comprises at least one of a mixture comprising dichloromethane (DCM) and methanol (MeOH), a mixture comprising 2-methyltetrahydrofuran (MeTHF) and MeOH, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylacetamide (DMAc), or any mixture thereof.

[0208] Aspect 7 provides the following: Purification of (K) (a) adding water to a first reaction system containing (K) to produce a two-phase solution; (b) separating the biphasic solution to obtain a first aqueous phase and a first organic phase; (c) adding an organic solvent to the first aqueous phase to obtain a second two-phase solution; (d) basifying the second biphasic solution to a pH of 8 to 11 to obtain a basified biphasic solution; and (e) separating the basified biphasic solution to obtain a second aqueous phase and a second organic phase comprising (K). 7. The method according to any one of aspects 1 to 6, comprising:

[0209] Aspect 8 provides the following: Purification of (K) (a) providing crude (K) in a solvent comprising 2-propanol to provide a dilute crude solution of (K); the diluted crude solution of (K) has a concentration of about 110 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (K) to obtain a concentrated crude solution of (K), The concentrated crude solution of (K) has a concentration of about 220 g / L to about 280 g / L; (c) cooling the concentrated (K) crude solution to a temperature of about 20°C to obtain a purified (K) slurry; and (d) filtering the purified (K) slurry to obtain (K). 8. The method according to any one of aspects 1 to 7, comprising:

[0210] Aspect 9 provides the following: Purification of (K) (a) providing crude (K) in a solvent comprising MeOH to provide a crude solution of (K); the crude solution of (K) has a concentration of about 200 g / L to about 300 g / L; (b) heating the crude solution of (K) to a temperature of about 50°C to obtain a hot crude solution of (K); (c) cooling the hot crude solution of (K) to a temperature of about 20°C to obtain a cooled (K) slurry; (d) adding a solvent comprising methyl tert-butyl ether (MTBE) to the cooled (K) slurry to obtain a purified (K) slurry; and (e) filtering the refined (K) slurry to obtain (K). 8. The method according to any one of aspects 1 to 7, comprising:

[0211] Aspect 10 provides the following: 2-Methoxy-4-(B(OR 1a )(OR 1b ))-Benzaldehyde (H): TIFF2025526864000044.tif23128 and 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (F): TIFF2025526864000045.tif18128 in the presence of a palladium catalyst and a base to prepare (I), In the formula, each R 1a and R 1b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 1a and R 1b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl; A method according to any one of aspects 1 to 9.

[0212] Aspect 11 provides the following: The method of embodiment 10, wherein the palladium catalyst comprises Pd(PPh3)4.

[0213] Aspect 12 provides the following: 12. The method of embodiment 10 or 11, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0214] Aspect 13 provides the following: 13. The method of any one of aspects 10 to 12, wherein the base comprises K2CO3.

[0215] Aspect 14 provides the following: A method according to any one of aspects 10 to 13, wherein the reaction of (H) with (F) is carried out in the presence of a solvent.

[0216] Aspect 15 provides the following: 15. The method of embodiment 14, wherein the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF), dimethylformamide (DMF), and water.

[0217] Aspect 16 provides the following: 16. The method according to any one of aspects 10 to 15, wherein the reaction of (H) with (F) is carried out at a temperature of about 65°C to about 70°C.

[0218] Aspect 17 provides the following: A method according to any one of aspects 10 to 16, wherein the purification of (I) comprises the step of adding N-acetylcysteine to the reaction of (H) with (F).

[0219] Aspect 18 provides the following: 4-Z 2 -2-Methoxybenzaldehyde (G): TIFF2025526864000046.tif18128, wherein Z 2 is selected from the group consisting of Cl, Br, and I; (G) A method according to any one of aspects 10 to 17, wherein (H) is prepared by reacting (H) with a boronating reagent in the presence of a palladium catalyst and a base.

[0220] Aspect 19 provides the following: The method of embodiment 18, wherein the boronating reagent comprises bis(pinacolato)diboron.

[0221] Aspect 20 provides the following: 20. The method of embodiment 18 or 19, wherein the palladium catalyst comprises Pd(dppf)Cl.

[0222] Aspect 21 provides the following: Aspect 21. The method of any one of aspects 18-20, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5.0 mol %.

[0223] Aspect 22 provides the following: 22. The method of any one of aspects 18 to 21, wherein the base comprises KOAc.

[0224] Aspect 23 provides the following: A method according to any one of aspects 18 to 22, wherein the reaction of (G) with a boronating reagent is carried out in the presence of a solvent.

[0225] Aspect 24 provides the following: 24. The method of embodiment 23, wherein the solvent comprises dimethylformamide (DMF) or toluene.

[0226] Embodiment 25 provides the following: A method according to any one of aspects 18 to 24, wherein the reaction of (G) with the boronating reagent is carried out at a temperature of about 80°C to about 90°C.

[0227] Embodiment 26 provides the following: Purification of (H) (a) adding N-acetylcysteine to the reaction of (G) with a boronating reagent; and (b) adding activated carbon to the reaction of (G) with a boronating reagent. 26. The method according to any one of aspects 18 to 25, comprising at least one of:

[0228] Aspect 27 provides the following: Purification of (H) (a) providing crude (H) in a solvent comprising 2-propanol to provide a dilute crude solution of (H); (H) the diluted crude solution has a concentration of about 390 g / L to about 430 g / L; (b) at least partially evaporating the diluted crude solution of (H) to obtain a concentrated crude solution of (H), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (H) to a temperature of about 50° C. and optionally maintaining that temperature for about 1.5 hours; (c) cooling the concentrated crude (H) solution to a temperature of about 6° C. to obtain a purified (H) slurry, wherein the cooling step is optionally carried out for about 3 hours; and (d) filtering the refined (H) slurry to obtain (H). 27. The method according to any one of aspects 18 to 26, comprising:

[0229] Embodiment 28 provides the following: 6-(3-Z 1 -2-chlorophenyl)-2-methoxynicotinaldehyde (D): TIFF2025526864000047.tif18128, wherein Z 1 is selected from the group consisting of Br and I; (D) and 2,3-dichloro-4-(B(OR 2a )(OR 2b ))-Pyridine (E): TIFF2025526864000048.tif17128 in the presence of a palladium catalyst and a base to prepare (F); In the formula, each R 2a and R 2b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 2a and R 2b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl; A method according to any one of aspects 10 to 17.

[0230] Aspect 29 provides the following: R 2a and R 2b is each independently H.

[0231] Aspect 30 provides the following: 30. The method of embodiment 28 or 29, wherein the palladium catalyst comprises Pd(amphos)Cl.

[0232] Aspect 31 provides the following: Aspect 31. The method of any one of aspects 28 to 30, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0233] Aspect 32 provides the following: Aspect 32. The method of any one of aspects 28 to 31, wherein the base comprises K2HPO4.

[0234] Aspect 33 provides the following: 33. The method of any one of aspects 28-32, wherein reacting (D) with (E) comprises adding (E) to a reaction vessel containing (D), wherein (E) is optionally added to the vessel containing (D) over about 3.5 hours.

[0235] Embodiment 34 provides the following: A method according to any one of aspects 28 to 33, wherein the reaction of (D) with (E) is carried out in the presence of a solvent.

[0236] Embodiment 35 provides the following: 35. The method of embodiment 34, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF), dimethylacetamide (DMAc), and / or water.

[0237] Embodiment 36 provides the following: The method of any one of aspects 28 to 35, wherein the reaction of (D) with (E) is carried out at a temperature of about 65°C to about 70°C.

[0238] Aspect 37 provides the following: A method according to any one of aspects 28 to 36, wherein the purification of (F) comprises adding N-acetylcysteine to the reaction of (D) and (E).

[0239] Embodiment 38 provides the following: Purification of (F) (a) providing crude (F) in a solvent comprising 2-propanol to provide a dilute crude solution of (F); (F) the diluted crude solution has a concentration of about 100 g / L to about 150 g / L; (b) at least partially evaporating the diluted crude solution of (F) to obtain a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (F) to a temperature of about 40° C. to about 55° C. and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (F) solution to a temperature of about 20° C. to about 25° C. to obtain a crude (F) slurry, wherein the cooling step is optionally carried out over a period of about 3 hours; and (d) filtering the crude (F) slurry to obtain (F), wherein the filtering step optionally further comprises washing with a solvent comprising 2-propanol. 38. The method according to any one of embodiments 28 to 37, comprising:

[0240] Aspect 39 provides the following: 6-(2-chloro-3-(B(OR 3a )(OR 3b ))phenyl)-2-methoxynicotinaldehyde (D'): TIFF2025526864000049.tif18128 and 2,3-dichloro-4-Z 1 -pyridine (E'): TIFF2025526864000050.tif17128, wherein Z 1 is selected from the group consisting of Br and I, (E') in the presence of a palladium catalyst and a base to prepare (F), In the formula, each R 3a and R 3b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 3a and R 3b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl; A method according to any one of aspects 10 to 17.

[0241] Embodiment 40 provides the following: 40. The method of embodiment 39, wherein (D') is 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde.

[0242] Aspect 41 provides the following: 41. The method of embodiment 39 or 40, wherein the palladium catalyst comprises Pd(dppf)Cl.

[0243] Aspect 42 provides the following: 42. The method of any one of embodiments 39-41, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0244] Aspect 43 provides the following: Aspect 43. The method of any one of aspects 39 to 42, wherein the base comprises K2CO3.

[0245] Embodiment 44 provides the following: A method according to any one of aspects 39 to 43, wherein the reaction of (D') with (E') is carried out in the presence of a solvent.

[0246] Embodiment 45 provides the following: The method of embodiment 44, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and water.

[0247] Embodiment 46 provides the following: 46. The method of any one of aspects 39 to 45, wherein the reaction of (D') with (E') is carried out at a temperature of about 55°C.

[0248] Aspect 47 provides the following: A method according to any one of aspects 39 to 46, wherein the purification of (F) comprises the step of adding N-acetylcysteine to the reaction of (D') and (E').

[0249] Embodiment 48 provides the following: Purification of (F) (a) providing crude (F) in 2-propanol to provide a dilute crude solution of (F), (F) the diluted crude solution has a concentration of about 100 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (F) to obtain a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (F) to a temperature of about 50°C to about 55°C and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (F) solution to a temperature of about 20°C to about 25°C to obtain a purified (F) slurry; and (d) filtering the refined (F) slurry to obtain (F). 48. The method according to any one of embodiments 39 to 47, comprising:

[0250] Aspect 49 provides the following: (D): TIFF2025526864000051.tif18128, wherein Z 1 is selected from the group consisting of Br and I; (D) A method according to any one of aspects 39 to 48, wherein (D') is prepared by reacting (D') with a boronating reagent in the presence of a palladium catalyst and a base.

[0251] Embodiment 50 provides the following: 50. The method of embodiment 49, wherein the boronating reagent comprises bis(pinacolato)diboron.

[0252] Embodiment 51 provides the following: 51. The method of embodiment 49 or 50, wherein the palladium catalyst comprises Pd(dppf)Cl.

[0253] Embodiment 52 provides the following: 52. The method of any one of embodiments 49 to 51, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 7 mol %.

[0254] Embodiment 53 provides the following: 53. The method of any one of aspects 49 to 52, wherein the base comprises KOAc.

[0255] Embodiment 54 provides the following: A method according to any one of aspects 49 to 53, wherein the reaction of (D) with the boronating reagent is carried out in the presence of a solvent.

[0256] Embodiment 55 provides the following: 55. The method of embodiment 54, wherein the solvent comprises dimethylformamide (DMF) and / or toluene.

[0257] Embodiment 56 provides the following: A method according to any one of aspects 49 to 55, wherein the reaction of (D) with the boronating reagent is carried out at a temperature of about 90°C to about 100°C.

[0258] Embodiment 57 provides the following: Purification of (D') (a) adding N-acetylcysteine to the reaction of (D) with a boronating reagent; and (b) adding activated carbon to the reaction of (D) with a boronating reagent; 57. The method according to any one of embodiments 49 to 56, comprising at least one of:

[0259] Embodiment 58 provides the following: Purification of (D') (a) providing crude (D') in a solvent comprising 2-propanol to provide a crude solution of (D'); the crude solution of (D') has a concentration of about 140 g / L to about 180 g / L; (c) cooling the crude solution of (D') to a temperature of about 0°C to about 5°C to obtain a purified (D') slurry; and (d) filtering the refined (D') slurry to obtain (D'). 58. The method of any one of embodiments 49 to 57, comprising:

[0260] Embodiment 59 provides the following: 1-(B(OR 4a )(OR 4b ))-2-chloro-3-Z 1 -Benzene (B): TIFF2025526864000052.tif17128 and 6-Z 2 -2-Methoxynicotinaldehyde (C): TIFF2025526864000053.tif13128 in the presence of a palladium catalyst and a base to prepare (D), In the formula, Z 1 is selected from the group consisting of Br and I; In the formula, Z 2 is selected from the group consisting of Cl, Br, and I; In the formula, each R 4a and R 4b are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 4a and R 4b may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl; A method according to any one of embodiments 28 to 38 and 49 to 58.

[0261] Embodiment 60 provides the following: 60. The method of embodiment 59, wherein (B) is 2-(3-bromo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0262] Embodiment 61 provides the following: 61. The method of embodiment 59 or 60, wherein the palladium catalyst comprises Pd(PPh3)4.

[0263] Embodiment 62 provides the following: 62. The method of any one of embodiments 59-61, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0264] Embodiment 63 provides the following: 63. The method of any one of aspects 59-62, wherein the base comprises K2CO3.

[0265] Embodiment 64 provides the following: A method according to any one of aspects 59 to 63, wherein the reaction of (B) with (C) is carried out in the presence of a solvent.

[0266] Embodiment 65 provides the following: 65. The method of embodiment 64, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

[0267] Embodiment 66 provides the following: 66. The method of any one of aspects 59 to 65, wherein the reaction of (B) with (C) is carried out at a temperature of about 50°C to about 60°C.

[0268] Embodiment 67 provides the following: A method according to any one of aspects 59 to 66, wherein the purification of (D) comprises adding N-acetylcysteine to the reaction of (B) and (C).

[0269] Embodiment 68 provides the following: (D) Purification of (a) providing crude (D) in a solvent comprising 2-propanol to provide a diluted crude solution of (D); (D) the diluted crude solution has a concentration of about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to obtain a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (D) to a temperature of about 50°C to about 55°C and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (D) solution to a temperature of about 20° C. to about 25° C. to obtain a purified (D) slurry; and (d) filtering the refined (D) slurry to obtain (D). 68. The method of any one of embodiments 59 to 67, comprising:

[0270] Embodiment 69 provides the following: (a) To form an arylmagnesium intermediate, 1-Z 1 -2-chloro-3-Z 1 -Benzene (A): TIFF2025526864000054.tif17128, wherein Z 1 is independently selected at each occurrence from the group consisting of Br and I; with an organomagnesium halide; and (b) reacting the aryl magnesium intermediate with a borate 69. The method of any one of embodiments 59 to 68, wherein (B) is prepared by:

[0271] Embodiment 70 provides the following: Borate is: TIFF2025526864000055.tif10128, In the formula, each R 5a , R 5b , and R 5c are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 5a , R 5b , and R 5c any two selected from the group consisting of may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl; 70. The method of embodiment 69.

[0272] Aspect 71 provides the following: The method of embodiment 69 or 70, wherein the borate comprises 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0273] Embodiment 72 provides the following: 72. The method of any one of aspects 69-71, wherein the organomagnesium halide comprises i-PrMgCl, wherein the i-PrMgCl is a solution comprising i-PrMgCl optionally complexed with LiCl (i.e., an i-PrMgCl·LiCl solution).

[0274] Embodiment 73 provides the following: A method according to any one of aspects 69 to 72, wherein the reaction of (A) with the organomagnesium halide is carried out in a solvent.

[0275] Embodiment 74 provides the following: 74. The method of embodiment 73, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0276] Embodiment 75 provides the following: A method according to any one of aspects 69 to 74, wherein the reaction of (A) with the organomagnesium halide is carried out at a temperature of from about -25°C to about -15°C.

[0277] Embodiment 76 provides the following: 76. The method of any one of embodiments 69-75, wherein the reaction of the arylmagnesium intermediate with the borate is carried out at a temperature of about −18° C. to about −15° C., and the reaction is subsequently optionally warmed to a temperature of about 2° C.

[0278] Aspect 77 provides the following: (a) To form an arylmagnesium intermediate, 1-Z 1 -2-chloro-3-Z 1 -Benzene (A): TIFF2025526864000056.tif17128, wherein Z 1 is independently selected at each occurrence from the group consisting of Br and I; and providing an organomagnesium halide; (b) reacting the aryl magnesium intermediate with a borate to provide a boronic ester intermediate; and (c) a boronic ester intermediate; 6-Z 2 -2-Methoxynicotinaldehyde (C): TIFF2025526864000057.tif13128, wherein Z 2 is selected from the group consisting of Cl, Br, and I; (C) in the presence of a palladium catalyst and a base. The method according to any one of embodiments 28 to 38 and 49 to 58, wherein (D) is prepared by

[0279] Embodiment 78 provides the following: 78. The method of embodiment 77, wherein the organomagnesium halide comprises i-PrMgCl, wherein the i-PrMgCl is optionally a solution comprising i-PrMgCl complexed with LiCl (i.e., an i-PrMgCl·LiCl solution).

[0280] Embodiment 79 provides the following: 79. The method of embodiments 77 and 78, wherein the reaction of (A) with the organomagnesium halide is carried out in a solvent.

[0281] Embodiment 80 provides the following: 80. The method of embodiment 79, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0282] Embodiment 81 provides the following: A method according to any one of aspects 77 to 80, wherein the reaction of (A) with the organomagnesium halide is carried out at a temperature of from about -25°C to about -15°C.

[0283] Embodiment 82 provides the following: 82. The method of any one of embodiments 77-81, wherein the reaction of the arylmagnesium intermediate with the borate is carried out at a temperature of about −18° C. to about −15° C., and the reaction is subsequently optionally warmed to a temperature of about 2° C.

[0284] Embodiment 83 provides the following: Borate is: TIFF2025526864000058.tif10128, In the formula, each R 5a , R 5b , and R 5c are each independently selected from the group consisting of C1-C6 alkyl and C3-C8 cycloalkyl; or R 5a , R 5b , and R 5c any two selected from the group consisting of may be taken together with the atom to which they are attached to form a C2-C3 heterocycloalkyl; A method according to any one of embodiments 77 to 82.

[0285] Embodiment 84 provides the following: Aspect 84. The method of any one of aspects 77 to 83, wherein the borate comprises 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0286] Embodiment 85 provides the following: Aspect 85. The method of any one of aspects 77 to 84, wherein the palladium catalyst comprises Pd(PPh3)4.

[0287] Embodiment 86 provides the following: Aspect 86. The method of any one of aspects 77 to 85, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0288] Embodiment 87 provides the following: Aspect 87. The method of any one of aspects 77-86, wherein the base comprises K2CO3.

[0289] Embodiment 88 provides the following: A method according to any one of embodiments 77 to 87, wherein the reaction of the boronic ester intermediate with (C) is carried out in the presence of a solvent.

[0290] Embodiment 89 provides the following: 89. The method of embodiment 88, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

[0291] Embodiment 90 provides the following: A method according to any one of embodiments 77 to 89, wherein the reaction of the boronic ester intermediate with (C) is carried out at a temperature of from about 50°C to about 60°C.

[0292] Aspect 91 provides the following: Aspect 91. The method of any one of aspects 77 to 90, wherein purifying (D) comprises adding N-acetylcysteine to the reaction of (C) with the boronic ester intermediate.

[0293] Embodiment 92 provides the following: (D) Purification of the following: (a) providing crude (D) in a solvent comprising 2-propanol to provide a diluted crude solution of (D); (D) the diluted crude solution has a concentration of about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to obtain a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (D) to a temperature of about 50°C to about 55°C and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (D) solution to a temperature of about 20° C. to about 25° C. to obtain a purified (D) slurry; and (d) filtering the refined (D) slurry to obtain (D). 92. The method of any one of embodiments 77 to 91, comprising:

[0294] The terms and expressions employed herein are used as terms of description rather than limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, but is recognized as allowing various modifications within the scope of the aspects of the present application.Thus, although the present application describes specific embodiments and optional features, it should be understood that modifications and variations of the compositions, methods, and concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the aspects of the present application.

Claims

1. below: 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)phenyl)pyridin-4-yl)phenyl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-7-one (K). To generate a first reaction system comprising: 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (I): and 2,6-diazaspiro[3.4]octan-7-one (J): in the presence of a reducing agent and a base. A method for preparing (K) or a salt or solvate thereof, comprising:

2. The reducing agent is NaBH(OAc) 3 2. The method of claim 1, wherein

3. The base is NaOMe or i-PrNEt 2 3. The method of claim 1 or 2, comprising:

4. 4. The method of any one of claims 1 to 3, wherein (J) is selected from the group consisting of 2,6-diazaspiro[3.4]octan-7-one hydrochloride, 2,6-diazaspiro[3.4]octan-7-one hydrobromide, 2,6-diazaspiro[3.4]octan-7-one trifluoroacetate, 2,6-diazaspiro[3.4]octan-7-one mesylate, and 2,6-diazaspiro[3.4]octan-7-one tosylate.

5. 5. The process of claim 1, wherein the reaction of (I) with (J) is carried out in the presence of a solvent.

6. 6. The method of claim 5, wherein the solvent comprises at least one of a mixture comprising dichloromethane (DCM) and methanol (MeOH), a mixture comprising 2-methyltetrahydrofuran (MeTHF) and MeOH, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylacetamide (DMAc), or any mixture thereof.

7. Purification of (K) (a) adding water to a first reaction system containing (K) to form a two-phase solution; (b) separating the biphasic solution to obtain a first aqueous phase and a first organic phase; (c) adding an organic solvent to the first aqueous phase to obtain a second two-phase solution; (d) basifying the second biphasic solution to a pH of 8 to 11 to obtain a basified biphasic solution; and (e) separating the basified biphasic solution to obtain a second aqueous phase and a second organic phase comprising (K).

7. The method of any one of claims 1 to 6, comprising:

8. Purification of (K) (a) providing crude (K) in a solvent comprising 2-propanol to provide a dilute crude solution of (K); the diluted crude solution of (K) has a concentration of about 110 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (K) to obtain a concentrated crude solution of (K), the concentrated crude solution of (K) has a concentration of about 220 g / L to about 280 g / L; (c) cooling the concentrated (K) crude solution to a temperature of about 20°C to obtain a purified (K) slurry; and (d) filtering the purified (K) slurry to obtain (K).

8. The method of any one of claims 1 to 7, comprising:

9. Purification of (K) (a) providing crude (K) in a solvent comprising MeOH to provide a crude solution of (K); the crude solution of (K) has a concentration of about 200 g / L to about 300 g / L; (b) heating the crude solution of (K) to a temperature of about 50°C to obtain a hot crude solution of (K); (c) cooling the hot crude solution of (K) to a temperature of about 20°C to obtain a cooled (K) slurry; (d) adding a solvent comprising methyl tert-butyl ether (MTBE) to the cooled (K) slurry to obtain a purified (K) slurry; and (e) filtering the refined (K) slurry to obtain (K).

8. The method of any one of claims 1 to 7, comprising:

10. 2-Methoxy-4-(B(OR 1a )(OR 1b ))-Benzaldehyde (H): and 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (F): in the presence of a palladium catalyst and a base to prepare (I), In the formula, each R 1a and R 1b However, each independently C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; or R 1a and R 1b together with the atoms to which they are bonded, C 2 ~C 3 may form a heterocycloalkyl, 10. The method of any one of claims 1 to 9.

11. The palladium catalyst is Pd(PPh 3 ) 4 11. The method of claim 10, comprising:

12. 12. The method of claim 10 or 11, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

13. The base is K 2 CO 3 13. The method of any one of claims 10 to 12, comprising:

14. 14. The method of any one of claims 10 to 13, wherein the reaction of (H) with (F) is carried out in the presence of a solvent.

15. 15. The method of claim 14, wherein the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF), dimethylformamide (DMF), and water.

16. 16. The method of any one of claims 10 to 15, wherein the reaction of (H) with (F) is carried out at a temperature of about 65°C to about 70°C.

17. The method according to any one of claims 10 to 16, wherein the purification of (I) comprises adding N-acetylcysteine to the reaction of (H) with (F).

18. 4-Z 2 -2-Methoxybenzaldehyde (G): wherein Z 2 is selected from the group consisting of Cl, Br, and I; (G) 18. The method of any one of claims 10 to 17, wherein (H) is prepared by reacting (H) with a boronating reagent in the presence of a palladium catalyst and a base.

19. 20. The method of claim 18, wherein the boronating reagent comprises bis(pinacolato)diboron.

20. The palladium catalyst is Pd(dppf)Cl 2 20. The method of claim 18 or 19, comprising:

21. 21. The method of any one of claims 18-20, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 5.0 mol%.

22. 22. The method of any one of claims 18 to 21, wherein the base comprises KOAc.

23. 23. The method of any one of claims 18 to 22, wherein the reaction of (G) with a boronating reagent is carried out in the presence of a solvent.

24. 24. The method of claim 23, wherein the solvent comprises dimethylformamide (DMF) or toluene.

25. 25. The method of any one of claims 18 to 24, wherein the reaction of (G) with a boronating reagent is carried out at a temperature of about 80°C to about 90°C.

26. Purification of (H) (a) adding N-acetylcysteine to the reaction of (G) with a boronating reagent; and (b) adding activated carbon to the reaction of (G) with a boronating reagent.

26. The method of any one of claims 18 to 25, comprising at least one of:

27. Purification of (H) (a) providing crude (H) in a solvent comprising 2-propanol to provide a dilute crude solution of (H); the diluted crude solution of (H) has a concentration of about 390 g / L to about 430 g / L; (b) at least partially evaporating the diluted crude solution of (H) to obtain a concentrated crude solution of (H), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (H) to a temperature of about 50° C. and optionally maintaining that temperature for about 1.5 hours; (c) cooling the concentrated crude (H) solution to a temperature of about 6° C. to obtain a purified (H) slurry, wherein the cooling step is optionally carried out for about 3 hours; and (d) filtering the refined (H) slurry to obtain (H).

27. The method of any one of claims 18 to 26, comprising:

28. 6-(3-Z 1 -2-chlorophenyl)-2-methoxynicotinaldehyde (D): wherein Z 1 is selected from the group consisting of Br and I; (D) and 2,3-dichloro-4-(B(OR 2a )(OR 2b ))-Pyridine (E): in the presence of a palladium catalyst and a base to prepare (F), In the formula, each R 2a and R 2b However, each independently C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; or R 2a and R 2b together with the atoms to which they are bonded, C 2 ~C 3 may form a heterocycloalkyl, 18. The method of any one of claims 10 to 17.

29. R 2a and R 2b and each independently is H.

30. The palladium catalyst is Pd(amphos)Cl 2 30. The method of claim 28 or 29, comprising:

31. 31. The method of any one of claims 28-30, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 5 mol%.

32. The base is K 2 HPO 4 32. The method of any one of claims 28 to 31, comprising:

33. 33. The method of any one of claims 28-32, wherein reacting (D) with (E) comprises adding (E) to a reaction vessel containing (D), wherein (E) is optionally added to the vessel containing (D) over a period of about 3.5 hours.

34. 34. The method of any one of claims 28 to 33, wherein the reaction of (D) with (E) is carried out in the presence of a solvent.

35. 35. The method of claim 34, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF), dimethylacetamide (DMAc), and / or water.

36. 36. The method of any one of claims 28 to 35, wherein the reaction of (D) with (E) is carried out at a temperature of about 65°C to about 70°C.

37. The method of any one of claims 28 to 36, wherein the purification of (F) comprises adding N-acetylcysteine to the reaction of (D) with (E).

38. Purification of (F) (a) providing crude (F) in a solvent comprising 2-propanol to provide a dilute crude solution of (F); the diluted crude solution of (F) has a concentration of about 100 g / L to about 150 g / L; (b) at least partially evaporating the diluted crude solution of (F) to obtain a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (F) to a temperature of about 40° C. to about 55° C. and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (F) solution to a temperature of about 20° C. to about 25° C. to obtain a crude (F) slurry, wherein the cooling step is optionally carried out over a period of about 3 hours; and (d) filtering the crude (F) slurry to obtain (F), wherein the filtering step optionally further comprises washing with a solvent comprising 2-propanol.

38. The method of any one of claims 28 to 37, comprising:

39. 6-(2-chloro-3-(B(OR 3a )(OR 3b ))Phenyl)-2-methoxynicotinaldehyde (D'): and 2,3-dichloro-4-Z 1 -pyridine (E'): wherein Z 1 is selected from the group consisting of Br and I, (E') in the presence of a palladium catalyst and a base to prepare (F), In the formula, each R 3a and R 3b However, each independently C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; or R 3a and R 3b together with the atoms to which they are bonded, C 2 ~C 3 may form a heterocycloalkyl, 18. The method of any one of claims 10 to 17.

40. 40. The method of claim 39, wherein (D') is 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde.

41. The palladium catalyst is Pd(dppf)Cl 2 41. The method of claim 39 or 40, comprising:

42. 42. The method of any one of claims 39-41, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 5 mol%.

43. The base is K 2 CO 3 43. The method of any one of claims 39 to 42, comprising:

44. 44. The method of any one of claims 39 to 43, wherein the reaction of (D') with (E') is carried out in the presence of a solvent.

45. 45. The method of claim 44, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and water.

46. 46. The method of any one of claims 39 to 45, wherein the reaction of (D') with (E') is carried out at a temperature of about 55°C.

47. The method of any one of claims 39 to 46, wherein the purification of (F) comprises adding N-acetylcysteine to the reaction of (D') with (E').

48. Purification of (F) (a) providing crude (F) in 2-propanol to provide a dilute crude solution of (F), the diluted crude solution of (F) has a concentration of about 100 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (F) to obtain a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (F) to a temperature of about 50°C to about 55°C and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated crude (F) solution to a temperature of about 20° C. to about 25° C. to obtain a purified (F) slurry; and (d) filtering the refined (F) slurry to obtain (F).

48. The method of any one of claims 39 to 47, comprising:

49. (D)： wherein Z 1 is selected from the group consisting of Br and I; (D) 49. The method of any one of claims 39 to 48, wherein (D') is prepared by reacting (D') with a boronating reagent in the presence of a palladium catalyst and a base.

50. 50. The method of claim 49, wherein the boronating reagent comprises bis(pinacolato)diboron.

51. The palladium catalyst is Pd(dppf)Cl 2 51. The method of claim 49 or 50, comprising:

52. 52. The method of any one of claims 49-51, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 7 mol%.

53. 53. The method of any one of claims 49 to 52, wherein the base comprises KOAc.

54. 54. The method of any one of claims 49 to 53, wherein the reaction of (D) with the boronating reagent is carried out in the presence of a solvent.

55. 55. The method of claim 54, wherein the solvent comprises dimethylformamide (DMF) and / or toluene.

56. 56. The method of any one of claims 49-55, wherein the reaction of (D) with the boronating reagent is carried out at a temperature of about 90°C to about 100°C.

57. Purification of (D') (a) adding N-acetylcysteine to the reaction of (D) with a boronating reagent; and (b) adding activated carbon to the reaction of (D) with a boronating reagent.

57. The method of any one of claims 49 to 56, comprising at least one of:

58. Purification of (D') (a) providing crude (D') in a solvent comprising 2-propanol to provide a crude solution of (D'); the crude solution of (D') has a concentration of about 140 g / L to about 180 g / L; (c) cooling the crude solution of (D') to a temperature of about 0°C to about 5°C to obtain a refined (D') slurry; and (d) filtering the refined (D') slurry to obtain (D').

58. The method of any one of claims 49 to 57, comprising:

59. 1-(B(OR 4a )(OR 4b ))-2-chloro-3-Z 1 -Benzene (B): And, 6-Z 2 -2-Methoxynicotinaldehyde (C): in the presence of a palladium catalyst and a base to prepare (D), In the formula, Z 1 is selected from the group consisting of Br and I; In the formula, Z 2 is selected from the group consisting of Cl, Br, and I; In the formula, each R 4a and R 4b However, each independently C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; or R 4a and R 4b together with the atoms to which they are bonded, C 2 ~C 3 may form a heterocycloalkyl, 59. The method of any one of claims 28 to 38 and 49 to 58.

60. 60. The method of claim 59, wherein (B) is 2-(3-bromo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

61. The palladium catalyst is Pd(PPh 3 ) 4 61. The method of claim 59 or 60, comprising:

62. 62. The method of any one of claims 59-61, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 5 mol%.

63. The base is K 2 CO 3 63. The method of any one of claims 59 to 62, comprising:

64. 64. The method of any one of claims 59 to 63, wherein the reaction of (B) with (C) is carried out in the presence of a solvent.

65. 65. The method of any of claims 64, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

66. 66. The method of any one of claims 59-65, wherein the reacting of (B) with (C) is carried out at a temperature of from about 50°C to about 60°C.

67. The method of any one of claims 59 to 66, wherein purifying (D) comprises adding N-acetylcysteine to the reaction of (B) and (C).

68. (D) Purification of (a) providing crude (D) in a solvent comprising 2-propanol to provide a diluted crude solution of (D); the diluted crude solution of (D) has a concentration of about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to obtain a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (D) to a temperature of about 50°C to about 55°C and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated (D) crude solution to a temperature of about 20° C. to about 25° C. to obtain a purified (D) slurry; and (d) filtering the refined (D) slurry to obtain (D).

68. The method of any one of claims 59 to 67, comprising:

69. (a) To form an arylmagnesium intermediate, 1-Z 1 -2-chloro-3-Z 1 -Benzene (A): wherein Z 1 is independently selected at each occurrence from the group consisting of Br and I; with an organomagnesium halide; and (b) reacting the aryl magnesium intermediate with a borate The method of any one of claims 59 to 68, wherein (B) is prepared by

70. Borate is: and In the formula, each R 5a , R 5b , and R 5c However, each independently C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; or R 5a , R 5b , and R 5c Any two selected from the group consisting of, together with the atoms to which they are attached, are C 2 ~C 3 may form a heterocycloalkyl, 70. The method of claim 69.

71. 71. The method of claim 69 or 70, wherein the borate comprises 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

72. 72. The method of any one of claims 69-71, wherein the organomagnesium halide comprises i-PrMgCl, wherein the i-PrMgCl is a solution comprising i-PrMgCl optionally complexed with LiCl (i.e., an i-PrMgCl.LiCl solution).

73. 73. The method of any one of claims 69-72, wherein the reaction of (A) with the organomagnesium halide is carried out in a solvent.

74. 74. The method of claim 73, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF).

75. 75. The method of any one of claims 69-74, wherein the reaction of (A) with the organomagnesium halide is carried out at a temperature of about -25°C to about -15°C.

76. 76. The method of any one of claims 69-75, wherein the reaction of the arylmagnesium intermediate with the borate is carried out at a temperature of about -18°C to about -15°C, and the reaction is subsequently optionally warmed to a temperature of about 2°C.

77. (a) To form an arylmagnesium intermediate, 1-Z 1 -2-chloro-3-Z 1 -Benzene (A): wherein Z 1 is independently selected at each occurrence from the group consisting of Br and I; and providing an organomagnesium halide; (b) reacting the arylmagnesium intermediate with a borate to provide a boronic ester intermediate; and (c) a boronic ester intermediate; 6-Z 2 -2-Methoxynicotinaldehyde (C): wherein Z 2 is selected from the group consisting of Cl, Br, and I; (C) in the presence of a palladium catalyst and a base. The method of any one of claims 28 to 38 and 49 to 58, wherein (D) is prepared by

78. 78. The method of claim 77, wherein the organomagnesium halide comprises i-PrMgCl, wherein the i-PrMgCl is a solution comprising i-PrMgCl optionally complexed with LiCl (i.e., an i-PrMgCl.LiCl solution).

79. 79. The method of any one of claims 77 and 78, wherein the reaction of (A) with the organomagnesium halide is carried out in a solvent.

80. 80. The method of claim 79, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF).

81. 81. The method of any one of claims 77-80, wherein the reaction of (A) with the organomagnesium halide is carried out at a temperature of about -25°C to about -15°C.

82. 82. The method of any one of claims 77-81, wherein the reaction of the arylmagnesium intermediate with the borate is carried out at a temperature of about -18°C to about -15°C, and the reaction is subsequently optionally warmed to a temperature of about 2°C.

83. Borate is: and In the formula, each R 5a , R 5b , and R 5c However, each independently C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; or R 5a , R 5b , and R 5c Any two selected from the group consisting of, together with the atoms to which they are attached, are C 2 ~C 3 may form a heterocycloalkyl, 83. The method of any one of claims 77 to 82.

84. 84. The method of any one of claims 77-83, wherein the borate comprises 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

85. The palladium catalyst is Pd(PPh 3 ) 4 85. The method of any one of claims 77 to 84, comprising:

86. 86. The method of any one of claims 77-85, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 5 mol%.

87. The base is K 2 CO 3 87. The method of any one of claims 77 to 86, comprising:

88. 88. The process of any one of claims 77-87, wherein the reaction of the boronic ester intermediate with (C) is carried out in the presence of a solvent.

89. 89. The method of any of claims 88, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

90. 90. The process of any one of claims 77-89, wherein the reaction of the boronic ester intermediate with (C) is carried out at a temperature of from about 50°C to about 60°C.

91. 91. The method of any one of claims 77-90, wherein purifying (D) comprises adding N-acetylcysteine to the reaction of (C) with the boronic ester intermediate.

92. (D) Purification of the compound (D) (a) providing crude (D) in a solvent comprising 2-propanol to provide a diluted crude solution of (D); the diluted crude solution of (D) has a concentration of about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to obtain a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (D) to a temperature of about 50°C to about 55°C and optionally further maintaining that temperature for about 1 hour; (c) cooling the concentrated (D) crude solution to a temperature of about 20° C. to about 25° C. to obtain a purified (D) slurry; and (d) filtering the refined (D) slurry to obtain (D).

92. The method of any one of claims 77 to 91, comprising:

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