A substituted 1-aryl-1apos, a substituted 1-aryl-1apos; -a heteroaryl compound and a substituted 1, 1apos; synthesis of bis-heteroaryl compounds and analogs thereof

Abstract

The present disclosure includes synthetic methods for the preparation of certain substituted 1-aryl-1 '-heteroaryl and 1, 1'-bisheteroaryl compounds that are useful in the treatment, amelioration and / or prevention of Hepatitis B Virus (HBV) infection in a patient, in particular, the compound 2-((6-(2-chloro-3-(3-chloro-2-(3-methoxy-4-((7-oxo-2, 3, 4, 5, 6, 6, 6-tetramethyl-3-oxo-2, 3, 4, 5-tetramethyl-3-oxo-2, 3, 4-tetramethyl-3-oxo-2, 3, 4-tetramethyl-3-oxo-2, 3, 4-tetramethyl-3-oxo-2, the invention relates to 2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl) pyridine-4-yl) phenyl)-2-methoxypyridine-3-yl) methyl)-2, 6-diazaspiro [3.4] octyl-7-ketone, and a preparation method of the 2, 6-diazaspiro [3.4] octane-2-yl) methyl) phenyl)-2, 6-diazaspiro [3.4] octyl-7-ketone. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 USC §119(e) to U.S. Provisional Patent Application No. 63,398,452, filed on August 16, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Hepatitis B virus (HBV) is a non-cytopathic hepadnavirus belonging to the family Hepadnaviridae. HBV infection is one of the most prevalent diseases in the world and is listed as a high priority area of ​​interest by the National Institute of Allergy and Infectious Diseases (NIAID). Although most people resolve the infection after acute symptoms, approximately 30% of cases become chronic. An estimated 350-400 million people worldwide have chronic hepatitis B, resulting in 500,000-1 million deaths each year, primarily due to the development of hepatocellular carcinoma, cirrhosis, and / or other complications.

[0004] There are a limited number of drugs currently approved for the treatment of chronic hepatitis B, including two preparations that inhibit alpha-interferon (standard and pegylated) and five nucleoside / nucleotide analogs that inhibit HBV DNA polymerase (lamivudine, adefovir, entecavir, telbivudine, and tenofovir). Currently, the options for first-line treatment are entecavir, tenofovir, and / or peginterferon alpha-2a. However, peginterferon alpha-2a achieves the desired serological milestone in only one-third of treated patients and is often associated with severe side effects. Entecavir and tenofovir are effective HBV inhibitors but require long-term or potentially lifelong administration to continuously suppress HBV replication and may ultimately fail due to the emergence of resistant virus. Therefore, there is an urgent need to introduce new, safe, and effective therapies for chronic hepatitis B.

[0005] Hepatitis D virus (HDV) is a small, circular, enveloped RNA virus that can reproduce only in the presence of HBV. Specifically, HDV requires the HBV surface antigen proteins to reproduce itself. Infection with HBV and HDV results in more severe complications than infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infection and rapid progression to cirrhosis, and an increased chance of developing liver cancer in chronic infection. When combined with HBV, hepatitis D has the highest mortality rate of all hepatitis infections. HDV is transmitted in a similar manner to HBV. Infection is primarily limited to people who are at high risk for HBV infection, particularly those who inject drugs and those receiving clotting factor concentrates.

[0006] Currently, there are no effective antiviral therapies available for the treatment of acute or chronic hepatitis D. Interferon-α given weekly for 12 to 18 months is the only licensed treatment for hepatitis D. Response to this therapy is limited, as serum HDV RNA is undetectable in only about a quarter of patients 6 months after treatment.

[0007] Therefore, there is a need in the art for novel compounds and / or compositions that can be used to treat, improve and / or prevent HBV infection in a subject. In certain embodiments, the compounds can be used in HBV infected patients, patients at risk of HBV infection and / or patients with drug-resistant HBV infection. In other embodiments, the HBV infected subject is further infected with HDV. There is also a need in the art to determine a scalable synthetic scheme that allows the preparation of large-scale batches of such compounds. The present disclosure addresses this need. Summary of the invention

[0008] The present disclosure provides a method 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) or a salt or solvate thereof:

[0009] DETAILED DESCRIPTION

[0010] The present disclosure relates in certain aspects to the discovery of scalable synthetic routes that allow for the reproducible, multi-procedural synthesis of certain substituted 1-aryl-1′-heteroaryl and substituted 1,1′-biheteroaryl compounds that are useful for treating, ameliorating and / or preventing hepatitis B virus (HBV) and / or hepatitis D virus (HDV) infection and related conditions in a subject.

[0011] The disclosures of PCT International Patent Application No. PCT / IB2022 / 052782 filed on March 25, 2022, U.S. Provisional Application No. 63 / 167,440 filed on March 29, 2021, and U.S. Provisional Application No. 63 / 291,666 filed on December 20, 2021 are incorporated herein by reference in their entirety.

[0012] definition

[0013] 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 those of ordinary skill in the art to which the present disclosure belongs. Generally, the nomenclature used herein and laboratory procedures in animal pharmacology, pharmaceutical science, separation science, and organic chemistry are well-known and commonly used in the art. It should be understood that the order of steps or the order for performing certain actions is unimportant as long as the present teaching remains operable. Any use of section headings is intended to assist in reading the document and should not be construed as restrictive; information associated with section headings may occur within or outside that particular section. All publications, patents, and patent documents cited in this document are incorporated herein by reference in their entirety, as if they were individually incorporated by reference.

[0014] In the present application, when a description is made that an element or component is included in a list of listed elements or components and / or selected from a list of listed elements or components, it should be understood that the element or component can be any one of the listed elements or components and can be selected from two or more of the listed elements or components.

[0015] In the methods described herein, actions may be performed in any order unless a time or sequence of operations is explicitly stated. In addition, specified actions may be performed simultaneously unless explicit declarative language states that they are performed separately. For example, a claimed X action and a claimed Y action may be performed simultaneously in a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0016] As used herein, the terms "a", "an" or "the" are used to include one or more, unless the context clearly indicates otherwise. The term "or" is used to represent a non-exclusive "or", unless otherwise stated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B".

[0017] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent in the context in which it is used. As used herein, when "about" refers to a measurable value such as an amount, a time duration, etc., it is intended to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are suitable for performing the disclosed methods.

[0018] As used herein, unless otherwise indicated, the term "alkenyl" used alone or in combination with other terms refers to a stable monounsaturated or diunsaturated straight or branched hydrocarbon radical having a specified number of carbon atoms. Examples include ethenyl, propenyl (or allyl), butenyl (crotyl), isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. An example of a functional group representing an alkene is -CH2-CH=CH2.

[0019] As used herein, unless otherwise indicated, the term "alkoxy" used alone or in combination with other terms refers to an alkyl group with a specified number of carbon atoms as defined elsewhere herein, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (or isopropoxy) and higher homologs and isomers, connected to the remainder of the molecule via an oxygen atom, unless otherwise indicated. Specific examples are (C1-C3) alkoxy groups, such as, but not limited to, ethoxy and methoxy.

[0020] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a alkyl radical having the specified number of carbon atoms (i.e., C1-C 10 alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0021] As used herein, unless otherwise indicated, the term "alkynyl" used alone or in combination with other terms refers to a stable straight or branched hydrocarbon group with a carbon-carbon triple bond having a specified number of carbon atoms. Non-limiting examples include ethynyl and propynyl, as well as higher homologues and isomers. The term "propargylic" refers to a group exemplified by -CH2-C≡CH. The term "homopropargylic" refers to a group exemplified by -CH2CH2-C≡CH.

[0022] As used herein, the term "aromatic" refers to a carbon or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, ie, having (4n+2) delocalized π (pi) electrons (where 'n' is an integer).

[0023] As used herein, unless otherwise indicated, the term "aryl", used alone or in combination with other terms, refers to a carbocyclic aromatic system containing one or more rings (usually one, two or three rings), wherein the rings may be linked together in a side chain manner, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracenyl and naphthyl. Aryl also includes, for example, a benzene ring or a naphthalene ring fused to one or more saturated or partially saturated carbocyclic rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl), which may be substituted at one or more carbon atoms of the aromatic ring and / or the saturated or partially saturated ring.

[0024] As used herein, the term "aryl-(C1-C6) alkyl" refers to a functional group in which a 1 to 6 carbon alkylene chain is attached to an aryl group, for example, -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 an aryl group is substituted. A specific example is a substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C6) alkyl" refers to a functional group in which a 1 to 3 carbon alkylene chain is attached to a heteroaryl group, for example, -CH2CH2-pyridyl. A specific example is heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C6) alkyl" refers to a heteroaryl-(C1-C6) alkyl functional group in which a heteroaryl group is substituted. A specific example is substituted heteroaryl -(CH2)-.

[0025] In one aspect, the terms "co-administered" and "co-administration" with respect to a subject refer to the administration of a compound and / or composition of the present disclosure to a subject and a compound and / or composition that may also treat or prevent a disease or disorder contemplated herein. In certain embodiments, the co-administered compounds and / or compositions are administered alone or in any combination as part of a monotherapy approach. The co-administered compounds and / or compositions may be formulated into a variety of solid, gel, and liquid formulations, mixtures of solids and liquids, and solutions in any combination.

[0026] As used herein, unless otherwise indicated, the term "cycloalkyl" by itself or as part of another substituent refers to a cyclic hydrocarbon having a specified number of carbon atoms (i.e., C3-C6 refers to a cyclic group including a cyclic group consisting of 3 to 6 carbon atoms) and includes straight chain, branched or cyclic substituents. Examples of (C3-C6) cycloalkyls 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, cyclooctyl, decahydronaphthyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decyl, decahydronaphthyl, 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.

[0027] As used herein, a "disease" is a condition in a subject's health in which the subject is unable to maintain homeostasis and, if the disease is not ameliorated, the subject's health continues to deteriorate.

[0028] As used herein, a "disorder" in a subject is a health state in which the subject is able to maintain homeostasis, but in which the subject's health state is less favorable than the health state in the absence of the disorder. If left untreated, the disorder does not necessarily lead to a further decline in the subject's health state.

[0029] As used herein, the term "halide" refers to a halogen atom with a negative charge. - ), chloride ion (Cl - ), bromide ion (Br - ) and iodide ion (I - ).

[0030] As used herein, unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0031] As used herein, unless otherwise indicated, the term "heteroalkenyl", by itself or in combination with another term, refers to a stable straight or branched monounsaturated or diunsaturated hydrocarbon radical consisting of the specified number of carbon atoms and one or two heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0032] As used herein, unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl consisting of a specified number of carbon atoms and one or two heteroatoms selected from O, N and S, and wherein the nitrogen atom and the sulfur atom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (one or more) may be located at any position of the heteroalkyl, including between the remainder of the heteroalkyl and the fragment to which it is connected, and connected to the carbon atom at the farthest end in the heteroalkyl. Examples include: -OCH2CH2CH3, -CH2CH2CH2OH, -CH2CH2NHCH3, -CH2SCH2CH3 and -CH2CH2S(=O)CH3. Up to two heteroatoms may be continuous, such as, for example, -CH2NH-OCH3 or -CH2CH2SSCH3.

[0033] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic characteristics. Polycyclic heteroaryl groups may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuranyl.

[0034] As used herein, unless otherwise indicated, the term "heterocycle" or "heterocyclyl" or "heterocyclic" by itself or as part of another substituent refers to an unsubstituted or substituted, stable monocyclic or polycyclic heterocyclic ring system comprising carbon atoms and at least one heteroatom selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Unless otherwise indicated, the heterocyclic ring system may be attached to any heteroatom or carbon atom that provides a stable structure. The heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is a heteroaryl.

[0035] 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, tetrahydrothiophane, 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-dioxepin, and hexamethyleneoxide.

[0036] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiazolyl, and 1,3,4-oxadiazolyl.

[0037] Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), dihydroindolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuranyl (such as, but not limited to, 3-, 4-, 5- The invention also includes benzofuranyl, benzothiophene (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzothiophene), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl and quinolizidinyl.

[0038] The foregoing listing of heterocyclyl and heteroaryl moieties is intended to be representative and not limiting.

[0039] As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful in the present disclosure and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of the compound to a subject.

[0040] As used herein, the term "pharmaceutically acceptable" refers to a relatively nontoxic material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compounds useful in the present disclosure, i.e., the material can be administered to a subject without causing adverse biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0041] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier that participates in carrying or transporting a compound useful in the present disclosure in or to a subject so that it can perform its intended function, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material. Typically, such a construct is 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 compounds useful in the present disclosure) and not harmful to the subject. Some examples of materials that can be used 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, ethylcellulose, 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; polyols, such as glycerol, 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; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, etc., that are compatible with the activity of the compounds useful in the present disclosure and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of compounds useful in the present disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the present 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.

[0042] As used herein, the language "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.

[0043] As used herein, a "pharmaceutically effective amount," "therapeutically effective amount," or "effective amount" of a compound is an amount of the compound sufficient to provide a beneficial effect to a subject to which the compound is administered.

[0044] As used herein, the terms "prevent," "preventing," and "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 when an agent or compound is initially administered. Diseases, conditions, and disorders are used interchangeably herein.

[0045] As used herein, the term "specifically bind" or "specifically binds" means that a first molecule binds preferentially to a second molecule (eg, a specific receptor or enzyme), but does not necessarily bind exclusively to the second molecule.

[0046] As used herein, the terms "subject" and "individual" and "patient" are used interchangeably and may refer to a human or non-human mammal or bird. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline, and murine mammals. In certain embodiments, the subject is a human.

[0047] As used herein, the term "substituted" means that an atom or group of atoms has replaced a hydrogen as a substituent attached to another group.

[0048] As used herein, the term "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl" or "substituted alkynyl" refers to an alkyl, cycloalkyl, alkenyl or alkynyl group as defined elsewhere herein, which is independently selected from halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), 1-methyl-imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, -C(=O)O(C1-C6)alkyl, trifluoromethyl, -C≡N, -C(= The alkyl group may be substituted with one, two or three substituents of -C(=O)NH2, -C(=O)NH(C1-C6)alkyl, -C(=O)N((C1-C6)alkyl)2, -SO2NH2, -SO2NH(C1-C6alkyl), -SO2N(C1-C6alkyl)2, -C(=NH)NH2 and -NO2, and in some embodiments contains one or two substituents independently selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2 and -C(=O)OH, and in some embodiments independently selected from halogen, alkoxy and -OH. Examples of substituted alkyl groups include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.

[0049] For aryl, aryl-(C1-C3) alkyl and heterocyclyl, the term "substituted" applied to the rings of these groups refers to any substitution level where such substitution is allowed, i.e., mono, di, tri, tetra or penta substitution. The substituents are independently selected, and the substitutions can be in any chemically accessible position. In certain embodiments, the number of substituents varies between 1 and 4. In other embodiments, the number of substituents varies between 1 and 3. In another embodiment, the number of substituents varies between 1 and 2. In yet other embodiments, the substituents are independently selected from C1-C6 alkyl, -OH, C1-C6 alkoxy, halogen, amino, acetamido and nitro. As used herein, when the substituent is an alkyl or alkoxy group, the carbon chain can be branched, straight or cyclic.

[0050] Unless otherwise indicated, when two substituents are taken together to form a ring having the indicated number of ring atoms (e.g., R 2 and R 3 The ring may be saturated or partially saturated and may be optionally substituted.

[0051] Whenever any of the terms or their prefix roots appear in the name of a substituent, the name should be interpreted as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or any of their prefix roots appear in the name of a substituent (e.g., arylalkyl, alkylamino), the name should be interpreted as including those limitations given elsewhere herein for "alkyl" and "aryl", respectively.

[0052] In certain embodiments, substituents of compounds are disclosed in groups or ranges. It is specifically intended that the description includes each and every individual subcombination of the members of these groups and ranges. For example, the term "C 1-6 The term “alkyl” is expressly intended to disclose individually 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.

[0053] As used herein, the terms "treat," "treating," and "treatment" refer to reducing the frequency or severity of symptoms experienced by a subject of a disease or disorder by administering an agent or compound to the subject.

[0054] Certain abbreviations used in this article 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.

[0055] Range: Throughout the disclosure, various aspects of the disclosure may be presented in range format. It should be understood that the description of the range format is only for convenience and brevity, and should not be construed as a rigid limitation on the scope of the disclosure. Therefore, the description of the range should be considered to have clearly disclosed all possible subranges and each numerical value within the range. For example, a description of a range such as from 1 to 6 should be considered to have clearly disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as a single numerical value within the range, for example, 1, 2, 2.7, 3, 4, 5, 5.3 and 6. For example, a range of "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 sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the statement "about X to Y" has the same meaning as "about X to about Y." Likewise, unless otherwise indicated, the statement "about X, Y, or Z" has the same meaning as "about X, about Y, or about Z." This applies regardless of the breadth of the range.

[0056] synthesis

[0057] The present disclosure further provides methods for preparing certain compounds of the present disclosure. The compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art, according to the procedures outlined herein. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or standard textbooks in the field.

[0058] It should be understood that, unless otherwise stated, where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by those skilled in the art through 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 altered for the purpose of optimizing the formation of the compounds described herein.

[0059] The processes described herein can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), 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).

[0060] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of suitable protecting groups may be easily determined by those skilled in the art. The chemical properties of protecting groups may be found in, for example, Greene et al., Protective Groups in Organic Synthesis, 2nd edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0061] The reactions or methods described herein can be carried out in a suitable solvent that can be easily selected by a technician in the field of organic synthesis. Suitable solvents are generally substantially non-reactive with reactants, intermediates and / or products at a temperature at which the reaction is carried out, i.e., at a temperature within the range of the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected.

[0062] The present disclosure includes methods 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 (also referred to as Compound (K)) or a salt, solvate, prodrug, isotopically labeled derivative and / or tautomer thereof, and any mixture thereof:

[0063]

[0064] In certain embodiments, the compound of formula (K) or its salt, solvate, prodrug, isotopically labeled derivative and / or tautomer can be prepared according to the non-limiting synthetic schemes outlined in Schemes 1-3, wherein Z 1 Each occurrence of is independently selected from Br and I, wherein Z 2 is selected from Cl, Br or I, and wherein R is selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, wherein any two R groups can be combined with the atoms to which they are bonded to form a C3-C4 heterocycloalkyl.

[0065] For example, commercially available 1-Z can be reacted by reacting (A) with a suitable organic magnesium halide, including but not limited to iPrMg·LiCl (i.e., Turbo-Grignard) at a suitable temperature (including but not limited to about -25°C to about -10°C) in the presence of a suitable solvent (including but not limited to 2-methyltetrahydrofuran (MeTHF)). 1 -2-Chloro-3-Z 1 -benzene (A) is converted to a boronate ester or boronic acid (B) to provide an organomagnesium intermediate, which is reacted with a boronate ester (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 about -10°C). In certain embodiments, for example, the boronate ester (B) can be converted to compound (D) without purification using the in situ generated compound (B) solution described herein. In other embodiments, compound (B) can be isolated and / or purified.

[0066] Compound (D) can be prepared by reacting compound (B) and heteroaryl halide (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) under suitable reaction conditions (including but not limited to a temperature of about 50°C to about 60°C). Therefore, in certain embodiments, compound (D) can be prepared from compound (A) without the need to purify the intermediate.

[0067] Compound (F) can be prepared by reacting an aromatic halide (D) and a boric ester or a boronic acid (E) in the presence of a suitable palladium catalyst (including but not limited to Pd(amphos)Cl2 (i.e., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)), a suitable base (including but not limited to K2HPO4) and a suitable solvent (including but not limited to a mixture of MeTHF, water and dimethylacetamide (DMAc)) under suitable conditions (including but not limited to a temperature of about 65°C to about 70°C).

[0068]

[0069]

[0070] In certain embodiments, compound (F) can be prepared by an alternative sequence as provided in Scheme 2.

[0071] Compound (D′) can be prepared by reacting compound (D) and a suitable borylation agent (including but not limited to bis(pinacolato)diboron (i.e., B2Pin2)) 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) under suitable reaction conditions (including but not limited to a temperature of about 90°C to about 100°C).

[0072] Compound (F) can be prepared by reacting (D') and (E') 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) under suitable reaction conditions (including but not limited to a temperature of about 55°C).

[0073]

[0074] Compound (H) can be prepared by reacting compound (G) and a suitable borylation agent (including but not limited to bis(pinacolato)diboron (i.e., B2Pin2)) 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) under suitable reaction conditions (including but not limited to a temperature of about 80°C to about 90°C).

[0075] Compound (I) can be prepared by reacting compound (H) and compound (F) 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) under suitable reaction conditions (including but not limited to a temperature of about 65°C to about 75°C).

[0076] Compound (K) can be prepared by reacting compound (I) and 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).

[0077]

[0078] It will be appreciated that the reactions or methods 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 described in Schemes 1-3.

[0079] In one aspect, the present disclosure provides a method 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) or a salt or solvate thereof:

[0080]

[0081] The method comprises making 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (I):

[0082]

[0083] and 2,6-diazaspiro[3.4]octan-7-one (J):

[0084]

[0085] The reaction is carried out in the presence of a reducing agent and a base to generate a first reaction system including (K).

[0086] In certain embodiments, the reducing agent comprises NaBH(OAc)3.

[0087] In certain embodiments, the base comprises NaOMe. In certain embodiments, the base comprises i-PrNEt2.

[0088] 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 methanesulfonate. In certain embodiments, (J) is 2,6-diazaspiro[3.4]octan-7-one toluenesulfonate.

[0089] In certain embodiments, the reaction of (I) and (J) occurs in the presence of a solvent.

[0090] 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 one of DCM, MeOH, MeTHF, THF, DMF and DMAc.

[0091] In certain embodiments, the purification of (K) comprises:

[0092] (a) adding water to a first reaction system including (K) to generate a biphasic solution;

[0093] (b) separating the biphasic solution to provide a first aqueous phase and a first organic phase;

[0094] (c) adding an organic solvent to the first aqueous solution to provide a second biphasic solution;

[0095] (d) basifying the second biphasic solution to a pH of 8-11 to provide an alkalized biphasic solution; and

[0096] (e) separating the basified biphasic solution to provide a second aqueous phase and a second organic phase comprising (K).

[0097] In certain embodiments, the purification of (K) comprises:

[0098] (a) adding water to a first reaction system including (K) to generate a biphasic solution;

[0099] (b) separating the biphasic solution to provide a first aqueous phase and a first organic phase;

[0100] (c) adding an organic solvent to the first aqueous solution to provide a second biphasic solution;

[0101] (d) adjusting the second biphasic solution to a pH of 8-11 to provide an alkaline biphasic solution;

[0102] (e) separating the basified biphasic solution to provide a second aqueous phase and a second organic phase;

[0103] (f) combining the first organic phase and the second organic phase to provide a third organic phase;

[0104] (g) adding water to the third organic phase to provide a third biphasic solution; and

[0105] (H) separating the third biphasic solution to provide a third aqueous phase and a final organic phase comprising (K).

[0106] In certain embodiments, the biphasic solution is stirred. In certain embodiments, the biphasic solution is stirred for a period of about 20 min.

[0107] In certain embodiments, the organic solvent comprises dichloromethane.

[0108] In certain embodiments, alkalization comprises adding a base selected from the group consisting of NaOH, KOH, LiOH, NaHCO3, K2CO3, CaCO3, Na2CO3, and K3PO4. In certain embodiments, NaOH is 3N NaOH.

[0109] In certain embodiments, the purification of (K) comprises:

[0110] (a) providing a crude product (K) in a solvent comprising 2-propanol to obtain a dilute crude solution of (K),

[0111] wherein the concentration of the diluted crude solution of (K) is from about 110 g / L to about 140 g / L;

[0112] (b) at least partially evaporating the dilute crude solution of (K) to provide a concentrated crude solution of (K),

[0113] wherein the concentration of the concentrated crude solution of (K) is from about 220 g / L to about 280 g / L; and

[0114] (c) cooling the concentrated crude solution of (K) to a temperature of about 20° C. to provide a purified slurry of (K); and

[0115] (d) filtering the purified (K) slurry to provide (K).

[0116] In certain embodiments, the purification of (K) comprises:

[0117] (a) providing a crude product (K) in a solvent comprising 2-propanol to obtain a dilute crude solution of (K),

[0118] wherein the concentration of the diluted crude solution of (K) is from about 110 g / L to about 140 g / L;

[0119] (b) at least partially evaporating the dilute crude solution of (K) to provide a concentrated crude solution of (K),

[0120] wherein the concentration of the concentrated crude solution of (K) is from about 220 g / L to about 280 g / L; and

[0121] wherein the at least partial evaporation optionally comprises heating the diluted crude solution of (K) to a temperature of about 40°C to 50°C, optionally for a period of about 2 hours;

[0122] (c) adding seed crystals of (K) in an amount of about 0.1% to 1.0% w / w of the crude product (K) to provide a crude product (K) slurry;

[0123] (d) heating the crude product (K) slurry at a temperature of about 50° C. to provide a heated crude product (K) slurry;

[0124] (e) cooling the heated crude product (K) slurry to a temperature of about 20° C. to provide a cooled crude product (K) slurry,

[0125] wherein cooling of the heated crude product (K) slurry occurs over a period of about 10 hours;

[0126] (f) stirring the cooled crude (K) slurry at a temperature of about 20° C. for a period of about 4 hours to provide a purified slurry of (K),

[0127] wherein stirring of the cooled crude product (K) occurs over a period of about 4 h;

[0128] (g) filtering the purified (K) slurry to provide (K).

[0129] In certain embodiments, the purification of (K) comprises:

[0130] (a) providing a crude product (K) in a solvent comprising MeOH to obtain a crude solution of (K),

[0131] wherein the concentration of the crude solution of (K) is from about 200 g / L to about 300 g / L;

[0132] (b) heating the crude solution of (K) to a temperature of about 50° C. to provide a hot crude solution of (K);

[0133] (c) cooling the hot crude solution of (K) to a temperature of about 20° C. to provide a cooled slurry of (K);

[0134] (d) adding a solvent including methyl tert-butyl ether (MTBE) to the cooled (K) slurry to provide a purified (K) slurry; and

[0135] (e) filtering the purified (K) slurry to provide (K).

[0136] In certain embodiments, the purification of (K) comprises:

[0137] (a) adding an aqueous NaCl solution to a first reaction system including (K) to generate a biphasic solution;

[0138] (b) separating the biphasic solution to provide a first aqueous phase and a first organic phase;

[0139] (c) washing the first aqueous phase one or more times with one or more organic solvents to provide a washed aqueous phase,

[0140] wherein the one or more organic solvents optionally include MeTHF and / or MEK;

[0141] (d) adding an organic solvent to the washed aqueous phase to provide a second biphasic solution,

[0142] wherein the organic solvent optionally comprises MEK;

[0143] (e) basifying the second biphasic solution to a pH of about 9.5 to about 10.5 to provide an alkalized second biphasic solution,

[0144] wherein the second biphasic solution is optionally alkalized with an aqueous solution,

[0145] wherein the aqueous solution optionally comprises at least one selected from the group consisting of Na2CO3, NaOH, KOH, LiOH, K2CO3, CaCO3, Na2CO3 and K3PO4;

[0146] (f) separating the alkalized second biphasic solution to provide a second aqueous phase and a second organic phase,

[0147] wherein the second aqueous phase is optionally washed with an organic solvent to provide a third organic phase which is combined with the second organic phase,

[0148] wherein the second organic phase is optionally washed with an aqueous NaCl solution,

[0149] wherein the second organic phase is optionally filtered through diatomaceous earth;

[0150] (g) at least partially evaporating the second organic phase and adding MeOH one or more times to obtain a solution of crude product (K) having a concentration of about 200 g / L to about 300 g / L;

[0151] (h) heating the crude solution of (K) to a temperature of about 50° C. to provide a hot crude solution of (K),

[0152] wherein the hot crude solution of (K) is optionally stirred for a period of about 3 h,

[0153] wherein seed crystals of (K) are optionally added to the hot crude solution of (K);

[0154] (i) cooling the hot crude solution of (K) to a temperature of about 20° C. to provide a cooled crude solution of (K),

[0155] wherein cooling occurs over a period of about 4 h;

[0156] (j) adding methyl tert-butyl ether (MTBE) to the cooled solution of (K) to provide a crude slurry of (K); and

[0157] (k) filtering the crude slurry of (K) to provide (K),

[0158] wherein (K) is optionally washed with a mixture comprising MeOH / MTBE, and

[0159] wherein (K) is optionally vacuum dried, optionally for a period of not less than 24 h.

[0160] In certain embodiments, by making 2-methoxy-4-(B(OR 1a )(OR 1b ))-Benzaldehyde(H):

[0161]

[0162] and 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (F):

[0163]

[0164] Reaction in the presence of a palladium catalyst and a base to prepare (I);

[0165] Each R 1a and R 1b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0166] or R 1a and R 1b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0167] In certain embodiments, the palladium catalyst comprises Pd(PPh3)4.

[0168] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0169] In certain embodiments, the base comprises K2CO3.

[0170] In certain embodiments, the reaction of (H) and (F) occurs in the presence of a solvent.

[0171] In certain embodiments, the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF), dimethylformamide (DMF), and water.

[0172] In certain embodiments, the reaction of (H) and (F) occurs at a temperature of about 65°C to about 70°C.

[0173] In certain embodiments, the purification of (I) comprises adding N-acetyl cysteine ​​to the reaction of (H) and (F). In certain embodiments, the N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0174] In certain embodiments, by using 4-Z 2 -2-Methoxybenzaldehyde (G):

[0175]

[0176] Where Z 2 is selected from Cl, Br and I;

[0177] The compound (H) can be prepared by reacting with a borylation agent in the presence of a palladium catalyst and a base.

[0178] 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.

[0179] In certain embodiments, the borylation agent is bis(pinacolato)diboron.

[0180] In certain embodiments, the palladium catalyst comprises Pd(dppf)Cl2.

[0181] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5.0 mol %.

[0182] In certain embodiments, the base comprises KOAc.

[0183] In certain embodiments, the reaction of (G) and the borylation agent occurs in the presence of a solvent.

[0184] In certain embodiments, the solvent comprises dimethylformamide (DMF) and / or toluene.

[0185] In certain embodiments, the reaction of (G) and the borylation agent occurs at a temperature of about 80°C to about 90°C.

[0186] In certain embodiments, the purification of (H) comprises at least one of the following:

[0187] (a) adding N-acetyl cysteine ​​to the reaction of (G) and a borylation reagent; and

[0188] (b) Adding activated carbon to the reaction of (G) and a boronating agent.

[0189] In certain embodiments, N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0190] In certain embodiments, purification of (H) comprises:

[0191] (a) providing crude (H) in a solvent comprising 2-propanol to obtain a dilute crude solution of (H),

[0192] wherein the concentration of the diluted crude solution of (H) is from about 390 g / L to about 430 g / L;

[0193] (b) at least partially evaporating the dilute crude solution of (H) to provide a concentrated crude solution of (H), wherein the at least partial evaporation optionally comprises heating the dilute crude solution of (H) to a temperature of about 50° C., and further optionally maintaining the temperature for a period of about 1.5 h;

[0194] (c) cooling the concentrated crude solution of (H) to a temperature of about 6° C. to provide a purified (H) slurry, wherein cooling optionally occurs over a period of about 3 hours; and

[0195] (d) Filtering the purified (H) slurry to provide (H).

[0196] In certain embodiments, by making 6-(3-Z 1 -2-chlorophenyl)-2-methoxynicotinaldehyde (D):

[0197]

[0198] Where Z 1 Selected from Br and I;

[0199] and 2,3-dichloro-4-(B(OR 2a )(OR 2b ))-Pyridine (E):

[0200]

[0201] Reaction in the presence of a palladium catalyst and a base to prepare (F);

[0202] Each R 2a and R 2b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0203] or R 2a and R 2b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0204] In certain embodiments, (D) is 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. In certain embodiments, (D) is 6-(3-iodo-2-chlorophenyl)-2-methoxynicotinaldehyde.

[0205] In certain embodiments, R 2a is H. In certain embodiments, R 2b It's H.

[0206] In certain embodiments, the palladium catalyst comprises Pd(amphos)Cl2.

[0207] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0208] In certain embodiments, the base comprises K2HPO4.

[0209] In certain embodiments, reacting (D) and (E) comprises adding (E) to a reaction vessel comprising (D), wherein (E) is optionally added to the vessel comprising (D) over a period of about 3.5 h.

[0210] In certain embodiments, the reaction of (D) and (E) occurs in the presence of a solvent.

[0211] In certain embodiments, the solvent includes at least one of 2-methyltetrahydrofuran (MeTHF), dimethylacetamide (DMAc), and / or water.

[0212] In certain embodiments, the reaction of (D) and (E) occurs at a temperature of about 65°C to about 70°C.

[0213] In certain embodiments, the purification of (F) comprises adding N-acetyl cysteine ​​to the reaction of (D) and (E). In certain embodiments, the N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0214] In certain embodiments, the purification of (F) comprises:

[0215] (a) providing a crude product (F) in a solvent comprising 2-propanol to obtain a dilute crude solution of (F),

[0216] wherein the concentration of the diluted crude solution of (F) is from about 100 g / L to about 150 g / L;

[0217] (b) at least partially evaporating the dilute crude solution of (F) to provide a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the dilute crude solution of (F) to a temperature of about 40° C. to about 55° C., and further optionally maintaining the temperature for a period of about 1 hour;

[0218] (c) cooling the concentrated crude solution of (F) to a temperature of about 20 to about 25° C. to provide a crude (F) slurry, wherein cooling optionally occurs over a period of about 3 hours; and

[0219] (d) filtering the crude (F) slurry to provide (F), wherein the filtering optionally further comprises washing with 2-propanol.

[0220] In certain embodiments, the purification of (F) further comprises:

[0221] (e) providing a solution of (F) obtained by performing steps (a)-(d) described elsewhere herein in a solvent comprising 2-propanol to provide a diluted first crop solution,

[0222] wherein the concentration of the diluted first harvest solution of (F) is about 100 g / L to about 150 g / L, and

[0223] wherein the diluted first harvest solution is obtained by dissolving (F) obtained by performing steps (a) to (d) described elsewhere herein (i.e., the first harvest (F)) in 2-methyltetrahydrofuran and performing solvent exchange with 2-propanol;

[0224] (f) at least partially evaporating the diluted first harvest solution of (F) to provide a concentrated first harvest solution of (F), wherein the at least partial evaporation optionally comprises heating the diluted first harvest solution of (F) to a temperature of about 40° C. to about 55° C., wherein the heating is optionally maintained for a period of about 1 hour;

[0225] (g) cooling the concentrated first harvest solution of (F) to obtain a first harvest (F) slurry, wherein cooling optionally comprises reducing the temperature to a temperature of about 20° C. to about 25° C., wherein cooling optionally occurs for a period of about 1 hour; and

[0226] (h) filtering the first harvest (F) slurry to provide a second harvest (F) (ie, purified (F) or (F)), wherein the filtering optionally further comprises washing with a solvent comprising 2-propanol.

[0227] In certain embodiments, by making 6-(2-chloro-3-(B(OR 3a )(OR 3b ))phenyl)-2-methoxynicotinaldehyde (D′):

[0228]

[0229] and 2,3-dichloro-4-Z 1 -Pyridine (E'):

[0230]

[0231] Where Z 1 Selected from Br and I;

[0232] Reaction in the presence of a palladium catalyst and a base to prepare (F);

[0233] Each R 3a and R 3b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0234] or R 3a and R 3b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0235] In certain embodiments, (E') is 2,3-dichloro-4-iodopyridine. In certain embodiments, (E') is 2,3-dichloro-4-bromopyridine.

[0236] In certain embodiments, (D') is 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde.

[0237] In certain embodiments, the palladium catalyst comprises Pd(dppf)Cl2.

[0238] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0239] In certain embodiments, the base comprises K2CO3.

[0240] In certain embodiments, the reaction of (D') and (E') occurs in the presence of a solvent.

[0241] In certain embodiments, the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

[0242] In certain embodiments, the reaction of (D') and (E') occurs at a temperature of about 55 °C.

[0243] In certain embodiments, purification of (F) comprises adding N-acetyl cysteine ​​to the reaction of (D') and (E'). In certain embodiments, N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0244] In certain embodiments, the purification of (F) comprises:

[0245] (a) providing crude product (F) in 2-propanol to obtain a dilute crude solution of (F),

[0246] wherein the concentration of the diluted crude solution of (F) is from about 100 g / L to about 140 g / L;

[0247] (b) at least partially evaporating the dilute crude solution of (F) to provide a concentrated crude solution of (F), wherein the at least partial evaporation optionally comprises heating the dilute crude solution of (F) to a temperature of about 50° C. to about 55° C., and further optionally maintaining the temperature for a period of about 1 hour;

[0248] (c) cooling the concentrated crude solution of (F) to a temperature of about 20° C. to about 25° C. to provide a purified (F) slurry; and

[0249] (d) filtering the purified (F) slurry to provide (F).

[0250] In certain embodiments, by making (D):

[0251]

[0252] Where Z 1 Selected from Br and I;

[0253] The compound (D') is prepared by reacting with a borylation agent in the presence of a palladium catalyst and a base.

[0254] In certain embodiments, (D) is 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. In certain embodiments, (D) is 6-(3-iodo-2-chlorophenyl)-2-methoxynicotinaldehyde.

[0255] In certain embodiments, the borylation reagent comprises bis(pinacolato)diboron.

[0256] In certain embodiments, the palladium catalyst comprises Pd(dppf)Cl2.

[0257] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 7 mol %.

[0258] In certain embodiments, the base comprises KOAc.

[0259] In certain embodiments, the reaction of (D) and the borylation agent occurs in the presence of a solvent.

[0260] In certain embodiments, the solvent includes at least one of dimethylformamide (DMF) and / or toluene.

[0261] In certain embodiments, the reaction of (D) and the borylation agent occurs at a temperature of about 90°C to about 100°C.

[0262] In certain embodiments, the purification of (D') comprises at least one of the following:

[0263] (a) adding N-acetyl cysteine ​​to the reaction of (D) and a borylation reagent; and

[0264] (b) Adding activated carbon to the reaction of (D) and a boronating agent.

[0265] In certain embodiments, N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0266] In certain embodiments, wherein the purification of (D') comprises:

[0267] (a) providing a crude product (D') in a solvent comprising 2-propanol to obtain a crude solution of (D'),

[0268] wherein the concentration of the crude solution of (D') is from about 140 g / L to about 180 g / L;

[0269] (c) cooling the crude solution of (D') to a temperature of about 0°C to about 5°C to provide a purified (D') slurry; and

[0270] (d) Filtering the purified (D') slurry to provide (D').

[0271] In certain embodiments, by making 1-(B(OR 4a )(OR 4b ))-2-Chloro-3-Z 1 -Benzene (B):

[0272]

[0273] and 6-Z 2 -2-Methoxynicotinaldehyde (C):

[0274]

[0275] Reaction in the presence of a palladium catalyst and a base to prepare (D);

[0276] Where Z 1 Selected from Br and I;

[0277] Where Z 2 is selected from Cl, Br and I;

[0278] Each R 4a and R 4b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0279] or R 4a and R 4b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0280] 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.

[0281] In certain embodiments, the palladium catalyst comprises Pd(PPh3)4.

[0282] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0283] In certain embodiments, the base comprises K2CO3.

[0284] In certain embodiments, the reaction of (B) and (C) occurs in the presence of a solvent.

[0285] In certain embodiments, the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF) and / or water.

[0286] In certain embodiments, the reaction of (B) and (C) occurs at a temperature of about 50°C to about 60°C.

[0287] In certain embodiments, wherein the purification of (D) comprises adding N-acetyl cysteine ​​to the reaction of (B) and (C). In certain embodiments, the N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0288] In certain embodiments, the purifying of (D) comprises:

[0289] (a) providing a crude product (D) in a solvent comprising 2-propanol to obtain a dilute crude solution of (D),

[0290] wherein the concentration of the diluted crude solution of (D) is from about 160 g / L to about 220 g / L;

[0291] (b) at least partially evaporating the dilute crude solution of (D) to provide a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the dilute crude solution of (D) to a temperature of about 50° C. to about 55° C., and further optionally maintaining the temperature for a period of about 1 hour;

[0292] (c) cooling the concentrated crude solution of (D) to a temperature of about 20° C. to about 25° C. to provide a purified slurry of (D); and

[0293] (d) filtering the purified (D) slurry to provide (D).

[0294] In certain embodiments, (B) is prepared by:

[0295] (a) Make 1-Z 1 -2-Chloro-3-Z 1 -Benzene (A):

[0296]

[0297] Where Z 1 Each occurrence of is independently selected from Br and I;

[0298] reacting with an organomagnesium halide to form an arylmagnesium intermediate; and

[0299] (b) reacting the aryl magnesium intermediate with a borate ester.

[0300] 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.

[0301] In certain embodiments, the borate ester is:

[0302]

[0303] Each R 5a , R 5b and R 5c Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0304] Among them, R 5a , R 5b and R 5c Any two of the may be combined with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl.

[0305] In certain embodiments, the boronate ester is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0306] In certain embodiments, the organomagnesium halide comprises i-PrMgCl, wherein i-PrMgCl is optionally a solution comprising i-PrMgCl complexed with LiCl (ie, i-PrMgCl·LiCl solution).

[0307] In certain embodiments, the reaction of (A) and the organomagnesium halide occurs in a solvent.

[0308] In certain embodiments, the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0309] In certain embodiments, the reaction of (A) and the organomagnesium halide occurs at a temperature of about -25°C to about -15°C.

[0310] In certain embodiments, the reaction of the aryl magnesium intermediate and the borate ester occurs at a temperature of about -18 °C to about -15 °C, wherein the reaction is optionally subsequently warmed to a temperature of about 2 °C.

[0311] In certain embodiments, (D) is prepared by:

[0312] (a) Make 1-Z 1 -2-Chloro-3-Z 1 -Benzene (A):

[0313]

[0314] Where Z 1 Each occurrence of is independently selected from Br and I;

[0315] reacting with an organomagnesium halide to form an arylmagnesium intermediate;

[0316] (b) reacting the aryl magnesium intermediate with a borate ester to provide a borate ester intermediate; and

[0317] (c) reacting the boronate intermediate with 6-Z 2 -2-Methoxynicotinaldehyde (C):

[0318]

[0319] Where Z 2 is selected from Cl, Br and I;

[0320] The reaction is carried out in the presence of a palladium catalyst and a base.

[0321] In certain embodiments, the organomagnesium halide comprises i-PrMgCl, wherein i-PrMgCl is optionally a solution comprising i-PrMgCl complexed with LiCl (ie, i-PrMgCl·LiCl solution).

[0322] In certain embodiments, the reaction of (A) and the organomagnesium halide occurs in a solvent.

[0323] In certain embodiments, the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0324] In certain embodiments, the reaction of (A) and the organomagnesium halide occurs at a temperature of about -25°C to about -15°C.

[0325] In certain embodiments, the reaction of the aryl magnesium intermediate and the borate ester occurs at a temperature of about -18 °C to about -15 °C, wherein the reaction is optionally subsequently warmed to a temperature of about 2 °C.

[0326] 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.

[0327] In certain embodiments, the borate ester is:

[0328]

[0329] Each R 5a , R 5b and R 5c Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0330] Or choose R 5a , R 5b and R 5c Any two of the may be combined with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl.

[0331] In certain embodiments, the boronate ester is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0332] In certain embodiments, the palladium catalyst comprises Pd(PPh3)4.

[0333] In certain embodiments, the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0334] In certain embodiments, the base comprises K2CO3.

[0335] In certain embodiments, the reaction of the boronate intermediate and (C) occurs in the presence of a solvent.

[0336] In certain embodiments, the solvent comprises at least one selected from 2-methyltetrahydrofuran (MeTHF) and water.

[0337] In certain embodiments, the reaction of the boronate intermediate and (C) occurs at a temperature of about 50°C to about 60°C.

[0338] In certain embodiments, the purification of (D) comprises adding N-acetyl cysteine ​​to the reaction of (C) and the boronate intermediate. In certain embodiments, the N-acetyl cysteine ​​is added as a solution. In certain embodiments, the N-acetyl cysteine ​​solution is about 1, 2, 3, 4, or 5 wt% N-acetyl cysteine.

[0339] In certain embodiments, the purifying of (D) comprises:

[0340] (a) providing a crude product (D) in a solvent comprising 2-propanol to obtain a dilute crude solution of (D),

[0341] wherein the concentration of the diluted crude solution of (D) is from about 160 g / L to about 220 g / L;

[0342] (b) at least partially evaporating the dilute crude solution of (D) to provide a concentrated crude solution of (D), wherein the at least partial evaporation optionally comprises heating the dilute crude solution of (D) to a temperature of about 50° C. to about 55° C., and further optionally maintaining the temperature for a period of about 1 hour;

[0343] (c) cooling the concentrated crude solution of (D) to a temperature of about 20° C. to about 25° C. to provide a purified slurry of (D); and

[0344] (d) filtering the purified (D) slurry to provide (D).

[0345] The compounds of the present disclosure may have one or more stereocenters, and each stereocenter may exist independently in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein include racemic, optically active, regioisomeric and stereoisomeric forms or combinations thereof having therapeutically useful properties as described herein. The preparation of optically active forms is achieved in any suitable manner, including, as non-limiting examples, by resolution of the racemic form using recrystallization techniques, synthesis from optically active raw materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. The compounds described herein by racemic formula further represent two enantiomers or any mixture thereof, or, in the presence of two or more chiral centers, all diastereomers or any mixture thereof.

[0346] In certain embodiments, the compounds of the present disclosure exist as tautomers. All tautomers are included within the scope of the compounds described herein.

[0347] 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 atomic mass number different from the atomic mass or atomic mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to 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 S. In certain embodiments, substitution with heavier isotopes such as deuterium provides greater chemical stability. Isotopically labeled compounds may be prepared by any suitable method or process using an appropriate isotopically labeled reagent in place of an otherwise unlabeled reagent.

[0348] In certain embodiments, 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.

[0349] In all embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention.Compounds of the present disclosure may contain any substituent or combination of substituents provided herein.

[0350] Salt

[0351] The compounds described herein may form salts with acids or bases, and such salts are included in the present disclosure. The term "salt" includes addition salts of free acids or bases useful in the methods of the present disclosure. The term "pharmaceutically acceptable salt" refers to salts having toxicity characteristics within a range useful in pharmaceutical applications. In certain embodiments, the salt is a pharmaceutically acceptable salt. However, pharmaceutically unacceptable salts may have properties such as high crystallinity, which have utility in the practice of the present disclosure, such as, for example, utility in the synthesis, purification or formulation of compounds useful in the methods of the present disclosure.

[0352] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include sulfates, hydrogen sulfates, 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 aliphatic, alicyclic, aromatic, araliphatic, 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, mandelic acid, pamoic acid (or 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). A salt may be composed of 1 molar equivalent, 1 or more than 1 molar equivalent of the acid or base moiety relative to any compound of the disclosure.

[0353] Suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, for example, ammonium salts and metal salts, including alkali metal, alkaline earth metal and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds, for example, by reacting a suitable acid or base with the compound.

[0354] Using only routine experiments, those skilled in the art will recognize or be able to determine many equivalents of the specific procedures, embodiments, claims and embodiments described herein. Such equivalents are considered to be within the scope of the present disclosure and are covered by the appended claims. For example, it should be understood that improvements in reaction conditions including but not limited to reaction time, reaction size / volume and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions such as nitrogen atmosphere and reducing agent / oxidant using art-recognized alternatives and using only routine experiments are within the scope of the present application.

[0355] It should be understood that no matter where numerical value and range are provided herein, the description of range format is only for convenience and simplicity, and should not be interpreted as a rigid limitation to the scope of the present disclosure. Therefore, all values ​​and ranges covered by these values ​​and ranges are intended to be covered within the scope of the present disclosure. In addition, the application also contemplates the upper or lower limit of the range of all values ​​falling within these ranges and the value. The description of the range should be considered to have clearly disclosed all possible sub-ranges and single values ​​within the range, and partial integers of the values ​​within the range when appropriate. For example, the description of the range from 1 to 6 should be considered to have clearly disclosed sub-ranges from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single values ​​within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3 and 6. Regardless of the breadth of the range, this applies.

[0356] The embodiments provided herein illustrate aspects of the present disclosure. However, they are by no means limitations of the teachings or disclosures of the present disclosure described herein. Embodiments are provided herein for illustrative purposes only, and the present disclosure is not limited to these embodiments, but encompasses all variations that are apparent due to the teachings provided herein.

[0357] Example

[0358] The present disclosure is now described with reference to the following examples. These examples are provided for illustrative purposes only, and the present disclosure is not limited to these examples, but encompasses all variations that are obvious as a result of the teaching provided herein.

[0359] Step 1-Synthesis of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde

[0360]

[0361] (a) Synthesis of 2-(3-bromo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0362]

[0363] MeTHF (2.6 L) and i-PrMgCl LiCl (2.64 L, 3.4 mol, 1.3 M THF solution) were added to a 30 L reactor in a nitrogen atmosphere. The resulting solution was cooled to a temperature of about -25°C to -15°C (e.g., -24°C). A solution of compound A (675.5 g, 2.5 mol) in MeTHF (1.06 L) was prepared in a separate 3 L reactor at a temperature of about 8°C to 25°C in a nitrogen atmosphere. The solution of compound A was added to the solution of i-PrMgCl LiCl using an addition funnel over a period of about 40 min while maintaining an internal temperature of about -25°C to -15°C. The resulting mixture was stirred at a temperature of about -20°C to -18°C for 45 min. Next, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (593.4 g, 3.2 mol, i-PrBPin) was slowly added to the reaction mixture using an addition funnel over a period of about 40 min while maintaining an internal temperature of about -18 ° C to -15 ° C. The resulting mixture was stirred for 30 min at a temperature of about -17 ° C to -15 ° C. The reaction mixture was then warmed to about 2 ° C over a period of about 30 min and stirred at this temperature for not less than 2 hours until the reaction was complete. The degree of completion of the reaction can be assessed by HPLC, where if no more than 0.5% of compound A remains, the reaction is considered complete. The reaction solution was diluted with MeTHF (4.3 L), and water (4.3 L) was slowly added over a period of 30 min while maintaining an internal temperature of about 8 ° C to 15 ° C. Aqueous HCl solution (1.16 L, 3 N) was added to adjust the pH of the aqueous layer to 6.5. The mixture was stirred for 30 min and then 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 about 4.2 L and used for subsequent reactions without purification.

[0364] (b) Synthesis of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde

[0365]

[0366] K2CO3(1.02kg, 7.4mol) and water(1.7L) were added to the 5L reactor, and the mixture was stirred to dissolve the solid. The atmosphere was evacuated and backfilled with nitrogen three times, and then nitrogen was sparged into the solution for a period of about 1.5h. To a separate 30L reactor, MeTHF(4.8L) and compound C(530g, 2.4mol) were added and stirred in a nitrogen atmosphere to provide a clear solution, and then a solution of compound B prepared as described elsewhere herein was added to the solution of compound C. The atmosphere of the container including the resulting reaction mixture was evacuated and backfilled with nitrogen three times, and then nitrogen was sparged into the reaction mixture for a period of about 45min. K2CO3 solution was transferred to the reaction mixture, and nitrogen was sparged into it for a period of about 10min. Next, Pd(PPh3)4(56.7g, 0.05mol) was added and nitrogen was sparged into the resulting mixture for a period of about 45min. The reaction mixture is heated to 55 ° C and stirred at this temperature for no less than 8h until the reaction is completed. The reaction completion can be assessed by HPLC, wherein if no more than 2.0% of compound C remains, the reaction is considered to be completed. After completion, MeTHF (5.3L) is slowly added to the reaction while maintaining an internal temperature of about 45 ° C to 55 ° C. Next, 2wt.% N-acetylcysteine ​​solution (4.2L) is slowly added to the reaction mixture while maintaining an internal temperature of about 42 ° C to 48 ° C. The contents are stirred for a time period of about 1.5h at this temperature and each layer is allowed to settle. Separate each layer and wash the organic layer with water (4.2L and 2.1L) twice at a temperature of about 42 ° C to 45 ° C. The organic layer is evaporated to a volume of about 2.6L and diluted to a volume of about 3.7L with MeTHF. The resulting slurry is subjected to a thermal cycle, wherein the temperature is raised to about 50 ° C and reduced to about 18 ° C, accompanied by stirring, and then stirred at a temperature of about 18 ° C for about 1.5h. The solid was filtered, washed with a mixture of MeTHF / n-heptane (1:1, 1.6 L), and dried at no higher than 50° C. for about 8 h to provide the title compound (690 g, 86% yield) as an off-white to gray solid. 1 H NMR (400 MHz, CDCl3) δ: 10.41 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 4.10 (s, 3H). MS (ESI+, m / z): calculated [C 13 H9BrClNO2+H] + : 327.96; measured value: 328.1.

[0367] Step 2-Synthesis of 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde

[0368]

[0369] Compound D (240g, 0.73mol) and MeTHF (4.2L) were added to the 10L reactor, and the mixture was stirred to dissolve the solid. The atmosphere of the reactor was evacuated and backfilled twice with nitrogen, and nitrogen was subsequently sprayed into the solution for a period of about 0.5h. K was added to another 2L reactor HPO (256g, 1.5mol), water (840mL), and stirred and dissolved. The atmosphere of the reactor was evacuated and backfilled twice with nitrogen, and nitrogen was subsequently sprayed into the solution for a period of about 1h. K was then transferred to the 10L reactor in a nitrogen atmosphere HPO solution. Pd (amphos) Cl (10.4g, 14.7mmol) was added to the reaction mixture, and nitrogen was subsequently sprayed for a period of about 0.5h. The reaction mixture was heated to a temperature of about 65°C to 70°C. Compound E (155.2g, 0.81mol), 2-MeTHF (600mL) and DMAc (600mL) were added to a separate reactor, and the mixture was stirred to dissolve the solid. The atmosphere of the reactor containing the compound E solution was evacuated and backfilled twice with nitrogen, and then nitrogen was sprayed into the solution for a period of about 0.5h. The degassed solution of compound E was slowly transferred to a 10L reaction mixture over a period of about 3.5h, while maintaining an internal temperature of about 65°C to 70°C. The mixture was stirred at this temperature for a period of about 1h. Additional compound E (7.0g, 36.5mmol) was added to the reaction mixture, and continued to heat for not less than 1h until the reaction was complete. The reaction completion can be assessed by HPLC, wherein if no more than 2.5% of compound D remains, the reaction is considered to be complete. In certain embodiments, additional compound E may be added to drive the reaction to complete. Next, 2-MeTHF (2.4L) was added to the reaction mixture, and the contents were then adjusted to a temperature of about 25°C to 30°C. 4 wt.% N-acetylcysteine ​​solution (2.4 L) was added to the reaction mixture, which was stirred at a temperature of about 20°C to 30°C for a period of about 20 min. The layers were separated, and the organic layer was washed with 10 wt.% NaCl solution (2.4 L), 5 wt.% Na2CO3 solution (2.4 L) and water (2.4 L) in sequence, then dried over Na2SO4 and filtered. The filtrate was evaporated at a temperature of about 40°C to 55°C and solvent exchanged with 2-propanol (2×2.4 L) to provide a solution with a final volume of 1.8 L. The solution was stirred at a temperature of about 40°C to 55°C for 1 h, and then cooled to a temperature of about 20°C to 25°C and stirred for another 1 h. The solid was filtered, washed with 2-propanol (720 mL) and dried at a temperature not higher than 50°C to obtain a crude product (241 g).

[0370] The crude product was redissolved in MeTHF (4.5 L), evaporated at a temperature of about 40° C. to 55° C., and solvent exchanged with 2-propanol (2×2.4 L) to a final volume of 1.8 L of solution. The solution was stirred at a temperature of about 40° C. to 55° C. for 1 h, and then cooled to a temperature of about 20° C. to 25° C. and stirred for another 1 h. The resulting solid was filtered, washed with 2-propanol (720 mL), and dried at a temperature not higher than 50° C. to provide the title compound as an off-white solid (213 g, 74% yield). 1 H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.23 ​​(d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.65-7.55 (m, 3H), 7.48 (d, J = 7.6 Hz, 1H), 4.06 (s, 3H). MS (ESI+, m / z): calculated [C 18 H 12 Cl3N2O2+H] + : 393.0; Measured value: 393.0.

[0371] Step 2 Synthesis of 6-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxynicotinaldehyde

[0372]

[0373] Compound D (17.0 g, 52.0 mmol), bis(pinacolato)diboron (15.9 g, 62.5 mmol), toluene (170 mL), DMF (102 mL) were added to a 500 mL reactor, and the mixture was degassed by sparging nitrogen into the solution, with stirring, for a period of about 15 min. Potassium acetate (15.3 g, 156.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (2.12 g, 2.6 mmol) were added to the solution, and the mixture was degassed by sparging nitrogen into the solution, for a period of about 15 min. The reaction solution was heated to a temperature of about 95° C. to 100° C., and stirred at this temperature for not less than 4 h until the reaction was complete. The reaction completion can be assessed by HPLC, where the reaction is considered complete if no more than 1% of compound D remains. The reaction mixture was adjusted to a temperature of about 50° C., and then a 5 wt.% solution of N-acetylcysteine ​​(170 mL) was added. The reaction mixture was cooled to a temperature of about 20°C to 30°C, stirred for 1h, and the layers were allowed to settle. The layers were separated, and the organic layer was washed with 10wt.% NaCl (2×170mL). Activated carbon (8.5g) was added to the organic layer, the mixture was stirred for about 1.5h, and the suspension was filtered through diatomaceous earth. The filtrate was evaporated and solvent exchanged with 2-propanol (3×85mL). The volume was adjusted to about 90mL, and the solution was stirred for 1h at a temperature of about 20°C to 25°C. The resulting suspension was cooled to a temperature of about 0°C to 5°C and stirred for 1h. The resulting solid was filtered, washed with cold 2-propanol (35mL) and dried at a temperature not higher than 50°C to provide the title compound as a brown solid (14.5g, 76% yield). 1 H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.71-7.68 (m, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 4.04 (s, 3H), 1.34 (s, 12H). MS (ESI+, m / z): calculated [C 19 H 21 BClNO 4+ H] + : 374.1; measured value: 374.1.

[0374] Step 2 Synthesis of 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde

[0375]

[0376] MeTHF (225 mL) and water (49.5 mL) were added to a 1 L reactor and degassed by sparging nitrogen into the solution for a period of about 15 min. Compound E' (11.0 g, 40.1 mmol) and K2CO3 (16.6 g, 120.4 mmol) were added, and the mixture was stirred and sparged with nitrogen for a period of about 15 min. Pd(dppf)Cl2.CH2Cl2 (1.3 g, 1.6 mmol) was added and nitrogen was sparged into the mixture for about 15 min. The reaction mixture was heated to a temperature of about 55° C. at which temperature the solution became clear and colorless. In another 250 mL reactor, compound D' (15.0 g, 40.1 mmol) and MeTHF (75 mL) were added and the solution was degassed by sparging with nitrogen, with stirring for a period of about 15 min. Next, the solution of compound D' is slowly added to the 1L reactor over a period of about 1.5h, while the reaction temperature is maintained at about 50°C to 60°C. The reaction mixture is stirred at 55°C for not less than 12h until the reaction is complete. The degree of reaction completion can be assessed by HPLC, wherein if no more than 2.0% of compound E' remains, the reaction is deemed to be complete. The reaction mixture is adjusted to a temperature of about 50°C, and a 5wt.% N-acetylcysteine ​​solution (150mL) is added. The reaction mixture is cooled and stirred at a temperature of about 20°C to 30°C for a period of about 1h. MeTHF (150mL) and 5wt%NaCl (75mL) are added to the reaction mixture. The mixture is stirred for 5min, then the layers are allowed to settle, and the aqueous layer is separated. The organic layer is washed with 10wt.%NaCl (75mL), dried over MgSO4, and filtered. The filtrate is evaporated to a volume of about 45mL, and the solvent is exchanged into 2-propanol (2×120mL). Next, additional 2-propanol (75 mL) was added and the solvent was evaporated until the total volume of the solution was about 105 mL. The resulting suspension was heated to a temperature of about 50° C. to 55° C. and maintained at this temperature for a period of about 1 h. Next, the solution was cooled to a temperature of about 20° C. to 25° C. and stirred for 1 h. The resulting solid was filtered, washed with 2-propanol (30 mL), and dried at a temperature not higher than 55° C. to provide the title compound as a light brown solid (12.5 g, 79% yield).

[0377] Step 3-Synthesis of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0378]

[0379] 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) were added to a 15 L reactor. The atmosphere of the resulting suspension was evacuated and backfilled with nitrogen three times, and then nitrogen was sprayed into the suspension for a period of about 1 h. Next, Pd(dppf)Cl2 (48.0 g, 65.6 mmol) was added, and nitrogen was sprayed into the mixture for a period of about 30 min. The reaction mixture was heated to a temperature of about 85 ° C and stirred for not less than 7 h until the reaction was determined to be complete by HPLC. The reaction completion can be assessed by HPLC, where if no more than 1.0% of compound G remains, the reaction is considered to be complete. The reaction mixture was cooled to 27 ° C, and then N-acetylcysteine ​​solution (4.7 L, 5 wt%) was added while maintaining an internal temperature of about 23 ° C to 31 ° C, and stirred for 1 h. Next, separate each phase, and 5wt%NaCl (4.7L) is added to the organic layer. Stir the mixture and filter through diatomite. Allow the filtrate to settle, separate each phase, and wash the organic layer with 5wt%NaCl (4.7L). Activated carbon (235.0g) is added to the organic layer and the mixture is stirred for 1.5h, then filtered through diatomite. The filtrate is evaporated to a volume of about 1L and the solvent is exchanged into 2-propanol (2×4.7L) to provide a solution with a volume of about 1.2L. The solution is heated to a temperature of about 50°C, and maintained at this temperature for a time period of about 1.5h, then slowly cooled to a temperature of about 6°C in a time period of about 3h, and stirred at this temperature for a time period of about 1.5h. The resulting solid is filtered, washed with 2-propanol (2×0.45L) and dried for 12h at a temperature not higher than 50°C, to provide the title compound, which is a light brown solid (492.0g, yield 86%). 1 H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 7.6, 0.8 Hz, 1H), 7.39 (s, 1H), 3.97 (s, 3H), 1.35 (s, 12H). MS (ESI+, m / z): calculated [C 14 H 20 BO4+H] + :263.15; measured value:263.2.

[0380] Step 4-Synthesis of 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde

[0381]

[0382] In 5L reactor, add K2CO3(526.6g, 3.8mol) and water (2.0L), and stir the mixture to promote solid dissolution.The atmosphere of solution is evacuated and backfilled with nitrogen four times, and degassed the solution by spraying nitrogen into solution subsequently, lasting the time period of about 2h.In independent 30L reactor, add MeTHF(7.5L), DMF(2.0L), compound F(500.0g, 1.27mol) and compound H(349.6g, 1.33mol), and stir the mixture to promote solid dissolution.The atmosphere of solution is evacuated and backfilled with nitrogen four times, and degassed the solution by spraying nitrogen into solution subsequently, lasting the time period of about 1h.Next, by K2CO3 solution adds in reaction solution, then adds Pd(PPh3)4(44.0g, 0.04mol), and sprays nitrogen into gained mixture, lasting the time period of about 1h. The reaction mixture is heated to a temperature of about 65°C to 70°C, and stirred at this temperature for no less than 3h, until the reaction is complete. The reaction completion can be assessed by HPLC, wherein if no more than 1.0% of compound F remains, the reaction is considered to be complete. The reaction mixture is adjusted to a temperature of about 60°C, then 5wt.% N-acetylcysteine ​​solution (5.0L) is slowly added over a period of about 40min. The reaction mixture is cooled to a temperature of about 22°C over a period of about 1.5h, and stirred at this temperature for 1.5h. The resulting solid is filtered, washed with water (7.5L), and washed with EtOH (2.5L). The wet cake is dried at a temperature of about 50°C to provide the title compound, as a tan solid (581g, 92% yield). 1 HNMR (400MHz, CDCl3) δ10.53 (s, 1H), 10.42 (s, 1H), 8.69 (d, J = 4.8, 1H), 8.20 (d, J = 7.7, 1H), 7.93 (d, J = 8.0Hz, 1H), 7. 74 (dd, J=7.7, 1.7Hz, 1H), 7.52 (t, J=7.7Hz, 1H), 7.47-7.34 (m, 4H), 7.32 (d, J=4.8Hz, 1H), 4.13 (s, 3H), 4.00 (d, 3H). MS (ESI+, m / z): Calculate [C 26 H 19 Cl2N2O 4+ H] + :493.07; measured value:493.1.

[0383] 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

[0384]

[0385] Compound J (332.3 g, 2.04 mol), CH2Cl2 (13.4 L) and MeOH (2.9 L) were added to a 50 L reactor, and the mixture was stirred. Next, NaOMe (110 g, 2.04 mol, 25 wt.% MeOH solution) was added, and the resulting slurry was stirred for 30 min at a temperature of about 15° C. to 20° C. Compound I (420.0 g, 0.851 mol) was added, and the mixture was stirred for 1 h at a temperature of about 22° C. to 28° C. The slurry was cooled to a temperature of about 18° C., and NaBH(OAc)3 (1.08 kg, 5.1 mol) was added in batches (i.e., 3 portions, each portion of which was added at intervals of about 20 min). The reaction mixture was stirred for not less than 1 h until the reaction was determined to be complete. The degree of completion of the reaction can be assessed by HPLC, wherein if no more than 1.0% of Compound I remains, the reaction is deemed to be complete. Water (8.4 L) was added to the reaction mixture, and the resulting clear biphasic mixture was stirred for a period of about 20 min at a temperature of about 20° C. to 25° C. Each layer was allowed to settle and separate. The aqueous layer was washed with CH2Cl2 (6.3 L). CH2Cl2 (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 stirred for 20 min, and then the phases were separated. The aqueous layer was further extracted with CH2Cl2 (2.1 L), and the combined organic layers were washed with water (4.2 L). The aqueous layer was extracted again with CH2Cl2 (2.1 L), and the combined organic layers were filtered through a Na2SO4 pad. The filtered solution was concentrated in vacuo, and solvent exchanged with 2-propanol (2×2.1 L) at a temperature of about 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 provide a fine slurry, which was stirred at a temperature of about 50° C. for a period of about 2 h and then gradually cooled to a temperature of about 20° C. over a period of about 10 h. The resulting thick slurry was stirred at the same temperature (i.e., about 20° C.) for a period of about 4 h. The solid was filtered and washed with 2-propanol (840 mL). The wet cake was vacuum dried at 55° C. for not less than 24 h to provide the title compound as a white to off-white solid (533 g, 88% yield). 1HNMR (400MHz, CDCl3) δ: 8.63 (d, J=4.8Hz, 1H), 7.71 (dd, J=1.7, 7.7Hz, 1H), 7.62 (d, J=7.5Hz, 1H) , 7.46 (t, J=7.7Hz, 1H), 7.387.31 (m, 2H), 7.30 (dd, J=1.7, 7.7Hz, 1H), 7.28-7.23 (m, 3H), 5.74 (br s, 1H), 5.68(br s, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.70 (s, 2H), 3.65 (s, 2H), 3.61 (s, 2H), 3.58 (s, 2H), 3.40-3.28 (m, 8H), 2.56 (s, 2H), 2.54 (s, 2H); MS (ESI+, m / z): calculated [C 38 H 38 Cl2N6O 4+ H] + :713.2; measured value:713.2.

[0386] In certain embodiments, the recrystallization described herein utilizes seed crystals of Compound K to facilitate recrystallization. In certain embodiments, seed crystals of Compound K are prepared as described in step 5, except that seed crystals are not added to facilitate recrystallization.

[0387] 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

[0388]

[0389] 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 for 1 h at a temperature of about 15 ° C to 20 ° C. Compound I (700.0 g, 1.42 mol) was added, and the mixture was stirred for 1.5 h at 33 ° C to 35 ° C. The slurry was cooled to a temperature of about 15 ° C to 20 ° C, and NaBH (OAc) 3 (1.8 kg, 8.5 mol) was added in batches (ie, 4 portions, each of which was added at intervals of about 20 min). The reaction mixture was warmed to 20 ° C to 25 ° C and stirred for not less than 1 h until the reaction was completed. The reaction completion can be assessed by HPLC, wherein if no more than 1.0% of Compound I remains, the reaction is considered to be complete. 10% NaCl (9L) was added to the reaction mixture, and the resulting clear biphasic mixture was stirred for a period of about 20 min at a temperature of about 20°C to 25°C. The layers were allowed to settle and separated. The organic layer was extracted with 10% NaCl (3.5L). The combined aqueous layer was washed with MeTHF (3.5L) and MEK (2×7L) in sequence. MEK (14L) was added to the aqueous phase, and the pH of the aqueous layer was adjusted to pH 9.5-10.5 using 20wt% aqueous Na2CO3 (9L). The resulting mixture was stirred for 20min, and then the phases were separated. The aqueous layer was further extracted with MEK (2×9L). The combined organic layer was washed with 24wt% NaCl (7L). The organic layer was filtered through a Na2SO4 pad. The filtered solution was diluted with MeOH (3.5L) and concentrated in vacuo, and solvent exchanged with three portions of MeOH (17L) at a temperature of about 40°C to 50°C. The final volume of the solution was adjusted to a volume of about 3.5 L. The solution was stirred at 48 ° C to 50 ° C and inoculated with compound K (3.5 g) to provide a fine slurry, which was stirred for a period of about 3 h at a temperature of about 50 ° C and then gradually cooled to a temperature of about 20 ° C over a period of about 4 h. The resulting thick slurry was stirred at the same temperature (i.e., about 20 ° C) for a period of about 10 h. MTBE (7 L) was added and the slurry was stirred for 4 h. The solid was filtered and washed with 30% MeOH / MTBE (2 × 1.4 L). The wet cake was vacuum dried at 65 ° C for not less than 24 h to provide the title compound as a white to off-white solid (760 g, 74% yield).

[0390] In certain embodiments, the compound K obtained by the methods described herein may contain more residual MTBE. Excess MTBE can be reduced by preparing a slurry of the separation material in hot MeOH, cooling the slurry to ambient temperature, filtering, washing with MeOH, and drying. In certain embodiments, the recrystallization described herein utilizes a solvent other than MTBE as an anti-solvent.

[0391] Examples of implementation methods

[0392] The following exemplary embodiments are provided, and their numbering should not be construed as designating their importance:

[0393] Embodiment 1 provides a method 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) or a salt or solvate thereof:

[0394]

[0395] The method comprises making 6-(2-chloro-3-(3-chloro-2-(4-formyl-3-methoxyphenyl)pyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (I):

[0396]

[0397] and 2,6-diazaspiro[3.4]octan-7-one (J):

[0398]

[0399] The reaction is carried out in the presence of a reducing agent and a base to generate a first reaction system including (K).

[0400] Embodiment 2 provides the method of embodiment 1, wherein the reducing agent is NaBH(OAc)3.

[0401] Embodiment 3 provides the method of embodiment 1 or 2, wherein the base comprises NaOMe or i-PrNEt2.

[0402] Embodiment 4 provides the method of any one of embodiments 1-3, wherein (J) is selected from 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 methanesulfonate and 2,6-diazaspiro[3.4]octan-7-one toluenesulfonate.

[0403] Embodiment 5 provides the method of any one of embodiments 1-4, wherein the reaction of (I) and (J) occurs in the presence of a solvent.

[0404] Embodiment 6 provides 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.

[0405] Embodiment 7 provides the method of any one of embodiments 1-6, wherein the purification of (K) comprises:

[0406] (a) adding water to the first reaction system comprising (K) to generate a biphasic solution;

[0407] (b) separating the biphasic solution to provide a first aqueous phase and a first organic phase;

[0408] (c) adding an organic solvent to the first aqueous phase to provide a second biphasic solution;

[0409] (d) alkalizing the second biphasic solution to a pH of 8-11 to provide an alkalized biphasic solution; and

[0410] (e) separating the basified biphasic solution to provide a second aqueous phase and a second organic phase comprising (K).

[0411] Embodiment 8 provides the method of any one of embodiments 1-7, wherein the purification of (K) comprises:

[0412] (a) providing a crude product (K) in a solvent comprising 2-propanol to obtain a dilute crude solution of (K),

[0413] wherein the concentration of the diluted crude solution of (K) is from about 110 g / L to about 140 g / L;

[0414] (b) at least partially evaporating the diluted crude solution of (K) to provide a concentrated crude solution of (K),

[0415] wherein the concentration of the concentrated crude solution of (K) is from about 220 g / L to about 280 g / L;

[0416] (c) cooling the concentrated crude solution of (K) to a temperature of about 20° C. to provide a purified slurry of (K); and

[0417] (d) filtering the purified (K) slurry to provide (K).

[0418] Embodiment 9 provides the method of any one of embodiments 1-7, wherein the purification of (K) comprises:

[0419] (a) providing a crude product (K) in a solvent comprising MeOH to obtain a crude solution of (K),

[0420] wherein the crude solution of (K) has a concentration of about 200 g / L to about 300 g / L;

[0421] (b) heating the crude solution of (K) to a temperature of about 50° C. to provide a hot crude solution of (K);

[0422] (c) cooling the hot crude solution of (K) to a temperature of about 20° C. to provide a cooled slurry of (K);

[0423] (d) adding a solvent comprising methyl tert-butyl ether (MTBE) to the cooled (K) slurry to provide a purified (K) slurry; and

[0424] (e) filtering the purified (K) slurry to provide (K).

[0425] Embodiment 10 provides the method of any one of embodiments 1-9, wherein by making 2-methoxy-4-(B(OR 1a )(OR 1b ))-Benzaldehyde(H):

[0426]

[0427] and 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (F):

[0428]

[0429] Reaction in the presence of a palladium catalyst and a base to prepare (I);

[0430] Each R 1a and R 1b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0431] or R 1a and R1b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0432] Embodiment 11 provides the method of embodiment 10, wherein the palladium catalyst comprises Pd(PPh3)4.

[0433] Embodiment 12 provides 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 %.

[0434] Embodiment 13 provides the method of any one of embodiments 10-12, wherein the base comprises K2CO3.

[0435] Embodiment 14 provides the method of any one of embodiments 10-13, wherein the reaction of (H) and (F) occurs in the presence of a solvent.

[0436] Embodiment 15 provides the method of embodiment 14, wherein the solvent comprises at least one of 2-methyltetrahydrofuran (MeTHF), dimethylformamide (DMF), and water.

[0437] Embodiment 16 provides the method of any of embodiments 10-15, wherein the reaction of (H) and (F) occurs at a temperature of about 65°C to about 70°C.

[0438] Embodiment 17 provides the method of any one of embodiments 10-16, wherein the purification of (I) comprises adding N-acetyl cysteine ​​to the reaction of (H) and (F).

[0439] Embodiment 18 provides the method of any one of embodiments 10-17, wherein by making 4-Z 2 -2-Methoxybenzaldehyde (G):

[0440]

[0441] Where Z 2 is selected from Cl, Br and I;

[0442] The compound (H) can be prepared by reacting with a borylation agent in the presence of a palladium catalyst and a base.

[0443] Embodiment 19 provides the method of embodiment 18, wherein the borylation reagent comprises bis(pinacolato)diboron.

[0444] Embodiment 20 provides the method of embodiment 18 or 19, wherein the palladium catalyst comprises Pd(dppf)Cl2.

[0445] Embodiment 21 provides the method of any of embodiments 18-20, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5.0 mol %.

[0446] Embodiment 22 provides the method of any one of embodiments 18-21, wherein the base comprises KOAc.

[0447] Embodiment 23 provides the method of any one of embodiments 18-22, wherein the reaction of (G) and the borylation reagent occurs in the presence of a solvent.

[0448] Embodiment 24 provides the method of embodiment 23, wherein the solvent comprises dimethylformamide (DMF) or toluene.

[0449] Embodiment 25 provides the method of any one of embodiments 18-24, wherein the reaction of (G) and the boration agent occurs at a temperature of about 80°C to about 90°C.

[0450] Embodiment 26 provides the method of any one of embodiments 18-25, wherein the purification of (H) comprises at least one of the following:

[0451] (a) adding N-acetyl cysteine ​​to the reaction of (G) and the borylation reagent; and

[0452] (b) adding activated carbon to the reaction of (G) and the boronating agent.

[0453] Embodiment 27 provides the method of any one of embodiments 18-26, wherein the purification of (H) comprises:

[0454] (a) providing crude (H) in a solvent comprising 2-propanol to obtain a dilute crude solution of (H),

[0455] wherein the concentration of the diluted crude solution of (H) is from about 390 g / L to about 430 g / L;

[0456] (b) at least partially evaporating the diluted crude solution of (H) to provide 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 further optionally maintaining the temperature for a period of about 1.5 h;

[0457] (c) cooling the concentrated crude solution of (H) to a temperature of about 6° C. to provide a purified (H) slurry, wherein the cooling optionally occurs over a period of about 3 hours; and

[0458] (d) filtering the purified (H) slurry to provide (H).

[0459] Embodiment 28 provides the method of any one of embodiments 10-17, wherein by making 6-(3-Z 1 -2-chlorophenyl)-2-methoxynicotinaldehyde (D):

[0460]

[0461] Where Z 1 Selected from Br and I;

[0462] and 2,3-dichloro-4-(B(OR 2a )(OR 2b ))-Pyridine (E):

[0463]

[0464] Reaction in the presence of a palladium catalyst and a base to prepare (F);

[0465] Each R 2a and R 2b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0466] or R 2a and R 2b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0467] Embodiment 29 provides the method of embodiment 28, wherein R 2a and R 2b Each is independently H.

[0468] Embodiment 30 provides the method of embodiment 28 or 29, wherein the palladium catalyst comprises Pd(amphos)Cl2.

[0469] Embodiment 31 provides the method of any of embodiments 28-30, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0470] Embodiment 32 provides the method of any one of embodiments 28-31, wherein the base comprises K2HPO4.

[0471] Embodiment 33 provides the method of any one of embodiments 28-32, wherein the reaction of (D) and (E) comprises adding (E) to a reaction vessel comprising (D), wherein (E) is optionally added to the vessel comprising (D) over a period of about 3.5 h.

[0472] Embodiment 34 provides the method of any one of embodiments 28-33, wherein the reaction of (D) and (E) occurs in the presence of a solvent.

[0473] Embodiment 35 provides the method of embodiment 34, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF), dimethylacetamide (DMAc) and / or water.

[0474] Embodiment 36 provides the method of any one of embodiments 28-35, wherein the reaction of (D) and (E) occurs at a temperature of about 65°C to about 70°C.

[0475] Embodiment 37 provides the method of any one of embodiments 28-36, wherein purification of (F) comprises adding N-acetyl cysteine ​​to the reaction of (D) and (E).

[0476] Embodiment 38 provides the method of any one of embodiments 28-37, wherein the purification of (F) comprises:

[0477] (a) providing a crude product (F) in a solvent comprising 2-propanol to obtain a dilute crude solution of (F),

[0478] wherein the concentration of the diluted crude solution of (F) is about 100 g / L to about 150 g / L;

[0479] (b) at least partially evaporating the diluted crude solution of (F) to provide 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 further optionally maintaining the temperature for a period of about 1 hour;

[0480] (c) cooling the concentrated crude solution of (F) to a temperature of about 20° C. to about 25° C. to provide a crude (F) slurry, wherein the cooling optionally occurs over a period of about 3 hours; and

[0481] (d) filtering the crude (F) slurry to provide (F), wherein the filtering optionally further comprises washing with a solvent comprising 2-propanol.

[0482] Embodiment 39 provides the method of any one of embodiments 10-17, wherein by making 6-(2-chloro-3-(B(OR 3a )(OR 3b ))phenyl)-2-methoxynicotinaldehyde (D′):

[0483]

[0484] and 2,3-dichloro-4-Z 1-Pyridine (E'):

[0485]

[0486] Where Z 1 Selected from Br and I;

[0487] Reaction in the presence of a palladium catalyst and a base to prepare (F);

[0488] Each R 3a and R 3b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0489] or R 3a and R 3b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0490] Embodiment 40 provides 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;

[0491] Embodiment 41 provides the method of embodiment 39 or 40, wherein the palladium catalyst comprises Pd(dppf)Cl2.

[0492] Embodiment 42 provides 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%.

[0493] Embodiment 43 provides the method of any one of embodiments 39-42, wherein the base comprises K2CO3.

[0494] Embodiment 44 provides the method of any one of embodiments 39-43, wherein the reaction of (D') and (E') occurs in the presence of a solvent.

[0495] Embodiment 45 provides the method of embodiment 44, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and water.

[0496] Embodiment 46 provides the method of any one of embodiments 39-45, wherein the reaction of (D') and (E') occurs at a temperature of about 55 °C.

[0497] Embodiment 47 provides the method of any one of embodiments 39-46, wherein purification of (F) comprises adding N-acetyl cysteine ​​to the reaction of (D') and (E').

[0498] Embodiment 48 provides the method of any one of embodiments 39-47, wherein the purification of (F) comprises:

[0499] (a) providing crude product (F) in 2-propanol to obtain a dilute crude solution of (F),

[0500] wherein the concentration of the diluted crude solution of (F) is about 100 g / L to about 140 g / L;

[0501] (b) at least partially evaporating the diluted crude solution of (F) to provide 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 further optionally maintaining the temperature for a period of about 1 hour;

[0502] (c) cooling the concentrated crude solution of (F) to a temperature of about 20° C. to about 25° C. to provide a purified (F) slurry; and

[0503] (d) filtering the purified (F) slurry to provide (F).

[0504] Embodiment 49 provides the method of any one of embodiments 39-48, wherein by causing (D):

[0505]

[0506] Where Z 1 Selected from Br and I;

[0507] The compound (D') is prepared by reacting with a borylation agent in the presence of a palladium catalyst and a base.

[0508] Embodiment 50 provides the method of embodiment 49, wherein the borylation reagent comprises bis(pinacolato)diboron.

[0509] Embodiment 51 provides the method of embodiment 49 or 50, wherein the palladium catalyst comprises Pd(dppf)Cl2.

[0510] Embodiment 52 provides the method of any one of embodiments 49-51, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol% to about 7 mol%.

[0511] Embodiment 53 provides the method of any one of embodiments 49-52, wherein the base comprises KOAc.

[0512] Embodiment 54 provides the method of any one of embodiments 49-53, wherein the reaction of (D) and the borylation reagent occurs in the presence of a solvent.

[0513] Embodiment 55 provides the method of embodiment 54, wherein the solvent comprises dimethylformamide (DMF) and / or toluene.

[0514] Embodiment 56 provides the method of any one of embodiments 49-55, wherein the reaction of (D) and the boration agent occurs at a temperature of about 90°C to about 100°C.

[0515] Embodiment 57 provides the method of any one of embodiments 49-56, wherein the purification of (D') comprises at least one of:

[0516] (a) adding N-acetyl cysteine ​​to the reaction of (D) and the borylation reagent; and

[0517] (b) adding activated carbon to the reaction of (D) and the boronating agent.

[0518] Embodiment 58 provides the method of any one of embodiments 49-57, wherein the purification of (D') comprises:

[0519] (a) providing a crude product (D') in a solvent comprising 2-propanol to obtain a crude solution of (D'),

[0520] wherein the crude solution of (D') has a concentration of about 140 g / L to about 180 g / L;

[0521] (c) cooling the crude solution of (D') to a temperature of about 0°C to about 5°C to provide a purified (D') slurry; and

[0522] (d) filtering the purified (D') slurry to provide (D').

[0523] Embodiment 59 provides the method of any one of embodiments 28-38 and 49-58, wherein by making 1-(B(OR 4a )(OR 4b ))-2-Chloro-3-Z 1 -Benzene (B):

[0524]

[0525] and 6-Z 2 -2-Methoxynicotinaldehyde (C):

[0526]

[0527] Reaction in the presence of a palladium catalyst and a base to prepare (D);

[0528] Where Z 1 Selected from Br and I;

[0529] Where Z2 is selected from Cl, Br and I;

[0530] Each R 4a and R 4b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0531] or R 4a and R 4b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

[0532] Embodiment 60 provides the method of embodiment 59, wherein (B) is 2-(3-bromo-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0533] Embodiment 61 provides the method of embodiment 59 or 60, wherein the palladium catalyst comprises Pd(PPh3)4.

[0534] Embodiment 62 provides 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 %.

[0535] Embodiment 63 provides the method of any one of embodiments 59-62, wherein the base comprises K2CO3.

[0536] Embodiment 64 provides the method of any one of embodiments 59-63, wherein the reaction of (B) and (C) occurs in the presence of a solvent.

[0537] Embodiment 65 provides the method of embodiment 64, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

[0538] Embodiment 66 provides the method of any one of embodiments 59-65, wherein the reaction of (B) and (C) occurs at a temperature of about 50°C to about 60°C.

[0539] Embodiment 67 provides the method of any one of embodiments 59-66, wherein the purification of (D) comprises adding N-acetyl cysteine ​​to the reaction of (B) and (C).

[0540] Embodiment 68 provides the method of any one of embodiments 59-67, wherein the purifying of (D) comprises:

[0541] (a) providing a crude product (D) in a solvent comprising 2-propanol to obtain a dilute crude solution of (D),

[0542] wherein the concentration of the diluted crude solution of (D) is from about 160 g / L to about 220 g / L;

[0543] (b) at least partially evaporating the diluted crude solution of (D) to provide 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 further optionally maintaining the temperature for a period of about 1 hour;

[0544] (c) cooling the concentrated crude solution of (D) to a temperature of about 20° C. to about 25° C. to provide a purified slurry of (D); and

[0545] (d) filtering the purified (D) slurry to provide (D).

[0546] Embodiment 69 provides the method of any one of embodiments 59-68, wherein (B) is prepared by:

[0547] (a) Make 1-Z 1 -2-Chloro-3-Z 1 -Benzene (A):

[0548]

[0549] Where Z 1 Each occurrence of is independently selected from Br and I;

[0550] reacting with an organomagnesium halide to form an arylmagnesium intermediate; and

[0551] (b) reacting the aryl magnesium intermediate with a borate ester.

[0552] Embodiment 70 provides the method of embodiment 69, wherein the borate ester is:

[0553]

[0554] Each R 5a , R 5b and R 5c Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0555] Or choose R 5a , R 5b and R 5c Any two of the may be combined with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl.

[0556] Embodiment 71 provides the method of embodiment 69 or 70, wherein the boronate ester comprises 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0557] Embodiment 72 provides the method of any of embodiments 69-71, wherein the organomagnesium halide comprises i-PrMgCl, wherein the i-PrMgCl is optionally a solution comprising i-PrMgCl complexed with LiCl (ie, i-PrMgCl.LiCl solution).

[0558] Embodiment 73 provides the method of any one of embodiments 69-72, wherein the reaction of (A) and the organic magnesium halide occurs in a solvent.

[0559] Embodiment 74 provides the method of embodiment 73, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0560] Embodiment 75 provides the method of any one of embodiments 69-74, wherein the reaction of (A) and the organomagnesium halide occurs at a temperature of about -25°C to about -15°C.

[0561] Embodiment 76 provides the method of any one of embodiments 69-75, wherein the reaction of the aryl magnesium intermediate and the borate occurs at a temperature of about -18°C to about -15°C, wherein the reaction is optionally subsequently warmed to a temperature of about 2°C.

[0562] Embodiment 77 provides the method of any one of embodiments 28-38 and 49-58, wherein (D) is prepared by:

[0563] (a) Provide 1-Z 1 -2-Chloro-3-Z 1 -Benzene (A):

[0564]

[0565] Where Z 1 Each occurrence of is independently selected from Br and I;

[0566] and an organomagnesium halide to form an arylmagnesium intermediate;

[0567] (b) reacting the aryl magnesium intermediate with a borate ester to provide a borate ester intermediate; and

[0568] (c) making the boronate intermediate and 6-Z 2 -2-Methoxynicotinaldehyde (C):

[0569]

[0570] Where Z 2 is selected from Cl, Br and I;

[0571] The reaction is carried out in the presence of a palladium catalyst and a base.

[0572] Embodiment 78 provides 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 (ie, i-PrMgCl.LiCl solution).

[0573] Embodiment 79 provides the method of embodiments 77 and 78, wherein the reaction of (A) and the organomagnesium halide occurs in a solvent.

[0574] Embodiment 80 provides the method of embodiment 79, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF).

[0575] Embodiment 81 provides the method of any of embodiments 77-80, wherein the reaction of (A) and the organomagnesium halide occurs at a temperature of about -25°C to about -15°C.

[0576] Embodiment 82 provides the method of any of embodiments 77-81, wherein the reaction of the aryl magnesium intermediate and the borate occurs at a temperature of about -18°C to about -15°C, wherein the reaction is optionally subsequently warmed to a temperature of about 2°C.

[0577] Embodiment 83 provides the method of any one of embodiments 77-82, wherein the borate ester is:

[0578]

[0579] Each R 5a , R 5b and R 5c Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl,

[0580] Or choose R 5a , R 5b and R 5c Any two of the may be combined with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl.

[0581] Embodiment 84 provides the method of any one of embodiments 77-83, wherein the boronate ester comprises 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0582] Embodiment 85 provides the method of any one of embodiments 77-84, wherein the palladium catalyst comprises Pd(PPh3)4.

[0583] Embodiment 86 provides the method of any one of embodiments 77-85, wherein the palladium catalyst is present in an amount ranging from about 0.1 mol % to about 5 mol %.

[0584] Embodiment 87 provides the method of any one of embodiments 77-86, wherein the base comprises K2CO3.

[0585] Embodiment 88 provides the method of any one of embodiments 77-87, wherein the reaction of the boronate intermediate and (C) occurs in the presence of a solvent.

[0586] Embodiment 89 provides the method of embodiment 88, wherein the solvent comprises 2-methyltetrahydrofuran (MeTHF) and / or water.

[0587] Embodiment 90 provides the method of any one of embodiments 77-89, wherein the reaction of the boronate intermediate and (C) occurs at a temperature of about 50°C to about 60°C.

[0588] Embodiment 91 provides the method of any one of embodiments 77-90, wherein purification of (D) comprises adding N-acetyl cysteine ​​to the reaction of (C) and the boronate intermediate.

[0589] Embodiment 92 provides the method of any one of embodiments 77-91, wherein the purifying of (D) comprises:

[0590] (a) providing a crude product (D) in a solvent comprising 2-propanol to obtain a dilute crude solution of (D),

[0591] wherein the concentration of the diluted crude solution of (D) is from about 160 g / L to about 220 g / L;

[0592] (b) at least partially evaporating the diluted crude solution of (D) to provide 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 further optionally maintaining the temperature for a period of about 1 hour;

[0593] (c) cooling the concentrated crude solution of (D) to a temperature of about 20° C. to about 25° C. to provide a purified slurry of (D); and

[0594] (d) filtering the purified (D) slurry to provide (D).

[0595] The terms and expressions used herein are descriptive rather than limiting, and the use of these terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications can be made within the scope of the embodiments of the present application. Therefore, it should be understood that although the present application describes specific embodiments and optional features, those of ordinary skill in the art may make modifications and variations to the compositions, methods, and concepts disclosed herein, and such modifications and variations are considered to be within the scope of the embodiments of the present application.

Claims

1. A method 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) or its salt or solvate: The method comprises making 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): The reaction is carried out in the presence of a reducing agent and a base to generate a first reaction system including (K).

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

3. The method of claim 1 or 2, wherein the base comprises NaOMe or i-PrNEt2.

4. The method according to any one of claims 1 to 3, wherein (J) is selected from 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 methanesulfonate and 2,6-diazaspiro[3.4]octan-7-one toluenesulfonate.

5. The method according to any one of claims 1 to 4, wherein the reaction of (I) and (J) occurs in the presence of a solvent.

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. The method according to any one of claims 1 to 6, wherein the purification of (K) comprises: (a) adding water to the first reaction system comprising (K) to generate a biphasic solution; (b) separating the biphasic solution to provide a first aqueous phase and a first organic phase; (c) adding an organic solvent to the first aqueous phase to provide a second biphasic solution; (d) basifying the second biphasic solution to a pH of 8-11 to provide an alkalized biphasic solution; and (e) separating the basified biphasic solution to provide a second aqueous phase and a second organic phase comprising (K).

8. The method according to any one of claims 1 to 7, wherein the purification of (K) comprises: (a) providing a crude product (K) in a solvent comprising 2-propanol to obtain a dilute crude solution of (K), wherein the concentration of the diluted crude solution of (K) is from about 110 g / L to about 140 g / L; (b) at least partially evaporating the dilute crude solution of (K) to provide a concentrated crude solution of (K), wherein the concentration of the concentrated crude solution of (K) is from about 220 g / L to about 280 g / L; (c) cooling the concentrated crude solution of (K) to a temperature of about 20° C. to provide a purified slurry of (K); and (d) filtering the purified (K) slurry to provide (K).

9. The method according to any one of claims 1 to 7, wherein the purification of (K) comprises: (a) providing a crude product (K) in a solvent comprising MeOH to obtain a crude solution of (K), wherein 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 provide a hot crude solution of (K); (c) cooling the hot crude solution of (K) to a temperature of about 20° C. to provide a cooled slurry of (K); (d) adding a solvent comprising methyl tert-butyl ether (MTBE) to the cooled (K) slurry to provide a purified (K) slurry; and (e) filtering the purified (K) slurry to provide (K).

10. The method according to any one of claims 1 to 9, wherein the 2-methoxy-4-(B(OR 1a )(OR 1b ))-Benzaldehyde(H): and 6-(2-chloro-3-(2,3-dichloropyridin-4-yl)phenyl)-2-methoxynicotinaldehyde (F): Reaction in the presence of a palladium catalyst and a base to prepare (I); Each R 1a and R 1b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl, or R 1a and R 1b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

11. The method of claim 10, wherein the palladium catalyst comprises Pd(PPh3)4.

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 method of any one of claims 10-12, wherein the base comprises K2CO3.

14. The process according to any one of claims 10 to 13, wherein the reaction of (H) and (F) occurs in the presence of a solvent.

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

16. The method of any one of claims 10-15, wherein the reaction of (H) and (F) occurs at a temperature of about 65°C to about 70°C.

17. The method of any one of claims 10-16, wherein purification of (I) comprises adding N-acetyl cysteine ​​to the reaction of (H) and (F).

18. The method according to any one of claims 10 to 17, wherein the 4-Z 2 -2-Methoxybenzaldehyde (G): Where Z 2 is selected from Cl, Br and I; The compound (H) can be prepared by reacting with a borylation agent in the presence of a palladium catalyst and a base.

19. The method of claim 18, wherein the borylation agent comprises bis(pinacolato)diboron.

20. The method of claim 18 or 19, wherein the palladium catalyst comprises Pd(dppf)Cl2.

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

23. The method of any one of claims 18-22, wherein the reaction of (G) and the boronating agent occurs in the presence of a solvent.

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

25. The method of any one of claims 18-24, wherein the reaction of (G) and the boronating agent occurs at a temperature of about 80°C to about 90°C.

26. The method of any one of claims 18-25, wherein the purification of (H) comprises at least one of: (a) adding N-acetyl cysteine ​​to the reaction of (G) and the borylation reagent; and (b) adding activated carbon to the reaction of (G) and the boronating agent.

27. The method of any one of claims 18-26, wherein the purification of (H) comprises: (a) providing crude (H) in a solvent comprising 2-propanol to obtain a dilute crude solution of (H), wherein the concentration of the diluted crude solution of (H) is from about 390 g / L to about 430 g / L; (b) at least partially evaporating the diluted crude solution of (H) to provide 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 further optionally maintaining the temperature for a period of about 1.5 h; (c) cooling the concentrated crude solution of (H) to a temperature of about 6° C. to provide a purified (H) slurry, wherein the cooling optionally occurs over a period of about 3 hours; and (d) filtering the purified (H) slurry to provide (H).

28. The method according to any one of claims 10 to 17, wherein the 1 -2-chlorophenyl)-2-methoxynicotinaldehyde (D): Where Z 1 Selected from Br and I; and 2,3-dichloro-4-(B(OR 2a )(OR 2b ))-Pyridine (E): Reaction in the presence of a palladium catalyst and a base to prepare (F); Each R 2a and R 2b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl, or R 2a and R 2b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

29. The method according to claim 28, wherein R 2a and R 2b Each is independently H.

30. The method of claim 28 or 29, wherein the palladium catalyst comprises Pd(amphos)Cl2.

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 method of any one of claims 28-31, wherein the base comprises K2HPO4.

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

34. The method of any one of claims 28-33, wherein the reaction of (D) and (E) occurs in the presence of a solvent.

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

36. The method of any one of claims 28-35, wherein the reaction of (D) and (E) occurs at a temperature of about 65°C to about 70°C.

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

38. The method of any one of claims 28-37, wherein the purification of (F) comprises: (a) providing a crude product (F) in a solvent comprising 2-propanol to obtain a dilute crude solution of (F), wherein the concentration of the diluted crude solution of (F) is about 100 g / L to about 150 g / L; (b) at least partially evaporating the diluted crude solution of (F) to provide 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 further optionally maintaining the temperature for a period of about 1 hour; (c) cooling the concentrated crude solution of (F) to a temperature of about 20° C. to about 25° C. to provide a crude (F) slurry, wherein the cooling optionally occurs over a period of about 3 hours; and (d) filtering the crude (F) slurry to provide (F), wherein the filtering optionally further comprises washing with a solvent comprising 2-propanol.

39. The method according to any one of claims 10-17, wherein the 3a )(OR 3b ))phenyl)-2-methoxynicotinaldehyde (D'): and 2,3-dichloro-4-Z 1 -Pyridine (E'): Where Z 1 Selected from Br and I; Reaction in the presence of a palladium catalyst and a base to prepare (F); Each R 3a and R 3b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl, or R 3a and R 3b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

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 method of claim 39 or 40, wherein the palladium catalyst comprises Pd(dppf)Cl2.

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 method of any one of claims 39-42, wherein the base comprises K2CO3.

44. The method of any one of claims 39-43, wherein the reaction of (D') and (E') occurs in the presence of a solvent.

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

46. ​​The method of any one of claims 39-45, wherein the reaction of (D') and (E') occurs at a temperature of about 55°C.

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

48. The method of any one of claims 39-47, wherein the purification of (F) comprises: (a) providing crude product (F) in 2-propanol to obtain a dilute crude solution of (F), wherein the concentration of the diluted crude solution of (F) is about 100 g / L to about 140 g / L; (b) at least partially evaporating the diluted crude solution of (F) to provide 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 further optionally maintaining the temperature for a period of about 1 hour; (c) cooling the concentrated crude solution of (F) to a temperature of about 20° C. to about 25° C. to provide a purified (F) slurry; and (d) filtering the purified (F) slurry to provide (F).

49. The method of any one of claims 39-48, wherein the step of: Where Z 1 Selected from Br and I; The compound (D') is prepared by reacting with a borylation agent in the presence of a palladium catalyst and a base.

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

51. The method of claim 49 or 50, wherein the palladium catalyst comprises Pd(dppf)Cl2.

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

54. The method of any one of claims 49-53, wherein the reaction of (D) and the borylation agent occurs in the presence of a solvent.

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

56. The method of any one of claims 49-55, wherein the reaction of (D) and the boronating agent occurs at a temperature of about 90°C to about 100°C.

57. The method of any one of claims 49-56, wherein purification of (D') comprises at least one of: (a) adding N-acetyl cysteine ​​to the reaction of (D) and the borylation reagent; and (b) adding activated carbon to the reaction of (D) and the boronating agent.

58. The method of any one of claims 49-57, wherein the purification of (D') comprises: (a) providing a crude product (D') in a solvent comprising 2-propanol to obtain a crude solution of (D'), wherein 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 provide a purified (D') slurry; and (d) filtering the purified (D') slurry to provide (D').

59. The method according to any one of claims 28-38 and 49-58, wherein the 4a )(OR 4b ))-2-Chloro-3-Z 1 -Benzene (B): and 6-Z 2 -2-Methoxynicotinaldehyde (C): Reaction in the presence of a palladium catalyst and a base to prepare (D); Where Z 1 Selected from Br and I; Where Z 2 is selected from Cl, Br and I; Each R 4a and R 4b Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl, or R 4a and R 4b Can combine with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl group.

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 method of claim 59 or 60, wherein the palladium catalyst comprises Pd(PPh3)4.

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 method of any one of claims 59-62, wherein the base comprises K2CO3.

64. The method of any one of claims 59-63, wherein the reaction of (B) and (C) occurs in the presence of a solvent.

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

66. The method of any one of claims 59-65, wherein the reaction of (B) and (C) occurs at a temperature of about 50°C to about 60°C.

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

68. The method of any one of claims 59-67, wherein the purification of (D) comprises: (a) providing a crude product (D) in a solvent comprising 2-propanol to obtain a dilute crude solution of (D), wherein the concentration of the diluted crude solution of (D) is from about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to provide 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 further optionally maintaining the temperature for a period of about 1 hour; (c) cooling the concentrated crude solution of (D) to a temperature of about 20° C. to about 25° C. to provide a purified slurry of (D); and (D) filtering the purified (D) slurry to provide (D).

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

70. The method of claim 69, wherein the borate ester is: Each R 5a , R 5b and R 5c Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl, Or choose R 5a , R 5b and R 5c Any two of the may be combined with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl.

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

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

73. The method of any one of claims 69-72, wherein the reaction of (A) and the organomagnesium halide occurs in a solvent.

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

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

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

77. The method of any one of claims 28-38 and 49-58, wherein (D) is prepared by: (a) Provide 1-Z 1 -2-Chloro-3-Z 1 -Benzene (A): Where Z 1 Each occurrence of is independently selected from Br and I; and an organomagnesium halide to form an arylmagnesium intermediate; (b) reacting the aryl magnesium intermediate with a borate ester to provide a borate ester intermediate; and (c) making the boronate intermediate and 6-Z 2 -2-Methoxynicotinaldehyde (C): Where Z 2 is selected from Cl, Br and I; The reaction is carried out in the presence of a palladium catalyst and a base.

78. The method of claim 77, wherein the organic magnesium halide comprises i-PrMgCl, wherein the i- PrMgCl Optionally, it is a solution comprising i-PrMgCl complexed with LiCl (ie, i-PrMgCl.LiCl solution).

79. The process of any one of claims 77 and 78, wherein the reaction of (A) and the organomagnesium halide occurs in a solvent.

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

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

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

83. The method of any one of claims 77-82, wherein the borate ester is: Each R 5a , R 5b and R 5c Each is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl, Or choose R 5a , R 5b and R 5c Any two of the may be combined with the atoms to which they are bonded to form a C2-C3 heterocycloalkyl.

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

85. The method of any one of claims 77-84, wherein the palladium catalyst comprises Pd(PPh3)4.

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 method of any one of claims 77-86, wherein the base comprises K2CO3.

88. The method of any one of claims 77-87, wherein the reaction of the boronate intermediate and (C) occurs in the presence of a solvent.

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

90. The method of any one of claims 77-89, wherein the reaction of the boronate intermediate and (C) occurs at a temperature of about 50°C to about 60°C.

91. The method of any one of claims 77-90, wherein purification of (D) comprises adding N-acetyl cysteine ​​to the reaction of (C) and the boronate intermediate.

92. The method of any one of claims 77-91, wherein the purifying of (D) comprises: (a) providing a crude product (D) in a solvent comprising 2-propanol to obtain a dilute crude solution of (D), wherein the concentration of the diluted crude solution of (D) is from about 160 g / L to about 220 g / L; (b) at least partially evaporating the diluted crude solution of (D) to provide 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 further optionally maintaining the temperature for a period of about 1 hour; (c) cooling the concentrated crude solution of (D) to a temperature of about 20° C. to about 25° C. to provide a purified slurry of (D); and (d) filtering the purified (D) slurry to provide (D).

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