WO2010135350A2

WO2010135350A2 - Biphenyl intermediate compounds and methods for the preparation of a dual angiotensin ii and endothelin a receptor antagonist

Info

Publication number: WO2010135350A2
Application number: PCT/US2010/035294
Authority: WO
Inventors: Lin Zhi; Jason Pickens; Cornelius A. Van Oeveren; Ian Henderson
Original assignee: Pharmacopeia, Llc
Priority date: 2009-05-20
Filing date: 2010-05-18
Publication date: 2010-11-25
Also published as: WO2010135350A3

Abstract

Disclosed herein are methods and compounds useful in preparing N-(3,4-dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en-3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide.

Description

BIPHENYL INTERMEDIATE COMPOUNDS AND METHODS FOR THE PREPARATION OF A DUAL ANGIOTENSIN II AND ENDOTHELIN A

RECEPTOR ANTAGONIST

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 61/179,927, filed May 20, 2009, which is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

[0002] This invention relates to compounds and methods that may be useful in making therapeutically active compounds such as N-(3,4-dimethyl-5-isoxazolyl)-2-(4-(2- butyl-4-oxo-l,3-diazospiro[4.4]non-l-en-3yl)methyl-2 ethoxymethylphenyl)phenylsulfonamide (Compound 1), a dual angiotensin II and endothelin A receptor antagonist (DARA).

Description of the Related Art

[0003] Angiotensin II (Angll) and endothelin- 1 (ET-I) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including diabetic nephropathy, heart failure, chronic or persistently evaluated blood pressure. Currently, angiotensin receptor blockers (ARBs), which block the activity of Angll, are widely used as a treatment for diabetic nephropathy, heart failure, chronic or persistently evaluated blood pressure. In addition, there is a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET-I activity.

[0004] It is also known that Angll and ET-I work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of Angll at its receptor, but also limit the production of ET-I. Similarly, ERAs block ET- 1 activity and inhibit the production of Angll. Consequently, simultaneously blocking Angll and ET-I activities may offer better efficacy than blocking either substance alone. [0005] In well-validated rat models of human hypertension, the combination of an ARB and an ERA results in a synergistic effect. Furthermore, although ARBs are the standard of care for patients with diabetic nephropathy, improved efficacy with the coadministration of an ERA has been reported in Phase 2 clinical development.

[0006] There are preclinical and initial clinical data suggesting that compared to either mechanism alone, simultaneously blocking angiotensin II and endothelin 1 at their respective receptors, ATI and ETA, may provide an improved treatment option for several cardiovascular diseases.

[0007] N-(3,4-dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3- diazospiro[4.4]non-l-en-3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1) is a dual angiotensin II and endothelin A receptor antagonist (DARA), and thus may provide this improved treatment option for several cardiovascular diseases.

SUMMARY OF THE INVENTION

[0008] Some embodiments provide a method of preparing Compound 1 :

this method comprises reacting a compound with a suitable co-reactant described herein, wherein the compound is represented by any of Formulas I- VI:

(Formula I) (Formula II) (Formula III) (Formula IV)

(Formula V) (Formula VI) or a salt thereof; wherein R¹ is halo or OR^A; R^A is hydrogen or R^D; R² and R³ are independently CH₃, CH₂F, CH₂Cl, CH₂Br, CH₂I, CH₂OR^B, CHO, CO₂R^B, CONR^BR^C, CH(NR^B)OR^C, CH(OR^B)OR^C, C(OR^B)₂OR^C, or CN; each R^B and each R^c are independently hydrogen, R^D, C0R^D, or SO₂R^D; each R^D is independently optionally substituted C₁-Cg alkyl, optionally substituted C₁-C₈ heteroalkyl, or optionally substituted aryl; R⁴ is Cl, Br, I, or OSO₂R⁰; and R⁵ is halogen, OH, OCOR⁰, or OSO₂R⁰.

[0009] Some embodiments provide compound 1, prepared according to a method disclosed herein. Some embodiments provide a compound of Formula I, II, III, IV, V, or VI. Some embodiments provide a composition comprising at least two different compounds, wherein: each of the two compounds is represented by Formula I, II, III, or IV; or each of the two compounds is represented by any of Formulas V or VI.

[0010] These and other embodiments are described in greater detail below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. Herein, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting.

[0012] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose. Definitions

[0013] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0014] As used herein, the following terms are defined with the following meanings, unless expressly stated otherwise.

[0015] The term "optionally substituted," refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) which are independently selected from: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may be linked to form a ring. In some of these embodiments, the substituent has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. In some embodiments, any substituents are halo, nitro, CN, CO₂H, optionally substituted Cj- _I2 alkyl, Ci_-6 alkyl, or Ci_-3 alkyl, optionally substituted C_{M 2} heteroalkyl, Ci_-6 heteroalkyl, Ci_-3 heteroalkyl, or optionally substituted C_4-I0 aryl.

[0016] The term "alkyl," alone or in combination, refers to a hydrocarbon moiety having no double or triple bonds. In certain embodiments, alkyls are optionally substituted. Whenever it appears herein, a numerical range, such as "1 to 8" or "Ci-C₈", refers to each integer in the given range; e.g., "Cj-C₈ alkyl" means that an alkyl group comprises only 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms). Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. Examples of substituted alkyls include alkoxy alkyls wherein the alkoxy portion is C_1-6 alkoxy such as methoxy, ethoxy, propoxy isomers, butoxy isomers, etc.; hydroxylalkyls such as hydroxymethyl, hydroxy ethyl, hydroxypropyl isomers, hydroxybutyl isomers, hydroxypentyl isomers, hydroxyhexyl isomers, etc.; alkyl halides such as monohaloalkyl (such as chloromethyl, chloroethyl isomers, chloropropyl isomers, etc.); fluoroalkyl (such as CH_2F, CHF₂, CH₂CF₃, etc.) or perfluoroalkyl (e.g. CF₃, CF₂CF₃, C₃F₇, C₄F₉, etc.),

[0017] The term "heteroalkyl" alone or in combination, refers to alkyl wherein at least one carbon atom, and optionally, one or more hydrogens attached to the carbon atom, is replaced by at least heteroatom. For example, in some embodiments heteroalkyl may be alkyl wherein at least one carbon or hydrogen atom is replaced by at least one of

0, S, N, F, Cl, Br, or I. In some embodiments, heteralkyl refers to alkyl having at least one of the following heteratom replacements: 1) replacing a C with N⁺ (e.g. CH₂NH₃ ⁺ instead of CH₂CH₃), 2) replacing a CH with N (e.g. -NHCH₃ instead Of-CH₂CH₃), or 3) replacing a CH₂ with O or S (e.g. CH₂OCH₃ instead of CH₂CH₂CH₃). Whenever it appears herein, a numerical range, such as "1 to 8" or "Ci-C₈", refers to each integer in the given range; e.g., "Ci-C₈ heteroalkyl" means that a heteroalkyl group comprises only

1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms). Examples of heteralkyl include ethers such as alkoxyl and glycol ethers, thioethers, alcohols, polyols, thiols, etc.

[0018] The term "aryl" refers to an aromatic ring or ring system, as ordinarily understood by those of ordinary skill in the art. In some embodiments, this refers to a group comprising a covalently closed planar ring having a delocalized π-electron system comprising 4n+2 π electrons, where n is an integer (e.g. 2, 6, 10, 14, etc.). Aryl rings or ring systems may be formed by five, six, seven, eight, nine, or more than nine atoms. Aryl may be optionally substituted. Examples of aryl, or aromatic groups include, carbocyclic aryl such as phenyl, naphthyl, etc; or heteroaryl such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, quinoxaline, etc. Since aryl may be optionally substituted, it may carry any substituent. In some embodiments, the substituents on aryl may include a carboxylic aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci_-6 alkoxy, a Ci_-6 alkyl, a Ci_-6 hydroxyalkyl, a Cj_-6 aminoalkyl, a Cj_-6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, aryl is substituted at one or more of the para, meta, and/or ortho positions. Examples of aryl comprising substitutions include, but are not limited to, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4- cyanophenyl, dimethylphenyl, hydroxynaphthyl, hydroxymethylphenyl,

(trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l-yl)phenyl.

[0019] The term "halo" refers to a halogen atom such as F, Cl, Br, or I.

[0020] The term "salt" has the ordinary meaning understood by those of ordinary skill in the art. In some embodiments, a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some embodiments, a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, 4-(2-hydroxyethyl)-morpholine, l-(2- hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like. In some embodiments, a salt is selected from acetate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, cholinate, clavulanate, citrate, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabanine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subaceatate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, tromethamine, trimethylammonium, and valerate salts.

[0021] The term "base" has the ordinary meaning understood by those of ordinary skill in the art. Examples of a base include, but are not limited to, a metal hydroxide such as sodium hydroxide, lithium hydroxide, calcium hydroxide, etc; a carbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate, etc.; an amine such as ammonia, an alkyl amine, etc.; a metal amide such as lithium bis- trimethylsilylamide, etc; a metal alkoxide such as potassium tert-butoxide; etc.

[0022] The term "transition metal" has the ordinary meaning understood by those of ordinary skill in the art. Examples of transition metals include, but are not limited to, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, Au, Hg, etc.

[0023] The term "metal catalyst" has the ordinary meaning understood by those of ordinary skill in the art. In some embodiments, a metal catalyst is a chemical species comprising a metal such as a coordination compound. In some embodiments, the presence of the metal catalyst accelerates a direct or indirect reaction between: two or more groups on a compound, or a reaction between at least two or more compounds, as compared to the rate of reaction between the groups or compounds without the catalyst.

[0024] As used herein, phrase such as "reacting a compound of Formula IV with Compound A," or a similar term with respect to other compounds, is intended to refer to both direct and indirect reaction. In direct reaction, the compound of Formula IV, as added, directly reacts with Compound A as added. In indirect reaction, at least one additional component (such as a catalyst) in the reaction mixture forms a derivative (such as an activated adduct, a reactive intermediate, etc.) to one or both of the compounds followed by a reaction of one derivative with the other compound or derivative. Similarly, as used herein a phrase such as "an intramolecular reaction of a compound of Formula I which comprises reacting the -SO₂R¹ with R³" is intended to refer to both direct and indirect reaction between -SO₂R¹ and R³, where the two groups may directly react, or one or both groups may form a derivative, and the derivative reacts with the other group or derivative.

[0025] As used herein, the term "protecting group" has the ordinary meaning understood to those of ordinary skill in the art. In some embodiments, a protecting group is a group which is sufficiently stable under the reaction conditions specified to survive the reaction at least long enough to substantially convert a reactant compound into a product compound. In some embodiments, the protecting group is stable under basic conditions and is not reactive to a metal catalyst. Some examples of useful protecting groups include, but are not limited to,

[0026] While compounds of Formulas I, II, III, IV, V, and VI may have many uses, in some embodiments, any of these compounds may be used to prepare Compound 1. Compound 1 is a dual angiotensin II and endothelin A receptor antagonist which may be useful to treat several cardiovascular diseases.

Compound 1

[0027] In any relevant structural formula, R¹ may be halo, such as F, Cl, Br, or I; or alternatively, OR^Λ, wherein R^Λ is independently hydrogen or R^D. In some embodiments R¹ is Cl or OH.

[0028] In any relevant structural formula, R² and R³ may independently be CH₃, CH₂F, CH₂Cl, CH₂Br, CH₂I, CH₂OR⁸, CHO, CO₂R^B, CONR^BR^C, CH(NR^B)OR^C, CH(OR^B)OR^C, C(OR^B)₂OR^C, or CN. In some embodiments, R² is CH₂F, CH₂Cl, CH₂Br, CH₂I, or CH₂OH. In some embodiments, R and R are the same. In some embodiments, R² and R³ are CH₃ or CH₂Br.

[0029] In any relevant structural formula, R and R may be independently hydrogen, R^D, COR^D, SO₂R^D. In some embodiments, R^B and R^c may be optionally linked to form a ring. For example, CONR^BR^C may comprise a structures such as the ones shown below.

[0030] In any relevant structural formula, R⁴ may be Cl, Br, I, or OSO₂R⁰, and R⁵ is halogen, OH, OCOR⁰, or OSO₂R⁰. In some embodiments, R⁴ is Br. In some embodiments, R⁵ is OSO₂R⁰.

[0031] In any relevant structural formula, R° may be optionally substituted Ci-Cg alkyl (e.g. methyl; ethyl; propyl isomers such as n-propyl, isopropyl, etc.; cyclopropyl; butyl isomers; cycloobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.; pentyl isomers; cyclopentyl isomers; hexyl isomers; cyclohexyl isomers; heptyl isomer; cycloheptyl isomers; octyl isomers; cyclooctyl isomers; etc.), optionally substituted Ci-Cg heteroalkyl (e.g. haloalkyl such as perfluoroalkyl, including CF₃, C₂F₅, C₃F₇, C₄F₉, C₅Fn, C₆F₁₃, C₇Fj₅, C₈F_n, etc.; ethers such as -(CH₂CH₂O)_I-8-; etc.), or optionally substituted aryl (e.g. phenyl, including alkylphenyl such as methylphenyl; pyridine; thiophene; furene; etc.). In some embodiments, R° is methyl, ethyl, phenyl, or methylphenyl.

Methods for Preparation of Compound 1

Scheme I

(metal catalyst)

Formula I

[0032] In some embodiments, a compound of Formula VII is directly or indirectly reacted with a compound of Formula VIII. For example, Scheme I shows such an embodiment wherein the reaction optionally occurs in the presence of a metal catalyst. In some embodiments, the reaction of Scheme I may be any standard biaryl coupling reaction. For example, some embodiments comprise standard metal mediated conditions, such as a palladium(O) catalyst in the presence of a phosphine ligand, such as triphenylphosphine. In some embodiments, the compound of Formula VII and the compound of Formula VIII are combined in a solvent and a catalyst is added. In some embodiments, the reaction is carried out in the presence of a base such as aqueous potassium carbonate. [0033] In these embodiments, R² and R³ are as described above. R⁶ is Li, MgCl, MgBr, MgI, a transition metal, Cl, Br, I, or OSO₂R⁰. R⁷ is H, Li, MgCl, MgBr, MgI, a transition metal, F, Cl, Br, I, OH, B(OH)₂, OCOR⁰, or OSO₂R⁰. R^A R^B, R^c and R° are as described above.

[0034] In some embodiments, specific coupling conditions may be selected based on the specific identities of R⁶ and R⁷. For example, in some embodiments, a phenylsufonic acid or ester may be directly ortho lithiated by butyllithium at a reduced temperature such as dry ice temperature (-78 °C) so that R⁷ may be Li. If desired, this compound may then be trans-metalated with zinc or copper so that R⁷ may be Zn or Cu. In embodiments such as those wherein R⁷ is Zn or Cu, compounds of Formula VIII may react with a coupling partner of Formula VII wherein R⁴ is Br or Cl. In other embodiments, a compound of Formula VIII wherein R⁷ is Li may be converted to a boronic acid or ester by addition of a borate so that R⁷ is B(OH)₂). These compounds may react with a compound of Formula VII wherein R⁴ is Br under a palladium catalyzed condition to provide a compound of Formula I.

[0035] In some embodiments, the compound of Formula I may be further modified to provide a derivative compound for conversion to a compound of Formula II. In some embodiments, the derivative compound is also represented by Formula I.

[0036] Some embodiments provide a composition comprising a compound of Formula VII and a compound of Formula VIII. Some embodiments provide a composition comprising a compound of Formula VII and a compound of Formula I. Some embodiments provide a composition comprising a compound of Formula VIII and a compound of Formula I. Some embodiments provide a composition comprising at least two different compounds, wherein each compound is represented by Formula I. For example, in some embodiments, the composition may comprise a first compound and a second compound, wherein both compounds are represented by Formula I, and wherein R¹ is isopropyl in the first compound and R¹ is OH in the second compound. In some embodiments, the composition may comprise a first compound and a second compound, wherein both compounds are represented by Formula I, and wherein both of R² and R³ are CH₃ in the first compound, and at least one of R² and R³ is CH₂Br in the second compound. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc. Scheme II

group

⁴ Formula Il 5

[0037] In some embodiments, the compound of Formula I, prepared as described above or by some other method, undergoes a process comprising an intramolecular reaction used to provide the compound of Formula II. In these embodiments, the intramolecular reaction may comprise reacting SO₂R¹ with R³.

[0038] Scheme II depicts some embodiments related to the direct or indirect intramolecular reaction of compounds of Formula I. In some embodiments, the cyclic structure of compounds of Formula II may be generated via an intramolecular cyclization of 4 (a compound of Formula I where R³ may be methyl with a leaving group and R¹ may be hydroxyl) such that an oxygen of the sulfonic acid moiety acts as a nucleophile to displace the leaving group. If compound 4 is prepared using the process described in Scheme I above, the leaving group may be either introduced before or after the biaryl coupling reaction, and sulfonate oxygen as the nucleophile (as indicated as structure 4). In other embodiments, R³ may be hydroxymethyl, wherein the hydroxyl moiety as the nucleophile and R¹ may serve as the leaving group (as indicated as structure 5).

[0039] In some embodiments, the compound of Formula II may be further modified to provide a derivative compound for conversion to a compound of Formula III. In some embodiments, the derivative compound is also represented by Formula II.

[0040] Some embodiments provide a composition comprising a compound of Formula I and a compound of Formula II. Some embodiments provide a composition comprising at least two different compounds, wherein each compound is represented by Formula II. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc. Scheme III

ethanol

Formula III

[0041] In some embodiments, the compound of Formula II, prepared as described above or by some other method, is directly or indirectly reacted with ethanol to provide the compound of Formula III, as shown in Scheme III. In some embodiments, the reaction is carried out at an elevated temperature such as at least about 40°C, about 50°C, or about 60⁰C to about 8O⁰C, about 100⁰C, or about 200⁰C. In some embodiments, R¹ is OH or OEt.

[0042] In some embodiments, the compound of Formula III may be further modified to provide a derivative compound for conversion to a compound of Formula IV. In some embodiments, the derivative compound is also represented by Formula III.

[0043] Some embodiments provide a composition comprising a compound of Formula II and a compound of Formula III. Some embodiments comprise at least two different compounds, each represented by Formula III. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc. Scheme IV

[0044] In some embodiments, the compound of Formula III, prepared as described above or by some other method, is directly or indirectly reacted with Compound B to provide the compound of Formula IV. Scheme IV depicts some embodiments related to this reaction. In some of these embodiments, compounds of Formula III may be further represented by structure 6, wherein R² may be a methyl with a substituent which is a leaving group such as bromide, chloride, an alcohol derivative, etc. If the compound of Formula III is prepared by the ring opening reaction described above in Scheme III, the leaving group may be introduced either before or after that reaction. Treatment of compounds of structure 6 with compound B (either in the form of a free base or salt) yields compounds of Formula IV. In some embodiments, this reaction, or any reaction of a compound of Formula III with Compound B, occurs in the presence of a base.

[0045] In some embodiments, the compound of Formula IV may be further modified to provide derivative compound for conversion to Compound 1. In some embodiments, the derivative compound is also represented by Formula IV.

[0046] Some embodiments provide a composition comprising a compound of Formula III and a compound of Formula IV. Some embodiments provide a composition comprising a compound of Formula III and Compound B. Some embodiments provide a composition comprising a compound of Formula IV and Compound B. Some embodiments provide a composition comprising at least two different compounds, wherein each compound is represented by Formula IV. For example, in some embodiments, the composition may comprise a first compound and a second compound, wherein both compounds are represented by Formula IV, and wherein R¹ is OH in the first compound, and R¹ is Cl, Br, or I in the second compound. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc. Scheme V

Formula IV 1

[0047] In some embodiments, the compound of Formula IV, prepared as described above or by some other method, is directly or indirectly reacted with Compound A to provide Compound 1. Scheme V depicts one embodiment related to this process. In some embodiments, R¹ may be Cl which reacts with the aminoisoxazole of compound A in the presence of a base to give Compound 1. In some embodiments, this reaction occurs in the presence of a base.

[0048] Some embodiments provide a composition comprising a compound of Formula IV and Compound 1. Some embodiments provide a composition comprising a compound of Formula IV and Compound A. Some embodiments provide a composition comprising a Compound A and Compound 1. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc.

Alternative Methods for Preparation of Compound 1 Scheme VI

Formula Vl

[0049] In some embodiments, the compound of Formula V is directly or indirectly reacted with Compound B to provide a compound of Formula VI, as depicted in Scheme VI. In some embodiments, this reaction occurs in the presence of a base. [0050] In some embodiments, the compound of Formula VI may be further modified to provide derivative compound for conversion to Compound 1. In some embodiments, the derivative compound is also represented by Formula VI.

[0051] Some embodiments provide a composition comprising a compound of Formula V and a compound of Formula VI. Some embodiments provide a composition comprising a compound of Formula V and Compound B. Some embodiments provide a composition comprising a compound of Formula VI and Compound B. Some embodiments provide a composition comprising at least two different compounds, wherein each compound is represented by Formula VI. For example, in some embodiments, the composition may comprise a first compound and a second compound, wherein both compounds are represented by Formula VI, and wherein R is OH in the first compound, and R⁶ is OSO₂R⁰ in the second compound. In some of these embodiments, R^D is Ci_-6 alkyl or optionally substituted phenyl. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc. Scheme VII

Formula Vl

[0052] In some embodiments, the compound of Formula VI, prepared as described above or by some other method, is directly or indirectly reacted with a compound of Formula IX to provide Compound 1, as depicted in Scheme VII.

[0053] With respect to Formula IX, M is H, Li, MgCl, MgBr, MgI, a transition metal or a transition metal ion (such as Pd, Zn, Cu, or ions of these metals), halogen, OH, B(OR^D)OR^E, OCOR⁰, or OSO₂R⁰. R° and R^E can independently be any groups described above for R . R is a protecting group such as methoxymethyl. In some embodiments, the reaction occurs in the presence of a metal catalyst. In some embodiments, compounds of Formula IX may be prepared by a sulfonamide directed ortho metalation, a halogen facilitated metalation, or boron mediated metal insertion.

[0054] Some embodiments provide a composition comprising a compound of Formula VI and Compound 1. Some embodiments provide a composition comprising a compound of Formula VI and a compound of Formula IX. Some embodiments provide a composition comprising a compound of Formula IX and Compound 1. In some embodiments providing a composition with at least two different compounds, the two compounds may represent compounds at different stages of a reaction process, such as a reactant and an intermediate, a reactant and a product, an intermediate and a product, etc.

Examples

[0055] The following examples, including experiments and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention.

Example 1 Isopropyl 2-(2,4-dimethylphenyl)benzenesulfonate (Compound 11)

[0056] A solution of isopropyl 2-(4,4,5,5-tetramethyl-l,3-dioxolan-2- yl)benzenesulfonate (0.65 g, 2.0 mmol, 1.0 equiv) and l-bromo-2,4-dimethylbenzene (0.37 g, 2.1 mmol, 1.05 equiv) in toluene (15 mL) was degassed, and Pd(OAc)₂ was added followed by tri(o-tolyl)phosphine, and 3 mL of a degassed 2N aqueous K₂CO₃ solution. The mixture was stirred at 80⁰C for 20 hours and then water (10 mL) was added and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20:1 hexanes/EtOAc) to afford Compound 11. ¹H NMR (500 MHz, CDCIa) 8.13 (dd, J = 8.1, 1.2 Hz, IH), 7.61 (ddd, J = 7.6, 7.6, 1.4 Hz, IH), 7.50 (ddd, J = 8.1, 7.6, 1.4 Hz, IH), 7.26 (dd, J = 7.5, 1.2 Hz, IH), 7.08-7.01 (m, 3H), 4.73- 4.65 (m, IH), 2.36 (s, 3H), 2.03 (s, 3H), 1.26 (d, J= 6.3 Hz, 3H), 1.15 (d, J= 6.3 Hz, 3H).

Example 2 2-(2,4-Dimethylphenyl)benzenesulfonic acid (Compound 12)

[0057] To a solution of isopropyl 2-(2,4-dimethylphenyl)benzenesulfonate (Compound 11) (0.64 g, 2.1 mmol, 1.0 equiv) in TFA (9 mL) was added 1 rnL of water, and the mixture was stirred at 80-100 °C for 4 hours. The solvent was removed in-vacuo eventually affording the title compound as a tan solid. ¹H NMR (500 MHz, CD3OD) 8.07 (dd, J= 7.5, 1.0 Hz, IH), 7.45 (ddd, J= 7.0, 7.0, 1.5 Hz, IH), 7.39 (ddd, J= 8.0, 7.5, 1.0 Hz, IH), 7.10-7.06 (m, 2H), 6.99 (s, IH), 6.93 (d, J= 7 Hz, IH) 2.31 (s, 3H), 2.01 (s, 3H).

Example 3

( 1 -Bromomethylbenzo [3 ,4-d])benzo [ 1 ,2-fJ -2-oxa- 1 , 1 -dioxo- 1 -thiocycloheptane

(Compound 13)

[0058] A solution of 2-(2,4-dimethylphenyl)benzenesulfonic acid (Compound 12) (0.5 g, 1.9 mmol) in 50 mL of anhydrous acetonitrile was prepared and transferred to a round-bottom flask. After flushing with nitrogen gas, N-bromosuccinimide (0.75 g, 4.2 mmol) was added followed by 50 mg (0.2 mmol) of benzoyl peroxide. The solution was heated at reflux for 3 hours. The solvent was removed in-vacuo and the resulting syrup purified by silica gel chromatography (1 :1 hexanes/EtOAc) to yield Compound 13 as a white solid. ¹H NMR (500 MHz, CD3CN) 8.12 (d, J = 7.5 Hz, IH), 7.92 (t, J = 7.5 Hz, IH), 7.78 (d, J= 7.5 Hz, IH), 7.74-7.71 (m, 2H), 7.68-7.65 (m, 2H), 5.12 (s, 2H), 4.70 (s, 2H). Example 4 2-(4-Bromomethyl-2-ethoxymethylphenyl)benzenesulfonic acid (Compound 14)

[0059] A solution of 20 mg (0.058 mmol) of (l-bromomethylbenzo[3,4- d])benzo[l,2-f]-2-oxa-l,l-dioxo-l-thiocycloheptane (Compound 13) in ethanol was stirred at elevated temperature until the starting material was consumed to give crude product (compound 14) that was used directly in the next step without isolation or purification.

Example 5

2-(4-((2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl>2- ethoxymethylphenyl)benzenesulfonic acid (Compound 15)

[0060] To the above ethanol solution of crude 2-(4-bromomethyl-2- ethoxymethylphenyl)benzenesulfonic acid (Compound 14) described in Example 4 was added approximately 25 mL of anhydrous DMF. The ethanol was removed from the system under reduced pressure. Approximately 15 mg (0.065 mmol) of 2-butyl-l,3- diazaspiro[4.4]non-l-en-4-one (compound 7 in Scheme IV) was added followed by 300 μL of a IM solution of lithium bis-trimethylsilylamide in THF. The solution was allowed to stir at room temperature for 3 hours. The solvents were removed under reduced pressure and the remaining residue purified by preparative RP-HPLC employing a Cl 8 column and gradient elution (H₂O:MeCN) affording the title compound as a white solid; [M+H]+ calcd for C₂₇H₃₄N₂O₅S 499.21, found, 499.31 ; ¹H NMR (500 MHz, CD3CN) 8.04 (t, J= 5.5 Hz, IH), 7.44-7.10 (m, 2H), 7.28 (s, IH), 7.22 (d, J= 8.0 Hz, 2H), 7.08- 7.04 (m, 2H), 4.74 (br s, 2H), 4.32 (d, J= 13.0 Hz IH), 4.13 (d, J= 13.0 Hz IH), 3.40- 3.31 (m, 2H), 2.66 (t, J= 8 Hz, 2H), 2.18-2.13 (m, 5H), 1.96-1.90 (m, 2H obscured by solvent), 1.48 (m, 2H), 1.27 (s, J= 7 Hz, 2H), 1.16 (t, J= 7 Hz, 3H), 0.78 (t, J= 7.5 Hz, 3H).

Example 6

2-(4-((2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl>2- ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16)

[0061] To a solution of DMF (155 μL, 2 mmol, 2 equiv.) in dichloromethane (5 mL) at 0 ⁰C was added dropwise oxalyl chloride (175 μL, 2 mmol, 2 equiv.) followed by a dichloromethane (5 mL) solution of 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l- en-3-yl)methyl)-2-ethoxymethylphenyl)benzenesulfonic acid (Compound 15) (0.50 g, 1.0 mmol). The resulting mixture was stirred at 0 ⁰C for ~2 hours, diluted with additional dichloromethane (25 mL), washed with saturated sodium bicarbonate solution (10 mL), water (10 mL), and brine (10 mL), dried over sodium sulfate, and then concentrated to give crude sulfonyl chloride (compound 16) that was used without purification.

Example 7

N-(3,4-Dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en- 3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1)

[0062] To a solution of 5-amino-3,4-dimethylisoxazole (60 mg, 0.54 mmol) in THF at -60 °C was added dropwise potassium tert-butoxide (1 mL of 1 M solution) followed by a solution of crude 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3- yl)methyl)-2-ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16) (0.28 g, 0.54 mmol) in THF (4 mL). The resulting mixture was stirred at about -60 °C for 1 hour, allowed to warm to room temperature overnight, and then quenched with IN HCl solution to about pH 4. Standard workup of extraction with ethyl acetate, washing with water, drying, and concentration provided the final compounds as a white solid. ¹H NMR (400 MHz, CDCl₃) 8.03 (dd, J = 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J = 7.5, 2H), 1.37 (sextet, J = 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H).

Example 8 l-Bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17)

[0063] To a solution of ethyl 4-bromo-3-ethoxymethylbenzoate (9.4 g, 33 mmol) in toluene (56 mL) at about -10 ⁰C was added 51 g of a 20% diisobutylaluminum hydride solution in toluene (ca. 70 mmol). The reaction was stirred at the same temperature for about 30 minutes until the reduction was completed, and then quenched with icy 5% NaOH solution to keep the temperature below about 10 °C. Organic phase of the resulting mixture was separated and the aqueous phase was extracted with toluene. The combined organic phase was concentrated in vacuo to a final volume of ~60 mL toluene solution of l-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17) that was used in next step without purification.

Example 9 l-Bromo-2-ethoxymethyl-4-methanesulfonyloxymethylbenzene (Compound 18)

[0064] To a solution of 1 -bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17) (8.4 g, 33 mmol) in toluene (60 mL) prepared in Example 8 at about -10 °C was added methanesulfonyl chloride (7.9 g, 68 mmol). The reaction was stirred at the same temperature for about 30 minutes until the reduction was completed, and then quenched with icy water to keep the temperature at about 0 °C. The organic layer was separated and washed again with icy water to provide a crude product solution of 1 - bromo-2-ethoxymethyl-4-methanesulfonyloxymethylbenzene (Compound 18) that was used without purification.

Example 10

1 -Bromo-4-((2-butyl-4-oxo- 1 ,3 -diazaspiro [4.4]non- 1 -en-3 -yl)methy l)-2- ethoxymethylbenzene bisoxalic acid salt (Compound 19)

[0065] To the crude solution of 1 -bromo-2-ethoxymethyl-4- methanesulfonyloxymethylbenzene (Compound 18) (1 1 g, 33 mmol) in toluene (80 mL) prepared in Example 9 was added a 75% solution of methyltributylammonium chloride in water (0.47 mL). The resulting mixture was added to a solution of 2-butyl-4-oxo-l,3- diazaspiro[4.4]non-l-ene (compound 7 in Scheme VI) (7.5 g, 32 mmol) in dichloromethane (33 mL) pretreated with a 10 M NaOH solution (23 mL). The reaction mixture was stirred at room temperature for 2 hours until compound 18 was not longer detectable by HPLC analysis and then was quenched with water (40 mL). After stirring about 10 minutes, the organic layer was separated and aqueous layer was extracted with toluene. The combined organic phase was washed with water and concentrated to a small volume. Filtration through a silica gel pad using ethyl acetate as solvent followed by concentration yielded 1 -bromo-4-((2-buty 1-4-oxo- 1 ,3 -diazaspiro [4.4]non- 1 -en-3 - yl)methyl)-2-ethoxymethylbenzene as a crude oil product.

[0066] The crude oil was dissolved in ethyl acetate (22 mL) and warmed to around 50 °C. Anhydrous oxalic acid (4.6 g) was added to the warm solution at once and the resulting mixture was stirred until a solution was obtained. The mixture was cooled gradually and the bisoxalic acid salt (compound 19) was crystallized. Filtration and drying provided pure product (compound 19) in 50-60% yield from ethyl 4-bromo-3- ethoxymethylbenzoate in 3 steps. ¹H NMR (400 MHz, CDCl₃) 12.32 (bs, 4H), 7.58 (d, J = 7.8, IH), 7.36 (s, IH), 7.12 (d, J= 7.8, IH), 4.90 (s, 2H), 4.56 (s, 2H), 3.68 (q, J= 7.5, 2H), 2.87-2.77 (m, 2H), 2.40-1.95 (m, 8H), 1.62-1.53 (m, 2H), 1.38-1.28 (m, 4H), and 1.82 (t, J= 7.5, 3H).

Example 11

[0067] To a suspension of l-bromo-4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non- l-en-3-yl)methyl)-2-ethoxymethylbenzene bisoxalic acid salt (Compound 19) (5.0 g, 8.3 mmol) in toluene (20 niL) under nitrogen was added water (30 mL) and pH was adjusted to 8-9 by addition of a 2 M NaOH solution at room temperature. The organic phase was separated and mixed with 2-(N-(3,4-dimethyl-5-isoxazolyl)-N- methoxymethylamino)sulfonylphenylboronic acid pinacol ester (Scheme VII, Formula IX, where R⁸ is methoxymethyl and M = boronic acid pinacol ester) (3.6 g, 8.5 mmol), bis(dibenzylideneacetone)palladium(0) (Pd(dba)₂) (0.12 g), and a standard phosphine ligand. After a 2 M sodium carbonate solution was added, the reaction mixture was warmed to 70 ⁰C and stirred until the reaction was complete by HPLC analysis. The reaction was cooled to room temperature and quenched with water, and then separated in phases. The organic phase was treated with activated carbon, filtered through a pad of silica gel, and was concentrated to afford a crude mixture.

[0068] The crude reaction mixture was dissolved in ethanol (40 mL) after palladium catalyst was removed and was treated with 6 M HCl solution (ca. 40 mL). The mixture was warmed to 75-80 °C and stirred for about 2 hours until the reaction was completed by HPLC analysis. After the mixture was cooled to room temperature, the pH of the mixture was adjusted to 8 by addition of 10 M NaOH solution. The mixture was stirred for 2 more hours and the pH was adjusted to 6 by adding 2 M HCl and the crystal seeds. Filtration of the crystalline solid followed by drying provided N-(3,4-dimethyl-5- isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en-3yl)methyl-2- ethoxymethylphenyl)phenylsulfonamide (Compound 1) as a white solid. ¹H NMR (400 MHz, CDCIa) 8.03 (dd, J= 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J= 7.5, 2H), 1.37 (sextet, J= 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H).

[0069] Although the invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I, II, III, IV, V, or VI:

(Formula I) (Formula II) (Formula III) (Formula IV)

(Formula V) (Formula VI) or a salt thereof; wherein R¹ is halo or OR^Λ;

R^A is hydrogen or R^D;

R² and R³ are independently CH₃, CH₂F, CH₂Cl, CH₂Br, CH₂I, CH₂OR^B, CHO, CO₂R^B, CONR^BR^C, CH(NR^B)OR^C, CH(OR^B)OR^C, C(OR^B)₂OR^C, or CN; each R^B and each R^c is independently hydrogen, R^D, COR^D, or SO₂R⁰; each R^D is independently optionally substituted Cj-C₈ alkyl, optionally substituted Cj-C₈ heteroalkyl, or optionally substituted aryl;

R⁴ is Cl, Br, I, or OSO₂R^D; and

R⁵ is halogen, OH, OCOR^D, or OSO₂R⁰.

2. The compound of claim 1, wherein R¹ is OH.

3. The compound of claim 1, wherein R² is CH₂F, CH₂Cl, CH₂Br, CH₂I, or CH₂OH.

4. The compound of claim 3, wherein R² is CH₂Br.

5. The compound of claim 1, wherein R° is methyl, ethyl, phenyl, or methylphenyl.

6. The compound of claim 1, represented by Formula I.

7. The compound of claim 6, wherein R² and R³ are the same.

8. The compound of claim 7, wherein R² and R³ are CH₃ or CH₂Br.

9. The compound of claim 1, represented by Formula II or III.

10. The compound of claim 1, represented by Formula IV.

11. The compound of claim 10, wherein R¹ is Cl or OH.

12. The compound of claim 1 , represented by Formula V or VI.

13. The compound of claim 12, wherein R is Br.

14. The compound of claim 12, wherein R⁵ is OSO₂R .

15. A method of preparing Compound 1:

wherein the method comprises reacting a compound of Formula IV :

with Compound A:

wherein R¹ is halo or OR^A; R^A is hydrogen or R^D; each R^D is independently optionally substituted Ci-Cg alkyl, optionally substituted Ci-C₈ heteroalkyl, or optionally substituted aryl.

16. The method of claim 15, wherein reacting the compound of Formula IV with Compound A occurs in the presence of a base.

17. The method of claim 15, further comprising providing the compound of Formula IV by a process comprising reacting a compound of Formula III :

with Compound B:

wherein R² is CH₃, CH₂F, CH₂Cl, CH₂Br, CH₂I, CH₂OR^B, CHO, CO₂R^B,

³R^C, CH(NR^B)OR^C, CH(OR^B)OR^C, C(OR^B)₂OR^C, or CN; and each R^B and each R^c is independently hydrogen, R^D, COR^D, or SO₂R⁰.

18. The method of claim 17, wherein reacting the compound of Formula III with Compound B occurs in the presence of a base.

19. The method of claim 17, further comprising providing the compound of Formula III by a process comprising reacting a compound of Formula II

with ethanol.

20. The method of claim 19, further comprising providing the compound of Formula II by a process comprising an intramolecular reaction of a compound of Formula I:

wherein the intramolecular reaction comprises reacting SO₂R 1 1 . w..:ijt.ih. r R> 3 ;. and R³ is CH₃, CH₂F, CH₂Cl, CH₂Br, CH₂I, CH₂OR⁸, CHO, CO₂R^B,

CH(OR^D)OR^U, C(OR^B)₂OR^C, or CN.

21. The method of claim 20, further comprising providing the compound of Formula I by a process comprising reacting a compound of Formula VII:

with a compound of Formula VIII:

wherein R⁶ is Li, MgCl, MgBr, MgI, a transition metal, Cl, Br, I, or OSO₂R^D; and

R⁷ is H, Li, MgCl, MgBr, MgI, a transition metal, F, Cl, Br, I, OH, B(OH)₂, OCOR^D, or OSO₂R^D.

22. The method of claim 21, wherein reacting the compound of Formula VII with the compound of Formula VIII occurs in the presence of a metal catalyst.

23. A method of preparing compound 1 :

wherein the method comprises reacting a compound of Formula VI

with a compound of Formula IX:

wherein M is H, Li, MgCl, MgBr, MgI, a transition metal, halogen, OH, B(OR^D)OR^E, OCOR^D, or OSO₂R⁰;

R⁴ is Cl, Br, I, or OSO₂R⁰ ; each R° and each R^E is independently optionally substituted Ci-C₈ alkyl, optionally substituted Ci-C₈ heteroalkyl, or optionally substituted aryl; and

R⁸ is a protecting group.

24. The method of claim 21 , wherein reacting a compound of Formula VI with a compound of Formula IX occurs in the presence of a metal catalyst.

25. The method of claim 23, further comprising providing the compound of Formula VI by a process comprising reacting a compound of Formula V:

with Compound B

wherein R⁵ is halogen, OH, OCOR^D, or OSO₂R^D.

26. The method of claim 25, wherein reacting the compound of Formula V with Compound B occurs in the presence of a base.

27. Compound 1 , prepared according to the method of claim 25.

28. A composition comprising at least two different compounds, wherein: each of the two compounds is represented by Formula I, II, III, or IV;

(Formula I) (Formula II) (Formula III) (Formula IV) or a salt thereof; or each of the two compounds is represented by any of Formulas V or VI

(Formula V) (Formula VI) or a salt thereof; wherein R¹ is halo or OR^A;

R^A is hydrogen or R^D;

R² and R³ are independently CH₃, CH₂F, CH₂Cl, CH₂Br, CH₂I, CH₂OR⁸, CHO, CO₂R^B, CONR^BR^C, CH(NR^B)OR^C, CH(OR^B)OR^C, C(OR^B)₂OR^C, or CN; each R^B and each R^c is independently hydrogen, R^D, COR^D, or SO₂R⁰; each R^D is independently optionally substituted Cj-C₈ alkyl, optionally substituted Ci-C₈ heteroalkyl, or optionally substituted aryl;

R⁴ is Cl, Br, I, or OSO₂R^D; and

R⁵ is halogen, OH, OCOR^D, or OSO₂R⁰.