Process for preparing 2-isopropyl-5-(isoquinolin-3-YL)benzene-1,3-diol

Abstract

The present invention provides processes for the preparation of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof and novel intermediates used therein.

Description

Attorney Docket No. 143989-005402PROCESS FOR PREPARING 2-ISOPROPYL-5-(ISOQUINOLIN-3-YL)BENZENE- 1,3-DIOLCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 708,803 filed October 18, 2024, the entire contents of which are incorporated by reference.SUMMARY OF THE INVENTION

[0002] Some embodiments of the present invention provide a process for the preparation of the compound of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof, comprising: a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):CD; b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):Attomey Docket No. 143989-005402c) hydrolysing the compound of Formula (2) to form a compound of Formulad) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula (3B);f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):Attorney Docket No. 143989-005402 g) halogenating the compound of Formula (4) to form a compound of Formula (5):h) aromatizing the compound of Formula (5) to form the compound of Formula (6HC1):(6HC1); and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a base to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0003] Some embodiments of the present invention describe a process for preparing a compound of Formula (6HC1)(6HC1).

[0004] Some embodiments of the present invention describe a process for preparing a compound of Formula (6MA)Attorney Docket No. 143989-005402(6MA).

[0005] Some embodiments of the present invention describe a process for preparing a citric acid cocrystal of a compound of Formula (6)(6).

[0006] Some embodiments of the present invention describe a compound of Formula(1)(1), and processes for preparing same.

[0007] Some embodiments of the present invention describe a compound of Formula(2)and processes for preparing same.

[0008] Some embodiments of the present invention describe a compound of FormulaAttorney Docket No. 143989-005402and processes for preparing same.

[0009] Some embodiments of the present invention describe a compound of Formula(3A)(3A), and processes for preparing same.

[0010] Some embodiments of the present invention describe a compound of Formula(3B)and processes for preparing same.

[0011] Some embodiments of the present invention describe a compound of Formula(4), and processes for preparing same.Attorney Docket No. 143989-005402

[0012] Some embodiments of the present invention describe a compound of Formula(5)and processes for preparing same.

[0013] Some embodiments of the present invention describe a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6),and a pharmaceutically acceptable excipient; wherein the pharmaceutically acceptable salt has a chemical purity of at least 95% by weight and wherein the pharmaceutically acceptable salt is selected from maleate or hydrochloride.

[0014] Some embodiments of the present invention describe a pharmaceutical composition comprising a citric acid cocrystal of a compound of Formula (6),and a pharmaceutically acceptable excipient; wherein the citric acid cocrystal of the compound of Formula (6) has a chemical purity' of at least 95% by weight.BRIEF DESCRIPTION OF THE FIGURES

[0015] Fig. 1 shows the FT-IR spectrum of a compound of Formula (6).

[0016] Fig. 2 shows the FT-IR spectrum of the compound of Formula (6HC1).

[0017] Fig. 3 shows the FT-IR spectrum of the compound of Formula (6MA).Attorney Docket No. 143989-005402

[0018] Fig. 4 shows the FT-IR spectrum of the citric acid cocrystal of the compound of Formula (6).

[0019] Fig. 5 shows the!H NMR spectrum of the compound of Formula (6)

[0020] Fig. 6 shows the 'H NMR spectrum of the compound of Formula (6HC1) at 400MHz.

[0021] Fig. 7 shows the ’H NMR spectrum of the compound of Formula (6HC1) at 600 MHz.

[0022] Fig. 8 shows the1H NMR spectrum of the compound of the citric acid cocrystal of the compound of Formula (6).

[0023] Fig. 9 shows the ' H NMR spectrum of the compound of Formula (6MA).DETAILED DESCRIPTION OF THE INVENTION

[0024] 2-Isopropyl-5-(isoquinolin-3-yl)benzene-l,3-diol, of Formula (6)(6), is an Aryl hydrocarbon Receptor (AhR) agonist useful for treating inflammatory disorders. Isopropyl-5-(isoquinolin-3-yl)benzene-l,3-diol and its synthesis is described in U.S. Patents 11,267,788 and 11,548,853; US Patent Publication 20230124135; and PCT Patent Publication W0200142231. The synthesis described therein requires coupling of the isoquinoline moiety with the benzene moitv and requires deprotection of the diol as the final step.

[0025] There exists a need for an efficient and scalable route for the large-scale manufacturing of the compound of Formula (6), in particular, one that and avoids the use of boronates and heavy metal catalysts, which are less environmentally friendly and expensive.

[0026] The present invention provides a number of embodiments relating to a process which is summarised in Scheme 1 below:Attorney Docket No. 143989-005402Scheme 1Preparation of the Compound of Formula (6)

[0027] Some embodiments describe a process for the preparation of a compound of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof, comprising: a) condensing a compound of formula SMI:(SMI),Attorney Docket No. 143989-005402 with methyl isobut l ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound ofFormula (3):d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3A) to form a compound ofFormula (3B):(3B);Attorney Docket No. 143989-005402 f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4); g) halogenating the compound of Formula (4) to form a compound of Formula (5):h) aromatizing the compound of Formula (5) to form a compound of Formula (6HC1):(6HC1); and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a base to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0028] In some embodiments the process further comprises recrystallizing the compound of Formula (6). In some embodiments recrystallization is carried out using ethyl acetate and heptane.Attorney Docket No. 143989-005402

[0029] In some embodiments the process further comprises contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6):(6MA).In some embodiments the process comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate.

[0030] In some embodiments the process further comprises contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6). In some embodiments the process comprises contacting the compound of Formula (6) with citric acid in isopropanol.

[0031] In some embodiments the process further comprises isolating the compound of Formula (3A) formed in step d). In some embodiments the process further comprises isolating the compound of Formula (4) in step f). In some embodiments the process further comprises isolating the compound of Formula (6HC1) formed in step h).

[0032] In some embodiments the compound of Formula (3A) formed in step d) is isolated prior to step e). In some embodiments the compound of Formula (4) formed in step f) is isolated prior to step g). In some embodiments the compound of Formula (6HC1) formed in step h) is isolated prior to step i). In some embodiments the compound of Formula (1) formed in step a) is not isolated prior to step b). In some embodiments the compound of Formula (2) formed in step b) is not isolated prior to step c). In some embodiments the compound of Formula (3) formed in step c) is not isolated prior to step d). In some embodiments the compound of Formula (3B) formed in step e) is not isolated prior to step f). In some embodiments the compound of Formula (5) formed in step g) is not isolated prior to step h).

[0033] In some embodiments the process according to any embodiment described herein is telescoped such that the compounds of some steps are not isolated. In some embodiments process steps a), b), c) and d) are telescoped and the compound of Formula (1), the compound of Formula (2) and the compound of Formula (3) are not isolated. In some embodiments process steps e) and f) are telescoped and the compound of Formula (3B) is notAttorney Docket No. 143989-005402 isolated. In some embodiments process steps g) and h) are telescoped and the compound of Formula (5) is not isolated.

[0034] In some embodiments the process for preparing the compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof, comprises: a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl malonate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxy lating the compound of Formula (3) to form a compound of Formula (3A):Attorney Docket No. 143989-005402dl) isolating the compound of Formula (3 A); e) esterifying the compound of Formula (3A) to form a compound of Formula (3B):f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4); fl) isolating the compound of Formula (4); g) halogenating the compound of Formula (4) to form a compound of Formula (5):h) aromatizing the compound of Formula (5) to form a compound of Formula (6HC1):Attorney Docket No. 143989-005402(6HC1); hl) isolating the compound of Formula (6HC1) and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a base to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0035] In some embodiments the condensing of a compound of Formula (SMI ) and methyl isobutyl ketone to form a compound of Formula (1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the solvent is ethanol. In some embodiments the solvent is tetrahydrofuran. In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of lithium, potassium or sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of 10% sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to a solutionAttorney Docket No. 143989-005402 comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1).

[0036] In some embodiments the contacting of diethyl malonate with a compound of Formula (1) to form a compound of Formula (2) is carried out in a suitable solvent or mixture of solvents. Tn some embodiments step b) comprises contacting diethyl malonate with the compound of Formula (1) in the presence of lithium bromide and tri ethylamine to form the compound of Formula (2). In some embodiments step b) comprises adding diethyl malonate, lithium bromide and triethylamine to the compound of Formula (1) followed by heating to form the compound of Formula (2). In some embodiments step b) comprises adding diethyl malonate, lithium bromide and triethylamine to the compound of Formula (1) in a suitable solvent or mixture of solvents, followed by heating to about 35 °C to form the compound of Formula (2). In some embodiments step b) comprises heating the compound of Formula (1) in a suitable solvent or mixture of solvents to about 35 °C. then sequentially adding diethyl malonate, tri ethylamine, and lithium bromide to form the compound of Formula (2).

[0037] In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) is carried out in a suitable solvent or mixture of solvents. In some embodiments step c) comprises contacting the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) with 6M aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) and 6M aqueous sodium hydroxide to about 35 °C to form the compound of Formula (3). In some embodiments step c) comprises heating a solution of the compound of Formula (2) in a suitable solvent or mixture of solvents to about 35 °C, then adding 6M aqueous sodium hydroxide to form the compound of Formula (3).

[0038] In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in a suitable solvent or mixture of solvents. In some embodiments step d) comprises contacting the compound of Formula (3) with aqueous hydrochloric acid to form the compound of Formula (3A). In some embodiments step d) comprises heating the compound of Formula (3) w ith aqueous 6M hydrochloric acid to form the compound of Formula (3 A). In some embodiments step d) comprises adding 6M aqueous hydrochloric acid to a compound of Formula (3) until a pH of about 4 to 5 is reached, followedAttorney Docket No. 143989-005402 by heating to form a compound of Formula (3 A). In some embodiments step d) comprises adding 6M aqueous hydrochloric acid to a solution of the compound of Formula (3) in a suitable solvent or mixture of solvents, until a pH of about 4 to 5 is reached, then heating the solution to about 100 °C to form a compound of Formula (3A). In some embodiments the decarboxylation of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in the presence of a base. In some embodiments the base in step d) is selected from tri ethyl amine, imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is tri ethyl amine. In some embodiments step d) comprises contacting the compound of Formula (3) with catalytic tri ethylamine to form the compound of Formula (3 A). In some embodiments step d) comprises heating the compound of Formula (3) with catalytic triethylamine to form the compound of Formula (3A). In some embodiments, the process further comprises isolating the compound of Formula (3 A).

[0039] In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) is carried out in a suitable solvent or mixture of solvents. In some embodiments step e) comprises contacting the compound of Formula (3A) with potassium carbonate and iodomethane to form the compound of Formula (3B). In some embodiments step e) comprises adding iodomethane to a mixture of the compound of Formula (3A), potassium carbonate and anhydrous dimethylformamide to form a compound of Formula (3B). In some embodiments step e) comprises contacting the compound of Formula (3 A) with thionyl chloride and methanol to form the compound of Formula (3B). In some embodiments the esterification is a Fischer esterification with an alcohol and an acid catalyst. In some embodiments step e) comprises contacting the compound of Formula (3 A) with hydrochloric acid and methanol, to form the compound of Formula (3B).

[0040] In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) is carried out in a suitable solvent or mixture of solvents. In some embodiments step f) comprises contacting the compound of Formula (3B) with potassium t- butoxide to form the compound of Formula (4). In some embodiments step f) comprises contacting the compound of Formula (3B) with IM potassium r-butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling the compound of Formula (3B), then adding IM potassium t-butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling the compound of Formula (3B) to about 0 °C, then adding IM potassium / -butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling a solution of the compound of Formula (3B) in a suitable solvent orAttorney Docket No. 143989-005402 mixture of solvents to about 0 °C, then adding IM potassium t-butoxide to form the compound of Formula (4). In some embodiments the compound of Formula (4) is isolated.

[0041] In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) is carried out in a suitable solvent or mixture of solvents. In some embodiments step g) comprises contacting the compound of Formula (4) with a halogenating agent to form the compound of Formula (5). In some embodiments step g) comprises contacting the compound of Formula (4) with l,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), or N-chlorosuccinimide. In some embodiments step g) comprises contacting the compound of Formula (4) with N-chlorosuccinimide to form the compound of Formula (5).

[0042] In some embodiments the aromatizing of a compound of Formula (5) to a compound of Formula (6HC1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the aromatizing of a compound of Formula (5) to a compound of Formula (6HC1) is optionally carried out with an additive reagent. In some embodiments the additive reagent is a quaternary ammonium salt. In some embodiments the quaternary ammonium salt is selected from the group consisting of tetrabutyl ammonium bromide, benzyltri ethyl ammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride and tetramethylammonium chloride. In some embodiments the quaternary ammonium salt is tetraethyl ammonium chloride. In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethyl ammonium chloride to give the compound of Formula (6HC1). In some embodiments step h) comprises heating the compound of Formula (5) in anhydrous acetonitrile in the presence of tetraethylammonium chloride to form the compound of Formula (6HC1). In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride in anhydrous acetonitrile to about 85 °C to form the compound of Formula (6 HC1). In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride in anhydrous acetonitrile to about 90 °C to form the compound of Formula (6 HC1). In some embodiments, the compound of Formula (6HC1) is isolated. In some embodiments the compound of Formula (6HC1) is further purified. In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding ethyl acetate until a slurry' is formed, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanolAttorney Docket No. 143989-005402 and slowly adding about ethyl acetate until a slurry is formed, cooling the slurry' to about 20 °C, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with 1.5 vol equivalents of ethanol and slowly adding about 4.5 vol equivalents of ethyl acetate until a slurry' is formed, cooling the slurry' to about 20 °C then isolating the solid purified compound of Formula (6HC1).

[0043] In some embodiments, the compound of Formula (5) is not isolated, and the additive reagent is added during step g) for convenience. In some embodiments the additive reagent is triethylammonium chloride. In some embodiments steps g)-h) comprise contacting the compound of Formula (4) with tetraethylammonium chloride and N-chlorosuccinimide to form the compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments steps g)-h) comprise combining the compound of Formula (4) with tetraethylammonium chloride, then adding anhydrous acetonitrile followed by addition of N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments steps g)-h) comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride, adding anhydrous acetonitrile followed by addition of N- chlorosuccinimide to form a compound of Formula (5), then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments the mixture of the compound of Formula (4) and tetraethylammonium chloride is dried under vacuum at about 40 °C prior to the addition of the anhydrous acetonitrile. In some embodiments the compound of Formula (4), tetraethylammonium chloride and anhydrous acetonitrile is azeotropically dried. In some embodiments the mixture of the compound of Formula (4), tetraethyl ammonium chloride and anhydrous acetonitrile is stirred at about 20 °C for at least one hour prior to administration of the N-chlorosuccinimide. In some embodiments the N-chlorosuccinimide is added in portions. In some embodiments the reaction mixture temperature is maintained at <27 °C during administration of the N-chlorosuccinimide. In some embodiments steps g)-h) comprise dry ing a mixture of the compound of Formula (4) with tetraethyl ammonium chloride at about 40 °C; then adding anhydrous acetonitrile and stirring the resulting mixture at about 20 °C; then adding N-chlorosuccinimide in portions while maintaining the reaction mixture temperature at <27 °C during administration of the N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments the reaction mixture temperature is maintained at <25 °C duringAttorney Docket No. 143989-005402 administration of the N-chlorosuccinimide. In some embodiments steps g)-h comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride at about 40 °C; then adding anhydrous acetonitrile and stirring the resulting mixture at about 20 °C; then adding N-chlorosuccinimide in portions while maintaining the reaction mixture temperature at <25 °C during administration of the N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments heating the compound of Formula (5) to form the compound of Formula (6HC1) is carried out at 85 °C to 90 °C. In some embodiments, the compound of Formula (6HC1) is isolated. In some embodiments the compound of Formula (6HC1) is further purified. In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding ethyl acetate until a slurry is formed, then isolating the solid purified compound of Formula (6HCL). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding about ethyl acetate until a slurry7is formed, cooling the slurry to about 20 °C, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with 1.5 vol equivalents of ethanol and slowly adding about 4.5 vol equivalents of ethyl acetate until a slurry7is formed, cooling the slurry to about 20 °C then isolating the solid purified compound of Formula (6HC1).

[0044] In some embodiments the conversion of a compound of Formula (6HC1) to a compound of Formula (6) is carried out in a suitable solvent or mixture of solvents. In some embodiments step i) comprises treating the compound of Formula (6HC1) with aqueous sodium bicarbonate to form the compound of Formula (6). In some embodiments step i) comprises treating the compound of Formula (6HC1) in a solution of ethyl acetate / ethanol with aqueous sodium bicarbonate to form the compound of Formula (6). In some embodiments the compound of Formula (6) is isolated.

[0045] Some embodiments describe a process for preparing of a compound of Formula(6)Attorney Docket No. 143989-005402 or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof comprising: a) contacting a compound of formula (SMI):(SMI), with methyl isobutyl ketone in the presence of sodium hydroxide, to form a compound of Formula (1):b) treating the compound of Formula (1) with diethyl malonate, in the presence of triethylamine and lithium bromide to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) with aqueous sodium hydroxide to form a compound of Formula (3):d) treating the compound of Formula (3) with aqueous hydrochloric acid to a pH of about 4 to 5 and heating to form a compound of Formula (3 A):Attorney Docket No. 143989-005402e) combining the compound of Formula (3 A), with potassium carbonate and anhydrous dimethylformamide, then adding iodomethane, to form a compound of Formula (3B);f) treating a cooled solution of the compound of Formula (3B) with potassium t- butoxide to form a compound of Formula (4):(4); g) contacting the compound of Formula (4) with N-chlorosuccinimide to form a compound of Formula (5):h) heating the compound of Formula (5) in the presence of tetraethylammonium chloride to form a compound of Formula (6 HC1):Attorney Docket No. 143989-005402 and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with aqueous sodium bicarbonate to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0046] In some embodiments the process further comprises recrystallizing the compound of Formula (6). In some embodiments recrystallization is carried out using ethyl acetate and heptane.

[0047] In some embodiments the process further comprises contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA):In some embodiments the process comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate.

[0048] In some embodiments the process further comprises contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6). In some embodiments the process comprises contacting the compound of Formula (6) with citric acid in isopropanol.

[0049] In some embodiments the process further comprises isolating the compound of Formula (3A) formed in step d). In some embodiments the process further comprises isolating the compound of Formula (4) in step f). In some embodiments the process further comprises isolating the compound of Formula (6HC1) formed in step h).

[0050] In some embodiments the compound of Formula (3A) formed in step d) is isolated prior to step e). In some embodiments the compound of Formula (4) formed in step f) is isolated prior to step g). In some embodiments the compound of Formula (6HC1) formed in step h) is isolated prior to step i). In some embodiments the compound of Formula (1) formedAttorney Docket No. 143989-005402 in step a) is not isolated prior to step b). In some embodiments the compound of Formula (2) formed in step b) is not isolated prior to step c). In some embodiments the compound of Formula (3) formed in step c) is not isolated prior to step d). In some embodiments the compound of Formula (3B) formed in step e) is not isolated prior to step f). In some embodiments the compound of Formula (5) formed in step g) is not isolated prior to step h).

[0051] Some embodiments describe a process for preparing of a compound of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof comprising: a) contacting a compound of formula (SMI):(SMI), with methyl isobutyl ketone in the presence of sodium hydroxide, to form a compound of Formula (1):(i); b) treating the compound of Formula (1) with diethyl mal onate, in the presence of triethylamine and lithium bromide to form a compound of Formula (2):Attorney Docket No. 143989-005402 c) hydrolysing the compound of Formula (2) with aqueous sodium hydroxide to form a compound of Formula (3):d) heating the compound of Formula (3) with catalytic triethylamine to form a compound of Formula (3 A):e) combining the compound of Formula (3 A), with potassium carbonate and anhydrous dimethylformamide, then adding iodomethane, to form a compound of Formula (3B):f) treating a cooled solution of the compound of Formula (3B) with potassium t- butoxide to form a compound of Formula (4):(4); g) contacting the compound of Formula (4) with N-chlorosuccinimide to form a compound of Formula (5):Attorney Docket No. 143989-005402h) heating the compound of Formula (5) in the presence of tetraethylammonium chloride to form a compound of Formula (6 HC1):and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a aqueous sodium bicarbonate to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0052] In some embodiments the process further comprises recrystallizing the compound of Formula (6). In some embodiments recrystallization is carried out using ethyl acetate and heptane.

[0053] In some embodiments the process further comprises contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA):In some embodiments the process comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate.Attorney Docket No. 143989-005402

[0054] In some embodiments the process further comprises contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6). In some embodiments the process comprises contacting the compound of Formula (6) with citric acid in isopropanol.

[0055] In some embodiments the process further comprises isolating the compound of Formula (3 A) formed in step d). In some embodiments the process further comprises isolating the compound of Formula (4) in step f). In some embodiments the process further comprises isolating the compound of Formula (6HC1) formed in step h).

[0056] In some embodiments the compound of Formula (3A) formed in step d) is isolated prior to step e). In some embodiments the compound of Formula (4) formed in step I) is isolated prior to step g). In some embodiments the compound of Formula (6HC1) formed in step h) is isolated prior to step i). In some embodiments the compound of Formula (1) formed in step a) is not isolated prior to step b). In some embodiments the compound of Formula (2) formed in step b) is not isolated prior to step c). In some embodiments the compound of Formula (3) formed in step c) is not isolated prior to step d). In some embodiments the compound of Formula (3B) formed in step e) is not isolated prior to step f). In some embodiments the compound of Formula (5) formed in step g) is not isolated prior to step h).

[0057] Some embodiments describe a process for preparing of a compound of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof comprising: a) contacting a compound of formula (SMI):(SMI), with methyl isobutyl ketone in the presence of 10% aqueous sodium hydroxide, to form a compound of Formula (1):Attorney Docket No. 143989-005402b) adding diethyl malonate, tri ethyl amine, and lithium bromide to the compound of Formula (6), followed by heating, to form a compound of Formula (2):c) heating the compound of Formula (2) with 6M aqueous sodium hydroxide to form a compound of Formula (3):d) adding 6M aqueous hydrochloric acid to a compound of Formula (3) until a pH of about 4 to 5 is reached, followed by heating to form a compound of Formula (3 A):e) adding iodomethane to a mixture of the compound of Formula (3 A), potassium carbonate and anhydrous dimethylformamide to form a compound of Formula (3B):Attorney Docket No. 143989-005402 f) cooling the compound of Formula (3B), then adding IM potassium / -butoxide to form a compound of Formula (4):(4); g) combining the compound of Formula (4) with anhydrous acetonitrile followed by addition of N-chlorosuccinimide to form a compound of Formula (5):h) heating the compound of Formula (5) in the presence of tetraethylammonium chloride and anhydrous acetonitrile to form a compound of Formula (6 HC1):and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a aqueous sodium bicarbonate to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0058] In some embodiments the process further comprises recry stallizing the compound of Formula (6). In some embodiments recrystallization is carried out using ethyl acetate and heptane.

[0059] In some embodiments the process further comprises contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA):Attorney Docket No. 143989-005402In some embodiments the process comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate.

[0060] In some embodiments the process further comprises contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6). In some embodiments the process comprises contacting the compound of Formula (6) with citric acid in isopropanol.

[0061] In some embodiments the process further comprises isolating the compound of Formula (3A) formed in step d). In some embodiments the process further comprises isolating the compound of Formula (4) in step f). In some embodiments the process further comprises isolating the compound of Formula (6HC1) formed in step h).

[0062] In some embodiments the compound of Formula (3A) formed in step d) is isolated prior to step e). In some embodiments the compound of Formula (4) formed in step f) is isolated prior to step g). In some embodiments the compound of Formula (6HC1) formed in step h) is isolated prior to step i). In some embodiments the compound of Formula (1) formed in step a) is not isolated prior to step b). In some embodiments the compound of Formula (2) formed in step b) is not isolated prior to step c). In some embodiments the compound of Formula (3) formed in step c) is not isolated prior to step d). In some embodiments the compound of Formula (3B) formed in step e) is not isolated prior to step f). In some embodiments the compound of Formula (5) formed in step g) is not isolated prior to step h).

[0063] In some embodiments the process according to any embodiment described herein is telescoped such that the compounds of some steps are not isolated. In some embodiments process steps a), b), c) and d) are telescoped and the compound of Formula (1), the compound of Formula (2) and the compound of Formula (3) are not isolated. In some embodiments process steps e) and I) are telescoped and the compound of Formula (3B) is not isolated. In some embodiments process steps g) and h) are telescoped and the compound of Formula (5) is not isolated.Attorney Docket No. 143989-005402

[0064] Some embodiments describe a process for preparing of a compound of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof comprising: a) contacting a compound of formula (SMI):(SMI), with methyl isobutyl ketone in the presence of 10% aqueous sodium hydroxide, to form a compound of Formula (1):b) adding diethyl malonate, tri ethyl amine, and lithium bromide to the compound of Formula (6), followed by heating, to form the compound of Formula (2):c) heating the compound of Formula (2) with 6M aqueous sodium hydroxide to form the compound of Formula (3):Attorney Docket No. 143989-005402d) heating the compound of Formula (3) and with triethylamine to form a compound of Formula (3 A):e) adding iodomethane to a mixture of the compound of Formula (3 A), potassium carbonate and anhydrous dimethylformamide to form a compound of Formula (3B);f) cooling the compound of Formula (3B), then adding IM potassium / -butoxide to form the compound of Formula (4):(4); g) combining the compound of Formula (4) with anhydrous acetonitrile followed by addition of N -chlorosuccinimide to form a compound of Formula (5):Attorney Docket No. 143989-005402 h) heating the compound of Formula (5) in the presence of tetraethylammonium chloride and anhydrous acetonitrile to form the hydrochloride salt of Formula (6 HC1):and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a aqueous sodium bicarbonate to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

[0065] In some embodiments the process further comprises recrystallizing the compound of Formula (6). In some embodiments recrystallization is carried out using ethyl acetate and heptane.

[0066] In some embodiments the process further comprises contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA):In some embodiments the process comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate.

[0067] In some embodiments the process further comprises contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6). In some embodiments the process comprises contacting the compound of Formula (6) with citric acid in isopropanol.Attorney Docket No. 143989-005402

[0068] In some embodiments the process further comprises isolating the compound of Formula (3A) formed in step d). In some embodiments the process further comprises isolating the compound of Formula (4) in step f). In some embodiments the process further comprises isolating the compound of Formula (6HC1) formed in step h).

[0069] In some embodiments the compound of Formula (3 A) formed in step d) is isolated prior to step e). In some embodiments the compound of Formula (4) formed in step f) is isolated prior to step g). In some embodiments the compound of Formula (6HC1) formed in step h) is isolated prior to step i). In some embodiments the compound of Formula (1) formed in step a) is not isolated prior to step b). In some embodiments the compound of Formula (2) formed in step b) is not isolated prior to step c). In some embodiments the compound of Formula (3) formed in step c) is not isolated prior to step d). In some embodiments the compound of Formula (3B) formed in step e) is not isolated prior to step f). In some embodiments the compound of Formula (5) formed in step g) is not isolated prior to step h).

[0070] In some embodiments the process according to any embodiment described herein is telescoped such that the compounds of some steps are not isolated. In some embodiments process steps a), b), c) and d) are telescoped and the compound of Formula (1), the compound of Formula (2) and the compound of Formula (3) are not isolated. In some embodiments process steps e) and I) are telescoped and the compound of Formula (3B) is not isolated. In some embodiments process steps g) and h) are telescoped and the compound of Formula (5) is not isolated.Process for preparing a compound of Formula (6MA)

[0071] Some embodiments herein describe a process for preparing a compound of Formula (6MA)(6MA); comprising contacting a compound of Formula (6)Attorney Docket No. 143989-005402with maleic acid to form the compound of Formula (6MA). In some embodiments the process comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate.

[0072] In some embodiments the compound of Formula (6) is prepared according to any embodiment described herein.

[0073] Some embodiments herein describe a process for preparing a compound of Formula (6MA)(6MA); comprising: a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):Attorney Docket No. 143989-005402c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):e) esterifying the compound of Formula (3A) to form a compound of Formula (3B):f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4);Attorney Docket No. 143989-005402 g) halogenating the compound of Formula (4) to form a compound of Formula (5):h) aromatizing the compound of Formula (5) to form a compound of Formula (6HC1):(6HC1); and i) treating the compound of Formula (6HC1) with a base to form a compound of Formula (6):(6); and j) contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA).

[0074] In some embodiments the process further comprises isolating the compound of Formula (3 A) formed in step d). Tn some embodiments the process further comprises isolating the compound of Formula (4) in step f). In some embodiments the process further comprises isolating the compound of Formula (6HC1) formed in step h).

[0075] In some embodiments the compound of Formula (3A) formed in step d) is isolated prior to step e). In some embodiments the compound of Formula (4) formed in step I) is isolated prior to step g). In some embodiments the compound of Formula (6HC1) formed in step h) is isolated prior to step i). In some embodiments the compound of Formula (1) formedAttorney Docket No. 143989-005402 in step a) is not isolated prior to step b). In some embodiments the compound of Formula (2) formed in step b) is not isolated prior to step c). In some embodiments the compound of Formula (3) formed in step c) is not isolated prior to step d). In some embodiments the compound of Formula (3B) formed in step e) is not isolated prior to step f). In some embodiments the compound of Formula (5) formed in step g) is not isolated prior to step h).

[0076] In some embodiments the process according to any embodiment described herein is telescoped such that the compounds of some steps are not isolated. In some embodiments process steps a), b), c) and d) are telescoped and the compound of Formula (1), the compound of Formula (2) and the compound of Formula (3) are not isolated. In some embodiments process steps e) and f) are telescoped and the compound of Formula (3B) is not isolated. In some embodiments process steps g) and h) are telescoped and the compound of Formula (5) is not isolated.

[0077] In some embodiments the condensing of a compound of Formula (SMI) and methyl isobutyl ketone to form a compound of Formula (1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the solvent is ethanol. In some embodiments the solvent is tetrahydrofuran. In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of lithium, potassium or sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of 10% sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1). InAttorney Docket No. 143989-005402 some embodiments step a) comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1).

[0078] In some embodiments the contacting of diethyl malonate with a compound of Formula (1 ) to form a compound of Formula (2) is carried out in a suitable solvent or mixture of solvents. In some embodiments step b) comprises contacting diethyl malonate with the compound of Formula (1) in the presence of lithium bromide and triethylamine to form the compound of Formula (2). In some embodiments step b) comprises adding diethyl malonate, lithium bromide, and triethylamine to the compound of Formula (1) followed by heating to form the compound of Formula (2). In some embodiments step b) comprises adding diethyl malonate, lithium bromide and triethylamine to the compound of Formula (1) in a suitable solvent or mixture of solvents, followed by heating to about 35 °C to form the compound of Formula (2). In some embodiments step b) comprises heating the compound of Formula (1) in a suitable solvent or mixture of solvents to about 35 °C, then sequentially adding diethyl malonate, triethylamine and lithium bromide to form the compound of Formula (2).

[0079] In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) is carried out in a suitable solvent or mixture of solvents. In some embodiments step c) comprises contacting the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) with 6M aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) and 6M aqueous sodium hydroxide to about 35 °C to form the compound of Formula (3). In some embodiments step c) comprises heating a solution of the compound of Formula (2) in a suitable solvent or mixture of solvents to about 35 °C, then adding 6M aqueous sodium hydroxide to form the compound of Formula (3).

[0080] In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in a suitable solvent or mixture of solvents. In some embodiments step d) comprises contacting the compound of Formula (3) with aqueous hydrochloric acid to form the compound of Formula (3A). In some embodiments step d) comprises heating the compound of Formula (3) with aqueous 6M hydrochloric acid to form the compound of Formula (3 A). In some embodiments step d) comprises adding 6M aqueousAttorney Docket No. 143989-005402 hydrochloric acid to a compound of Formula (3) until a pH of about 4 to 5 is reached, followed by heating to form a compound of Formula (3 A). In some embodiments step d) comprises adding 6M aqueous hydrochloric acid to a solution of the compound of Formula (3) in a suitable solvent or mixture of solvents, until a pH of about 4 to 5 is reached, then heating the solution to about 100 °C to form a compound of Formula (3A). In some embodiments the decarboxylation of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in the presence of a base. In some embodiments the base in step d) is selected from tri ethyl amine, imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is tri ethyl amine. In some embodiments step d) comprises contacting the compound of Formula (3) with catalytic tri ethylamine to form the compound of Formula (3 A). In some embodiments step d) comprises heating the compound of Formula (3) with catalytic triethylamine to form the compound of Formula (3A). In some embodiments, the process further comprises isolating the compound of Formula (3 A).

[0081] In some embodiments the esterifying of a compound of Formula (3A) to form a compound of Formula (3B) is carried out in a suitable solvent or mixture of solvents. In some embodiments step e) comprises contacting the compound of Formula (3A) with potassium carbonate and iodomethane to form the compound of Formula (3B). In some embodiments step e) comprises adding iodomethane to a mixture of the compound of Formula (3A), potassium carbonate and anhydrous dimethylformamide to form a compound of Formula (3B). In some embodiments step e) comprises contacting the compound of Formula (3 A) with thionyl chloride and methanol to form the compound of Formula (3B). In some embodiments the esterifying is a Fischer esterification with an alcohol and an acid catalyst. In some embodiments step e) comprises contacting the compound of Formula (3 A) with hydrochloric acid and methanol, to form the compound of Formula (3B).

[0082] In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) is carried out in a suitable solvent or mixture of solvents. In some embodiments step f) comprises contacting the compound of Formula (3B) with potassium t- butoxide to form the compound of Formula (4). In some embodiments step f) comprises contacting the compound of Formula (3B) with IM potassium f-butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling the compound of Formula (3B), then adding IM potassium f-butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling the compound of Formula (3B) to about 0 °C. then adding IM potassium f-butoxide to form the compound of Formula (4). In some embodimentsAttorney Docket No. 143989-005402 step f) comprises cooling a solution of the compound of Formula (3B) in a suitable solvent or mixture of solvents to about 0 °C, then adding IM potassium / -butoxide to form the compound of Formula (4). In some embodiments the compound of Formula (4) is isolated.

[0083] In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) is carried out in a suitable solvent or mixture of solvents. In some embodiments step g) comprises contacting the compound of Formula (4) with a halogenating agent to form the compound of Formula (5). In some embodiments step g) comprises contacting the compound of Formula (4) with l,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), or N-chlorosuccinimide. In some embodiments step g) comprises contacting the compound of Formula (4) with N-chlorosuccinimide to form the compound of Formula (5). In some embodiments step g) comprises contacting the compound of Formula (4) with tetraethylammonium chloride and N-chlorosuccinimide to form the compound of Formula (5).

[0084] In some embodiments the aromatizing of a compound of Formula (5) to form a compound of Formula (6HC1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the aromatizing of a compound of Formula (5) to a compound of Formula (6HC1) is optionally carried out with an additive reagent. In some embodiments the additive reagent is a quaternary ammonium salt. In some embodiments the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutyl ammonium chloride, tetraethyl ammonium chloride and tetramethylammonium chloride. In some embodiments the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride to give the compound of Formula (6HC1). In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride in anhydrous acetonitrile to form the compound of Formula (6HC1). In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride in anhydrous acetonitrile to about 85 °C to form the compound of Formula (6 HC1). In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride in anhydrous acetonitrile to about 90 °C to form the compound of Formula (6 HC1). In some embodiments, the compound of Formula (6HC1) is isolated. In some embodiments the compound of Formula (6HC1) is further purified. In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound ofAttorney Docket No. 143989-005402Formula (6HC1) with ethanol and slowly adding ethyl acetate until a slurry' is formed, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding about ethyl acetate until a slurry' is formed, cooling the slurry to about 20 °C, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with 1.5 vol equivalents of ethanol and slowly adding about 4.5 vol equivalents of ethyl acetate until a slurry' is formed, cooling the slurry to about 20 °C then isolating the solid purified compound of Formula (6HC1).

[0085] In some embodiments, the compound of Formula (5) is not isolated, and the additive reagent is added during step g) for convenience. In some embodiments the additive reagent is triethylammonium chloride. In some embodiments steps g)-h) comprise contacting the compound of Formula (4) with tetraethylammonium chloride and N-chlorosuccinimide to form the compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments steps g)-h) comprise combining the compound of Formula (4) with tetraethylammonium chloride, then adding anhydrous acetonitrile followed by addition of N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments steps g)-h) comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride, adding anhydrous acetonitrile followed by addition of N- chlorosuccinimide to form a compound of Formula (5), then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments the mixture of the compound of Formula (4) and tetraethylammonium chloride is dried under vacuum at about 40 °C prior to the addition of the anhydrous acetonitrile. In some embodiments the compound of Formula (4), tetraethylammonium chloride and anhydrous acetonitrile is azeotropically dried. In some embodiments the mixture of the compound of Formula (4), tetraethylammonium chloride and anhydrous acetonitrile is stirred at about 20 °C for at least one hour prior to administration of the N-chlorosuccinimide. In some embodiments the N-chlorosuccinimide is added in portions. In some embodiments the reaction mixture temperature is maintained at <27 °C during administration of the N-chlorosuccinimide. In some embodiments steps g)-h) comprise drying a mixture of the compound of Formula (4) with tetraethyl ammonium chloride at about 40 °C; then adding anhydrous acetonitrile and stirring the resulting mixture at about 20 °C; then adding N-chlorosuccinimide in portions while maintaining the reaction mixtureAttorney Docket No. 143989-005402 temperature at <27 °C during administration of the N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments the reaction mixture temperature is maintained at <25 °C during administration of the N-chlorosuccinimide. In some embodiments steps g)-h comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride at about 40 °C; then adding anhydrous acetonitrile and stirring the resulting mixture at about 20 °C; then adding N-chlorosuccinimide in portions while maintaining the reaction mixture temperature at <25 °C during administration of the N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments heating the compound of Formula (5) to form the compound of Formula (6HC1) is carried out at 85 °C to 90 °C. In some embodiments, the compound of Formula (6HC1) is isolated. In some embodiments the compound of Formula (6HC1) is further purified. In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding ethyl acetate until a slurry' is formed, then isolating the solid purified compound of Formula (6HCL). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding about ethyl acetate until a slurry is formed, cooling the slurry to about 20 °C, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with 1.5 vol equivalents of ethanol and slowly adding about 4.5 vol equivalents of ethyl acetate until a slurry is formed, cooling the slurry to about 20 °C then isolating the solid purified compound of Formula (6HC1).

[0086] In some embodiments the conversion of a compound of Formula (6HC1) to a compound of Formula (6) is carried out in a suitable solvent or mixture of solvents. In some embodiments step i) comprises treating the compound of Formula (6HC1) with saturated sodium bicarbonate to form the compound of Formula (6). In some embodiments step i) comprises treating the compound of Formula (6HC1) in a solution of ethyl acetate / ethanol with saturated sodium bicarbonate to form the compound of Formula (6). In some embodiments the compound of Formula (6) is isolated.

[0087] In some embodiments the contacting in step j) comprises contacting the compound of Formula (6) with maleic acid in ethyl acetate to form the compound of Formula (6MA).Attorney Docket No. 143989-005402Process for preparing a citric acid solvate of a compound of Formula (6)

[0088] Some embodiments herein describe a process for preparing a citric acid cocrystal of a compound of Formula (6) comprising contacting a compound of Formula (6)with citric acid to form the citric acid cocrystal of the compound of Formula (6). In some embodiments the process comprises contacting the compound of Formula (6) with citric acid in isopropanol.

[0089] In some embodiments the compound of Formula (6) is prepared according to any embodiment described herein.

[0090] Some embodiments herein describe a process for preparing a citric acid cocrystal of a compound of Formula (6)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(i); b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):Attorney Docket No. 143989-005402c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):e) esterifying the compound of Formula (3A) to form a compound of Formula (3B):f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4);Attorney Docket No. 143989-005402 g) halogenating the compound of Formula (4) to form a compound of Formula (5):h) aromatizing the compound of Formula (5) to form a compound of Formula (6HC1):(6HC1); and i) treating the compound of Formula (6HC1) with a base to form the compound of Formula (6); and j ) contacting the compound of Formula (6) with citnc acid to form a citric acid cocrystal of the compound of Formula (6).

[0091] In some embodiments the condensing of a compound of Formula (SMI) and methyl isobutyl ketone to form a compound of Formula (1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the solvent is ethanol. In some embodiments the solvent is tetrahydrofuran. In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of lithium, potassium, or sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of 10% sodium hydroxide to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In someAttorney Docket No. 143989-005402 embodiments step a) comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments step a) comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1). In some embodiments step a) comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1).

[0092] In some embodiments the contacting of diethyl malonate with a compound of Formula (1) to form a compound of Formula (2) is carried out in a suitable solvent or mixture of solvents. In some embodiments step b) comprises contacting diethyl malonate with the compound of Formula (1) in the presence of lithium bromide and triethylamine to form the compound of Formula (2). In some embodiments step b) comprises adding diethyl malonate, lithium bromide, and triethylamine to the compound of Formula (1) followed by heating to form the compound of Formula (2). In some embodiments step b) comprises adding diethyl malonate, lithium bromide, and triethylamine to the compound of Formula (1) in a suitable solvent or mixture of solvents, followed by heating to about 35 °C to form the compound of Formula (2). In some embodiments step b) comprises heating the compound of Formula (1) in a suitable solvent or mixture of solvents to about 35 °C. then sequentially adding diethyl malonate, tri ethylamine, and lithium bromide to form the compound of Formula (2).

[0093] In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) is carried out in a suitable solvent or mixture of solvents. In some embodiments step c) comprises contacting the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) with 6M aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments step c) comprises heating the compound of Formula (2) and 6M aqueous sodium hydroxide to about 35 °C to form the compound of Formula (3). In some embodiments step c) comprises heating a solution of the compound of Formula (2) in a suitable solvent or mixtureAttorney Docket No. 143989-005402 of solvents to about 35 °C, then adding 6M aqueous sodium hydroxide to form the compound of Formula (3).

[0094] In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in a suitable solvent or mixture of solvents. In some embodiments step d) comprises contacting the compound of Formula (3) with aqueous hydrochloric acid to form the compound of Formula (3A). In some embodiments step d) comprises heating the compound of Formula (3) with aqueous 6M hydrochloric acid to form the compound of Formula (3 A). In some embodiments step d) comprises adding 6M aqueous hydrochloric acid to a compound of Formula (3) until a pH of about 4 to 5 is reached, followed by heating to form a compound of Formula (3 A). In some embodiments step d) comprises adding 6M aqueous hydrochloric acid to a solution of the compound of Formula (3) in a suitable solvent or mixture of solvents, until a pH of about 4 to 5 is reached, then heating the solution to about 100 °C to form a compound of Formula (3A). In some embodiments the decarboxylation of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in the presence of a base. In some embodiments the base in step d) is selected from triethylamine, imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is tri ethyl amine. In some embodiments step d) comprises contacting the compound of Formula (3) with catalytic tri ethylamine to form the compound of Formula (3 A). In some embodiments step d) comprises heating the compound of Formula (3) with catalytic triethylamine to form the compound of Formula (3A). In some embodiments, the process further comprises isolating the compound of Formula (3 A).

[0095] In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) is carried out in a suitable solvent or mixture of solvents. In some embodiments step e) comprises contacting the compound of Formula (3A) with potassium carbonate and iodomethane to form the compound of Formula (3B). In some embodiments step e) comprises adding iodomethane to a mixture of the compound of Formula (3A), potassium carbonate and anhydrous dimethylformamide to form a compound of Formula (3B). In some embodiments step e) comprises contacting the compound of Formula (3 A) with thionyl chloride and methanol to form the compound of Formula (3B). In some embodiments the esterification is a Fischer esterification with an alcohol and an acid catalyst. In some embodiments step e) comprises contacting the compound of Formula (3 A) with hydrochloric acid and methanol, to form the compound of Formula (3B).Attorney Docket No. 143989-005402

[0096] In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) is carried out in a suitable solvent or mixture of solvents. In some embodiments step f) comprises contacting the compound of Formula (3B) with potassium t- butoxide to form the compound of Formula (4). In some embodiments step f) comprises contacting the compound of Formula (3B) with IM potassium f-butoxide to form the compound of Formula (4). In some embodiments step I) comprises cooling the compound of Formula (3B). then adding IM potassium z-butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling the compound of Formula (3B) to about 0 °C, then adding IM potassium z-butoxide to form the compound of Formula (4). In some embodiments step f) comprises cooling a solution of the compound of Formula (3B) in a suitable solvent or mixture of solvents to about 0 °C, then adding IM potassium z-butoxide to form the compound of Formula (4). In some embodiments the compound of Formula (4) is isolated.

[0097] In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) is carried out in a suitable solvent or mixture of solvents. In some embodiments step g) comprises contacting the compound of Formula (4) with a halogenating agent to form the compound of Formula (5). In some embodiments step g) comprises contacting the compound of Formula (4) with l,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), or N-chlorosuccinimide. In some embodiments step g) comprises contacting the compound of Formula (4) with N-chlorosuccinimide to form the compound of Formula (5).

[0098] In some embodiments the aromatizing of a compound of Formula (5) to form a compound of Formula (6HC1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the aromatizing of a compound of Formula (5) to a compound of Formula (6HC1) is optionally carried out with an additive reagent. In some embodiments the additive reagent is a quaternary ammonium salt. In some embodiments the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyhriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride and tetramethylammonium chloride. In some embodiments the quaternary ammonium salt is tetraethyl ammonium chloride. In some embodiments step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride to give the compound of Formula (6HC1). In some embodiments step h) comprises heating the compound of Formula (5) in anhydrous acetonitrile in the presence of tetraethylammonium chloride to form the compound of Formula (6HC1). In some embodiments step h) comprisesAttorney Docket No. 143989-005402 heating the compound of Formula (5) in anhydrous acetonitrile in the presence of tetraethylammonium chloride to about 85 °C to form the compound of Formula (6 HC1). In some embodiments step h) comprises heating the compound of Formula (5) in anhydrous acetonitrile in the presence of tetraethylammonium chloride to about 90 °C to form the compound of Formula (6 HC1). In some embodiments, the compound of Formula (6HC1) is isolated. In some embodiments the compound of Formula (6HC1) is further purified. In some embodiments the compound of Formula (6HC1) is further purified by crystallization. In some embodiments the compound of Formula (6HC1) is further purified by crystallization with ethanol and ethyl acetate. In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding ethyl acetate until a slurry is formed, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding about ethyl acetate until a slurry is formed, cooling the slurry to about 20 °C, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with 1.5 vol equivalents of ethanol and slowly adding about 4.5 vol equivalents of ethyl acetate until a slurry is formed, cooling the slurry to about 20 °C then isolating the solid purified compound of Formula (6HC1).

[0099] In some embodiments, the compound of Formula (5) is not isolated, and the additive reagent is added during step g) for convenience. In some embodiments the additive reagent is triethylammonium chloride. In some embodiments steps g)-h) comprise contacting the compound of Formula (4) with tetraethylammonium chloride and N-chlorosuccinimide to form the compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments steps g)-h) comprise combining the compound of Formula (4) with tetraethylammonium chloride, then adding anhydrous acetonitrile followed by addition of N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments steps g)-h) comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride, adding anhydrous acetonitrile followed by addition of N- chlorosuccinimide to form a compound of Formula (5), then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments the mixture of the compound of Formula (4) and tetraethylammonium chloride is dried under vacuum at about 40 °C prior to the addition of the anhydrous acetonitrile. In some embodiments the compound ofAttorney Docket No. 143989-005402Formula (4), tetraethylammonium chloride and anhydrous acetonitrile is azeotropically dried. In some embodiments the mixture of the compound of Formula (4), tetraethylammonium chloride and anhydrous acetonitrile is stirred at about 20 °C for at least one hour prior to administration of the N-chlorosuccinimide. In some embodiments the N-chlorosuccinimide is added in portions. In some embodiments the reaction mixture temperature is maintained at <27 °C during administration of the N-chlorosuccinimide. In some embodiments steps g)-h) comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride at about 40 °C; then adding anhydrous acetonitrile and stirring the resulting mixture at about 20 °C; then adding N-chlorosuccinimide in portions while maintaining the reaction mixture temperature at <27 °C during administration of the N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments the reaction mixture temperature is maintained at <25 °C during administration of the N-chlorosuccinimide. In some embodiments steps g)-h comprise drying a mixture of the compound of Formula (4) with tetraethylammonium chloride at about 40 °C; then adding anhydrous acetonitrile and stirring the resulting mixture at about 20 °C; then adding N-chlorosuccinimide in portions while maintaining the reaction mixture temperature at <25 °C during administration of the N-chlorosuccinimide to form a compound of Formula (5) then heating the compound of Formula (5) to form the compound of Formula (6HC1). In some embodiments heating the compound of Formula (5) to form the compound of Formula (6HC1) is carried out at 85 °C to 90 °C. In some embodiments, the compound of Formula (6HC1) is isolated. In some embodiments the compound of Formula (6HC1) is further purified. In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding ethyl acetate until a slurry is formed, then isolating the solid purified compound of Formula (6HCL). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with ethanol and slowly adding about ethyl acetate until a slurry is formed, cooling the slurry to about 20 °C, then isolating the solid purified compound of Formula (6HC1). In some embodiments the compound of Formula (6HC1) is purified by contacting crude compound of Formula (6HC1) with 1.5 vol equivalents of ethanol and slowly adding about 4.5 vol equivalents of ethyl acetate until a slurry is formed, cooling the slurry to about 20 °C then isolating the solid purified compound of Formula (6HC1).

[0100] In some embodiments the conversion of a compound of Formula (6HC1) to a compound of Formula (6) is carried out in a suitable solvent or mixture of solvents. In someAttorney Docket No. 143989-005402 embodiments step i) comprises treating the compound of Formula (6HC1) with aqueous sodium bicarbonate to form the compound of Formula (6). In some embodiments step i) comprises treating the compound of Formula (6HC1) in a solution of ethyl acetate / ethanol with aqueous sodium bicarbonate to form the compound of Formula (6). In some embodiments the compound of Formula (6) is isolated.

[0101] In some embodiments the contacting in step j) comprises contacting the compound of Formula (6) with citric acid in isopropanol to form the citric acid cocrystal of the compound of Formula (6).Preparation of compound of Formula (1)

[0102] Some embodiments describe a process for preparing a compound of Formula (1)comprising condensing a compound of formula (SMI):(SMI), with methyl isobutyl ketone to form the compound of Formula (1).

[0103] In some embodiments the condensing of a compound of Formula (SMI) and methyl isobutyl ketone to form a compound of Formula (1) is carried out in a suitable solvent or mixture of solvents. In some embodiments the solvent is ethanol. In some embodiments the solvent is tetrahydrofuran. In some embodiments the condensing comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of lithium, potassium or sodium hydroxide to form the compound of Formula (1). In some embodiments the condensing comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of sodium hydroxide to form the compound of Formula (1). In some embodiments the condensing comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of 10% sodium hydroxide to form the compound of Formula (1). In some embodiments the condensing comprises adding aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form theAttorney Docket No. 143989-005402 compound of Formula (1). In some embodiments the condensing) comprises adding 10% aqueous sodium hydroxide to the compound of Formula (SMI) and methyl isobutyl ketone to form the compound of Formula (1). In some embodiments the condensing comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments the condensing comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and ethanol to form the compound of Formula (1). In some embodiments the condensing comprises adding aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1). In some embodiments the condensing comprises adding 10% aqueous sodium hydroxide to a solution comprising the compound of Formula (SMI), methyl isobutyl ketone and tetrahydrofuran; followed by heating to form the compound of Formula (1).Preparation of compound of Formula (2)

[0104] Some embodiments describe a process for preparing a compound of Formula(3A)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):Attorney Docket No. 143989-005402and b) contacting diethyl malonate with the compound of Formula (1 ) to form a compound of Formula (2).

[0105] In some embodiments the condensing of a compound of Formula (SMI) with methyl isobutyl ketone to form a compound of Formula (1) is performed according to any embodiment described herein.

[0106] In some embodiments the contacting of diethyl malonate with the compound ofFormula (1) to form a compound of Formula (2) is carried out in a suitable solvent or mixture of solvents. In some embodiments the contacting of diethyl malonate with the compound of Formula (1) to form a compound of Formula (2) comprises contacting diethyl malonate with the compound of Formula (1) in the presence of lithium bromide and tri ethylamine to form the compound of Formula (2). In some embodiments the contacting of diethyl malonate with the compound of Formula (I) to form a compound of Formula (2) comprises adding diethyl malonate, lithium bromide, and triethylamine to the compound of Formula (1) followed by heating to form the compound of Formula (2). In some embodiments the contacting of diethyl malonate with the compound of Formula (1) to form a compound of Formula (2) comprises adding diethyl malonate lithium bromide and tri ethylamine to the compound of Formula (1) in a suitable solvent or mixture of solvents, followed by heating to about 35 °C to form the compound of Formula (2). In some embodiments the contacting of diethyl malonate with the compound of Formula (1) to form a compound of Formula (2) comprises heating the compound of Formula (1) in a suitable solvent or mixture of solvents to about 35 °C, then sequentially adding diethyl malonate, triethylamine, and lithium bromide to form the compound of Formula(2).Preparation of compound of Formula (3)

[0107] Some embodiments describe a process for preparing a compound of Formula(3)Attorney Docket No. 143989-005402comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):and c) hydrolysing the compound of Formula (2) to form the compound of Formula (3).

[0108] In some embodiments the condensing of a compound of Formula (SMI) with methyl isobutyl ketone to form a compound of Formula (1) is performed according to any embodiment described herein.

[0109] In some embodiments the contacting of diethyl malonate with the compound of Formula (1) to form a compound of Formula (2) is performed according to any embodiment described herein.Attorney Docket No. 143989-005402

[0110] In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) is carried out in a suitable solvent or mixture of solvents. In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) comprises contacting the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) comprises heating the compound of Formula(2) with aqueous sodium hydroxide to form the compound of Formula (3). In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula(3) comprises heating the compound of Formula (2) with 6M aqueous sodium hydroxide to form the compound of Formula (3).. In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) comprises heating the compound of Formula (2) and 6M aqueous sodium hydroxide to about 35 °C to form the compound of Formula (3). In some embodiments the hydrolysing of a compound of Formula (2) to form a compound of Formula (3) comprises heating a solution of the compound of Formula (2) in a suitable solvent or mixture of solvents to about 35 °C, then adding 6M aqueous sodium hydroxide to form the compound of Formula (3).Preparation of compound of Formula (3 A)[OHl] Some embodiments herein describe a process for preparing a compound of Formula (3 A)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):Attorney Docket No. 143989-005402b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form the compound of Formula (3):and a) decarboxylating the compound of Formula (3) to form a compound of Formula (3 A).

[0112] In some embodiments the condensing of a compound of Formula (SMI) with methyl isobutyl ketone to form a compound of Formula (1) is performed according to any embodiment described herein.

[0113] In some embodiments the contacting of diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2) is performed according to any embodiment described herein.

[0114] In some embodiments the hydrolysing of the compound of Formula (2) to form the compound of Formula (3) is performed according to any embodiment described herein.

[0115] In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in a suitable solvent or mixture of solvents.Attorney Docket No. 143989-005402In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3 A) comprises contacting the compound of Formula (3) with aqueous hydrochloric acid to form the compound of Formula (3 A). In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3A) comprises heating the compound of Formula (3) with aqueous 6M hydrochloric acid to form the compound of Formula (3A). In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3A) comprises adding 6M aqueous hydrochloric acid to a compound of Formula (3) until a pH of about 4 to 5 is reached, followed by heating to form a compound of Formula (3A). In some embodiments the decarboxylating of a compound of Formula (3) to form a compound of Formula (3A) comprises adding 6M aqueous hydrochloric acid to a solution of the compound of Formula (3) in a suitable solvent or mixture of solvents, until a pH of about 4 to 5 is reached, then heating the solution to about 100 °C to form a compound of Formula (3 A). In some embodiments the decarboxylation of a compound of Formula (3) to form a compound of Formula (3 A) is carried out in the presence of a base. In some embodiments the base in step d) is selected from triethylamine, imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments the base in step d) is triethylamine. In some embodiments step d) comprises contacting the compound of Formula (3) with catalytic triethyl amine to form the compound of Formula (3 A). In some embodiments step d) comprises heating the compound of Formula (3) with catalytic triethylamine to form the compound of Formula (3A). In some embodiments, the process further comprises isolating the compound of Formula (3 A).Preparation of compound of Formula (3B)

[0116] Some embodiments describe a process for preparing a compound of Formula(3B)comprising a) condensing a compound of formula SMI :Attorney Docket No. 143989-005402(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(1)- b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):and e) esterifying the compound of Formula (3 A) to form the compound of Formula (3B).Attorney Docket No. 143989-005402

[0117] In some embodiments the condensing of a compound of Formula (SMI) with methyl isobutyl ketone to form a compound of Formula (1) is performed according to any embodiment described herein.

[0118] In some embodiments the contacting of diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2) is performed according to any embodiment described herein.

[0119] In some embodiments the hydrolysing of the compound of Formula (2) to form the compound of Formula (3) is performed according to any embodiment described herein.

[0120] In some embodiments the decarboxylation of the compound of Formula (2) to form the compound of Formula (3) is as described in any embodiment described herein.

[0121] In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) is carried out in a suitable solvent or mixture of solvents. In some embodiments step e) comprises contacting the compound of Formula (3A) with thionyl chloride and methanol to form the compound of Formula (3B). In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) comprises a Fischer esterification with an alcohol and an acid catalyst. In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) comprises contacting the compound of Formula (3 A) with hydrochloric acid and methanol, to form the compound of Formula (3B). In some embodiments the esterifying of a compound of Formula (3A) to form a compound of Formula (3B) comprises contacting the compound of Formula (3 A) with potassium carbonate and iodomethane to form the compound of Formula (3B). In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) comprises adding iodomethane to a mixture of the compound of Formula (3 A), potassium carbonate and anhydrous dimethylformamide to form a compound of Formula (3B).

[0122] Some embodiments describe a process for preparing a compound of Formula (4)comprisingAttorney Docket No. 143989-005402 a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl malonate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B):Attorney Docket No. 143989-005402and f) cyclizing the compound of Formula (3B) to form the compound of Formula (4).

[0123] In some embodiments the condensing of a compound of Formula (SMI) with methyl isobutyl ketone to form a compound of Formula (1) performed according to any embodiment described herein.

[0124] In some embodiments the contacting of diethyl malonate with the compound of Formula (1) to form a compound of Formula (2) is performed according to any embodiment described herein.

[0125] In some embodiments the hydrolysing of the compound of Formula (2) to form the compound of Formula (3) is performed according to any embodiment described herein.

[0126] In some embodiments the decarboxylation of the compound of Formula (2) to form the compound of Formula (3) is performed according to any embodiment described herein.

[0127] In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) is as performed according to embodiment described herein.

[0128] In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) is carried out in a suitable solvent or mixture of solvents. In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) comprises contacting the compound of Formula (3B) with potassium / -butoxide to form the compound of Formula (4). In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) comprises contacting the compound of Formula (3B) with IM potassium / -butoxide to form the compound of Formula (4). In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) comprises cooling the compound of Formula (3B), then adding IM potassium / -butoxide to form the compound of Formula (4). In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) comprises cooling the compound of Formula (3B) toAttorney Docket No. 143989-005402 about 0 °C, then adding IM potassium / -butoxide to form the compound of Formula (4). In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) comprises cooling a solution of the compound of Formula (3B) in a suitable solvent or mixture of solvents to about 0 °C, then adding IM potassium / -butoxide to form the compound of Formula (4). In some embodiments the compound of Formula (4) is isolated.

[0129] Some embodiments describe a process for preparing a compound of Formula(5)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(1)- b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):(2): c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):Attorney Docket No. 143989-005402d) decarboxylating the compound of Formula (3) to form a compound of Formula(3A):e) esterifying the compound of Formula (3A) to form a compound of Formula(3B):f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4); g) halogenating the compound of Formula (4) to form the compound of Formula(5).

[0130] In some embodiments the condensing of a compound of Formula (SMI) with methyl isobutyl ketone to form a compound of Formula (1) is performed according to any embodiment described herein.

[0131] In some embodiments the contacting of diethyl malonate with the compound of Formula (1) to form a compound of Formula (2) is performed according to any embodiment described herein.Attorney Docket No. 143989-005402

[0132] In some embodiments the hydrolysing of the compound of Formula (2) to form the compound of Formula (3) is performed according to any embodiment described herein.

[0133] In some embodiments the decarboxylation of the compound of Formula (3) to form the compound of Formula (3A) performed according to any embodiment described herein.

[0134] In some embodiments the esterifying of a compound of Formula (3 A) to form a compound of Formula (3B) is performed according to any embodiment described herein.

[0135] In some embodiments the cyclizing of a compound of Formula (3B) to form a compound of Formula (4) is performed according to any embodiment described herein

[0136] In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) is carried out in a suitable solvent or mixture of solvents. In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) comprises contacting the compound of Formula (4) with a halogenating agent to form the compound of Formula (5). In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) comprises contacting the compound of Formula (4) with 1,3-dichl oro-5, 5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), orN- chlorosuccinimide. In some embodiments the halogenating of a compound of Formula (4) to form a compound of Formula (5) comprises contacting the compound of Formula (4) with N- chlorosuccinimide to form the compound of Formula (5). Compound of the Invention

[0137] Some embodiments describe a compound of Formula (1)(1).

[0138] Some embodiments describe a compound of Formula (2)Attorney Docket No. 143989-005402

[0139] Some embodiments describe a compound of Formula (3)

[0140] Some embodiments describe a compound of Formula (3 A)

[0141] Some embodiments describe a compound of Formula (3B)

[0142] Some embodiments describe a compound of Formula (4)(4).

[0143] Some embodiments describe a compound of Formula (5)

[0144] Some embodiments describe a compound of Formula (1)Attorney Docket No. 143989-005402prepared by a process comprising condensing a compound of formula (SMI):(SMI), with methyl isobutyl ketone to form the compound of Formula (1).

[0145] Some embodiments describe a compound of Formula (2)prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methy l isobutyl ketone to form a compound of Formula (1):and b) contacting diethyl mal onate with the compound of Formula (1) to form the compound of Formula (2).

[0146] Some embodiments describe a compound of Formula (3)Attorney Docket No. 143989-005402prepared by a process comprising. a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl malonate with the compound of Formula (1) to form a compound of Formula (2):and c) hydrolysing the compound of Formula (2) to form the compound of Formula (3).

[0147] Some embodiments describe a compound of Formula (3A)Attorney Docket No. 143989-005402 prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):c) hydroly sing the compound of Formula (2) to form a compound of Formulaand d) decarboxylating the compound of Formula (3) to form the compound ofFormula (3A).

[0148] Some embodiments describe a compound of Formula (3B)Attorney Docket No. 143989-005402prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl malonate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formulad) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):Attorney Docket No. 143989-005402(3A); and e) esterifying the compound of Formula (3 A) to form the compound of Formula (3B).

[0149] Some embodiments describe a compound of Formula (4)prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1 ):b) contacting diethyl malonate with the compound of Formula (1) to form a compound of Formula (2):Attorney Docket No. 143989-005402 c) hydrolysing the compound of Formula (2) to form a compound of Formulad) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B);(3B); and cyclizing the compound of Formula (3B) to form the compound of Formula (4).

[0150] Some embodiments describe a compound of Formula (5)prepared by a process comprising a) condensing a compound of formula SMI :Attorney Docket No. 143989-005402(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(1)- b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound of Formula(3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B);Attorney Docket No. 143989-005402f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):halogenating the compound of Formula (4) to form the compound of Formula (5).Pharmaceutical Compositions

[0151] Embodiments herein describe a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6), and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable salt has a chemical purity of at least 95% by weight and wherein the pharmaceutically acceptable salt of the compound of Formula (6) is selected from maleate or hydrochloride. In some embodiments the pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6MA), and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable salt has a chemical purity of at least 95% by weight. In some embodiments the pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6HC1), and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable salt has a chemical purity’ of at least 95% by weight.

[0152] Embodiments herein describe a pharmaceutical composition comprising a citric acid cocrystal of a compound of Formula (6), and a pharmaceutically acceptable excipient wherein the citric acid cocrystal of the compound of Formula (6) has a chemical purity of at least 95% by weight.

[0153] Some embodiments herein describe a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (6), and a pharmaceutically acceptable excipient; wherein the pharmaceutically acceptable salt has a chemical purity of at least 95% and wherein the pharmaceuticallyAttorney Docket No. 143989-005402 acceptable salt is selected from maleate or hydrochloride. In some embodiments the pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6MA), and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable salt has a chemical purity of at least 95% by weight. In some embodiments the pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6HC1), and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable salt has a chemical purity of at least 95% by weight.

[0154] Some embodiments herein describe a pharmaceutical composition comprising a therapeutically effective amount of a citric acid cocrystal of a compound of Formula (6), and a pharmaceutically acceptable excipient wherein the citric acid cocrystal of the compound of Formula (6) has a chemical purity of at least 95% by weight.

[0155] Methods of preparing pharmaceutical compositions of a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal of the compound of Formula (6) are familiar to those skilled in the art, which are described in Remington: The Science and Practice of Pharmacy, 21stEdition 2006.

[0156] In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof prepared by any process described herein, has a chemical purity of at least 80% by weight. In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof prepared by any process described herein, has a chemical purity of at least 85% by weight. In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof has a chemical purity of at least 90% by weight. In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof prepared by any process described herein, has a chemical purity of at least 95% by weight. In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof prepared by any process described herein, has a chemical purity of at least 99% by weight. In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof prepared by any process described herein, has a chemical purity of about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, by weight. In some embodiments, a compound of Formula (6) or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof prepared by any process described herein, has aAttorney Docket No. 143989-005402 chemical purity of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. by weight.DEFINITIONS

[0157] The articles "a" and "an" as used herein mean "one or more" or "at least one," unless otherwise indicated. That is. reference to any element of the present invention by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements is present.

[0158] The term '‘about” when used before a numerical designation, e g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by ±10%, ±5% or ±1%.

[0159] References herein to compounds of specified Formula and “salts thereof’ cover the compounds as free bases, or as salts thereof, for example as pharmaceutically acceptable salts thereof. For a review of suitable pharmaceutically acceptable salts see Berge et al., J. Pharm. Sci., 66: 1-19, (1977).

[0160] The term “excipient” or “pharmaceutically acceptable excipient” refers to pharmacologically inactive substances that are added to a pharmaceutical preparation in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release, disintegration or dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrating agents, lubricants, and glidants.

[0161] Throughout the description and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated step but not to the exclusion of any other step or group of steps.

[0162] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification. Various embodiments of the present invention will be illustrated with reference to the following non-limiting examples. The following examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.Attorney Docket No. 143989-005402

[0163] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.EXAMPLES

[0164] Example 1: Synthesis of a compound of Formula (6) Method A

[0165] Preparation of the compound of Formula (3 A)

[0166] Step a):

[0167] A solution of sodium hydroxide (NaOH, 25.6 g, 318 mmol, 0.1 equiv.) in water (102 mL) was added slowly to a stirring solution of isoquinoline-3-carbaldehyde (500 g, 3.18 mol, 1 equiv.), methyl isobutyl ketone (MIBK. 335 g, 3.34 mol, 1.05 equiv.) and ethanol (2000 mL) and the reaction mixture was stirred for 3 hours at 20 ± 5 °C. A solution of ammonium chloride (312 g) in water (1770 mL) was added slowly, keeping a temperature of 20 ± 5 °C. Methyl / e / 7-bul l ether (MTBE, 1850 mL) was added, the layers separated, the aqueous layer was extracted with MTBE (1110 mL), and the combined organic layers were washed with water (2.5 L), followed by brine (1.5 L). The organic phase was dried by azeotropic distillation using tetrahydrofuran (THF, 2.5 L) and toluene (2 L) until water content was < 0.1%. The mixture was diluted with MTBE (1 L) to a total solution volume of 2.5 L. This solution was used directly in Step b).

[0168] Step b):

[0169] Diethyl malonate (61 1 g, 3.82 mol, 1 .2 equiv.), triethylamine (NEts, 386 g, 3.82 mol, 1.2 equiv.) and lithium bromide (55 g, 0.64 mol, 0.2 equiv.) were added sequentially and the reaction mixture was stirred for 17 hours at 35 ± 5 °C. The reaction mixture was used directly in Step c).Attorney Docket No. 143989-005402

[0170] Step c):

[0171] A solution of NaOH (672 g, 8.4 mol, 2.2 equiv. based on diethyl malonate) in water (1040 mL) was added slowly to the solution prepared in the previous step with vigorous agitation of the two-phase reaction mixture at 35 ± 5 °C for 4 hours. The layers were separated, the aqueous layer was extracted with MTBE (1.5 L) and used directly in Step d).

[0172] Step d):

[0173] The aqueous solution prepared in the previous step was adjusted to a pH of about 4 to 5, using 6M aqueous hydrochloric acid (920 mL) and the reaction mixture heated to reflux (95 - 100 °C) with stirred for 16 hours. Upon cooling to 20 °C, dichloromethane (1.5 L) and 6M aqueous hydrochloric acid (700 mL) were added to obtain a pH of 2 in the aqueous phase. The aqueous layer was removed, and the organic layer containing the product was distilled under atmospheric pressure to a volume of 1.5 L. Heptane (1.4 L) was added slowly at room temperature, followed by MTBE (0.5 L) and 3M aqueous NaOH (1.6 L) to obtain a pH of 14 in the aqueous phase. The layers were separated, and the aqueous phase was extracted with MTBE (1.5 L) and adjusted to pH 5 using a combination of 6M aqueous hydrochloric acid (0.7 L) and 50% NaOH. Dichloromethane to a total volume 12 L. The dichloromethane solution was vacuum distilled to a volume of 3 L. Heptane (3 L) was added slow ly over a period of 19 hours at room temperature. The resulting slurry w as aged at room temperature for 2 hours. The slurry w as filtered via filtration. The filter cake was washed with 2:1 heptane / di chloromethane (0.6 L), followed by heptane (1 L). The resulting solid was dried under vacuum at 75 °C for 5 days to give 663.7 g Compound 3A as a light brown solid. Yield 69.7%, purity 99.65%. 'H-NMR, (DMSO-d6, 400.16 MHz, ppm): 5 12.06 (s, 1H); 9.24 (s, 1H); 8.06 (d, 1H); 7.90 (d, 1H); 7.74 (m, 1H); 7.65 (s, 1H); 7.61 (m, 1H); 3.77 (m, 1H); 3.05 (dd, 1H); 2.80 (dd, 1H); 2.73 (dd, 1H); 2.62 (dd, 1H); 2.22 (m, 2H); 1.92 (m, 1H); 0.74 (d, 3H); 0.72 (d, 3H).

[0174] Preparation of the compound of Formula (4)Attorney Docket No. 143989-005402Compound 4

[0175] Step e)

[0176] lodomethane (329 g, 2.3 mol, 1.05 equiv.) was added slowly to a mixture of Compound 3A (660 g, 2.2 mol, 1 equiv ), potassium carbonate (335 g, 2.4 mol, 1.1 equiv ), and anhydrous dimethylformamide (0.2 L). The reaction mixture was stirred at room temperature for 20 hours and a solution of ammonium chloride (520 g) in water (2.95 L) was added slowly. MTBE (3.3L) was added, the layers separated, and the aqueous phase extracted with MTBE (2 L). The combined organic layers were washed with water (3.3 L), brine (2 L) and treated with activated charcoal (200 g) for 16 hours. The charcoal was removed by filtration, washed with MTBE (6.6 L) and the combined MTBE filtrates and wash was dried by azeotropic distillation using portionwise addition of TEIF until the water content of the reaction solution was < 0.1%. The THF / MTBE solution was further concentrated under vacuum to a volume of 2 L and used directly in Step 1).

[0177] Step f)

[0178] The solution prepared in Step e) was cooled to 0 °C and a IM solution of potassium te / 7-butoxide (2.7 L) in THF was added slowly, and the reaction mixture was stirred at 0 ± 5 °C for 18 hours. A solution of ammonium chloride (520 g) in water (2.95 L) was added slowly to the reaction mixture, followed by ethyl acetate (EtOAc, 3.3 L). The layers were separated, and the aqueous phase extracted twice with EtOAc (2 L). then adjusted to pH 8 with 2M hydrochloric acid ( 1 L). Further extraction was carried out with EtOAc following addition of a small amount of ammonium hydroxide and a large amount of water. The combined organic layers were washed with brine (6.6 L) and concentrated under vacuum to a volume of 8 L,Attorney Docket No. 143989-005402 followed by concentration at atmospheric pressure to a volume of 2.5 L. The mixture was cooled from 80 °C to 0 °C over a period of 16 hours. The resulting slurry was stirred at 0 °C for 4 hours, and the product isolated by filtration. The filter cake was washed with three portions of cold ethyl acetate (1.3 L total), and the solids were dried under vacuum at 60 °C. Compound 4 was obtained, after drying, in 73.7% yield (378 g,) and 92.7% purity7. 'H-NMR (DMSO-d6, 400.16 MHz, ppm): 5 9.28 (s, 1H); 8.08 (d, 1H); 7.88 (d, 1H); 7.75 (m, 1H); 7.68 (s, 1H); 7.63 (m, 1H); 3.52 (m, 1H); 3.12 (m, 1H); 2.78 (dd, 2H); 2.64 (dd, 2H); 1.10 (d, 6H).

[0179] Preparation of the compound of Formula (6)

[0180] Step g)

[0181] A mixture of Compound 4 (427.44 g, 1.5 mol, 1 equiv.) and tetraethylammonium chloride (TEAC, 504 g, 3.0 mol, 2 equiv.) was dried under vacuum at 40 °C for 16 hours. Anhydrous acetonitrile (1.7 L) was added, and the slurry stirred at 20 °C for 1 hour. A-chlorosuccinimide (NCS. 223 g, mol. 1.7 mol, 1.1 equiv.) was charged portionwise, keeping the temperature below725 °C and the reaction mixture was stirred at 20 °C for 1 hour. The resulting slurry was used directly in Step h).

[0182] Step h)

[0183] The mixture prepared in the previous step was heated, with stirring to 90 °C for 21 hours, cooled to 20 °C and water (3.8 L) added very slowly. The resulting slurry was stirred at 20 °C for 21 hours, filtered, and the filter cake washed with 9:4 water / acetonitrile (1.3 L). The solids were partially dried under vacuum at room temperature for 5 hours then slurried with ethanol (720 mL) at 20 °C for 21h, EtOAc (720 mL) was added, and the mixture was further stirred for 2.5 hours, filtered and the filter cake w ashed with 1:1 ethanol / ethyl acetateAttorney Docket No. 143989-005402(300 mL). Compound 6HC1 was obtained, after drying, in 86% yield (283 g) and 99.37% purity'. 'H-NMR (DMSO-d6, 400.16 MHz, ppm): 5 9.74 (s, 1H); 9.62 (bs, 1H); 8.45 (d,lH); 8.40 (s, 1H); 8.25 (d, 1H); 8.07 (t, 1H); 7.88 (t, 1H); 6.96 (s, 2H); 3.53 (septet, 1H); 1.30 (d, 6H). Fig. 6.

[0184] Step i)

[0185] Compound 6HC1 (310 g. 0.98 mol, 1 eq.) was combined with EtOAc (1.5 L) and ethanol (620 mL). The slurry was stirred at room temperature for 1 hour, and aqueous sodium bicarbonate (1.2 L) added. The biphasic mixture was stirred for 30 minutes before separating the aqueous and organic layers. The aqueous layer was extracted with EtOAc (450 mL), and the combined organics were washed twice with water (1.5 L). A small amount of brine was used to facilitate phase separation following the water washes. The organic layer was washed with brine (100 mL), (required filtration and additional EtOAc and water to break emulsion) and treated with a suspension of activated charcoal (80 g) in ethyl acetate (600 mL) for 48 hours. The charcoal was removed via filtration and washed with EtOAc (4.2 L). The ethyl acetate solution was concentrated under vacuum to a volume of 1.2 L, heated to 60 °C and heptane (1.9 L) was added slowly, maintaining an internal temperature of 60 °C. The resulting slurry' was cooled to 20 °C over a period of 8 hours, heptane (300 mL) was added, and the product isolated by filtration. The filter cake was ashed with 7:3 heptane / ethyl acetate (600 mL). Compound 6 was obtained, after drying in 79.9% yield (219 g).

[0186] Example 2: Synthesis of a compound of Formula (6) Method B

[0187] Preparation of the compound of Formula (3 A)

[0188] Step a):Attorney Docket No. 143989-005402

[0189] An aqueous solution of NaOH (0.89 kg, 0.1 equivalent) was charged to a solution of isoquinoline-3-carboxaldehyde (SMI, 3.50 kg. 1.0 equivalent) and MIBK (2.45 kg, 1.1 eq.) in THF (15.6 kg). The reaction mixture was heated at 50 °C for 7 hours, followed by addition of aqueous ammonium chloride (18.20 kg) and MTBE (13 kg). The mixture was stirred, the layers separated, and the organic layer washed with aqueous NaCl solution (14 kg). The organic phase was concentrated, toluene (15.20 kg) was added, and the solution was concentrated again. Finally, MTBE (7.80 kg) was added to the concentrated solution, which was used directly in step b).

[0190] Step b):

[0191] Diethyl malonate (4.28 kg. 1.2 equiv.), NEh (2.71 kg, 1.2 equiv.), and lithium bromide (0.39 kg, 0.2 equiv.) were added to the reaction mixture obtained from Step a). The resulting mixture was stirred at 35 °C for 3 hours and then used directly in Step c).

[0192] Step c):

[0193] With vigorous stirring, a 6M NaOH (13.60 kg, 2.5 equiv. relative to diethyl malonate) was added to the reaction mixture obtained from step b). The resulting mixture was stirred at 35 °C for 16 hours., water was added, and the layers separated. The organic layer was extracted with IM NaOH (10.9 kg), the combined aqueous phases were acidified to pH 2.6 using 6M HC1 (15.0 kg) and extracted with dichloromethane (23.2 kg followed by 3.5 kg). The combined organic layers were concentrated to 11 L volumes and used directly in step d).

[0194] Step d):

[0195] To the dichloromethane (DCM) solution obtained from step c), toluene (15.2 kg) and NEE (0.56 kg, 0.25 equiv.) were added. The solution was distilled at atmospheric pressure at 80 °C to remove DCM. The temperature was increased to 95 °C and maintained for 4 hours, the reaction mixture cooled to 20 °C and IM NaOH (23.7 kg) added. The layers were separated, the aqueous phase extracted with MTBE (2 x 10.4 kg). DCM (69.6 kg) was added to the aqueous solution and the pH of the biphasic mixture was adjusted to 4.6 with 6M HC1 (4.1 kg). The layers were separated and the DCM solution of Compound 3A was filtered and concentrated to 18L. Heptane (23.9 kg) was slowly added at 40 °C to crystallize the product. The product slurry was slowly cooled to 10 °C, filtered and wash with DCM:Heptane (1:2 v / v, 6.3 kg). Compound 3A was obtained after drying in 66% yield (4.4 kg) and 99.7% purity.

[0196] Preparation of the compound of Formula (4)Attorney Docket No. 143989-005402Compound 4

[0197] Step e)

[0198] lodomethane (3.24 kg, 1.05 equiv.) was slowly added to a stirred mixture of Compound 3 A (6.5 kg), potassium carbonate (3.3 kg, 1.1 equiv.), and anhydrous dimethylformamide (25 L final volume). The reaction mixture was stirred at 20 °C for 12 hours, aqueous ammonium chloride (34. 1 kg) was added followed by MTBE (24 kg), the biphasic mixture was stirred, and the layers separated. The aqueous phase was extracted with MTBE (24 kg), and the combined organic layers washed with water (33 kg) and brine (22.4 kg). The organic phase was treated with activated charcoal (2 kg) for 20 hours, filtered to remove the charcoal, which was washed with MTBE (98 kg). The MTBE solution was concentrated to 33L, THF (2 x 29 kg) was added and concentration continued to achieve a water content of < 0.1%. The resulting solution (33 L) was used directly in step f).

[0199] Step f)

[0200] The solution from step e) was cooled to 0 °C. A IM solution of potassium tert- butoxide (23.9 kg) was slowly charged, and the reaction mixture was stirred at 0 °C for at least 3 hours. An aqueous solution of Nal fiPO-i (52.1 kg) was added to the reaction mixture, followed by EtOAc (29 kg). After vigorous agitation, the layers were separated, the aqueous, layer extracted with EtOAc (18 kg) and the combined organic layers washed with water (33 kg) then brine (22.4 kg). The EtOAc was concentrated under vacuum to a volume of 33L, additional EtOAc (29 kg) added and concentration continued at atmospheric pressure to a final volume of 33L. The mixture was cooled from 80 °C to 0 °C, over a period of at least 20 hours.Attorney Docket No. 143989-005402The resulting si urry was stirred at 0 °C for 4 hours, then filtered and washed cold ethyl acetate (12 kg). Compound 4 was obtained, after drying, in 57% yield (3.50 kg) and 99.9% purity.

[0201] Preparation of the compound of Formula (6 HC1)

[0202] Step g)

[0203] Compound 4 (3.5 kg) and TEAC (4.1 kg, 2 equiv.) were dried under vacuum at 40 °C for 16 hours. Anhydrous acetonitrile (11 kg) was added and the mixture was stirred at 20 °C for 1 hour. NCS (1.8 kg, 1.1 equiv.) was added in six equal portions while maintaining the temperature below 27 °C. The reaction mixture was stirred at 20 °C for 30 minutes and the resultant mixture is used directly in Step h).

[0204] Step h)

[0205] The mixture prepared in step g) was heated to 85 °C and stirred for 16 hours, cooled to 20 °C, over a period of about 6 hours, and water (31.5 kg) slowly added with continuous stirring. The resulting slurry was then stirred at 20 °C for 13 hours, filtered and the filter cake washed with acetonitrile: heptane (2:5 v / v, 6.6 kg) then heptane (4.8 kg). Compound 6HC1 was obtained, after drying, in 75% yield (2.95 kg) and 98.9% purity. ’HNMR (600 MHz, DMSO-ds) b: 9.65 (s, 1H); 8.39 - 8.32 (m, 2H); 8.20 (d, J = 8.1 Hz, 1H); 8.03 - 7.98 (m, 1H); 7.82 (t, J = 7.6 Hz, 1H); 6.93 (d, J = 2.2 Hz, 2H); 3.49 (p, J = 7. 1 Hz, 1H); 1.26 (d, J = 7. 1 Hz, 6H) Fig. 7. The hydroxy protons for the compound of Formula (6) are not observed (so total 15 protons observed). There is a broad singlet at ~ 9.5 ppm which can be from the proton at the protonated site.Attorney Docket No. 143989-005402

[0206] Preparation of the compound of Formula (6)

[0207] Step i)

[0208] Compound 6 HC1 (1.75 kg) was stirred in ethanol (2.1 kg) for 9 hours and EtOAc (7.1 kg) added slowly. The slurry’ was agitated at 20 °C for 2 hours, filtered, the solids were washed with EtOAc:ethanol (3: 1 v / v, 4.8 kg) and dried to a constant weight. The dried Compound 6HC1 was dissolved in a mixture of EtOAc (9.5 kg), ethanol (2.8 kg) and aqueous sodium bicarbonate (11 kg) and the solution was stirred for 40 minutes. The layers were separated, the aqueous layer was extracted with EtOAc (4. 1 kg) and the combined organic layers were washed with water (8.7 kg) followed by brine (1.5 kg), then water (8.7 kg), and then treated with activated charcoal (0.44 kg) for 15 hours at 20 °C. The charcoal was removed by filtration and washed with ethyl acetate (24.7 kg). The ethyl acetate solution was concentrated under vacuum to a volume of ~ 7L, heated to ~50 °C, and heptane (8.4 kg) was added slowly while maintaining a temperature of ~50 °C. The resulting slurry was cooled to 20 °C over a period of 11.5 hours. The product was collected by filtration and washed with heptane:EtOAc (7:3v / v, 3.6 kg). Compound 6 was obtained, after drying, in 78% yield (1.21 kg) and 100% purity’.NMR (600 MHz, dmso) 8: 9.35 (s, 1H); 9.20 (s, 2H); 8.11 (dd, J = 8.3, 1.2 Hz, 1H); 8.05 - 8.00 (m, 2H); 7.77 (ddd, J = 8. 1, 6.7. 1.2 Hz, 1H); 7.64 (ddd, J = 8.0, 6.7, 1.1 Hz, lH): 7.13 (s, 2H); 3.49 (p. J =7.1 Hz, 1H); 1.28 (d, J = 7.1 Hz, 6H).

[0209] Example 3: Synthesis of the compound of Formula (6MA)

[0210] To 5.0 grams of a compound of Formula (6) and 1.1 molar equivalent of maleic acid was added 10 mb of ethyl acetate and the mixture was stirred at 25 °C. Thickening of the mixture was observed and additional 10 mL aliquots of ethyl acetate was added until a uniform slurry’ was obtained. The mixture was stirred overnight and after 24 hours, an additional 10 mL of ethyl acetate was added. The mixture was stirred an additional 2 days, the product isolated by filtration, and washed with cold ethyl acetate (5mL x 2) Compound 6MA was obtained, after drying, as a white solid: 'H-NMR. (DMSO-de, 600 MHz, ppm) A 9.37 (d, J = 1.1 Hz. 1H); 9.22 (s. 2H); 8.13 (dd, J = 8.1, 1.2 Hz. 1H); 8.06 (d. J = 1.5 Hz, 1H); 8.04 (dd, J = 8.4, 1.1 Hz, 1H); 7.78 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H); 7.65 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H);Attorney Docket No. 143989-0054027. 11 (d, J = 0.9 Hz, 2H); 6.26 (d, J = 0.7 Hz, 2H); 3.52 - 3.44 (m, 1H); 1.28 (d, J = 7. 1 Hz, 6H) Fig- 9 All 17 protons for compound of Formula (6) observed including the hydroxy’ group protons. Peak at 6.26 ppm is for the two olefin protons in maleic acid

[0211] Example 4: Synthesis of a cocrystal of the compound of Formula (6)

[0212] To 5.0 grams of a compound of Formula (6) and 1.1 molar equivalent of citric acid was added lOmL of isopropanol and the mixture was stirred at 25 °C. Thickening of the mixture was observed and additional 10 mL of isopropanol was added till a uniform slurry was obtained. This reaction mixture was stirred overnight and after 24 hours an additional 28 mL of isopropanol was added. This mixture was stirred for an additional 2 days, the product was isolated by filtration and washed with cold isopropanol (5mL x 2). Citric acid cocrystal of Compound 6 was obtained, after drying, as a white solid: ’H-NMR. (DMSO-de, 600 MHz, ppm) 8: 9.35 (s, 1H); 9.20 (d, J = 1.1 Hz, 2H); 8.11 (dd, J = 8.2, 1.3 Hz, 1H); 8.05 - 8.00 (m, 2H); 7.77 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H); 7.64 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H); 7.13 (d, J = 1.2 Hz. 2H); 3.54 - 3.44 (m. 1H); 2.75 (dd, J = 15.3, 1.5 Hz, 2H); 2.65 (dd, J = 15.4. 1.5 Hz. 2H); 1.28 (d, J = 7. 1 Hz, 6H). Fig. 8. All 17 protons for Formula (6) observed including the hydroxy group protons. Peaks at 2. 75 and 2. 65 ppm are for the two sets of aliphatic -CH2 protons in citric acid.

[0213] Example 5: Justification of Maleic Acid salt and Citric Acid Cocrystal

[0214] It was expected that HC1, and perhaps the maleic acid, would form salts with the compound of Formula (6), since their pKa values are at least 2-3 units below that of the basic pKa(—4.5) of the isoquinoline group of the compound of Formula (6). The formation of a salt with HC1 (i.e., a compound of Formula (6HC1)) is consistent with the downfield shift of the isoquinoline protons in the 'H NMR spectrum of the compound of Formula (6HC1) (Fig.7) compared with that of the compound of Formula (6) (Fig. 5), especially the large shift of the 9.4 ppm signal from the proton adjacent to the nitrogen in the ring. The formation of a salt (i.e., proton transfer) with maleic acid (i.e., a compound of Formula (6MA)) is supported by NMR and the significant pKa difference from the compound of Formula (6). The 1 : 1 stoichiometry of the maleic acid with the compound of Formula (6) in the isolated solid was confirmed by the two olefinic protons from the maleate observed at 6.26 ppm in the 'H NMR spectrum of the salt (the compound of Formula (6MA), Fig. 9). Note that despite the characterization of the maleate as a salt, the isoquinoline protons are not shifted in the NMRAttorney Docket No. 143989-005402 spectrum, perhaps from loss of the salt in DMSO because of shifts in the pKa values in this solvent relative to water (J. Phys. Chem. A 2004, 108, 166-171).

[0215] Citric acid has been characterized as cocrystal, as the co-formers have intact carbonyl stretches present just above 1700 cm'1in the FTIR spectrum of the crystals (See Fig. 4). Cocrystal formation is more likely than for the other acids, as the first pKa(~3) for citric acid is one unit closer to that of the API, than is that of maleic acid (pKa 1.9).

Claims

Attorney Docket No. 143989-005402CLAIMS1. A process for the preparation of a compound of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof, comprising: a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):(2); c) hydrolysing the compound of Formula (2) to form a compound of Formula(3):Attorney Docket No. 143989-005402d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B):(3B); f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4); g) halogenating the compound of Formula (4) to form a compound of Formula(5):h) aromatizing the compound of Formula (5) to form a compound of Formula(6HC1):Attorney Docket No. 143989-005402(6HC1); and i) optionally performing one or more additional steps selected from a. treating the compound of Formula (6HC1) with a base to form the compound of Formula (6); b. converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and c. converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

2. The process of claim 1. wherein the condensing in step a) comprises contacting the compound of Formula (SMI) with methyl isobutyl ketone in the presence of sodium hydroxide to form the compound of Formula (1).

3. The process of either of claims 1 or 2, wherein the contacting in step b) comprises contacting the diethyl malonate with the compound of Formula (1) in the presence of lithium bromide and triethylamine to form the compound of Formula (2).

4. The process of any one of claims 1 to 3, wherein the hydrolysing in step c) comprises contacting the compound of Formula (2) with aqueous sodium hydroxide to form the compound of Formula (3).

5. The process of any one of claims 1 to 4, wherein the decarboxylating in step d) comprises contacting the compound of Formula (3) with catalytic triethylamine to form the compound of Formula (3 A)6. The process of any one of claims 1 to 4, wherein the decarboxylating in step d) comprises contacting the compound of Formula (3) with aqueous hydrochloric acid to form the compound of Formula (3 A).Attorney Docket No. 143989-0054027. The process of any one of claims 1 to 6, wherein the esterifying in step e) comprises contacting the compound of Formula (3 A) with potassium carbonate and iodomethane to form the compound of Formula (3B).

8. The process of any one of claims 1 to 7, wherein the cyclizing in step f) comprises contacting a compound of Formula (3B) with potassium / -butoxide to form the compound of Formula (4).

9. The process of any one of claims 1 to 8, wherein the halogenation in step g) comprises contacting the compound of Formula (4) with N-chlorosuccinimide to form the compound of Formula 5.

10. The process of any one of claims 1 to 9, wherein aromatizing in step h) comprises heating the compound of Formula (5) in the presence of tetraethylammonium chloride to give the compound of Formula (6HC1).

11. The process of any one of claims 1 to 10, wherein the base in step i) is sodium bicarbonate.

12. The process of claim 11, further comprising contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA):

13. The process of claim 11, further comprising contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6).

14. A process for the preparation of a compound of Formula (6)Attorney Docket No. 143989-005402 or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof comprising: a) contacting a compound of formula (SMI ):(SMI), with methyl isobutyl ketone in the presence of sodium hydroxide, to form a compound of Formula (1):(i); b) treating the compound of Formula (1) with diethyl malonate, in the presence of triethylamine and lithium bromide to form a compound of Formula (2):c) hydroly zing the compound of Formula (2) with aqueous sodium hydroxide to form a compound of Formula (3):d) treating the compound of Formula (3) wi th aqueous hydrochloric acid to a pH of about 4 to 5 and heating to form a compound of Formula (3 A):Attorney Docket No. 143989-005402e) combining the compound of Formula (3 A), with potassium carbonate and anhydrous dimethylformamide, then adding iodomethane, to form a compound of Formula (3B);f) treating a cooled solution of the compound of Formula (3B) with potassium t- butoxide to form a compound of Formula (4):(4); g) contacting the compound of Formula (4) N-chlorosuccinimide to form a compound of Formula (5):h) heating the compound of Formula (5) in the presence of tetraethylammonium chloride to form a compound of Formula (6 HC1):Attorney Docket No. 143989-005402 and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a saturated sodium bicarbonate to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

15. A process for preparing a compound of Formula of Formula (6)or a pharmaceutically acceptable salt or pharmaceutically acceptable cocrystal thereof comprising: a) contacting a compound of formula (SMI):(SMI), with methyl isobutyl ketone in the presence of sodium hydroxide, to form a compound of Formula (1 ):(i); b) treating the compound of Formula (1) with diethyl mal onate, in the presence of tnethylamine and lithium bromide to form a compound of Formula (2):Attorney Docket No. 143989-005402c) hydrolysing the compound of Formula (2) with aqueous sodium hydroxide to form a compound of Formula (3):d) heating the compound of Formula (3) with catalytic triethylamine to form a compound of Formula (3 A):e) combining the compound of Formula (3 A), with potassium carbonate and anhydrous dimethylformamide, then adding iodomethane, to form a compound of Formula (3B):f) treating a cooled solution of the compound of Formula (3B) with potassium l- butoxide to form a compound of Formula (4):Attorney Docket No. 143989-005402(4); g) contacting the compound of Formula (4) with N-chlorosuccinimide to form a compound of Formula (5):h) heating the compound of Formula (5) in the presence of tetraethylammonium chloride to form a compound of Formula (6 HC1):and i) optionally performing one or more additional steps selected from(1) treating the compound of Formula (6HC1) with a saturated sodium bicarbonate to form the compound of Formula (6);(2) converting the compound of Formula (6) to a pharmaceutically acceptable salt of the compound of Formula (6); and(3) converting the compound of Formula (6) to a pharmaceutically acceptable cocrystal of the compound of Formula (6).

16. The process of either one of claims 14 or 15, further comprising treating the compound of Formula (6) with maleic acid to form the compound of Formula (6MA):Attorney Docket No. 143989-00540217. The process of either of claims 14 or 15, further comprising treating the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6).

18. A process for preparing a compound of Formula (6MA)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):Attorney Docket No. 143989-005402d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B):(3B); f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):(4); g) halogenating the compound of Formula (4) to form a compound of Formula(5):h) aromatizing the compound of Formula (5) to form the compound of Formula(6HC1):Attorney Docket No. 143989-005402(6HC1); i) treating the compound of Formula (6HC1) with a base to form a compound ofFormula (6):(6); and j) contacting the compound of Formula (6) with maleic acid to form the compound of Formula (6MA).

19. A process for preparing a citric acid cocrystal of a compound of Formula (6),comprising: a) condensing a compound of formula SMI:(SMI), with methyl isobutyl ketone to form a compound of Formula (1):Attorney Docket No. 143989-005402 b) contacting diethyl malonate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formulad) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula (3B):f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):Attorney Docket No. 143989-005402g) halogenating the compound of Formula (4) to form a compound of Formula(5); aromatizing the compound of Formula (5) to form a compound of Formula(6HC1).(6HC1); i) treating the compound of Formula (6HC1) with a base to form the compound of Formula (6)(6); and j) contacting the compound of Formula (6) with citric acid to form a citric acid cocrystal of the compound of Formula (6).

20. A process for preparing a compound of Formula (1)Atorney Docket No. 143989-005402 comprising condensing a compound of formula (SMI):(SMI), with methyl isobutyl ketone to form the compound of Formula (1).

21. A process for preparing a compound of Formula (2)a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):and b) contacting diethyl malonate with the compound of Formula (1 ) to form the compound of Formula (2).

22. A process for preparing a compound of Formula (3)(3);Attorney Docket No. 143989-005402 comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):(2); c) hydrolysing the compound of Formula (2) to form the compound of Formula (3).

23. A process for preparing a compound of Formula (3 A)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):Attorney Docket No. 143989-005402b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formulad) decarboxylating the compound of Formula (3) to form the compound of Formula (3 A).

24. A process for preparing a compound of Formula (3B)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):Attorney Docket No. 143989-005402b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formulad) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):e) esterifying the compound of Formula (3 A) to form the compound of Formula (3B).

25. A process for preparing a compound of Formula (4)Attorney Docket No. 143989-005402comprising a) condensing a compound of formula SM I :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula ( 1 ) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula(3):d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):Attorney Docket No. 143989-005402(3A); e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B); f) cyclizing the compound of Formula (3B) to form the compound of Formula26. A process for preparing a compound of Formula (5)comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):Attomey Docket No. 143989-005402c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound of Formula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula (3B);f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):Attorney Docket No. 143989-005402 g) halogenating the compound of Formula (4) to form the compound of Formula(5).

27. A compound of Formula (1)28. A compound of Formula29. A compound of Formul30. A compound of Formula (3 A)31. A compound of Formula (3B)Atorney Docket No. 143989-00540232. A compound of Formula (4)(4).

33. A compound of Formula (5)34. A compound of Formula (1)prepared by a process comprising condensing a compound of formula (SMI):(SMI), with methyl isobutyl ketone to form the compound of Formula (1).

35. A compound of Formula (2)Attorney Docket No. 143989-005402prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):and b) contacting diethyl mal onate with the compound of Formula (1 ) to form the compound of Formula (2).

36. A compound of Formula (3)prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):Attorney Docket No. 143989-005402b) contacting diethyl mal onate with the compound of Formula (1 ) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form the compound of Formula(3).

37. A compound of Formula (3 A)prepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(1): b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):Atorney Docket No. 143989-005402c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form the compound ofFormula (3 A).

38. A compound of Formula (3B)comprising a) condensing a compound of formula SMI:(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(i); b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):Attorney Docket No. 143989-005402c) hydrolysing the compound of Formula (2) to form a compound of Formula(3):d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3 A) to form the compound of Formula(3B).

39. A compound of Formula (4)prepared by a process comprising a) condensing a compound of formula SMI :Attorney Docket No. 143989-005402(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(1)- b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula (3):d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B):Attorney Docket No. 143989-005402f) cyclizing the compound of Formula (3B) to form the compound of Formulaprepared by a process comprising a) condensing a compound of formula SMI :(SMI), with methyl isobutyl ketone to form a compound of Formula (1):(i); b) contacting diethyl mal onate with the compound of Formula (1) to form a compound of Formula (2):c) hydrolysing the compound of Formula (2) to form a compound of Formula(3):Attorney Docket No. 143989-005402(3); d) decarboxylating the compound of Formula (3) to form a compound ofFormula (3A):(3A); e) esterifying the compound of Formula (3 A) to form a compound of Formula(3B):(3B); f) cyclizing the compound of Formula (3B) to form a compound of Formula (4):g) halogenating the compound of Formula (4) to form the compound of FormulaCS).

41. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (6),-1 IOAttorney Docket No. 143989-005402and a pharmaceutically acceptable excipient wherein the pharmaceutically acceptable salt of the compound of Formula (6) has a chemical purity of at least 95% by weight and wherein the pharmaceutically acceptable salt is selected from maleate or hydrochloride.

42. The pharmaceutical composition of claim 41 wherein the pharmaceutically acceptable salt of the compound of Formula (6) is a compound of Formula (6MA):(6MA).

43. The pharmaceutical composition of claim 41 wherein the pharmaceutically acceptable salt of the compound of Formula (6) is a compound of Formula (6HC1):(6HC1);44. A pharmaceutical composition comprising a citric acid cocrystal of a compound of Formula (6),Attorney Docket No. 143989-005402 and a pharmaceutically acceptable excipient wherein the citric acid cocrystal of the compound of Formula (6) has a chemical purity of at least 95% by weight.

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