NZ711315B2 - Processes for the preparation of an apoptosis-inducing agent - Google Patents

Abstract

Provided herein is a process for the preparation of an apoptosis-inducing agent (A1), and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the process provided herein.

Description

PROCESSES FOR THE PREPARATION OF AN APOPTOSIS-INDUCING AGENT This application claims the beneft of United States Provisional Application No. 61/780,621, fled March 13, 2013, and United States Provisional Application No. 61/947,850, fled March 4, 2014, each of which is hereby incorporated by refrence herein in its entirety.

FIELD Provided herein are processes fr the preparation of an apoptosis-inducing agent, and chemical intermediates thereof Also provided herein are novel chemical intermediates related to the processes provided herein.

BACKGROUND 4-( 4-{[2-( 4-chlorophenyl)-4,4-dimethylcyclohexenyl]methyl} piperazinyl)- N-( {3-nitro[ ( tetahydro-2H-pyranylmethyl)amino ]phenyl} sulfnyl)( 1 H-pyrrolo[2,3- b ]pyridinyloxy)benzamide (hereafer, "Compound 1 ") and 4-( 4-{[2-( 4-chlorophenyl)-4,4- dimethylcyclohexenyl]methyl} piperazinyl)-N-( {3-nitro[ (1R,4R)-[ 4-hydroxy methylcyclohexyl ]methyl)amino ]phenyl} sulfnyl)( 1 H-pyrrolo[2,3-b ]pyridin yloxy )benzamide (hereafer, "Compound 2") are each potent and selective Bcl-2 inhibitors having, inter alia, antitumor activity as apoptosis-inducing agents.

Compound 1 has the frmula: Compound 2 has the frmula: Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. U.S. Patent Publication No. 2010/0305122 describes Compound 1, Compound 2, and other compounds which exhibit potent binding to a Bcl-2 family protein, and pharmaceutically acceptable salts thereof. U.S. Patent Publication Nos. 2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds. U.S. Patent Publication No. 2012/0129853 describes methods for the treatment of systemic lupus erythematosus, lupus nephritis or Sjogren’s Syndrome comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1. The disclosures of U.S. 2010/0305122; 2012/0108590; 2012/0129853; 2012/0157470 and 2012/0277210 are hereby incorporated by reference herein in their entireties.

SUMMARY [0006a] In a first aspect of the invention, there is provided a process for the preparation of a compound of formula A1: (A1), wherein R is selected from and ; which comprises: (a) combining a compound of formula (K): wherein R is C to C alkyl, 1 12 with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L): (L); and (b'') combining the compound of formula (L) with 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, an organic solvent, and either a compound of formula (N), to provide a compound of formula (A1) wherein R is : or a compound of formula (P), to provide a compound of formula (A1) wherein R is (P); thereby providing a compound of formula (A1); wherein the compound of formula (K) is prepared by: (d) combining a compound of formula (D): with a compound of formula (I): (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).

Provided herein are processes for the preparation of compounds of formula A1: (A1), wherein R is selected from and .

Also provided herein are compounds of the formulae: wherein R is C to C 2 alkyl; and processes fr their preparation.

DETAILED DESCRIPTION Provided herein is a process fr the preparation of compounds of frmula : 1 " H -� � / H N N ' " (Al) 2 - '·,,, wherein R is selected fom and which comprises: a combining a compound of frmula : ( ) K) C0 R wherein R is C to C 1 12 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of frmula (L): 0 o- C02 H L); and (b") combining the compound of frmula (L) with l-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylami nopyridine (DMAP), an organic solvent, and either a compound of frmula () to provide a compound of frmula (Al) wherein R is -�-o : or a compound of frmula (P), to provide a compound of frmula (Al) wherein R is thereby providing a compound of frmula (Al). n one em o 1ment, R 1s . • ,� 1 In another embodiment, R is \··,,, In some embodiments, R is C to C alkyl. In some embodiments, R is C to C alkyl. 1 6 1 4 In some embodiments, R is selected fom the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butl, iso-butl and neo-butyl. In some embodiments, R is tert-butyl.

In one embodiment, the process provided herein frther comprises: (c") combining a compound of frmula (M): with a tertiary amine base, an organic solvent, and either (tetrahydro-2H-pyran yl)methanamine or a salt thereof, to provide the compound of frmula (N), or (1R,4R) ( aminomethyl)methylcyclohexanol or a salt thereof, to provide the compound of frmula (P).

In one embodiment, the (1R,4R)(aminomethyl)methylcyclohexanol salt of step ( c") is the p-toluenesulfnic acid salt.

In another embodiment, the process provided herein frther comprises: (d) combining a compound of frmula (D): wherein R is C to C alkyl, 1 12 with a compound of frmula (I): a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of frmula (K).

In some embodiments, the phosphine ligand is a compound of frmula ( ): NMe2 ( ).

In other embodiments, the phosphine ligand is selected fom: In another embodiment, the process provided herein frther comprises: (e) combining a compound of frmula (B) with a compound of frmula (C): wherein R is C to C 2 alkyl, and a tert-butoxide salt in an organic solvent to provide the compound of frmula (D).

In another embodiment, the process provided herein frther comprises: combining a compound of frmula ( ): with R MgX in an aprotic organic solvent; wherein R is C to C alkyl; and Xis Cl, Br or I; and (g) combining a C to C 2 alkyl chlorofrmate or a di-(C to C 2 alkyl)dicarbonate 1 1 1 1 with the product of step (f, to provide the compound of frmula (C).

In another embodiment, the process provided herein frther comprises: (h) combining a compound of frmula (E): with DMF and POCh to provide a compound of frmula (F): C:(F); (i) combining the compound of frmula (F) with a source of palladium and 4- chlorophenylboronic acid in an organic solvent to provide a compound of frmula (G): Cl� G () combining the compound of frmula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of frmula H : (H);ad (k) combining the compound of frmula (H) with hydrochloric acid to provide the compound of frmula I).

In one embodiment, the process comprises step (a), step (b"), step (c") and step (d).

In one embodiment, the process comprises step (a), step (b"), step c"), step ( d) and step ( e ). In one embodiment, the process comprises step (a), step (b"), step (c"), step (d), step (e), step ( and step (g). In another embodiment the process comprises step (a), step (b"), step (c"), step (d), step ( e ), step ( , step (g), step (h), step (i), step () and step (k).

In one embodiment, the process comprises steps (a), (b") and (d). In another embodiment, the process comprises steps (a), (b"), (d) and (e). In another embodiment, the process comprises steps (a), (b"), (d), (h), (i), () and (k). In another embodiment, the process comprises steps (a), (b"), (c"), (d), (h), (i), ) and (k). In another embodiment, the process comprises steps (a), (b"), (d), ( , (g), (h), (i), () and (k). In another embodiment, the process (k). , (g), (h), (i), () and steps (a), (b"), (d), (e), ( comprises f Also provided herein is a process fr the preparation of Compound 1 of the frmula: 0 ( and which comprises: (a) combining a compound of frmula K : wherein R is C 1 to C 2 alkyl, with a tert butoxide salt, an aprotic organic solvent, and water to provide a compound of frmula (b) combining the compound of frmula ( ) with a compound of frmula (N): (L); 1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of frmula (1 ).

In some embodiments, R is C to C alkyl. In some embodiments, R is C to C alkyl. 1 6 1 4 In some embodiments, R is selected fom the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butl, iso-butl and neo-butyl. In some embodiments, R is tert-butyl.

In one embodiment, the process fr the preparation of Compound 1 frther compnses: (c) combining a compound of frmula (M): with (tetrahydro-2H-pyranyl)methanamine, a tertiary amine base, and an organic solvent to provide the compound of frmula (N).

In another embodiment, the process fr the preparation of Compound 1 frther compnses: (d) combining a compound of frmula (D): wherein R is C to C 2 alkyl, with a compound of frmula (I): a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of frmula (K).

In some embodiments, the phosphine ligand is a compound of frmula (J): In other embodiments, the phosphine ligand is selected fom: In another embodiment, the process fr the preparation of Compound 1 frther compnses: (e) combining a compound of frmula (B) with a compound of frmula (C): wherein R is C to C 2 alkyl, and a tert-butoxide salt in an organic solvent to provide the compound of frmula (D).

In another embodiment, the process fr the preparation of Compound 1 frther compnses: ( combining a compound of frmula (A with R MgX in an aprotic organic solvent; wherein R is C to C alkyl; and Xis Cl, Br or I; and (g) combining a C to C 2 alkyl chlorofrmate or a di-(C to C 2 alkyl)dicarbonate 1 1 1 1 with the product of step (f, to provide the compound of frmula (C).

In another embodiment, the process fr the preparation of Compound 1 frther compnses: (h) combining a compound of frmula (E): with DMF and POCh to provide a compound of frmula (F): C ( ); (i) combining the compound of frmula (F) with a source of palladium and 4- chlorophenylboronic acid in an organic solvent to provide a compound of frmula (G): l� G C ( ); () combining the compound of frmula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of frmula (H): (H);ad (k) combining the compound of frmula (H) with hydrochloric acid to provide the compound of frmula (I).

In one embodiment, the process fr the preparation of Compound 1 comprises steps (a) through ( d). In one embodiment, the process fr the preparation of Compound 1 comprises steps (a) through ( e ). In another embodiment, the process fr the preparation of Compound 1 comprises steps (a) through (g). In another embodiment, the process fr the preparation of Compound 1 comprises steps (a) through (k).

In one embodiment, the process fr the preparation of Compound 1 comprises steps ( a), (b) and ( d). In another embodiment, the process fr the preparation of Compound 1 comprises steps (a), (b), (d) and (e). In another embodiment, the process fr the preparation of Compound 1 comprises steps (a), (b), (d), (h), (i), G) and (k). In another embodiment, the process fr the preparation of Compound 1 comprises steps ( a), (b ), ( c ), ( d), (h), (i), G) and (k).

In another embodiment, the process fr the preparation of Compound 1 comprises steps (a), (b ), (d), (f, (g), (h), (i), G) and (k). In another embodiment, the process fr the preparation of Compound 1 comprises steps (a), (b), (d), (e), (f, (g), (h), (i), G) and (k).

Also provided herein is a process fr the preparation of Compound 2 of the frmula: 0 o- 1 " HN-* : 1 NH - '' 11 , .. ,, N N ' ·., which comprises: (a) combining a compound of frmula (K): C0 R wherein R is C to C 2 alkyl, with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of frmula (L): C02H (b') combining the compound of frmula ( ) with a compound of frmula (P): H2N N -*� �_,,, OH ·,, (P) and 1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), 4-dimethylaminopyridine (DMAP), and an organic solvent to provide the compound of frmula (2).

In some embodiments, R is C to C alkyl. In some embodiments, R is C to C alkyl. 1 6 1 4 In some embodiments, R is selected fom the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butl, iso-butl and neo-butyl. In some embodiments, R is tert-butyl.

In one embodiment, the process fr the preparation of Compound 2 frther compnses: (c') combining a compound of frmula (M): with (1R,4R)(aminomethyl)methylcyclohexanol or a salt thereof, a tertiary amine base, and an organic solvent to provide the compound of frmula (P).

In one embodiment, the (1R,4R)(aminomethyl)methylcyclohexanol salt of step ( c') is the p-toluenesulfnic acid salt. 8 In some embodiments, the method fr the preparation of Compound 2 frther [003 ] comprises step ( d) as described above fr the preparation of Compound 1.

In some embodiments, the method fr the preparation of Compound 2 frther comprises step ( e) as described above fr the preparation of Compound 1.

In some embodiments, the method fr the preparation of Compound 2 frther comprises step (f and step (g) as described above fr the preparation of Compound 1.

In some embodiments, the method fr the preparation of Compound 2 frther comprises step (h), step (i), step () and step (k) as described above fr the preparation of Compound 1.

In one embodiment, the process fr the preparation of Compound 2 comprises step (a), step (b'), step (c') and step (d). In one embodiment, the process fr the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d) and step (e). In one embodiment, the process fr the preparation of Compound 2 comprises step (a), step (b'), step (c'), step (d), step ( e ), step (f and step (g). In another embodiment the process fr the preparation of Compound 2 comprises step ( a), step (b'), step ( c'), step ( d), step ( e ), step (f, step (g), step (h), step (i), step () and step (k).

In one embodiment, the process fr the preparation of Compound 2 comprises steps ( a), (b') and ( d). In another embodiment, the process fr the preparation of Compound 2 comprises steps (a), (b'), (d) and (e). In another embodiment, the process fr the preparation of Compound 2 comprises steps (a), (b'), (d), (h), (i), () and (k). In another embodiment, the process fr the preparation of Compound 2 comprises steps (a), (b'), (c'), (d), (h), (i), () and (k).

In another embodiment, the process fr the preparation of Compound 2 comprises steps ( a), (b'), (d), (f, (g), (h), (i), () and (k). In another embodiment, the process fr the preparation of Compound 2 comprises steps (a), (b'), (d), (e), (f, (g), (h), (i), () and (k).

In some embodiments, in step (a) the tert-butoxide salt is selected fom the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step (a) the tert-butoxide salt is sodium tert-butoxide. In some embodiments, in step (a) the tert­ butoxide salt is potassium tert-butoxide. [004 ] In some embodiments, in step (a) the aprotic organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrof ran, and mixtures thereof In some embodiments, in step (a) the aprotic organic solvent is 2-methyltetrahydrofran.

In some embodiments, in step (b ), step (b') and/or step (b") the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step (b ), step (b') and/or step (b") the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step (b ), step (b') and/or step (b") the organic solvent is dichloromethane.

In some embodiments, in step (c), step (c') and/or step (c") the tertiary amine base is N ,N-diisopropylethylamine.

In some embodiments, in step ( c ), step ( c') and/or step ( c") the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step ( c ), step ( c') and/or step ( c") the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step ( c ), step ( c') and/or step ( c") the organic solvent is acetonitrile.

In some embodiments, in step ( d) the compound of frmula (I) is frst combined with a base prior to the combining of step ( d). In some embodiments, the base is an inorganic base.

In some embodiments, the base is an organic base. In some embodiments, the base is selected fom the group consisting of K3P04, Na3P04, NaOH, KOH, K C03 or Na C03. In some embodiments, the base is K3P04. In some embodiments, in step ( d) the compound of frmula (I) is frst combined with a base in one or more solvents prior to the combining of step ( d).

In some embodiments, in step ( d) the source of palladium is Pd dba3 or [(cinnamyl)PdCl]z. In some embodiments, in step (d) the source of palladium is Pd dba3.

In some embodiments, in step ( d) the tert-butoxide salt is selected fom the group consisting of sodium tert-butoxide and potassium tert-butoxide.

In some embodiments, in step ( d) the tert-butoxide salt is anhydrous. In some embodiments, in step ( d) the tert-butoxide salt is anhydrous sodium tert-butoxide.

In some embodiments, in step ( d) the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step ( d) the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMP A, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step ( d) the aprotic organic solvent is a mixture of THF and toluene.

In some embodiments, step (d) frther comprises the fllowing steps: (1) combining the tert-butoxide salt with the compound of frmula (I) in an aprotic organic solvent; (2) combining the source of palladium, the compound of frmula (J), and the compound of frmula (D) in an aprotic organic solvent; and (3) adding the mixture of step (1) to the mixture of step (2).

In some embodiments, in step ( d) the mixture resulting fom step (2) is fltered prior to step (3).

In some embodiments, step ( d) is carried out under an atmosphere of nitrogen or argon. [005 ] In some embodiments, in step ( d) a catalytic amount of the source of palladium is used relative to the amount of compound (I). In some embodiments, the source of palladium is Pd dba and the catalytic amount of Pd dba is fom about 0.5 mole percent to about 2 mole 2 3 2 3 percent. In one embodiment, the catalytic amount of Pd dba is about 0.75 mole percent.

In some embodiments, in step ( d) a catalytic amount of the compound of frmula (J) is used relative to the amount of compound (I). In some embodiments, the catalytic amount of the compound of frmula (J) is fom about 1 mole percent to about 5 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is fom about 1 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is fom about 2 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is fom about 1 mole percent to about 2 mole percent.

In one embodiment, the catalytic amount of the compound of frmula (J) is about 1 mole percent or about 2 mole percent.

In some embodiments, in step ( e) the tert-butoxide salt is selected fom the group consisting of sodium tert-butoxide and potassium tert-butoxide. In some embodiments, in step ( e) the tert-butoxide salt is sodium tert-butoxide. In some embodiments, in step ( e) the tert­ butoxide salt is potassium tert-butoxide.

In some embodiments, in step ( e) the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step ( e) the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMP A, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step (e) the organic solvent is DMF.

In some embodiments, in step (f, R is C to C alkyl. In some embodiments, R is isopropyl.

In some embodiments, in step (f, R is methyl and the C to C alkyl chlorofrmate is methyl chlorofrmate. In some embodiments, R is ethyl and the C to C alkyl chlorofrmate is ethyl chlorofrmate. In some embodiments, R is tert-butl and the di-(C to C 2 alkyl)dicarbonate is di-tert-butyl dicarbonate.

In some embodiments, in step (f the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMP A, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step (f the aprotic organic solvent is THF.

In some embodiments, in step (i) the source of palladium is Pd(OAc) .

In some embodiments, in step (i) the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step (i) the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMP A, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step (i) the organic solvent is acetonitrile.

In some embodiments, step (i) comprises combining tetrabutylammonium bromide with the compound of frmula (F), a source of palladium and 4-chlorophenylboronic acid in the organic solvent.

In some embodiments, in step G) the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step G) the organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMP A, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, in step G), the organic solvent is a mixture of THF and toluene. In some embodiments, the mixture of THF and toluene is about 1: 1 by volume.

In some embodiments, step G) frther comprises producing the compound of frmula (H) as a crystalline solid. In some embodiments, step G) frther comprises: (1) adding an aqueous solution to the mixture of step G) to produce an aqueous and an organic phase; (2) separating the organic phase fom the mixture of step (1 ); (3) concentrating the organic phase; and ( 4) adding an organic solvent to the mixture of step (3) to produce the compound of frmula (H) as a crystalline solid.

In some embodiments of step ( 4) of step (), the organic solvent is acetonitrile. In some embodiments of step ( 4) of step (), the organic solvent is acetonitrile and the mixture is heated to about 80 °C.

In some embodiments, step (4) of step () frther comprises cooling the mixture to about 10 °C to about -10 °C. In some embodiments, step ( 4) of step () frther comprises cooling the mixture to about -10 °C, and isolating the compound of frmula (H) as a crystalline solid by fltering the mixture.

In some embodiments, the combining of step (k) is in an organic solvent. In some embodiments, the organic solvent is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert­ butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof In some embodiments, the organic solvent is isopropanol.

In some embodiments, step (k) frther comprises producing the compound of frmula (I) as a crystalline solid. In some embodiments, the combining of step (k) is in an organic solvent, and step (k) frther comprises isolating the compound of frmula (I) as a crystalline solid by fltering the mixture.

In some embodiments, the combining of step (k) is in an organic solvent, and step (k) frther comprises cooling the mixture to about 10 °C to about -10 °C to produce the compound of frmula (I) as a crystalline solid.

In some embodiments, the combining of step (k) is in isopropanol, and step (k) frther comprises cooling the mixture to about 10 °C to about -10 °C to produce the compound of frmula (I) as a crystalline solid. In some embodiments, the combining of step (k) is in isopropanol, and step (k) frther comprises cooling the mixture to about -5 °C to produce the compound of frmula (I) as a crystalline solid, and isolating the compound of frmula (I) as a crystalline solid by fltering the mixture.

Also provided herein is a process of preparing a compound of frmula (C): wherein R is C to C 2 alkyl, which comprises (a) combining a compound of frmula (A): to C alkyl; and Xis Cl, Br or I; and with R MgX in an aprotic organic solvent; wherein R is C (b) combining a C to C 2 alkyl chlorofrmate or a di-(C to C 2 alkyl)dicarbonate 1 1 1 1 with the product of step ( a), to provide the compound of frmula (C).

In some embodiments, R is C to C alkyl. In some embodiments, R is C to C alkyl. 1 6 1 4 In some embodiments, R is selected fom the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butl, iso-butl and neo-butyl. In some embodiments, R is tert-butyl. [00 ] In some embodiments, R is C to C alkyl. In some embodiments, R is isopropyl. [00 8] In some embodiments of the process of preparing a compound of frmula (C), the organic solvent of step (a) is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2- butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments the organic solvent of step (a) is THF. [00 ] In one embodiment, R is C to C alkyl.

In one embodiment, R is selected fom the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.

In one embodiment, R is selected fom the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl; and R is isopropyl.

In one embodiment, R is tert-butl and R is isopropyl.

In some embodiments of the process of preparing a compound of frmula (C), in step (b ), R is methyl and the C to C alkyl chlorofrmate is methyl chlorofrmate. In some 1 12 embodiments, R is ethyl and the C to C alkyl chlorofrmate is ethyl chlorofrmate. In some 1 12 embodiments, R is tert-butyl and the di-(C to C alkyl)dicarbonate is di-tert-butyl dicarbonate. 1 12 Also provided herein is a process fr the preparation of a compound of frmula (D): wherein R is C to C alkyl, 1 12 which comprises: (x) combining a compound of frmula (B): H (B); with a compound of frmula (C): and a tert-butoxide salt in an organic solvent to provide the compound of frmula (D).

In one embodiment, R is tert-butyl.

In some embodiments, the process of preparing the compound of frmula (D) frther comprises steps (x') and (x"): (x') combining a compound of frmula (A): with R MgX in an aprotic organic solvent; wherein R is C to C alkyl; and Xis Cl, Br or I; (x") combining a C to C alkyl chlorofrmate or a di-(C to C alkyl)dicarbonate 1 12 1 12 with the product of step (x'), to provide the compound of frmula (C).

In some embodiments, in step (x) the tert-butoxide salt is selected fom the group consisting of sodium tert-butoxide and potassium tert-butoxide.

In some embodiments, the organic solvent of step (x) is selected fom the group consisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof. In some embodiments, the organic solvent of step (x) is DMF.

In some embodiments, in step (x'), R is a C to C alkyl. In some embodiments, R is isopropyl.

In some embodiments, in step (x"), the C to C 2 alkyl chlorofrmate is methyl chlorofrmate. In some embodiments, the C to C 2 alkyl chlorofrmate is ethyl chlorofrmate.

In some embodiments, the di-(C to C 2 alkyl)dicarbonate is di-tert-butyl dicarbonate.

In some embodiments, in step (x') the aprotic organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof In some embodiments, in step (x') the aprotic organic solvent is THF.

Also provided herein is a compound of the frmula (3): [009 ] In one embodiment, the compound of the frmula (3) is prepared by the fllowing steps: (y) combining a compound of frmula (B): with a compound of frmula (C): C0 R (C), wherein R is tert-butl, and a tert-butoxide salt in an organic solvent to provide the compound of frmula (D): A�� 7 y l � H (D), wherein R is tert-butyl; and (z) combining the compound of frmula (D), wherein R is tert-butyl; with a compound of frmula (I): a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent.

In one embodiment, the phosphine ligand of step ( z) is a compound of frmula (J): In other embodiments, the phosphine ligand is selected fom: In one embodiment, in step (z) the source of palladium is Pd dba .

In some embodiments, in step (z) the aprotic organic solvent is selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof In some embodiments, the aprotic organic solvent is is a mixture of THF and toluene.

In some embodiments, in step (z), the tert-butoxide salt is selected fom the group consisting of sodium tert-butoxide and potassium tert-butoxide.

In some embodiments, in step (z) the tert-butoxide salt is anhydrous sodium tert- butoxide or anhydrous potassium tert-butoxide.

In some embodiments, step (z) frther comprises the fllowing steps: (1) combining the tert-butoxide salt with the compound of frmula (I) in an aprotic organic solvent; (2) combining the source of palladium, the compound of frmula (J), and the compound of frmula (D) in an aprotic organic solvent; and (3) adding the mixture of step (1) to the mixture of step (2).

In some embodiments, in step (z) the mixture resulting fom step (2) is fltered prior to step (3).

In some embodiments, step (z) is carried out under an atmosphere of nitrogen or argon.

In some embodiments, in step (z) a catalytic amount of the source of palladium is used relative to the amount of compound (I). In some embodiments, the source of palladium is Pd dba and the catalytic amount of Pd dba is fom about 0.5 mole percent to about 2 mole 2 3 2 3 percent. In one embodiment, the catalytic amount of Pd dba is about 0.75 mole percent.

In some embodiments, when the phosphine ligand of step (z) is a compound fr frmula (J), a catalytic amount of the compound of frmula (J) is used relative to the amount of compound (I). In some embodiments, the catalytic amount of the compound of frmula (J) is fom about 1 mole percent to about 5 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is fom about 1 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is fom about 2 mole percent to about 4 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is fom about 1 mole percent to about 2 mole percent. In one embodiment, the catalytic amount of the compound of frmula (J) is about 1 mole percent or about 2 mole percent.

In another embodiment, provided herein are compounds of the frmulae: {:}-co tBu In some embodiments, the processes described herein are improved methods fr commercial chemical manufcturing of Compound 1 or Compound 2. Without being bound to a particular theory or mechanism of action, the processes described herein signifcantly improve the overall efciency and product yield of Compound 1 or Compound 2. Previous processes (e. . U.S. Patent Publication Nos. 2010/0305122 and 2012/0157470, and Interational Patent Publication Nos. and ) were fund to lack fasibility fr production of Compound 1 on a commercial scale. Thus, the processes provided herein represent improved methods fr the synthesis of compounds in quantities required fr clinical and/or commercial development. Improvements relative to these previous processes include, but are not limited to, overall yield of Compound 1 or Compound 2, overall process efciency and economics, mild reaction conditions, practical isolation/purifcation procedures, and viabilit fr commercialization.

The improved process provided herein involves a selective nucleophilic aromatic substitution reaction ("SnAr reaction") of compounds (B) and (C), which can be carried out under milder conditions with a shorter reaction time when compared to previously described processes as fund, fr example, in U.S. Patent Publication Nos. 2010/0305122 and 2012/0157470, and Interational Patent Publication Nos. and WO 2012/071336. Without being limited by theory, the improved SnAr reaction of compound (B) and (C) does not generate regioisomeric side products which necessitate frther purifcation to remove the side products, as was the case in previously described processes. The SnAr reaction in the previous process also requires a longer reaction time and harsh reaction conditions which result in a low overall yield relative to the processes described herein. Furthermore, the previous processes also require tedious purifcation of the intermediates which is impracticable on a large, commercial scale process. The processes described herein are more convergent than prior processes, resulting in a highly efcient cross-coupling reaction of compound (D) and the fee base of compound (I) in high yield. In some embodiments, the processes described herein utilize crystalline solid intermediates (H) and (I), which allow efcient purifcation by crystallization to remove impurities advantages not available in previously described processes.

The fllowing schemes illustrate one or more embodiments of the process provided herein. In some embodiments, the compound of frmula (D) is prepared fom compound (B) and compound (C) as shown in Scheme 1 below. The compound of frmula (B) may be prepared by techniques known in the art, e.g., as shown in and.!. Am. Chem.

Soc., 1959, 81: 743-747. The compound of frmula (C) may be prepared by techniques known in the art, e.g., as shown in and Tetrahedron Letters, 2008, 49(12), 2034-2037; or as shown in Scheme 2.

Scheme 1 l . .

KOtBu / DMF The compound of frmula (C) of Scheme 1 may prepared fom commercially available compound (A) as shown in Scheme 2 below, wherein "R MgX" represents a Grignard reagent wherein R is an alkyl group, and Xis Cl, Br or I. The electrophilic acetylating reagent of Scheme 2 can be, but is not limited to, methyl or ethyl chlorofrmate or BOC O.

Scheme 2 1. R MgBr 2. Electrophilic acylating reagent An exemplary reaction according to Scheme 2 is shown below. 1. iPrMgBr 0F 2. Boc O In another embodiment, the compound of frmula (I) is prepared fom compound (E) as shown in Scheme 3 below. Compound (E) is commercially available or may be prepared by techniques known in the art, e.g., as shown in U.S. 3,813,443 and Proceedings of the Chemical Societ, London, 1907, 22, 302.

Scheme 3 B THF, o tJ i · H � o I N tolunene r, DMF, POCl � � 0� - Cl) Cl - Pd(OAch MeCN In another embodiment, the compound of frmula (N) is prepared fom compound (M) as shown in Scheme 4 below. Compound (M) is commercially available or may be prepared by techniques known in the art, e.g., as shown in GB 585940 andJ Am. Chem. Soc., 1950, 72, 1215-1218.

Scheme 4 MeCN, DIEA 80 °C In another embodiment, the compound of frmula (P) is prepared fom compound (M) as shown in Scheme 4' below.

Scheme 4' CH3NO HQ H Toluene, 80 C CH MgBr HCI Toluene H N � N , -20 - 30 c 0 �r y e Fe 1) RaNi, wet/ H 9 THF Crabtree's cat. 2) MeCN / pTSA DCM, 30 C dr > 99% MeCN, DIEA 80 °C In another embodiment, the compound of frmula (1) is prepared fom compound (D) and compound (I) as shown in Scheme 5 below. Compound (J) may be prepared by techniques known in the art, e.g., as shown in and Organometallics, 2008, 27(21), 5605- 5611.

Scheme 5 C0 R ) C02H N C02R Br D 0 base ( ) L Pd dba3, otBu In another embodiment, the compound of frmula (2) is prepared fom compound (L) and compound (P) as shown in Scheme 6 below, wherein the preparation of compound (P) is as shown in Scheme 4' and the preparation of compound (L) is as shown in Scheme 5.

Scheme 6 In some embodiments, the preparation of the compound of frmula (K) fom compound (D) and compound (I) is air and/or moisture sensitive, and is therefre perfrmed under an inert atmosphere, e. . using nitrogen or argon gas.

Without being bound to a particular theory, the use of compound (D) as an intermediate in the preparation of the compound of frmula (1) and the compound of frmula (2) as shown above in Schemes 1 to 6 is an improvement over previously described processes fr the preparation of the compound of frmula (1) and the compound of frmula (2). In some embodiments, the improvements include higher product yields, shorter reaction times. In some embodiments, the improvements are provided when R is tert-butyl in compound (D).

Schemes 1 to 6 are non-limiting examples of the process provided herein. Solvents and/or reagents are known compounds and may be interchanged according to the knowledge of those skilled in the art.

Abbreviations used in Schemes 1 to 6 are as fllows: Ac acetyl BOC tert-butoxycarbonyl dba dibenzylidineacetone DIEA N ,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylfrmamide EDAC 1-ethyl(3-dimethylaminopropyl)carbodiimide HCl IPA isopropanol iPr isopropyl Me methyl n-Bu n-butyl tert-butl tetrahydrofran Unless indicated otherwise, the temperatures at which a reaction of Schemes 1 to 6 is conducted is not critical. In certain embodiments, when a temperature is indicated in a reaction, the temperature may be varied fom about plus or minus 0.1 °C, 0.5 °C, 1 °C, 5 °C, or 10 °C.

Depending upon which solvent is employed in a particular reaction, the optimum temperature may vary. In some embodiments, reactions are conducted in the presence of vigorous agitation sufcient to maintain an essentially unifrmly dispersed mixture of the reactants.

In conducting a reaction provided herein, neither the rate, nor the order, of addition of the reactants is critical unless otherwise indicated. Unless otherwise indicated, reactions are conducted at ambient atmospheric pressure. Unless otherwise indicated, the exact amount of reactants is not critical. In some embodiments, the amount of a reactant may be varied by about mole percent or about 10% by weight.

Unless otherwise indicated, the organic solvents used in the processes provided herein may be selected fom those commercially available or otherwise known to those skilled in the art. Appropriate solvents fr a given reaction are within the knowledge of the skilled person and include mixtures of solvents. Examples of organic solvents provided herein fr use include but are not limited to: pentane, hexane, heptane, cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone, dichloromethane, chlorofrm, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofran (THF), dimethylfrmamide (DMF), hexamethylphosphoramide (HMPA), N-methylpyrrolidinone (NMP), nitromethane, acetone, acetic acid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme, petroleum ether, dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, pyridine, 2-methyltetrahydrofran, and mixtures thereof.

In some embodiments, an organic solvent used in the processes provided herein is an aprotic organic solvent. As provided herein, an aprotic solvent is a solvent that does not contain an acidic hydrogen atom or a hydrogen atom that is capable of hydrogen bonding (e.g., is not bound to an oxygen or a nitrogen atom). The aprotic organic solvent may be selected fom the group consisting of dichloromethane, chlorofrm, acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine, 2-methyltetrahydrofran, and mixtures thereof In some embodiments, the aprotic organic solvent is THF. In some embodiments, the aprotic organic solvent is DMF. In some embodiments, the aprotic organic solvent is acetonitrile.

As provided herein, a "tertiary amine base" refrs to an amine that is substituted with three alkyl groups, e.g., tiethylamine or N,N-diisopropylethylamine.

As provided herein, a "catalytic amount" refrs to less than one molar equivalent of a reagent or reactant in a given reaction, as determined relative to another reagent or reactant in the reaction mixture. In some embodiments, a catalytic amount is described as a mole percent relative to another reagent or reactant in the reaction mixture.

As provided herein, a "source of palladium" refrs to a source of palladium in a stable oxidation state, i.e., Pd(0), Pd(I), Pd(II) and/or Pd(IV). The palladium may be fee metal, such as in a powder frm, or may be bound to one or more ligands, e.g., PdCb, Pd2dba3, PdCb(PPh3)2, Pd(PPh3)4, Pd(OAc)2 or [(cinnamyl)PdCl]z.

As provided herein, a "phosphine ligand" refrs to a compound of frmula PR' , wherein each R' is independently selected fom C 1 to C6 alkyl or phenyl, wherein the aryl group is optionally substituted by C1 to C6 alkyl, phenyl, trialkylamino, alkoxy or halo.

As provided herein, unless otherwise defned, the term "about" means that the value or amount to which it refrs can vary by± 5%, ± 2%, or± 1 %.

The products obtained by any of the processes provided herein may be recovered by conventional means, such as evaporation or extraction, and may be purifed by standard procedures, such as distillation, recrystallization or chromatography EXMPLES Compounds of the fllowing examples are shown in Schemes 1 to 6 above and were named using Chemdraw® Ultra software. In addition to the abbreviations described above with respect to the schemes provided herein, the fllowing abbreviations are used in the Examples: "HPLC" high pressure liquid chromatography; "IP" in process; "ML" mother liquor; "NLT" no less than; "NMT" no more than; "RB" round bottom; "RT" room temperature; "sm" starting material; "DCM" dichloromethane.

Unless indicated otherwise, compounds were characterized by HPLC and H NMR analysis and used in later reactions with or without purifcation. H NMR analysis was perfrmed at 400 MHz unless otherwise indicated. Unless specifed otherwise, product yield/purity was determined by weight, qNMR, and/or HPLC analysis.

Example 1: Synthesis of tert-butyl 4-bromofuorobenzoate (Compound (C)) To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4- bromofuorol-iodobenzene, "Compound (A)" (5 g, 1.0 eq) and THF (25 ml). The solution was cooled to -5 °C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the interal temperature below 0 °C. The mixture was stirred at 0 °C fr 1 h.

Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. Afer 1 h, the solution was quenched with 10 % citric acid (10 ml), and then diluted with 25 % NaCl (10 ml). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3 x ml). The crude oil was diluted with THF (5 ml), fltered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency 67%, potency adjusted yield 88%) NMR (DMSO-d6 was taken to the next step without frther purifcation. H 8 1.53 (s, 9H), 7.50-7.56 (m, lH), 7.68 (dd, J l0.5, 1.9 Hz, lH),7.74 (t, J 8.2 Hz, lH).

Example 2: Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy) bromobenzoate (Compound (D)) To a 3 L three-neck Morton fask were charged 1H-pyrrolo[2,3-b ]pyridinol (80.0 g, 1.00 eq.), tert-butyl 4-bromofuorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20 °C fr 15 min. The resulting solution was cooled to about zero to 5 °C. A solution of sodium tert-butoxide ( 62.0 g) in DMF ( 420 mL) was added slowly over 30 min while maintaining the interal temperature at NMT 10 °C, and rinsed with DMF (30 mL). The reaction mixture was stirred at 10 °C fr 1 hour (an of-white slurry) and adjusted the interal temperature to� 45 °C over 30 min. The reaction mixture was stirred at 45-50 °C fr 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion % by HPLC).

The solution was cooled to� 20 °C. The solution was stirred at 20 °C overight.

Water (1200 mL) was added slowly to the reaction mixture at <30 °C over lhour (slightly exothermic). The product slurry was adjusted to� 20 °C, and mixed fr NLT 2 hours.

The crude product was collected by fltration, and washed with water (400 mL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50 °C overight to give the crude product (236.7g).

Re-crystallization or Re-slurry: 230.7 g of the crude product, (otency adjusted: 200.7 g) was charged back to a 3L three-neck Morton fask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refuxing temperature over 1hr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refuxing temperature (78 °C). The slurry was mixed at refuxing temperature fr 30 min., and cooled down slowly to down to � -10 °C at a rate of approximate 10 °C/hour ), and mixed fr 2hr. The product was collected by fltation, and rinsed with heptane (200 ml).

The solid was dried under vacuum at� 50 °C overight to give 194.8 g, 86% isolated yield of the product as an of-white solid. MS-ESI 389.0 (M+ 1); mp: 190-191 °C (uncorrected).

H NMR (DMSO-d6 8 1.40 (s, 9H), 6.41 (dd, J 3.4, 1.7 Hz, lH), 7.06 (d, J l.8 Hz, lH), 7.40 (dd, J 8.3, 1.8 Hz, lH), 7.51 (t, J 3.4 Hz, lH), 7.58 (d, J 2.6 Hz, lH), 7.66 (d, J 8.3 Hz, lH), 8.03 (d, J 2.7 Hz, lH), 11.72 (s, lH, NH).

Example 3: Synthesis of 2-chloro-4,4-dimethylcyclohexanecarbaldehyde (Compound (F)) To a 500 mL RB fask were charged anhydrous DMF (33.4 g, 0.456mol) and CH Cb (80 mL). The solution was cooled down <-5 °C, and POCh (64.7 g, 0.422 mol) added slowly over 20 min @ <20 °C (exothermic), rinsed with CH Cb ( 6 mL ). The slightly brown solution was adjusted to 20 °C over 30 min, and mixed at 20 °C fr 1 hour. The solution was cooled back to< 5 °C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, �0.292 mol) was added, and rinsed with in CH Cb (10 mL) (slightly exothermic) at <20 °C. The solution was heated to refuxing temperature, and mixed overight (21 hours.).

To a 1000 mL three neck RB fask provided with a mechanical stirrer were charged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution, 130 g of 12% brine, and 130 mL of CH Cb. The mixture was stirred and cooled down to <5 °C. The above reaction mixture ( clear and brown) was transfrred, quenched into it slowly while maintaining the interal temperature <10 °C. The reaction vessel was rinsed with CH Cb (10 mL). The quenched reaction mixture was stirred at <10 °C fr 15 min. and allowed to rise to 20 °C. The mixture was stirred °C fr 15 min and allowed to settle fr 30 min. (some emulsion). The lower organic phase was separated. The upper aq. phase was back extacted with CH Cb (50 mL). The combined organic was washed with a mixture of 12% brine (150 g)-20% K P0 aq. solution (40 g). The organic was dried over MgS0 , fltered and rinsed with CH Cb (30 ml). The fltate was concentrated to dryness under vacuum to give a brown oil (57.0 g, potency 90.9wt% by qNMR, � 100%). H NMR (CDCh): 8 0.98 (s, 6H), 1.43 (t, J 6.4 Hz, 2H), 2.31 (tt, J 6.4, 2.2 Hz, 2H), 2.36 (t, J 2.2 Hz, 2H), 10.19 (s, lH).

Example 4: Synthesis of 2-( 4-chlorophenyl)-4,4-dimethylcyclohex enecarbaldehyde (Compound (G)) To a 250 mL pressure bottle were charged 2-chloro-4,4-dimethylcyclohex enecarbaldehyde (10.00 g), tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL).

The mixture was stirred at 20 °C fr 5 min. 21.0 wt% K C0 aq. solution (76.0 g) was added.

The mixture was stirred at room temperature (rt) fr NLT 5 min. fllowed by addition of 4- chlorophenylboronic acid (9.53 g) all at once. The mixture was evacuated and purged with N fr three times. Palladium acetate (66 mg, 0.5 mol %) was added all at once under N . The reaction mixture was evacuated and purged with N fr three times ( an orange colored mixture). The bottle was back flled with N and heated to �35 °C in an oil bath (bath temp �35 °C). The mixture was stirred at 30 °C overight (15 hours). The reaction mixture was cooled to RT, and pulled IP sample fom the upper organic phase fr reaction completion, typically starting material< 2% (orange colored mixture). Toluene (100 mL) and 5% NaHCO -2% L-Cysteine aq. solution (100 mL) were added. The mixture was stirred at 20 °C fr 60 min. The mixture was fltered through a pad of Ce lite to remove black solid, rinsing the fask and pad with toluene ( 10 mL). The upper organic phase was washed with 5% NaHCO aq. solution-2% L-Cysteine (100 mL) once more. The upper organic phase was washed with 25% brine (100 mL). The organic layer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87% assayed yield), and concentrated to � 1/3 volume ( � 35 mL ). The product solution was directly used in the next step without isolation. However, an analytical sample was obtained by removal of solvent to give a brown oil. HNMR (CDCh): 8 1.00 (s, 6H), 1.49 (t, J 6.6 Hz, 2H), 2.28 (t, J 2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, lH).

Example 5: Synthesis of tert-butyl 4-(( 4 '-chloro-5,5-dimethyl-3,4,5,6-tetrahydro­ [l,1 '-biphenyl]yl)methyl)piperazinecarboxylate (Compound (H)) To a 2 L three neck RB fask provided with a mechanical stirrer were charged a solution of 4'-chloro-5,5-dimethyl-3,4,5,6-tetahydro-[1,1 '-biphenyl]carbaldehyde (50.0g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20 °C fr 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the interal temperature rose to �29.5 °C in 15 min cooling may be needed). The yellow mixture was stirred at � 25 °C fr NL T 4hrs. A conversion of starting material to product of 99.5% was observed by HPLC afer a 3 hour reaction time. 12.5 wt % brine (500 g) was added slowly to quench the reaction. The mixture was stirred at 20 °C fr NL T 30 min and allowed to settle fr NLT 15 min. The lower aq. phase (�560 mL) was separated (note: leave any emulsion in the upper organic phase). The organic phase was washed with 10% citric acid solution (500 g x2). 500 g of 5% NaHCO aq. solution was charged slowly into the fask. The mixture was stirred at 20 °C fr NLT 30 min., and allowed to settle fr NL T 15 min. The upper organic phase was separated. 500 g of 25% brine aq. solution was charged. The mixture was stirred at 20 °C fr NLT 15 min., and allowed to settle fr NL T 15 min. The upper organic phase was concentrated to � 200 mL volume under vacuum. The solution was adjusted to� 30 °C, and fltered of the inorganic salt. Toluene (50 mL) was used as a rinse. The combined fltrate was concentrated to � 100 mL volume.

Acetonitrile ( 400 mL) was added, and the mixture heated to � 80 °C to achieve a clear solution.

The solution was cooled down slowly to 20 °C slowly at rate 10 °C/hour, and mixed at 20 °C overight (the product is crystallized out at �45-50 °C, if needed, seed material may be added at 50 °C). The slurry was continued to cool down slowly to � -10 °C at rate of 10 °C/hours. The slurry was mixed at� -10 °C fr NL T 6 hours. The product was collected by fltation, and rinsed with pre-cooled acetonitrile (lO0mL). The solid was dried under vacuum at 50 °C overight NMR (CDCh): 8 1.00 (72.0 g, 85%). MS-ESI: 419 (M+ 1); mp: 109-110 °C (uncorrected); H (s, 6H), 1.46 (s, 9H), 1.48 (t, J 6.5 Hz, 2H), 2.07 (s, br, 2H), 2.18 (m, 4H), 2.24 (t, J 6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98 (m, 2H), 7.29 (m, 2H).

Example 6: Synthesis of 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,1 '­ biphenyl]yl)methyl)piperazine dihydrochloride (Compound (1)) To a 2.0 L three-neck RB fask equipped with a mechanical stirrer were charged the Boe reductive amination product (Compound (H), 72.0 g) and IPA (720 mL). The mixture was stirred at rt fr 5 min, and 59.3g of concentrated hydrochloride aq. solution added to the slurry.

The reaction mixture was adjusted to an interal temperature of� 65 °C ( a clear and colorless solution achieved). The reaction mixture was agitated at� 65 °C fr NLT 12 hours.

The product slurry was cooled down to -5 °C slowly (10 °C/hour). The product slurry was mixed at� -5 °C fr NL T 2 hours, collected by fltration. The wet cake was washed with IPA (72 mL) and dried at 50 °C under vacuum overight to give 73.8 g (95%) of the desired product as a bis-hydrochloride IPA solvate (purit >99.5% peak area at 210 nm). MS-ESI: 319 (M+ 1); HNMR (D 0): 8 1.00 (s, 6H), 1.19 (d, J 6.0 Hz, 6H, IPA), 1.65 (t, J 6.l Hz, 2H), 2.14 (s, br, 2H), 2.26 (m, 2H), 3.36 (br, 4H), 3.55 (s, br, 4H), 3.82 (s, 2H), 4.02 (septet, J 6.0 Hz, lH, IPA), 7.16 (d, J 8.1 Hz, 2H), 7.45 (d, J 8.1 Hz, 2H); HNMR (CDCh): 8 0.86 (s, 6H), 1.05 (d, 6.0 Hz, 6H, IPA), 1.42 (t, J 6.l Hz, 2H), 2.02 (s, br, 2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89 (septet, J 6.0 Hz, lH, IPA), 7.11 (d, J 8.1 Hz, 2H), 7.41 (d, J 8.1 Hz, 2H).

Example 7: Synthesis of 3-nitro(((tetrahydro-2H-pyranyl)methyl)amino )­ benzenesulfonamide (Compound (N)) To a 500 mL three-neck RB fask equipped with a mechanical stirrer were charged the 4-chloronitrobenzenesulfnamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyranyl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an interal temperature of 80 °C and agitated fr no less than 12 hours.

The product solution was cooled down to 40 °C and agitated fr no less than 1 hour until precipitation observed. The product slurry was frther cooled to 20 °C. Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10 °C and agitated fr no less than 2 hours befre collected by fltration. The wet cake was washed with 1: 1 mix of acetonitrile:water ( 40 mL ). The wet cake was then reslurried in water (80 mL) at 40 °C fr no less than 1 hour befre collected by fltration. The wet cake was rinsed with water (20 mL ), and dried at 75 °C under vacuum to give 12.7 g of the desired product in 99.9% purity and in 91 % weight-adjusted yield. H NMR (DMSO-d ): 8 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, lH), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J 9.3 Hz, lH), 7.32 (s, NH , 2H), 7.81(dd, J 9.l , 2.3 Hz, lH), 8.45 (d, J 2.2 Hz, lH), 8.54 (t, J 5.9 Hz, lH, NH).

Example 8: Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((4'­ chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[ 1,1 '-biphenyl]yl)methyl)piperazinyl) benzoate (Compound (K)) General Considerations: this chemistry is considered air and moisture sensitive.

While the catalyst precursors in their solid, dry frm can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent frmation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use.

To a 2.0 L three-neck RB fask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% KP0 (285 ml) was added and the biphasic mixture was stirred fr 30 min. The layers were separated and the organic layer was washed with 25 % NaCl (145 ml). The organic layer concentrated to 120 g and used in the coupling reaction without frther purifcation.

NaOtBu ( 45.2 g) and Compound (I) in toluene solution (120 g solution - 30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen fr NLT 45 min. Pd dba (0.646 g), Compound (J) (0.399 g), and Compound (D) ( 40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 µm inline flter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml.).

The resulting mixture was heated to 55 °C with stirring fr NLT 16 h, then cooled to 22 °C. The mixture was diluted with 12% NaCl (300 g) fllowed by THF (300 ml). The layers were separated.

The organic layer was stirred with a feshly prepared solution of L-cysteine (15 g), NaHC0 (23 g), and water (262 ml). After 1 h the layers were separated.

The organic layer was stirred with a second feshly prepared solution of L-cysteine (15 g), NaHC0 (23 g), and water (262 ml). After 1 h the layers were separated. The organic layer was washed with 12 % NaCl (300 g), then fltered through a 0.45 µm inline flter. The fltered solution was concentrated in vacuo to� 300 mL, and chased three times with heptane (600 mL each) to remove THF.

The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 ml). The mixture was heated to 75 °C, held fr 15 min, and then cooled to 65 °C overNLT 15 min. Seed material was charged and the mixture was held at 65 °C fr 4 hours. The suspension was cooled to 25 °C over NL T 8 h, then held at 25 °C fr 4 hours. The solids were fltered and washed with cyclohexane (90 ml) and dried at 50 °C under vacuum.

Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155 ): 8 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J 6.4 Hz, 2H), 1.94 (s, 2H), °C. H NMR (DMSO-d 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02 - 3.19 (m, 4H), 6.33 (dd, J 3.4, 1.9 Hz, lH), 6.38 (d, J 2.4 Hz, lH), 6.72 (dd, J 9.0, 2.4 Hz, lH), 6.99 - 7.06 (m, 2H), 7.29 (d, J 2.7 Hz, lH), 7.30 - 7.36 (m, 2H), 7.41 - 7.44 (m, lH), 7.64 (t, J 6.7 Hz, lH), 7.94 (d, J 2.7 Hz, lH), 11.53 (s, lH).

Example 9: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridinyl)oxy)(4-((4'-chloro-5,5- dimethyl-3,4,5,6-tetrahydro-[l,1 '-biphenyl]yl)methyl)piperazinyl)benzoic acid (Compound (L)) Solution preparation: 10% KH PO (aq): KH PO (6 g) in water (56 g); 2 4 2 4 2:1 heptane/ 2-MeTHF: heptane (16 mL) in 2-MeTHF (8 mL).

Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55 °C until reaction completion. The reaction mixture was cooled to 22 °C, washed with the % KH PO solution (31 g) twice. The organic layer was then washed with water (30 g).

After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (�19 mL) and heated to no less than 50 °C. Heptane (23 ml) was slowly added. Alteratively, after removal of the aqueous layer, the organic layer was concentrated to 5 volumes and heated to no less than 70 °C and 5 volumes of heptane were slowly added. The resulting suspension was cooled to 10 °C. Solids were then collected by vacuum fltration with recirculation of the liquors and the flter cake washed with 2:1 heptane/ 2-MeTHF (24 ml). Drying of the solids at 80 °C under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. HNMR(DMSO-d ): 8 0.91 (s, 6H), 1.37 (t,J 6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J 2.3 Hz, lH), 6.34 (dd, J 3.4, 1.9 Hz, lH), 6.7 (dd, 9.0, 2.4 Hz, lH), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J 2.6 Hz, lH), 7.44 (t, J 3.0 Hz, lH), 7.72 (d, J 9.0 Hz, lH), 7.96 (d, J 2.7 Hz, lH) & 11.59 (m, lH).

Example 10: Synthesis of 4-( 4-{ [2-( 4-chlorophenyl)-4,4-dimethylcyclohexen yl] methyl} piperazinyl)-N-( {3-nitro[ ( tetrahydro-2H-pyran ylmethyl)amino] phenyl}sulfonyl)(1H-pyrrolo [2,3-b ]pyridinyloxy)benzamide (Compound (1)) Solution preparation prior to reaction: 10% Acetic Acid: Acetic Acid (37 mL) in water (333 g); 5% NaHCO : NaHCO (9 g) in water (176 g); 5% NaCl : NaCl (9 g) in water (176 Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25 °C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et N (8.7 g) and dichloromethane (120 mL). The resulting Acid (Compound (L)) solution was slowly charged to the initial suspension of Compound (N) and agitated until reaction completion. N,N-dimethylethylenediamine (9.4 g) was then charged to the reaction mixture with continued agitation. The reaction mixture was warmed to 35 °C and washed with 10% Acetic acid solution (185 mL) twice. The lower organic layer was diluted with more dichloromethane (75 mL) and methanol (12.5 mL). The organic, product layer was then washed with 5% NaHCO solution (185 mL) and then washed with 5% NaCl solution (185 mL) at 35 C. The lower, organic layer was separated and then concentrated to 8 vol (�256 mL) diluted with methanol (26 mL) and warmed to 38 C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10 C and then fltered.

The wet cake was washed twice with a 1: 1 mix of dichloromethane and ethyl acetate ( � 2 vol, 64 mL). Afer drying the wet cake at 90 C, 32 g (84%) of Compound (1) was isolated. H NMR (DMSO-d ): 8 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J 6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, lH), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J Hz, lH), 6.37 (dd, J 3.4, 1.9 Hz, lH), 6.66 (dd, J 9.1, 2.2 Hz, lH), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J 9.3, 2.3 Hz, lH), 8.02 (d, J 2. 61 Hz, lH), 8.54 (d, J 2. 33 Hz, lH), 8.58 (t, J 5.9 Hz, lH, NH), 11.65 (m, lH).

Example 11: Synthesis of ( (1R,4R)hydroxymethylcyclohexyl)-methanaminium 4-methylbenzenesulfonate Step A: 1.49 g of cyclohexanedione monoethylene acetal (1.0 equiv) and 15 mL of toluene were charged to a suitable reactor. The mixture was mixed fr 30 minutes at 10 C. 1 .4 M methylmagnesium bromide solution (2.32 eq) in Toluene-THF (75-25) was charged to another reactor and mixed at 15 C. The starting material solution was added to the Grignard solution dropwise at around 10 to 20 C in 4hrs (addition rate 0.lmL/min). The reaction progression was monitored by TLC. Upon reaction completion, the reaction mixture was charged to a 24 % ammonium chloride solution (20 mL) slowly at a temperature of 25oC. The reaction mixture was mixed and settled, organic layer was separated and aqueous layer was extracted with ethyl acetate (3 x 20 mL ). The combined organic layers were fltered over a bed of sodium sulfte and the fltrate was concentrated by distillation to dryness. 1.57 g. crude solids were isolated (95% yield) and carried to the next step. H NMR (400 MHz, Chlorofrm-d ) 8 ppm 3.88-4.01 (m, 4H), 1.85-1.96 (m, 2H), 1.08-1.64 (m, 7H). LCMS- (MS 310 and 292). Rf 0.074 by TLC (hexane-EtOAc 1-1).

Step B: 18 mL of 0.005 N hydrochloric acid solution (0.02 equiv) was charged to the distillation residue fom Step A. The reaction mixture was mixed at 70 C fr 3 hours and monitored by TLC. Upon reaction completion, the reaction mixture was cooled to 25 C and charged to another suitable reactor containing 22 mL of a 5% sodium chloride solution. The reaction mixture was mixed until all salt dissolved fllowed by extraction with Ethyl Acetate (8x200 mL). The combined organic layers were fltered over a bed of sodium sulfte and the fltate was concentrated by distillation to dryness. The product was isolated (99.38 % yield) and was used directly in the next step. iH NMR ( 400 MHz, Chlorofrm-d ) 8 ppm 2.68-2.80 (m, 2H), 2.16-2.39 (m, 3H), 1.77-2.04 (m, 4H), 1.41 (s, 3H), 1.33 (s, lH).

Step C: Step B product (0.25 g) was dissolved with toluene (5 ml) to a 25 mL three neck fask equipped with a Dean-Stark trap. Nitrogen was bubbled through the reactor to remove air. 0.585 g of nitromethane (5 equiv) was charged to the reactor fllowed by 0.052 g of N,N-dimethylethylenediamine (0.3 equiv). The reaction mixture was heated to refux, the water was removed by a Dean-Stark trap. The reaction mixture was mixed at refux fr 1 h and monitored by HPLC assay. The reaction mixture was then cooled to 20 C when HPLC product assay stabilized, concentrated then chased with EtOAc and heptane to dryness. The residue was purifed on a CombiFlash column (12 g column) fom Hexane/EtOAc 80-20 to 60-40. Fractions were analyzed by HPLC and TLC, product containing factions was distilled to dryness. A concentrated oil 0.23 g was obtained (68.09 % yield) and used in Step D. iH NMR ( 400 MHz, Chlorofrm-d ) 8 5.88-5.90 (bs, lH), 4.88-4.89 (bs, 2H), 2.16-2.40 (m, 4H), 1.78-1.85 (m, lH), 1.33 (s, 3H).

Step D: Crabtree's catalyst (0.471 g; 0.585 mmol) was added under nitrogen to a 450 mL stirred SS Parr reactor. The reactor was purged with nitrogen and a solution of the (S) methyl(nitromethyl)cyclohexenol (34.88 g; 58.5 mmol) in DCM (100 mL). Additional sparged DCM (80 mL) was added, the reactor was purged with argon, hydrogen and hydrogen pressure 100 psig. The mixture was agitated fr 4 hours at 30 C. Reaction progress was monitored by NMR, cConcentrated to an oil, chased 2 x with THF (50 mL) then diluted with THF (50 mL). The product was carried frther fr subsequent RaNi reduction in Step E. iH NMR (Chlorofrm-d ): 8 4.33 (dJ 7.3Hz, 2H), 4.32 ( 1 6.5 Hz, lH), 2.36 - 2.20 (m, lH), 1.92 - 1.69 (m, lH), 1.64 - 1.40 (m, lH), 1.39 - 1.18 (m, lH).

Step E: RaNi (* d / (d-1) or * 7/6) 2.04 g (20 wt%) was decanted 3 times with THF.

The RaNi, solution of (1R,4R)m ethyl(nitromethyl)cyclohexanol and THF (50 mL) were added under nitrogen in a 450 mL stirred SS Parr reactor. The reactor was purged with nitrogen, hydrogen and the hydrogenation was carried out at 40 psi fr 4 hours at 50 C. The reaction was monitored by GC and upon completion, it was fltered through a propylene flter fnnel with diatomaceous earth/polyethylene fitted disc to remove catalyst. THF was used as a rinse to extract residual product fom the flter cake. The combined fltrate gave an amber solution which was carried directly to next step. H NMR (400 MHz, Chlorofrm-d ) 8 2.61 (d, J 6.5 Hz, 2H), 1.25-1.50 (m, 12H), 0.80-1.17 (m, 3H).

Step F: 9.86 g of the solution of Step E was added to a 500 mL round bottom fask and distilled to dryness, chased twice with acetonitrile and then was dissolved in acetonitrile (100 mL). To the solution was added 4-methylbenzenesulfnic acid hydrate (11.68 g) upon which a solid precipitated out and temperature rose to 40 C. The slurry was mixed at 50 C fr 2 hours and cooled to 20 C fr 12 hours. Solids were fltered and washed with 40 mL acetonitile.

The wetcake was dried under vacuum to give 14.24 g of product (77% yield). H NMR (400 MHz, Deuterium Oxide-d ) 8 2.79 (d, J 7.0 Hz, 2H), 1.48-1.68 (m, 5H), 1.31-1.46 (m, 2H), 0.90-1.29 (m, 5H).

Example 12: Synthesis of 4-({[(1R,4R)hydroxymethylcyclohexyl]methyl}­ amino)nitrobenzenesulfonamide (Compound (P)) 4-chloronitrobenzenesulfnamide (6.5 g, 27.5 mmol) and ((1R,4R)hydroxy methylcyclohexyl)methanaminium 4-methylbenzenesulfnate (11.26 g, 35. 7 mmol) were combined in 35 mL of acetonitrile and stirred. N,N-diisopropylethylamine (8.88 g, 68.7 mmol) was added to the slurry at ambient temperature to result in an endotherm (200 to 17.5 C). After minutes, the reaction mixture was heated to 80 C and maintained at that temperature fr 24 hours. The reaction was monitored fr completion by HPLC. Upon completion of the reaction, the reaction mixture was cooled to 40 C. Water (32.5 mL) was added over 15 minutes and held fr 30 minutes. An additional 74.5 mL of water was added over 30 minutes. Solid product precipitated soon after the second portion of water was added. Afer stirring fr 1 hour at 40 C, the product mixture was allowed to cool to 20 C, stirred fr 12 hours, and then cooled to 0 with stirring fr 2 additional hours. The product was fltered and dried under vacuum to aford 8.8 g of product (Yield 93%; purity >99 pa%). H NMR (400 MHz, DMSO-d 8 ppm 8.52 (t, J 2.2 Hz, lH), 7.80 (dd, J 9.1, 2.3 Hz, lH), 7.24-7.30 (m, 3H), 4.23 = 5.9 Hz, lH), 8.45 (d, J (s, lH), 1.60-1.74 (m, 3H), 1.52-1.57 (m, 2H), 1.26-1.40 (m, 2H), 1.06-1.25 (m, 5H).

Example 13: Synthesis of 4-( 4-{ [2-( 4-chlorophenyl)-4,4-dimethylcyclohexen yl] methyl} piperazinyl)-N-( {3-nitro[ (lR,4R)-[ 4-hydroxy methylcyclohexyl] methyl)amino] phenyl} sulfonyl)(lH-pyrrolo [2,3-b] pyridin yloxy) benzamide (Compound (2)) The Sulfnamide 4-(((( 1R,4R)hydr oxymethylcyclohexyl)methyl)amino ) nitrobenzenesulfnamide (8.00 g, 23.29 mmol), EDAC-HCl (5.80 g, 30.3 mmol) and DMAP (8.54 g, 69.9 mmol) were mixed in DCM (186 mL, 14 vol) to a golden slurry. A solution of acid, 2-( ( 1 H-pyrrolo[2,3-b ]pyridinyl)oxy )( 4-( ( 4'-chloro-5 ,5-d imethyl-3 ,4,5 ,6-t etrahydro- [ 1, 1 '-biphenyl ]yl)methyl)piperazinyl)benzoic acid (13.3 g, 23.29 mmol) and TEA (6.49 mL, 46.6 mmol) in DCM (80mL, 6 vol) was added over 2.5 hrs by addition fnnel fllowed by a rinse with 10 mL DCM. After mixing fr 12 hours, Nl,Nl-dimethylethane-1,2-diamine (5.09 mL, 46.6 mmol) was added and stirring continued at 20 C fr 5 hours. The reaction mixture was washed with 10% HOAc (130mL, 3x). The organic layer was washed with 5% NaHCO3 (140mL) and 5% NaCl (140mL). The organic layer was dried over Na2SO4. and concentrated to volume of DCM solution. Methanol (10 vol, 140mL) was added dropwise over 2 hours, and the solution cooled to l 5 C upon which the product precipitated. The product mixture was cooled to 5 C and mixed fr 2 hours. Upon fltration of the solid and blow drying with nitrogen fr 2 hours, 17.35 g of product was obtained (Yield 83%; purity >99.5 pa %). H NMR (400 MHz, DMSO-d ) 8 ppm 11.57-11.59 (bs, lH), 8.48-8.52 (m, 2H), 7.97 (d, J = 2.6 Hz, lH), 7.73 (dd, J 9.2, 2.3 Hz, lH), 7.43-7.50 (m, 3H), 7.29-7.31 (m, 2H), 6.98-7.03 (m, 3H), 6.65 (dd, J 8.9, 2.3 Hz, lH), 6.35 (dd, J 3.4, 1.8 Hz, lH), 6.16 (d, J 2.2 Hz, lH), 4.41-4.44 (m, lH), 3.71-3.75 (m, 2H), 2.98-3.51 (m, llH), 2.74-2.76 (m, 3H), 2.02-2.26 (m, 6H), 1.88-1.92 (m, 2H), 1.47-1.70 (m, 5H), 1.24-1.40 (m, 4H), 1.08 (s, 5H), 0.89 (s, 6H).

All refrences cited herein are incorporated by refrence in their entiret. While the methods provided herein have been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifcations can be made without departing fom the spirit and scope as recited by the appended claims.

The embodiments described above are intended merely to be exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specifc compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims (24)

CLAIMS 1.:

1. A process for the preparation of a compound of formula A1: (A1), wherein R is selected from and ; which comprises: (a) combining a compound of formula (K): wherein R is C to C alkyl, 1 12 with a tert-butoxide salt, an aprotic organic solvent, and water to provide a compound of formula (L): (L); and (b'') combining the compound of formula (L) with 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, an organic solvent, and either a compound of formula (N), to provide a compound of formula (A1) wherein R is : or a compound of formula (P), to provide a compound of formula (A1) wherein R is (P); thereby providing a compound of formula (A1); wherein the compound of formula (K) is prepared by: (d) combining a compound of formula (D): with a compound of formula (I): (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (K).

2. The process of claim 1, wherein R is , and step (b'') comprises: (b'') combining the compound of formula (L) with 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, an organic solvent, and the compound of formula (N): (N); to provide a compound of formula (A1).

3. The process of claim 1, wherein R is , and the process further comprises: (c'') combining a compound of formula (M): with a tertiary amine base, an organic solvent, and (tetrahydro-2H-pyranyl)methanamine or a salt thereof, to provide the compound of formula (N).

4. The process of claim 1, wherein R is , and the process further comprises: (c'') combining a compound of formula (M): with a tertiary amine base, an organic solvent, and (1R,4R)(aminomethyl) methylcyclohexanol or a salt thereof, to provide the compound of formula (P).

5. The process of any one of claims 1-4, wherein in step (a) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

6. The process of any one of claims 3-5, wherein in step (c'') the tertiary amine base is N,N-diisopropylethylamine.

7. The process of any one of claims 1-6, wherein the compound of formula (I) is combined with a base prior to the combining of step (d).

8. The process of any one of claims 1-7, wherein in step (d) the source of palladium is Pd dba or [(cinnamyl)PdCl] . 2 3 2

9. The process of any one of claims 1-8, wherein the phosphine ligand of step (d) is a compound of formula (J): (J).

10. The process of any one of claims 1-9, wherein the source of palladium is Pd dba , a catalytic amount of Pd dba is used relative to the amount of compound (I), and 2 3 2 3 wherein the catalytic amount of Pd dba is from about 0.5 mole percent to about 2 mole percent.

11. The process of claim 9 or claim 10, wherein a catalytic amount of the compound of formula (J) is used relative to the amount of compound (I), and wherein the catalytic amount of the compound of formula (J) is from about 1 mole percent to about 5 mole percent.

12. The process of any one of claims 1-11, wherein in step (d) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert- butoxide.

13. The process of any one of claims 1-12, wherein the process further comprises: (e) combining a compound of formula (B) with a compound of formula (C): (B) (C) and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).

14. The process of claim 13, wherein in step (e) the tert-butoxide salt is selected from the group consisting of sodium tert-butoxide and potassium tert-butoxide.

15. The process of any one of claim 14 or claim 15, wherein the process further comprises: (f) combining a compound of formula (A): with R MgX in an aprotic organic solvent; wherein R is C to C alkyl and X is Cl, Br, or I; (g) combining a C to C alkyl chloroformate or a di-(C to C alkyl)dicarbonate 1 12 1 12 with the product of step (f), to provide the compound of formula (C).

16. The process of claim 15, wherein in step (f), R is isopropyl.

17. The process of claim 15 or claim 16, wherein in step (f), R is tert-butyl and the di-(C to C alkyl)dicarbonate is di-tert-butyl dicarbonate. 1 12

18. The process of any one of claims 1-17, wherein the process further comprises: (h) combining a compound of formula (E): with dimethylformamide and POCl to provide a compound of formula (F): (F); (i) combining the compound of formula (F) with a source of palladium and 4- chlorophenylboronic acid in an organic solvent to provide a compound of formula (G): (G); (j) combining the compound of formula (G) with BOC-piperazine and sodium triacetoxyborohydride in an organic solvent to provide a compound of formula (H): (H); and (k) combining the compound of formula (H) with hydrochloric acid to provide the compound of formula (I).

19. The process of claim 18, wherein in step (i) the source of palladium is Pd(OAc) .

20. The process of claim 18 or claim 19, wherein step (i) comprises combining tetrabutylammonium bromide with the compound of formula (F), the source of palladium and 4-chlorophenylboronic acid in the organic solvent.

21. The process of claim any one of claims 18-20, wherein step (j) further comprises producing the compound of formula (H) as a crystalline solid.

22. The process of claim any one of claims 18-21, wherein step (k) further comprises producing the compound of formula (I) as a crystalline solid.

23. The process of any one of claims 1-22, wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.

24. The process of any one of claims 1-23, wherein R is tert-butyl. AbbVie Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: