WO2007026221A2

WO2007026221A2 - Improved methods for preparing benzofused heteroaryl amide derivatives of thienopyridines

Info

Publication number: WO2007026221A2
Application number: PCT/IB2006/002371
Authority: WO
Inventors: Katheryn E. Harrison; Sean Timothy Neville; Robert William Scott; John Lloyd Tucker
Original assignee: Pfizer Inc.
Priority date: 2005-09-02
Filing date: 2006-08-31
Publication date: 2007-03-08
Also published as: WO2007026221A3; AR055625A1; JP2007084537A

Abstract

The invention relates to methods for preparing compounds of formulae (I) and (XI): or pharmaceutically acceptable salts or solvates thereof. Compounds of the formula (I) and (XI) Fare useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases.

Description

IMPROVED METHODS FOR PREPARING BENZQFUSED HETEROARYL AMIDE DERIVATIVES OF THIENOPYRIDINES

Field of the Invention The present invention provides improved methods for preparing benzofused heteroaryl amide derivatives of thienopyridines and intermediates thereof, which are useful in the treatment of hyperproliferative diseases, such as cancers and ophthalmic diseases such as age-related macular degeneration.

Background of the Invention U.S. Patent No. 6,869,962, which is hereby incorporated by reference in it's entirety, is directed to benzofused heteroaryl amide derivatives of thienopyridines having formula:

and to prodrugs or metabolites thereof, or pharmaceutically acceptable salts or solvates of said compounds, wherein Z, Y, R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined therein, which are useful as therapeutic agents for the treatment of hyperproliferative diseases, such as cancers and ophthalmic diseases such as age-related macular degeneration. Although methods for preparing such compounds were previously referred to, there remains a need in the art for new synthetic routes that are more efficient and cost effective.

The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in any country as of the priority date of any of the claims.

Summary of the Invention The present invention provides methods for preparing a compound of formula I:

I or a pharmaceutically acceptable salt or solvate thereof, wherein: Y iS -O-, -S- or -NH-; R¹ is H or C₁-C₆ alkyl: R² is H or C₁-C₆ alkyl: R³ is H or Ci-C₆ alky): and

R⁴ is C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylhydroxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylamino or C₁-C₆ alkyl C₃-C₁₀ cycloalkyl; comprising, a) formyiating a compound of formula Il to provided a compound of formula III; b) cyclizing the compound of formula III to provide a compound of formulal IV; c) alkylating the compound of formula IV to provide a compound of formula V:

H HI IV V d) coupling a compound of formula Vl with benzophenone hydrazone to provide a compound of formula VII, wherein W is a protecting group, and X is Cl, Br or I; e) alkylating the compound of formula VII to provide a compound of formula VIII; f) cyclizing the compound of formula VIII to provide a compound of formula IX; and g) removing W in the compound of formula IX to provide a compound of formula

X:

VI VII VIII

IX X and h) coupling the compound of formula V with the compound of formula X:

V X I

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula Il is formylated using an alkyl lithium reagent and N,N-dimethyl formamide.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the alkyl lithium reagent is n-butyl lithium.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula III is cyclized using glyoxal trimer, ammonium acetate and acetic acid.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the base is sodium f-butoxide.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula Vl is couple with benzophenone hydrazone using a palladium catalyst.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the palladium catalyst is palladium acetate.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula VII is alkylated with methyl tosylate in the presence of a base. In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula VIII is cyclized in acid with a compound of formula R³COCH₂CONHR⁴ to form the compound of formula IX, wherein R³ and R⁴ are as described.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the acid is methane sulfonic acid.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein W is benzyl.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein W is removed by catalytic hydrogenation.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the catalyst is a palladium catalyst.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the catalyst is palladium hydroxide.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the compound of formula V is couple to the compound of formula X in the presence of a base.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyi ethyl amine or mixtures thereof.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the base is cesium carbonate or sodium f-butoxide. In another aspect, the invention provides methods for preparing compounds of the formula I, further comprising a solvent.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the solvent is dimethylsulfoxide.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein the reaction is carried out at about 100 ⁰C.

In another aspect, the invention provides methods for preparing compounds of the formula I, wherein R¹, R², and R³ are methyl; and R⁴ is cyclopropyl.

In another aspect, the invention provides methods for preparing compounds of the formula Xl:

XI

or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is -O-, -S- or -NH-; R¹ is H or C₁-C₆ alkyl: R² is H or C₁-C₆ alkyl:

R³ is H or C₁-C₆ alkyl: and

R⁴ is C₁-C₆ alkyl, C₁ -C₆ alkylamino, C₁ -C₆ alkylhydroxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylamino or C₁-C₆ alkyl C₃-C₁₀ cycloalkyl; comprising, a) formylating a compound of formula Il to provided a compound of formula III; b) cyclizing the compound of formula III to provide a compound of formulal IV; c) alkylating the compound of formula IV to provide a compound of formula V:

d) alkylating the compound of formula Xl to provide a compound of formula XII, wherein W is a protecting group;

e) cyclizing the compound of formula XlI to provide a compound of formula XIII;

f) amidifying the compound of formula XII to provide a compound of formula XIV;

g) removing W in the compound of formula XIV to provide a compound of formula XV:

XIV xv

and,

h) coupling the compound of formula V with the compound of formula XV:

XV XI

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula Il is formylated using the alkyl lithium reagent and N, N-dimethyl formamide.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the alkyl lithium reagent is n-butyl lithium. In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula III is cyclized using glyoxal trimer, ammonium acetate and acetic acid to form the compound of formula IV.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base,

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the base is sodium f-butoxide.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula Xl is alkylated with a compound of formula R³CI-IXCOCO₂H in the presence of a base, wherein X is Cl, Br or I.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein R³ is CH₃; and X is Br.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the base is potassium carbonate.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula XII is cyclized in acid.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the acid is sulfuric acid.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula XIII is amidified using CDI and R⁴NH₂. In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein R⁴ is methyl.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein W is methyl.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein W is removed with methane sulfonic acid.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the compound of formula V is couple to the compound of formula XV in the presence of a base.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the base is cesium carbonate or sodium f-butoxide.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, further comprising a solvent.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the solvent is dimethylsulfoxide.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein the reaction is carried out at about 100°C.

In another aspect, the invention provides methods for preparing compounds of the formula Xl, wherein R¹, R³, and R⁴ is methyl.

In another aspect, the invention provides methods for preparing compounds of the formula V:

v or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ is H or C₁ -C₆ alkyl: and

X is Cl, Br or I;

III; IV; V:

Ii in rv V

In another aspect, the invention provides methods for preparing compounds of the formula V, wherein the compound of formula Il is formylated using an alkyl lithium reagent and N, N-dimethyl formamide.

In another aspect, the invention provides methods for preparing compounds of the formula V, wherein the alkyl lithium reagent is n-butyl lithium.

In another aspect, the invention provides methods for preparing compounds of the formula V, wherein the compound of formula III is cyclized using glyoxal trimer, ammoniuim acetate and acetic acid to form the compound of formula IV.

In another aspect, the invention provides methods for preparing compounds of the formula V, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base. In another aspect, the invention provides methods for preparing compounds of the formula V, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof.

In another aspect, the invention provides methods for preparing compounds of the formula V, wherein the base is sodium f-butoxide.

In another aspect, the invention provides methods for preparing compounds of the formula V, wherein R¹ is methyl; and X is Cl.

In another aspect, the invention provides methods for preparing compounds of the formula X:

X or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is -0-, -S- or -NH-; R²is H or C_rC₆ alkyl: R³ is H or C₁-C₆ alkyl: and

R⁴ is C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylhydroxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylamino or C₁-C₆ alkyl C₃-C₁₀ cycloalkyl; comprising, a) coupling a compound of formula Vl with bgenzophenone hydrazone to provide a compound of formula VII, wherein W is a protecting group, and X is Cl, Br or I; b) alkylating the compound of formula VII to provide a compound of formula VII; c) cyclizing the compound of formula VIII to provide a compound of formula IX; and d) removing W in the compound of formula IX to provide a compound of formula X:

VI VII VIII

IX X

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the compound of formula Vl is coupled with benzophenone hydrazone using a palladium catalyst. In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the palladium catalyst is palladium acetate.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the compound of formula VII is alkylated with methyl tosylate in the presence of a base. In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N-diisopropyl ethyl amine or mixtures thereof. In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the base is sodium t-butoxide.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the compound of formula VIII is cyclized in acid with a compound of formula R₃COCH₂CONHR⁴ to form the compound of formula IX, where in R³, and R⁴ are as described.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the acid is methane sulfonic acid.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein W is benzyl. In another aspect, the invention provides methods for preparing compounds of the formula X, wherein W is removed by catalytic hydrogenation.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the catalyst is a palladium catalyst.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein the catalyst is palladium hydroxide.

In another aspect, the invention provides methods for preparing compounds of the formula X, wherein R², and R³ are methyl; and R⁴ is cyclopropyl.

Some of the inventive compounds may exist in various stereoisomeric or tautomeric forms. The present invention encompasses all such cell proliferation-inhibiting compounds, including active compounds in the form of single pure enantiomers (i.e., essentially free of other stereoisomers), racemates, mixtures of enantiomers and/or diastereomers, and/or tautomers. Preferably, the inventive compounds that are optically active are used in optically pure form.

As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")), more preferably at least

95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.). Diasteromeric mixtures of the compounds of the present invention may be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as by chromatography or fractional crystallization. Enantiomers may be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomer mixtures and pure enantiomers are considered as part of the invention.

Additionally, the formulae are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms. Additional examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

The term "pharmaceutically acceptable" refers to pharmacologically acceptable agents being substantially non-toxic to the subject being administered the agent.

The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, .gamma.-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates.

If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such, as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2- acetoxybenzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid, methanes u If on ic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. As used herein, the terms "comprising" and "including" are used herein in their open, non-limiting sense.

As used herein, the term "alcohol" refers to the radical R-OH where R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl as defined above. Examples of alcohols include methanol, ethanol, propanol, phenol and the like. As used herein, the term "acyl" refers to -C(O)R, -C(O)OR, -OC(O)R or -OC(O)OR where R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl as defined herein.

As used herein, the term "alkyl" refers to straight or branched chain alkyl groups having from one to twelve carbon atoms, preferably from 1 to 6 carbons, and more preferably from 1 to 3 carbons. Exemplary alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.

As used herein, the term "alkenyl" refers to straight or branched chain alkenyl groups having from two to twelve carbon atoms, preferably from 2 to 6 carbons, and more preferably from 2 to 4 carbons. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2- methylprop-2-enyl, hex-2-enyl, and the like.

As used herein, the term "alkynyl" refers to straight- and branched-chain alkynyl groups having from two to twelve carbon atoms, preferably from 2 to 6 carbons, and more preferably from 2 to 4 carbons. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but- 3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.

As used herein, the term "amide" refers to the radical -C(O)N(R')(R") where R' and R" are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl and aryl as defined above; or R' and R" cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl as defined above.

As used herein, the term "alkoxy" refers to the radical -OR where R is an alkyl as defined above. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like. As used herein, the term "aryl" refers to monocyclic or polycyclic aromatic ring structures containing only carbon and hydrogen. Preferred aryl groups have from 4 to 20 ring atoms, preferably from 6 to 14 ring atoms, and more preferably from 6 to 10 ring atoms.

As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated. Preferred cycloalkyl groups include groups having from 3 to 12 ring atoms, more preferably from 5 to 10 ring atoms, and still more preferably from 5 to 6 ring atoms.

As used herein, the term "halogen" or refers to chlorine, fluorine, bromine or iodine. The term "halo" refers to chloro, fluoro, bromo or iodo.

As used herein, the term "heteroalkyl" refers to straight or branched chain alkyl groups containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.

As used herein, the term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The polycyclic heteroaryl group may be fused or non-fused and the like.

As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl.

As used herein, the term "heterocyclic" comprises both heterocycloalkyl and heteroaryl groups.

As used herein, the term "substituted" refers to that the group in question, e.g., alkyl group, etc., may bear one or more substituents.

The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent. The term "optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more substituents as defined herein. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated.

If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de- protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, New York (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.

Detailed Description of the Invention In the examples described below, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), N₁N- dimethylformamide (DMF), dichloromethane, toluene, and dioxane were purchased from Aldrich in Sure seal bottles and used as received. All solvents were purified using standard methods readily known to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally under a positive pressure of argon or nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed on glass-backed silica gel 60 F 254 plates Analtech (0.25 mm) and eluted with the appropriate solvent ratios (v/v), and are denoted where appropriate. The reactions were assayed by TLC and terminated as judged by the consumption of starting material.

Visualization of the TLC plates was done with a p-anisaldehyde spray reagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt % in ethanol) and activated with heat. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume unless otherwise indicated. Product solutions were dried over anhydrous Na₂SO₄ prior to filtration and evaporation of the solvents under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was done using Baker grade flash silica gel (47-61 μm) and a silica gel: crude material ratio of about 20:1 to 50:1 unless otherwise stated. Hydrogenolysis was done at the pressure indicated in the examples or at ambient pressure. ¹H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and

¹³C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDCI₃ solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD₃OD (3.4 and 4.8 ppm and 49.3 ppm), or internally tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR Spectrometer as neat oils, as KBr pellets, or as CDCI₃ solutions, and when given are reported in wave numbers (cm^' ¹). The mass spectra were obtained using LSIMS or electrospray. All melting points (mp) are uncorrected.

The compounds of the invention are prepared according to the following reaction schemes. As shown below, the compound of formula I is prepared by coupling the compound of formula V with the compound of formula X in the presence of a base and suitable solvent.

v X

The compound of formula V is prepared by formylating the thienopyridine compound of formula Il to provide the C-2 aldehyde compound of formula III. Cylization and alkylation of the compounds of formulae III and IV, respectively, provides the compound of formula V.

I V

The compound of formula X is prepared by coupling the 1 ,3 disubstituted phenyl compound of formula Vl with benzophenone hydrazone to provide the compound of formula VII. Alkylation, cyclization and deprotection of the W group of the compounds of formula VII, VIII and IX, respectively, provides the compound of formula X.

VI VII VIII

IX X Similarly, the compound of formula Xl is prepared by coupling the compound of formula V with the compound of formula XV in the presence of a base and suitable solvent.

V XV XI

The compound of formula V is prepared as described above.

The compound of formula XV is prepared by coupling the 1,3 disubstituted thiophenol compound of formula X with 2 keto butyric acid to provide the compound of formula XII.

Cyclization in the presence of acid provides the benzothiofuran compound of formula XIII.

Amidification and deprotection provides the compounds of formulae XIV and XV, respectively.

XI XII XIII

XIV XV

EXAMPLES Example 1 : Preparation of 7-chloro-thieno[3,2-b]pyridine-2-carboxaldehyde

A 5 liter, 3-neck, Argon purged flask is charged with 7-chloro-thieno[3,2-b]pyridine (150.0 g, 0.8843 mol) and tetrahydrofuran (750 mL) (note 1). The mixture is stirred at room temperature until the solids dissolve and then cooled in a dry ice/acetone bath to an internal temperature of -46 ⁰C (note 2). A solution of n-butyl lithium (390 mL, 2.5M in hexanes, 0.975 mol) is slowly added by addition funnel such that the internal temperature remains between - 43 and -46 ⁰C (note 3). After addition of the base, the solution is allowed to stir for 10 minutes, wherein the internal temperature drops to -66 ⁰C. Anhydrous N,N-dimethyl formamide (86.0 mL, 1.11 mol) is slowly added by addition funnel such that the internal temperature is held between -56 to -57 °C (note 4). The internal temperature is held at -62 ⁰C for 1 hour while the reaction is followed by HPLC (note 5). After 1 hour, the reaction is quenched by the addition of methanol (285 mL) and the cooling bath is removed (note 6). Aqueous hydrochloric acid (1.5 M, 160 mL (concentrated HCI added to 1,150 mL water)) is slowly added to the solution (note 7). After complete addition of the acid, the solution is sampled and the pH is measured (pH = 1) (note 8). The solution is stirred at room temperature for 30 minutes and saturated aqueous sodium bicarbonate (60 mL) is added. The solution is sampled to ensure that the pH is near neutral (note 9). The slurry is stirred for 5 minutes, filtered, and the cake rinsed with a mixture of water and methanol (2 X 530 mL solution containing 430 mL water and 100 mL methanol). The solids are given a final rinse with methyl tert-butyl ether (2 X 250 mL) and dried in a vacuum oven to provide 122.8 g (70%) of the title product as a white powder (notes 10, 11).

¹H NMR (300 MHz, d₆-DMSO): 7.80 (d, 1 , J=5.0), 8.63 (s, 1), 8.83 (d, 1 , J=5.0), 10.25 (S, 1). ¹³C (75 MHz, d₆-DMSO): 121.66, 135.14, 135.70, 137.68, 145.80, 150.20, 155.55, 186.36.

Notes:

1. The flask is equipped with an overhead stirrer, internal temperature probe, and Argon inlet. 2. The bath temperature is maintained at approximately -65 ⁰C. The internal temperature should be < -40 ⁰C.

3. This addition took 22 minutes. After approximately half of the base is added, a yellow/green precipitate is observed.

4. This addition took 8 minutes. 5. For HPLC monitoring, aliquots are withdrawn and dissolved in acetonitrile/water (70/30). HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 °C column chamber, flow rate = 1.0 ml_/min, % acetonitrile/% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 7-chloro-thieno[3,2- bjpyridine = 2.45 min, 7-chloro-thieno[3,2-b]pyridine-2-carboxaldehyde = 2.79 min, DMF = 1.68 min.

6. The methanol addition causes the internal temperature to rise immediately to -32 ⁰C.

7. The internal temperature continues to rise towards room temperature during the hydrochloric acid quench. After approximately half of the acid is added, solids begin to precipitate. This addition took 40 minutes.

8. Additional hydrochloric acid should be added if the pH is not <2.

9. Additional aqueous sodium bicarbonate should be added if the pH is not >6.

10. The product is dried in a vacuum oven at 45 to 50 ⁰C and 25 mm Hg. It is important to dry the product to the lowest water content achievable, probably by an aggressive LOD spec.

11. HPLC of the crude product shows 99% purity.

Example 2: Preparation of 7-chloro-2-(1 H-imidazol-2-yl)thieno[3,2-b]pyridine

A 3 liter, 3-neck Argon purged flask is charged with 7-chloro-thieno[3,2-b]pyridine-2- carboxaldehyde (110.07 g, 0.5569 mol) and methanol (1250 mL) (note 1). The slurry is stirred for approximately 5 minutes followed by addition of acetic acid (250 mL), glyoxal trimer (117.34 g, 1.675 mol eq. glyoxal) and ammonium acetate (258.07 g, 3.348 mol) (note 2). The mixture is stirred at room temperature and followed by HPLC (note 3). After 3.5 hours, HPLC analysis of the mixture shows 9.7% starting material and 48% product. After a total reaction time of 24 hours, HPLC analysis shows 6.4% starting material (note 4). Water (625 mL) is slowly added by addition funnel over 30 minutes. The resulting slurry is stirred an additional 15 minutes at room temperature. The slurry is filtered and the smoothed cake is rinsed with solvent mixture (2:1 methanol/water, 2 x 600 mL) (notes 5 and 6). The cake is given a final rinse with methylene chloride (600 mL) and the solids are dried in a vacuum oven to provide 78.33 g (60 %) of the title product as a brown powder (notes 7, 8). ¹H NMR (300 MHz, d₆-DMSO): 7.12 (br S, 1), 7.45 (br S, 1), 7.55 (d, 1 , J=5.1), 8.00 (s, 1), 8.62 (d, 1 , J=5.1), 13.1 (br s, 1). ¹³C (75 MHz, Cl₆-DMSO): 118.90, 119.72, 129.89, 131.54, 136.35, 139.25, 139.34, 140.22, 148.87, 157.46.

Notes: 1. The flask is equipped with an overhead stirrer, internal temperature probe, and Ar inlet.

2. Glyoxal trimer dihydrate has a molecular weight of 210.14. However, this provides 3 equivalents of glyoxal. The calculation of the moles takes this into account. For this particular procedure, the 117.34 g of the trimer represents 1.675 mol equivalents of glyoxal. 3. The dissolution is slightly endothermic. The internal temperature cools to 19

⁰C.

4. For HPLC monitoring, aliquots are withdrawn and dissolved in acetonitrile / water (70/30). HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 60% acetonitrile/40% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 7-chloro-2-thieno[3,2- b]pyridine = 2.79 min, 7-chloro-2-(1H-imidazol-2-yl)thieno[3,2-b]pyridine =1.69 min.

5. Research has shown that reaction time in excess of 24 hours is not beneficial.

6. Near completion of filtration, the cake cracks badly and requires smoothing prior to washing.

7. The pad is smoothed periodically as needed to maintain the cake without significant cracks. Upon complete filtration, the cake is smoothed carefully before the final wash.

8. The product is dried in a vacuum oven at 45-50 ⁰C and 25 mmHg. 9. HPLC of the crude product shows 93.4% purity.

Example 3: Preparation of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2- b]pyridine

A 3 liter, 3-neck Argon purged flask is charged with 7-chloro-2-(1H-imidazol-2- yl)thieno[3,2-b]pyridine (85.18 g, 0.3614 mol), tetrahydrofuran (1 ,275 mL) and methyl tosylate (65.0 mL, 0.431 mol) (note 1). The mixture is cooled in an ice/water bath to an internal temperature of 6 ⁰C. Solid sodium tert-butoxide is added in two portions to ensure control of the exotherm. The first addition of base (21.28 g, 0.221 mol) causes the internal temperature to rise to 9 ⁰C. After 5 minutes, the second portion of base (21.25 g, 0.221 mol) causes the internal temperature to rise to 11 ⁰C. After an additional 5 minutes, the cooling bath is removed and the solution is allowed to warm to room temperature. HPLC analysis 20 minutes after cooling bath removal shows 6.4% starting material remaining. After an additional 30 minutes, HPLC analysis shows no starting material remaining. Water (1 ,275 mL) is added and the solution is distilled at atmospheric pressure to remove tetrahydrofuran. The distillation is deemed to be complete when the internal temperature holds steady at 75 ⁰C. The solution is allowed to cool to room temperature over 3 hours. The slurry is filtered and the solids are rinsed with water (400 mL). The solids are dried in a vacuum oven to provide 79.06 g (87%) of the title product as a brown powder (notes 4, 5).

¹H NMR (300 MHz₁ d₆-DMSO): 4.01 (s, 3), 7.08 (d, 1 , J= 1.0), 7.44 (d, 1 , J=LO), 7.57 (1 , d, J=5.1), 7.95 (s, 1), 8.65 (d, 1 , J=5.1). ¹³C (75 MHz, d₆-DMSO): 34.84, 119.09, 120.85, 125.83, 128.58, 131.57, 136.07, 138.51 , 139.86, 148.79, 157.69. Notes:

1. The flask is equipped with an overhead stirrer, internal temperature probe, and Ar inlet. 2. Due to the insolubility of the reaction components, care must be taken to ensure the HPLC sample is homogeneous. Typically, an aliquot is removed and a few drops of 1M hydrochloric acid is added. The sample volume is made up with 40/60 acetonitrile/water solution and the mixture is sonicated to ensure complete dissolution. Additional acid may be added followed by sonication if the sample is not homogeneous 3. HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 ml_/min, 30% acetonitrile/70% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 7-chloro-2-(1H- imidazol-2-yl)thieno[3,2-b]pyridine = 2.7 min, 7-chloro-2-(1-methyl-1 H-imidazol-2- yl)thieno[3,2-b]pyridine =3.0 min, sodium tosylate = 1.7 min. 4. The product is dried under house vacuum with an air bleed at 50 ⁰C overnight.

5. HPLC of the crude product shows 98% purity.

Example 4: Preparation of N-(3-benzyloxyphenyl) benzophenone hydrazone

_{NaBr + tBu0H}

A 1 liter round bottom flask containing degassed toluene (400 mL) is charged with benzophenone hydrazone (32.86 g, 0.167 mol), palladium acetate (Pd(OAc)₂, 0.34 g, 0.0015 mol) and BINAP ((2,2'-bis(diphenylphosphino)-1,1'-binapthyl, 1.42 g, 0.0023 mol) (notes 1, 2).

The mixture is heated to 80 ⁰C for 15 minutes for activation of the catalyst (note 3). The heating is removed and the mixture is allowed to cool to 60 to 70 °C. 3-benzyloxy bromobenzene (40.07 g, 0.152 mol) and sodium tert-butoxide (20.42 g, 0.212 mol) are added (notes 4, 5) and the mixture is heated to 100 ⁰C with stirring for 2 hours (note 6). An aliquot is removed and analyzed by HPLC (notes 7, 8). Upon completion of the reaction, the mixture is allowed to cool below 45 ⁰C and is washed twice with water (1^st wash 400 ml, 2^nd wash 200 ml) (note 9). The organic layer is filtered through Celite^® (note 10) and the cake is washed with toluene (1 x 120 ml). The product-rich filtrate is distilled at atmospheric pressure to a total volume of 321 ml. After cooling below 70 ⁰C, isopropanol (265 ml_) is added and heating is resumed to displace toluene until a total volume of 321 ml is reached. This sequence is repeated 3 times for effective removal of the toluene (note 11). The solution is cooled below 70 ⁰C, and a sample is removed and analyzed by ¹H NMR (note 12). Upon acceptable toluene removal, the reaction is cooled below 60 ⁰C. Diisopropyl ether (265 ml) is added and heating is resumed to displace the isopropanol until a total volume of 321 ml is reached (note 13). This sequence is repeated 2 times for effective removal of the isopropanol. A sample is removed and analyzed by ¹H NMR (note 14). Upon acceptable removal of the isopropanol, the solution is allowed to cool to room temperature, at which point the solution becomes a slurry (note 15). After granulating for 40 minutes at ambient temperature, the slurry is cooled and granulated an additional 30 minutes at -10 °C. The tan solids are filtered at -10 °C and dried for 18 hours in a vacuum oven at 50 ⁰C to provide 47.85 g (83%) of the title product as a solid (notes 16 and 17). ¹H NMR of sample: (300 MHz, CDCI₃) 5.10 (s, 2H), 6.3-6.5 (dd, 1 H), 6.75-6.85 (s,

1 H), 7.0-7.1 (t, 1H), 7.2-7.7 (m, 16H), 10.12 (NH). Notes;

1. The flask is equipped with an overhead stirrer, internal temperature probe, and a condenser with nitrogen inlet. 2. Degassing is accomplished via nitrogen flow through a gas dispersion tube immersed in the toluene for 30 minutes.

3. The catalyst is activated when the color changes from a red-orange slurry to a deep purple-red or brown-red slurry; either color change indicates the activation of the catalyst. 4. Sodium tert-butoxide should be added quickly to minimize exposure to moisture.

5. If the sodium tert-butoxide is added above 70 ⁰C, color changes from a deep purple-red to a dark brown.

6. The initial dark red solution became a red-brown slurry. 7. The reaction is monitored for completion using HPLC. HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 °C column chamber, flow rate = 1.0 mL/min, 210 nm, lsocratic 70/30 acetonitrile/aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O). Method ends at 15 minutes. Retention times: N-(3-benzyloxyphenyl) benzophenone hydrazone = 8.7 min, 3- benzyloxy bromobenzene = 4.9 min, toluene = 3.3 min, benzophenone hydrazone = 2.5 min.

8. The reaction is deemed complete when less than 3% 3-benzyloxy bromobenzene remains as determined by HPLC. 9. Most solids will be dissolved in the first aqueous layer. Trace remaining insoluble material at the interface is taken with the aqueous layer during separations

10. This filtration is to remove residual insoluble material.

11. Solids typically precipitate during these additions, but return to solution upon heating. 12. There should be less than 7% toluene remaining in the solution as determined by NMR, before proceeding.

13. Solids typically precipitate during these additions, but return to solution upon heating.

14. There should be less than 25% of isopropanol remaining in the reaction (determined by NMR) prior to final cooling for product isolation.

15. Occasionally, solids failed to precipitate at room temperature. Seeding the solution resulted in slurry formation.

16. The reactor may be rinsed out with the mother liquor and this washed over cake to recover additional solids if deemed necessary. Rinsing with clean solvent is not recommended due to the high solubility of the product.

17. The purity by HPLC is 93% (210 nm) and 97% (254 nm).

Example 5: Preparation of N-(3-benzyloxyphenyl)-N-(methyl) benzophenone hydrazone

NaOTs + tBuOH

A 2 liter round bottom flask is charged with N-(3-benzyloxyphenyl) benzophenone hydrazone (49.84 g, 0.1317 mol) and methyl tert-butyl ether (500 mL) and is cooled to -10 ⁰C (notes 1 , 2). Sodium tert-butoxide (15.26 g, 0.1580 mol) is added in one portion and the mixture is stirred until the internal temp re-cools to -10 ⁰C (note 3). Methyl tosylate (21 ml, 0.1383 mol) in methyl tert-butyl ether (100 mL) is added while the reaction temperature is maintained at or below 0 ⁰C (note 4). After addition, the mixture is allowed to warm to room temperature (note 5). When the reaction temperature reaches 20 ⁰C, a sample is removed and analyzed by HPLC (notes 6, 7, 8). Upon completion of the reaction, DABCO^® (1 ,4- diazabicyclo [2.2.2]-octane, 0.75 g, 0.0066 mol) is added in a single charge and stirring is continued. After thirty minutes, a sample is removed and analyzed by HPLC (note 9). The slurry is added to a separatory funnel and extracted with water (3 x 249 mL) (note 10). The organic layer is filtered over Celite^® (note 11) and the cake is washed with methyl tert-butyl ether (200 mL). The product rich solution is distilled under atmospheric pressure to a total volume of 80 mL. After cooling to below 50 ⁰C, diisopropyl ether (174 mL) is added and heating is resumed to displace the methyl tert-butyl ether until a total volume of 159 ml is reached. This sequence is repeated and a sample is removed and analyzed by ¹H NMR (note 12). The solution is allowed to cool to 30 to 35 ⁰C, and is then seeded (note 13). The slurry is allowed to granulate for 12 hours at room temperature (note 14), followed by a two-hour granulation at -10 °C (note 15). The solids are filtered and dried to provide 41.59 g (80% yield) of the title product as a yellow solid (notes 16, 17 and 18).

¹H NMR of sample: (300 MHz, CDCI₃) 3.9 (s, 3H), 5.1 (s, 2H), 6.5-7.9 (m, 16H)

Notes:

1. The flask is equipped with mechanical stirrer, internal temperature probe, and nitrogen inlet.

2. The slurry should be cooled between -10 to 0 ⁰C.

3. Addition of sodium tert-butoxide is slightly exothermic and temperature increase of 2 to 3 ⁰C is typical.

4. Addition of methyl tosylate is exothermic. When added all at once, the reaction temperature typically rises approximately 10 ⁰C.

5. Warming to room temperature usually takes 2 hours.

6. HPLC sample is taken at 20 ⁰C.

7. The reaction is monitored for completion using HPLC. HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 210 nm, lsocratic 70/30 acetonitrile/aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O). Method ends at 15 minutes. Retention times: N-(3-benzyloxyphenyl)-N-(methyl) benzophenone hydrazone = 9.7 min, methyl tosylate = 2.5 min.

8. The reaction is deemed complete when less than or equal to 1% N-(3- benzyloxyphenyl) benzophenone hydrazone remains as determined by HPLC.

9. The reaction is deemed complete when the methyl tosylate peak at 2.5 minutes is less than 0.1% as determined by HPLC. 10. Most solids will be dissolved in the first aqueous extraction. Trace remaining insoluble material at the interface is taken with the aqueous layer during separations.

11. This filtration removes residual insoluble material.

12. There should be less than 10% of methyl tert-butyl ether remaining in the reaction as determined by ¹H NMR before proceeding. If required, additional diisopropyl ether may be added and distilled to remove methyl tert-butyl ether.

13. Seeding should be done between 25 to 35 ⁰C to avoid early product precipitation.

14. The slurry should be stirred at room temperature for at least 12 hours.

15. The slurry should be granulated for at least 2 hours at -5 to -10 ⁰C.

16. The reactor may be rinsed out with the mother liquor and this washed over the cake to recover additional solids if deemed necessary. Rinsing with clean solvent is not recommended due to the high solubility of the product.

17. The solids are dried for 21 hours under vacuum at 50 ⁰C.

18. The purity by HPLC is 98.7% (210 nm) and 98.6% (254 nm).

Example 6: Preparation of θ-benzyloxy-i^-dimethyl-IH-indol-S-carboxylic acid cyclopropyl amide

A 500 mL round bottom flask is charged with N-(3-benzyloxyphenyl)-N-(methyl) benzophenone hydrazone (41.22 g, 0.105 mol), acetoacetic cyclopropyl amide (16.36 g,

0.116 mol), ethanol (215 mL) and water (9.5 mL) and the mixture is cooled below 5 ⁰C (notes

1 , 2). Methanesulfonic acid (9.5 mL, 0.147 mol) is added in one portion (note 3). The cooling is removed and the mixture is heated to reflux for 6 hours (note 4). A sample is removed and analyzed by HPLC (notes 6, 7, 8). Upon completion of the reaction, the mixture is allowed to ' slowly cool to 40 ⁰C and stirred for 12 hours (note 9 & 10). The mixture is allowed to further slowly cool to room temperature and stirred for 3 hours (note 11 & 12). The solids are filtered and the cake is washed with ethanol (50 mL) and dried (note 17) to provide 35.1 g (60% yield) of the title product as a white solid (note 18). ¹H NMR of sample: (300 MHz, DMSO) 0.7-0.9 (m, 4H), 2.5 (s, 3H), 2.7 (m, 1H), 3.6 (s, 3H), 5.1 (s, 2H), 5.6 (NH), 6.9-7.8 (m, 8H).

Notes:

1. The flask is equipped with an overhead stirrer, internal temperature probe, and a condenser with nitrogen inlet.

2. The slurry should be cooled between 0 to 5 °C.

3. Addition of methanesulfonic acid is exothermic and temperature increase from 7 to 10 °C is typical.

4. . During heat ramp to reflux temperature, color changes are observed: olive green to a dark olive green.

5. HPLC sample is taken at just below reflux temperature.

6. The reaction is monitored for completion using HPLC. HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 210 nm, lsocratic 70/30 acetonitrile/aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O). Method ends at 15 minutes. Retention times: N-(3-benzyloxyphenyl)-N-(methyl) benzophenone hydrazone = 9.7 min, acetoacetic cyclopropyl amide = 1.6 min, benzophenone = 3.1 min, regioisomer = 2.8 min.

7. The reaction is deemed complete by HPLC when less than or equal to 4% acetoacetic cyclopropyl amide and 76-80% of total area is 6-benzyloxy-1 ,2-dimethyl-1 H-indol- 3-carboxylic acid cyclopropyl amide, benzophenone, and regioisomer combined.

8. Cooling down to 40 ^SC should take at least 1 hour. Slow crystallization is desired to grow larger crystals.

9. Temperature should be held at 40 ⁰C for at least 12 hours.

10. Cooling down to room temperature should take at least 1 hour.

11. The slurry should be granulated for at least 3 hours at room temperature.

12. The solids are dried for 21 hours under vacuum at 50 ⁰C.

13. The purity by HPLC is 95.1% (210 nm). Example 7: Preparation of 6-hydroxy-1 ,2-dimethyl-1 H-indol-3-carboxylic acid cyclopropyl amide

A 500 mL Parr chamber is charged with 6-benzyloxy-1 ,2-dimethyl-1H-indol-3- carboxylic acid cyclopropyl amide (8.01 g, 0.02395 mol), N,N-dimethyl acetamide (56 mL) and palladium hydroxide [Pd(OH)₂, 20 wt% (dry basis) on carbon, 50% wet] (0.81 g, 0.577 mmol)

(notes 1 , 2). The mixture is placed under 50 psi of hydrogen and shaken for 5 hours. The atmosphere is purged of hydrogen and replaced with nitrogen and an aliquot is removed and analyzed by HPLC (notes 3, 4). Upon completion of the reaction, the mixture is filtered through Celite^® (1.5 g), and the cake is washed with N,N-dimethyl acetamide (1 x 16 ml).

Water (120 mL) is added to the product rich filtrate and the solution is allowed to slowly cool to room temperature (notes 5 and 6). After granulating for 2 hours at room temperature, the slurry is filtered and the cake is washed with water (40 mL). The solids are dried for 15 hours in a vacuum oven at 50 ⁰C to provide 3.9 g (67 %) of the title product as an off-white solid (note 7).

¹H NMR (300 MHz, DMSO): 0.4-0.5 (m, 2H), 0.6-0.7 (m, 2H), 2.5-2.5 (s, 3H), 2.8-2.9 (m, 1 H), 3.55 (s, 3H)₁ 6.55-6.65 (d, 1H), 6.7 (s, 1 H), 7.4 -7.55 (m, 2H), 9.0 (s, HO).

Notes:

1. The chamber is equipped with a motorized stirrer, a nitrogen inlet, and a hydrogen inlet.

2. The chamber is purged with nitrogen three times and three times with hydrogen.

3. The reaction is monitored for completion using HPLC method "gradient S". Retention times: 6-hydroxy-1 ,2-dimethyl-1 H-indol-3-carboxylic acid cyclopropyl amide = 3.7 minutes; 6- benzyloxy-1 ,2-dimethyl-1 H-indol-3-carboxylic acid cyclopropyl amide = 11.8 minutes; toluene = 11.4 minutes; and N,N-dimethyl acetamide = 1.9 min.

4. The reaction is deemed complete when less than 0.3% 6-benzyloxy-1 ,2- dimethyl-1 H-indol-3-carboxylic acid cyclopropyl amide remains as determined by HPLC.

5. Addition of water is slightly exothermic. 6. Cooling typically required 30 to 60 minutes.

7. The purity by HPLC is 98.6% (210 nm).

Example 8: Preparation of 1,2-dimethyl-6-[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2- b]pyridine-7-yloxy]-1 H-indole-3-carboxylic acid cyclopropyl amide

A 100 ml. round bottom flask is charged with 6-hydroxy-1 ,2-dimethyl-1 H-indol-3- carboxylic acid cyclopropyl amide (1.00 g, 0.0041 mol), 7-chloro-2-(1-methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridine (1.16 g, 0.0046 mol) and dimethyl acetamide (10 mL). The mixture is cooled to below 5 °C and sodium tert-butoxide (0.63 g, 0.0066 mol) is added in one portion (notes 1 , 2, 3, 4). The mixture is heated to 75 °C with stirring for 23 hours and an aliquot is removed and analyzed by HPLC (notes 5, 6). Upon completion of the reaction, water (12 mL) is added to the hot solution in a single portion (note 7). Heating is removed and the slurry is allowed to slowly cool to room temperature over 1.5 hours. The slurry is granulated for 4 hours at room temperature and the solids are filtered and the cake is washed with water (15 mL) and dried to provide 1.35 g (72% yield) of the title product as a tan solid (notes 8 and 9).

¹H NMR of sample: (300 MHz, CDCI₃) 0.65-0.75 (m, 2H), 0.9-1.0 (m, 2H), 2.75 (s, 3H), 2.9-3.1 (m, 1 H), 3.7 (s, 3H), 4.0 (s, 3H), 6.0 (NH), 6.6 (d, 1 H), 7.0-7.1 (m, 2H), 7.2 (m, 2H), 7.65-7.7 (d, 1 H), 7.5 (s, 1 H), 8.5 (d, 1H).

Notes:

1. The flask is equipped with an overhead stirrer, internal temperature probe, and a nitrogen inlet.

2. The slurry should be cooled between 0 to 5 °C.

3. Sodium tert-butoxide should be added quickly to minimize exposure to moisture.

4. An exotherm is observed upon addition of sodium tert-butoxide. Typically, the temperature rises 5 to 10 ⁰C. 5. The reaction is monitored for completion using HPLC. HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 210 nm, lsocratic 30/70 acetonitrile/aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O). Method ends at 15 minutes. Retention times: 1 ,2-dimethyl-6-[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2- b]pyridine-7-yloxy]-1 H-indole-3-carboxylic acid cyclopropyl amide = 4.4 min, 6-hydroxy-1 ,2- dimethyl-1H-indol-3-carboxylic acid cyclopropyl amide (1.00 g, 0.0041 mol) = 3.6 min, 7- chloro-2-(1-methyl-iH-imidazol-2-yl)thieno[3,2-b]pyridine = 3.2 min, primary amide = 2.8 min.; dimethyl acetamide = 1.8 min.

6. The reaction is deemed complete when less than 0.5% 6-hydroxy-1 ,2- dimethyl-1H-indol-3-carboxylic acid cyclopropyl amide remains as determined by HPLC.

7. Upon addition of water, the temperature will drop. On this scale, the internal temp went from 75 ⁰C to ~ 64 °C.

8. The solids are dried for 18 h under vacuum at 50 ⁰C.

9. The purity by HPLC is 98% (210 nm).

Example 9: Re-crystallization of 1 ,2-dimethyl-6-[2-(1-methyl-1 H-imidazol-2-yl)thieno- [3,2-b]pyridine-7-yloxy]-1 H-indole-3-carboxylic acid cyclopropyl amide

A 50 mL round bottom flask is charged with crude 1 ,2-dimethyl-6-[2-(1-methyl-1H- imidazol-2-yl)thieno[3,2-b]pyridine-7-yloxy]-1 H-indole-3-carboxylic acid cyclopropyl amide(1.3 g, 2.84 mmol), DARCO^® G-60 (1.25 g, 0.3 wt/wt), methylene chloride (26 mL) and methanol

(13 mL) (note 1). The mixture is heated to reflux for 1.5 hours and is allowed to cool to 35 ⁰C

(note 2). The mixture is filtered at 35 ⁰C over Celite^® (note 3) and the cake washed with 2:1 methylene chloride/methanol (9.8 mL) (note 4). The product-rich solution is distilled at atmospheric pressure to a total volume of 15.6 mL. After cooling below reflux temperature, methanol (24.7 mL) is added and heating is resumed to displace methylene chloride until a total volume of 15.6 ml is reached (notes 5 and 6). The solution is allowed to slowly cool to room temperature over 1.5 hours and then allowed to granulate at room temperature for 3 hours. The solids are filtered and the cake is washed with methanol (4 mL) and dried to provide 1.1 g (85% yield) of the title product as an off white solid (notes 7 and 8).

¹H NMR of sample: (300 MHz, CDCI₃) 0.65-0.75 (m, 2H), 0.9-1.0 (m, 2H), 2.75 (s, 3H), 2.9-3.1 (m, 1H), 3.7 (s, 3H), 4.0 (s, 3H), 6.0 (NH), 6.6 (d, 1H), 7.0-7.1 (m, 2H), 7.2 (m, 2H), 7.65-7.7 (d, 1 H), 7.5 (s, 1H), 8.5 (d, 1 H).

Notes: 1. The flask is equipped with an internal temperature probe and a condenser with nitrogen inlet.

2. Reaction should be cooled between 35 to 40 ⁰C.

3. This filtration is to remove DARCO^® and residual insoluble material.

5 4. Filtrate should be a clear, light orange/brown color.

5. Solids typically precipitate before reaching the total volume of 15.6 mL after the addition of methanol.

6. Monitored the displacement of methylene chloride by boiling point temperatures (methylene chloride/methanol has an azeotropic boiling temperature of 38 °C

10 and methanol has a boiling temperature of 64 ⁰C). The distillation temperature should be 64 °C prior to final cooling for product isolation.

7. The solids are dried for 18 hours under vacuum at 50 °C.

8. The purity by HPLC is 98.3% (210 nm).

Example 10: Preparation of 3-(3-methoxyphenylthio)2-ketobutyric acid

NBS

AIBN

■j g

A 3 liter, 3-neck flask is charged with 2-ketobutyric acid (100.0 g, 0.9798 moles) and 1 ,2-dichloroethane (700 mL) (note 1). N-bromosuccinimide (226.9 g, 1.275 moles) is added to this solution in one portion (note 2). 2,2-azobisisobutyronitrile (4.02 g, 0.025 moles) is added and the mixture is heated to an internal temperature of 60 ⁰C (note 3). After 20 minutes, the 20 mixture is heated to an internal temperature of 80 ⁰C (note 4). The reaction is monitored by ¹H NMR analysis (notes 5 and 6). After a total heating time of 45 minutes, ¹H NMR shows approximately a 10:1 ratio of product to 2-ketobutyric acid. After an additional heating time of 20 minutes, ¹H NMR shows approximately a 16:1 ratio of product to 2-ketobutyric acid. The mixture is cooled to room temperature by immersion of the flask into an ice/water bath. To the cooled solution is added acetone (350 mL) and potassium carbonate (154.4 g, 1.117 mole) in portions to control the bubbling (note 7). 3-methoxybenzenethiol (110 mL, 0.887 moles) is added to the mixture by addition funnel (note 8). The reaction is monitored by HPLC. 5 minutes after the complete addition of the thiol, the reaction is deemed complete (notes 9 and 10). After a total reaction time of 15 minutes after thiol addition, the mixture is added to a separatory funnel and diluted with water (700 mL) and heptanes (600 mL). The solution is mixed well and the layers are allowed to settle. The lower aqueous phase containing the desired product (-1.3 L) is added back to the reaction flask. The upper organic phase (-1.5 L) is discarded (note 11). Heptane (350 mL) and dichloromethane (350 mL) are added to the aqueous solution and the flask is equipped with a pH meter and an overhead stirrer. The flask is immersed in an ice/water bath and stirred until the internal temperature is 15 ⁰C. Concentrated HCI (97 mL) is added by addition funnel while monitoring the internal pH of the aqueous phase at such a rate that the moderate bubbling and exotherm are controllable (note 12). The target pH is <2. After complete addition of the HCI, the pH of the aqueous layer is 1.9. The solution is added to a separatory funnel and the layers separated. The lower aqueous phase is discarded and the upper organic phase containing the desired product is washed with saturated aqueous sodium chloride (200 mL). The phases are separated and the organic phase is added to a clean flask (notes 13 and 14).

¹H NMR of the crude sample (quidkly dried to remove most solvents): (300 MHz, d₆- Acetone) 1.37 (d, 3, J=6.9), 3.81 (s, 3), 4.56 (q, 1 , J-6.9), 6.96 (dd, 1 , J=1.0, 2.5), 7.00-7.05 (m, 2H), 7.29 (t, 1 , J=8.2), -9.90 (v br s, 1).

Notes:

1. The flask is equipped with an overhead stirrer, an internal temperature probe, Argon inlet and condenser. The condenser has a gas-outlet at the top connected to a trap, where the outlet gas is bubbled through an aqueous solution of 75 g of Na₂S₂O₃ in 500 mL H₂O to trap any liberated bromine.

2. As the solids begin to dissolve, the internal temperature drops due to endothermic dissolution (to 13 ⁰C in this example).

3. After the internal temperature reaches 60 ⁰C, the solution is slowly self- heating and the internal temperature increases to 70⁰C over - 10 minutes.

4. After applying heat to raise the internal temperature to 75 ⁰C, the solution continues to heat over 10 minutes to a maximum temperature of 83 ⁰C. The internal temperature is held at 80 +/- 3 ⁰C. 5. During the reaction, an orange/red color develops. This color fades significantly towards the end of the reaction, allowing an indication of when sampling for completion is near.

6. The reaction is sampled and the majority of the solvent is removed from the sample by a slow stream of air. The crude oil is dissolved in dichloromethane for 1 H NMR analysis. The ratio of product to starting material is judged by the integration of the methyl doublet in the product (1.85 ppm) to the methyl triplet in the starting material (1.20 ppm).

7. The potassium carbonate is added while the solution is near room temperature (-20-22 ⁰C throughout). The complete addition takes 6 minutes.

8. The internal temperature is 20 ⁰C at the beginning of the 3- methoxybenzenethiol addition. The thiol is added at such a rate that bubbling and exothermicity are controlled. The total addition took 10 minutes at this scale. The maximum internal temperature during addition is 25 ⁰C.

9. For HPLC monitoring, aliquots were withdrawn and dissolved in acetonitrile/water (70/30). HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 "C column chamber, flow rate = 1.0 mL/min, 70% acetonitrile / 30% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 3- methoxybenzenethiol = 2.8 min, 3-(3-methoxyphenylthio)2-ketobutyric acid = 2.26 min.

10. The reaction after 5 minutes had <1 % 3-methoxybenzenethiol remaining by HPLC analysis.

11. The organic phase is analyzed by HPLC (note 9) and contained negligible product. The main impurity removed at this step is the 4.9 minute impurity believed to be the disulfide of 3-methoxybenzenethiol.

12. The internal temperature during the pH adjustment is 12 +/- 3 ⁰C.

13. The solution is held at room temperature overnight with no detectable degradation.

14. HPLC analysis (note 9) of the crude solution shows 3-(3-methoxyphenylthio)2- ketobutyric acid with a purity of 96.9%.

Example 11 : Preparation of 6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid

The crude product solution from Example 10 (theoretical amount: 213.0 g, 0.8865 moles, in -700 mL of 1 :1 methylene chloride/heptane solution) in a 2 liter flask is cooled in an ice/water bath until the internal temperature is 5 ⁰C (note 1). The mixture is stirred vigorously and concentrated sulfuric acid (115 mL) is added by addition funnel at such a rate that the internal temperature remains between 10 to 13 ⁰C (note 2). After complete addition of the acid, the ice/water bath is removed and replaced with a 20 ⁰C water bath. After 15 minutes, there were significant amounts of solids in the reaction solution. The reaction is monitored by HPLC analysis (note 3). 20 minutes after the cold bath is removed, the internal temperature is 25 ⁰C. Due to slow self-heating during the reaction, the bath temperature is re-adjusted to 19

⁰C (note 4). After 3.5 hours since the acid addition, HPLC analysis shows <3% of the starting material acid remaining (note 5). After a total reaction time of 6 hours after acid addition, the solution is cooled in an ice/water bath to an internal temperature of 10 ⁰C. Cold water (500 mL

, at 5 ⁰C) is added in one portion causing an increase in the internal temperature to 19 ⁰C (note 6). The mixture is stirred at room temperature for 20 minutes and the bilayer is filtered. The crude solids are rinsed with water (2 x 200 mL) (note 7). The wet cake is added back to the reaction flask followed by addition of acetonitrile (350 mL). The slurry is stirred at room temperature for one hour, filtered and the off-white cake is rinsed with acetonitrile (2 x 175 mL). The solids are dried to provide 108.69 g (55% over 2 steps) of the title product (note 8).

¹H NMR (300 MHz, d₆-DMSO): 2.75 (s, 3), 3.81 (s, 3), 7.03 (dd, 1, J=2.5, 9.0), 7.51

(d, 1, J=2.4), 8.22 (d, 1, J=9.0), -12.9 (v br s, 1). ¹³C NMR (75 MHz, d₆-DMSO): 16.39, 55.39, 104.66, 114.70, 122.66, 124.76, 132.16, 137.90, 148.80, 156.82, 164.77.

Notes:

1. The flask is equipped with an overhead stirrer and an Argon inlet.

2. This addition takes 14 minutes.

3. For HPLC monitoring, aliquots are withdrawn and dissolved in acetonitrile/water (70/30). HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 70% acetonitrile / 30% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 3-(3- methoxyphenylthio)2-ketobutyric acid = 2.8 min, 6-methoxy-2-methylbenzo[b]thiophene-3- carboxylic acid = 2.26 min. 4. The exothermic reaction is slow. A 20 ⁰C bath is unable to stabilize the internal temperature at 20 to 23 ⁰C. For larger scale, it is recommended that the jacket temperature be set to this range to control any exotherms.

5. After the uncyclized starting material drops below a few percent, the reaction can be worked up at any time. This particular reaction is ran longer than average.

6. Due to the exothermic mixing, the addition rate of water should be adjusted to control the exotherm at room temperature or below. The addition of precooled water is not necessary, but allows for quicker addition.

7. HPLC analysis of the aqueous layer of the filtrate shows negligible product. HPLC analysis of the organic layer of the filtrate shows the undesired cyclization isomer as the main component , along with a small amount of desired product.

8. The solids are dried in a vacuum oven at 45 ⁰C for 17 hours (~25 mm Hg).

9. The product is 99.4% pure by HPLC analysis, contains no detectable isomeric product and only a trace of methylene chloride by ¹H NMR analysis.

Example 12: Preparation of 6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide

A 3 liter, 3-neck flask is charged with 6-methoxy-2-methylbenzo[b]thiophene-3- carboxylic acid (100.0 g, 0.4500 mol) and tetrahydrofuran (900 mL) (notes 1 , 2). Carbonyldiimidazole (87.56 g, 0.5400 mol) is added to the slurry in one portion (notes 3, 4). After 15 minutes, the mixture is homogeneous and yellow in color. After 1 hour, HPLC analysis shows <1% of the 6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid remaining (note 5). The mixture is cooled to 10 ⁰C with an ice-water bath and methylamine (CH₃NH₂) solution (77.6 mL, 40% by wt. in water, 0.896 mol) is slowly added by addition funnel (note 6). After complete addition of the solution, the cold bath is removed and the mixture is allowed to warm to room temperature. After 3 hours, HPLC analysis shows <3% of the "acylimidizole" intermediate remaining wherein the reaction is deemed complete (note7). Water (900 mL) is added to the mixture and the mixture is distilled under atmospheric pressure to a total volume of 1.1 to 1.2 L (notes 8 and 9). The heating is removed and the solution is allowed to cool to room temperature overnight with continuous stirring. After 18 hours, the solution is filtered and the solids are rinsed with a 5:1 water/tetrahydrofuran solution (250 mL) (note 10). The white solids are dried to provide 99.50 g (94%) of the title product (notes 11, 12).

¹H (300 MHz, CDCI₃): 2.66 (s, 3), 3.07 (d, 3, J=4.9), 3.88 (s, 3), 5.93 (br s, 1), 6.99 (dd, 1 , J=2.4, 8.9), 7.23 (d, 1 J=2.4), 7.75 (d, 1 J=8.9). ¹³C(75 MHz, d_s-DMSO): 14.65, 25.95, 55.40, 104.82, 114.16, 123.33, 129.55, 132.08, 137.56, 138.62 156.77, 164.53.

Notes:

1. The flask is equipped with an overhead stirrer, internal temperature probe, and Ar inlet.

2. The starting material is only partially soluble in the solvent. 3. The addition of CDI is slightly endothermic. The internal temperature changed from 21 °C to 19 ⁰C.

4. The release of CO₂ is noticeable but well controlled.

5. For HPLC monitoring, aliquots are withdrawn and dissolved in acetonitrile/water (70/30). HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 40% acetonitrile/60% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 6-methoxy-2- methylbenzo[b]thiophene-3-carboxylic acid = 7.3 min., "acylimidazole" intermediate: 4.8 min.

Acylimidazole Intermediate 6. The methylamine solution is added at such a rate that the internal temperature remains between 8 and 15 °C.

7. See note 5 for HPLC conditions. Retention time: 6-methoxy-2- methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide = 4.5 min.

8. After water addition, a small amount of solids are visible. 9. During the distillation, crystallization increases and significant solids are present at the completion of the distillation. It may be necessary to seed the reaction during distillation.

10. The composition of the rinse solution is an estimated ratio of the solution composition after the distillation (measured by ¹H NMR analysis). 11. The solids are dried overnight in a vacuum oven at approximately 25 mm Hg and 45 to 50 ⁰C. KF shows 0.15% H₂O.

12. HPLC analysis shows 100% purity for the solids.

Example 13: Preparation of 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide

A 2 liter, 3-neck flask is charged with 6-methoxy-2-methylbenzo[b]thiophene-3- carboxylic acid cyclopropylamide (89.7 g, 0.381 mol), methionine (77.0 g, 0.516 mol) and methanesulfonic acid (MSA, 900 ml.) (note 1). Upon addition, the internal temperature of the mixture rose from 25 ⁰C to 35 ⁰C (note 2). After 20 minutes, the internal temperature cooled to 26 ⁰C and the second portion of methionine (76.2 g, 0.511 mol) is added causing the internal temperature to rise to 32 °C. After 25 minutes, the internal temperature cooled to 28 ⁰C and the third portion of methionine (75.5 g, 0.506 mol) is added causing the internal temperature to rise to 34 ⁰C. The mixture is heated to 60 ⁰C and monitored by HPLC analysis (note 3). After 2.75 hours, the reaction is 71 % completed. Heating is continued overnight for a total reaction time of 19 hours. HPLC shows no detectable 6-methoxy-2-methylbenzo[b]thiophene- 3-carboxylic acid cyclopropylamide and heating is discontinued. The mixture is cooled to room temperature with an ice/water bath. In a separate flask, water (1 ,350 mL) is cooled in an ice/water bath to an internal T = 7 °C (note 4). The reaction mixture is slowly added in portions to the cooled water at such a rate that the internal temperature of the water solution remains below 25 ⁰C (note 5). After complete addition, the mixture is stirred at room temperature overnight. The slurry is filtered and the cake is washed with water (2 x 200 mL). The wet cake is dried to provide 79.0 g (94%) of the title product as a white solid (notes 6, 7, 8). ¹H NMR (300 MHz, d₆-acetone): 2.58 (s, 3), 2.95 (d, 3, J=4.7), 6.91 (dd, 1 , J=2.3,

8.8), 7.22 (d, 1 , J=2.2), 7.25 (br s, 1), 7.70 (d, 1, J=8.8). ¹³C(75 MHz, d6-DMSO): 14.60, 25.96, 106.91 , 114.46, 123.36, 129.63, 131.03, 136.32, 138.63, 154.79, 164.69. Notes:

1. The flask is equipped with an overhead stirrer, internal temperature probe, and Argon inlet. The flask is immersed in a room temperature water bath.

2. The methionine is added in 3 portions to help control this exotherm. The jacket temperature can be lowered for more efficient cooling and smaller time intervals between methionine additions.

3. For HPLC monitoring, aliquots are withdrawn and dissolved in acetonitrile/water (70/30). HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 150 mm, 40 °C column chamber, flow rate=1.0 mL/min, 70% acetonitrile/30% aqueous ( 1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 215 nm. Retention times: 6-hydroxy-2- methylbenzo[b]thiophene-3-carboxylic acid = 2.1 min, 6-hydroxy-2-methylbenzo[b]thiophene- 3-carboxylic acid cyclopropylamide = 1.8 min. MSA = 1.5 min. 4. The 3-necked flask is equipped with an overhead stirrer.

5. Solids form upon addition of the methanesulfonic acid solution to the water. Stirring of the water solution is maintained throughout addition.

6. The product is dried in a vacuum oven at 45 to 50 ⁰C and 25 mm Hg. 7. HPLC of the crude product shows 98.9% purity. HPLC of the filtrate shows very little product. KF of product showed 1.3% water content.

8. A recrystallization of this product is under development to remove residual water, MSA, and methionine.

Example 14: Preparation of 6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid methyl amide

A 2 liter, 3-neck, Argon purged flask is charged with 7-chloro-2-(1-methyl-1H- imidazol-2-yl)thieno[3,2-b]pyridine (40.20 g, 0.1609 moles), 6-methoxy-2-methylbenzo[b]- thiophene-3-carboxylic acid cyclopropylamide (35.48 g, 0.1603 mol), cesium carbonate (89.79 g, 0.2756 mol) and dimethyl sulfoxide (300 mL) (note 1). The mixture is heated to 80 ⁰C with stirring for 7 hours. HPLC analysis shows 18% remaining 7-chloro-2-(1-methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridine (notes 2 and 3). Heating is continued for a total of 24 hours wherein HPLC analysis shows 4% 7-chloro-2-(1-methy!-1H-imidazol-2-yl)thieno[3,2-b]pyridine (note 4). The reaction is heated an additional 4 hours wherein HPLC analysis shows 3.2% 7-chloro- 2-(1 -methyl- 1H-imidazol-2-yl)thieno[3,2-b]pyridine. While still hot, water (800 mL) is added to the reaction mixture causing precipitation of the product (note 5). After 30 minutes, the solution is cooled to room temperature with a water bath. After the internal temperature is cooled to 25 ⁰C, the mixture is filtered, the solids are rinsed with water (1 x 300 mL, 1 x 100 mL) and are dried overnight (note 6). The dried cake is added to a 3 liter flask and methylene chloride (1 ,050 mL) and ethanol (700 mL) are added followed by DARCO^® (G-60, -100 mesh, 35 g). The slurry is heated to 40 ⁰C for approximately 30 minutes with stirring to dissolve the crude product. The solution is cooled slightly (30-35 ⁰C) over 40 minutes and filtered through Celite^® (note 7). The Celite^® cake is rinsed with solvent mixture (100 mL of 3:2 methylene chloride/ethanol). The filtrate is added to a clean, dry 2 liter flask (note 8). The solution is distilled under atmospheric pressure to remove methylene chloride. The desired product begins to crystallize at an internal temperature of approximately 60 ⁰C (note 9). The distillation is continued until the internal temperature reaches 75 ⁰C and the pot is held at this temperature for 15 to 20 min (note 10). The slurry is cooled to room temperature, filtered, and the solids are rinsed with ethanol (2 x 100 mL). The solids are dried to provide 45.09 g (65%) of the title product as a fluffy, off-white solid (notes 11 and 12).

¹H NMR (300 MHz, d₆-DMSO): 2.61 (s, 3), 2.84 (d, 3, J=4.6), 3.99 (s, 3), 6.71 (d, 1 , J=5.4), 7.03 (d, 1 , J=1.0), 7.33 (dd, 1 , J-2.3, 8.8), 7.41 (d, 1 , J=1.0), 7.86 (d, 1 , J=8.8), 7.89 (s,

1), 7.95 (d, 1, J=2.3), 8.28 (br q, 1 , J=4.6), 8.53 (d, 1 , J=534). ¹³C (75 MHz, d₆-DMSO): 14.81 ,

25.96, 34.82, 105.60, 114.22, 118.35, 120.94, 121.34, 124.09, 125.52, 128.37, 129.68,

136.14, 137.80, 138.36, 140.19, 141.16, 149.83, 150.14, 158.99, 159.44, 164.21.

Notes:

1. The flask is equipped with an overhead stirrer, an internal temperature probe, and Argon inlet.

2. Due to the insolubility of the reaction components, care must be taken to ensure the HPLC sample is homogeneous. Typically, an aliquot is removed and a few drops of 1M HCI is added. The sample volume is made up with 40/60 acetonitrile/water solution and the mixture sonicated to ensure complete dissolution. Additional HCI may be added followed by sonication if the sample is not homogenous.

3. HPLC conditions: Kromasil C4 column, 5 μm, 4.6 x 50 nm, 40 ⁰C column chamber, flow rate = 1.0 mL/min, 30% acetonitrile/70% aqueous (1.0 mL 70% HCIO₄ in 1 L H₂O) isocratic. Percentages reported are at 254 nm. Retention times: 7-chloro-2-(1-methyl- 1 H-imidazol-2-yl)thieno[3,2-b]pyridine = 3.10 min, 6-methoxy-2-methylbenzo[b]-thiophene-3- carboxylic acid cyclopropylamide = 3.55 min, 6-methoxy-2-methylbenzo[b]thiophene-3- carboxylic acid methyl amide = 4.04 min.

4. Due to the difficulty in purging large amounts of 7-chloro-2-(1-methyl-1H- imidazol-2-yl)thieno[3,2-b]pyridine, the reaction should be run to<5% 7-chloro-2-(1-methyl-1H- imidazol-2-yl)thieno[3,2-b]pyridine remaining.

5. The internal temperature remains between 50 to 60 ⁰C.

6. This cake is dried in a vacuum oven overnight at approximately 50 ⁰C. However, this is not necessary and in previous runs the cake is pulled to dripless and transferred directly to the next workup step.

7. The solution does not have to be warm during filtration as this solvent mixture is sufficient to dissolve all of the desired material. Note that this step is the "speck-free" filtration for large-scale synthesis. 8. The flask is equipped with a temperature probe, overhead stirrer, and distillation head.

9. The solution can be seeded prior to or at this point if desired.

10. Distillation is held until the head temperature reaches 75 °C, ensuring minimal methylene chloride residue.

11. The product is dried under house vacuum with an air bleed at 50 ⁰C overnight.

12. The final product is >99% pure by HPLC analysis. ¹H NMR analysis shows a trace of ethanol and methylene chloride.

Example 15: Preparation of 2-methyl-6-[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]- pyridine-7-yloxy]benzo[b]thiophene-3-carboxylic acid methyl amide besylate salt

A 2 liter, 3-neck flask is charged with 2-methyl-6-[2-(1-methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridine-7-yloxy]benzo[b]thiophene-3-carboxylic acid methyl amide (50.00 g, 0.1151 moles) and ethanol (450 mL). The resulting slurry is heated to 55 ⁰C (note 1). A solution of benzenesulfonic acid hydrate (22.15 g, 0.1257 moles) dissolved in water (50 mL) and ethanol (100 mL) is added to the slurry in one portion (note 2). The mixture is seeded with the title product and stirred for 30 minutes. Tetrahydrofuran (500 mL) is slowly added to the mixture by addition funnel and stirring is continued at 55 ⁰C for 15 minutes. The mixture is cooled to room temperature over 2 hours (note 3). The solution is filtered and the solids rinsed with solvent (220 mL of solution containing 120 mL of ethanol and 100 mL tetrahydrofuran). The solids are dried to provide 65.11 g (95%) of the title product as a yellow powder (notes 4 and 5). ¹H NMR (300 MHz, d₆-DMSO): 2.63 (s, 3), 2.85 (d, 3, J=4.5), 4.04 (s, 3), 6.90 (d, 1 ,

J=5.7), 7.23-7.35 (m, 3), 7.37 (dd, 1, J=2.3, 8.8), 7.58-7.62 (m, 3), 7.79 (d, 1, J=1.5), 7.91 (d, 1 , J=8.8), 8.02 (d, 1, J=2.3), 8.22 (s, 1), 8.27 (br q, 1 , J=4.4), 8.70 (d, 1 , J=5.7). Notes:

1. The flask is equipped with an overhead stirrer, an internal temperature probe, and addition funnel.

2. Addition of this solution lowered the internal temperature to 48 ⁰C. Within one minute, a nearly homogeneous solution is obtained. The internal temperature is held between 50 and 55 ⁰C by continued heating.

3. The tetrahydrofuran is added over 25 min. 4. The solids are dried under house vacuum at 50 ⁰C using an air bleed. 5. The solids are >99% pure by HPLC.

While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents.

Claims

ClaimsWhat is claimed is:

1. A method for preparing a compound of formula I:

I or a pharmaceutically acceptable salt or solvate thereof, wherein: Y iS -O-, -S- or -NH-; R¹ is H or C₁-C₆ alkyl: R² is H or C₁-C₆ alkyl: R³ is H or Ci-C₆ alkyl: and R⁴ is C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylhydroxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylamino or C₁-C₆ alkyl C₃-C₁₀ cycloalkyl; comprising, a) formylating a compound of formula Il to provided a compound of formula III; b) cyclizing the compound of formula III to provide a compound of formulal IV; c) alkylating the compound of formula IV to provide a compound of formula V:

Ii in rv V d) coupling a compound of formula Vl with benzophenone hydrazone to provide a compound of formula VII, wherein W is a protecting group, and X is Cl, Br or I; e) alkylating the compound of formula VII to provide a compound of formula VIII; f) cyclizing the compound of formula VIII to provide a compound of formula IX; and g) removing W in the compound of formula IX to provide a compound of formula X:

VI VII VIII

^{IX x} and h) coupling the compound of formula V with the compound of formula X:

v X

2. The method of claim 1 , wherein the compound of formula Il is formylated using an alkyl lithium reagent and N,N-dimethyl formamide.

3. The method of claim 2, wherein the alkyl lithium reagent is n-butyl lithium.

4. The method of claim 1, wherein the compound of formula HI is cyclized using glyoxal trimer, ammonium acetate and acetic acid.

5. The method of claim 1, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base.

6. The method of claim 5, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

7. The method of claim 6, wherein the base is sodium f-butoxide.

8. The method of claim 1 , wherein the compound of formula Vl is couple with benzophenone hydrazone using a palladium catalyst.

9. The method of claim 8, wherein the palladium catalyst is palladium acetate.

10. The method of claim 1, wherein the compound of formula VII is alkylated with methyl tosylate in the presence of a base.

11. The method of claim 10, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

12. The method of claim 11 , wherein the base is sodium f-butoxide.

13. The method of claim 1, wherein the compound of formula VIII is cyclized in acid with a compound of formula R³COCH₂CONHR⁴ to form the compound of formula IX, wherein R³ and R⁴ are as described.

14. The method of claim 13, wherein the acid is methane sulfonic acid.

15. The method of claim 1 , wherein W is benzyl.

16. The method of claim 15, wherein W is removed by catalytic hydrogenation.

17. The method of claim 16, wherein the catalyst is a palladium catalyst.

18. The method of claim 17, wherein the catalyst is palladium hydroxide.

19. The method of claim 1 , wherein the compound of formula V is couple to the compound of formula X in the presence of a base.

20. The method of claim 19, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

21. The method of claim 20, wherein the base is cesium carbonate or sodium t- butoxide.

22. The method of claim 21 , further comprising a solvent.

23. The method of claim 22, wherein the solvent is dimethylsulfoxide.

24. The method of claim 23, wherein the reaction is carried out at about 100 ⁰C.

25. The method of claim 24, wherein R¹, R², and R³ are methyl; and R⁴ is cyclopropyl.

26. A method for preparing a compound of formula Xl:

XI

or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is -0-, -S- or -NH-; Z is S; R¹ is H or C₁-C₆ alkyl:

R³ is H or C₁-C₆ alkyl: and

R⁴ is Ci-C₆ alkyl, C₁ -C₆ alkylamino, C₁ -C₆ alkylhydroxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylamino or C₁-C₆ alkyl C₃-C₁₀ cycloalkyl; comprising, a) formylating a compound of formula Il to provided a compound of formula III; b) cyclizing the compound of formula III to provide a compound of formulal IV; c) alkylating the compound of formula IV to provide a compound of formula V:

II III IV V

; and

e) cyclizing the compound of formula XII to provide a compound of formula XlIl;

f) amidifying the compound of formula XII to provide a compound of formula XIV;

g) removing W in the compound of formula XlV to provide a compound of formula XV:

and,

h) coupling the compound of formula V with the compound of formula XV:

xv XI

27. The method of claim 26, wherein the compound of formula Il is formylated using the alkyl lithium reagent and N, N-dimethyl formamide.

28. The method of claim 27, wherein the alkyl lithium reagent is n-butyl lithium.

29. The method of claim 26, wherein the compound offormula III is cyclized using glyoxal trimer, ammonium acetate and acetic acid to form the compound of formula IV.

30. The method of claim 26, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base,

31. The method of claim 30, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium /-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

32. The method of claim 31 , wherein the base is sodium f-butoxide.

33. The method of claim 26, wherein the compound of formula Xl is alkylated with a compound of formula R³CHXCOCO₂H in the presence of a base, wherein X is Cl, Br or I.

34. The method of claim 33, wherein R³ is CH₃; and X is Br.

35. The method of claim 33, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

36. The method of claim 35, wherein the base is potassium carbonate.

37. The method of claim 26, wherein the compound of formula XII is cyclized in acid.

38. The method of claim 37, wherein the acid is sulfuric acid.

39. The method of claim 26, wherein the compound of formula XIII is amidified using CDI and R⁴NH₂.

40. The method of claim 39, wherein R⁴ is methyl.

41. The method of claim 26, wherein W is methyl.

42. The method of claim 41 , wherein W is removed with methane sulfonic acid.

43. The method of claim 26, wherein the compound of formula V is couple to the compound of formula XV in the presence of a base.

44. The method of claim 43, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

45. The method of claim 44, wherein the base is cesium carbonate or sodium t- butoxide.

46. The method of claim 45, further comprising a solvent.

47. The method of claim 46, wherein the solvent is dimethylsulfoxide.

48. The method of claim 47, wherein the reaction is carried out at about 100⁰C.

49. The method of claim 48, wherein R¹, R³, and R⁴ is methyl.

50. A method for preparing a compound of formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ is H or C₁ -C₆ alkyl: and

X is Cl, Br or I;

comprising, d) formylating a compound of formula Il to provided a compound of formula III; e) cyclizing the compound of formula III to provide a compound of formulal IV; f) alkylating the compound of formula IV to provide a compound of formula V:

π πi iv v

51. The method of claim 50, wherein the compound of formula Il is formylated using an alkyl lithium reagent and N, N-dimethyl formamide.

52. The method of claim 51 , wherein the alkyl lithium reagent is n-butyl lithium.

53. The method of claim 50, wherein the compound of formula III is cyclized using glyoxal trimer, ammoniuim acetate and acetic acid to form the compound of formula IV.

54. The method of claim 50, wherein the compound of formula IV is alkylated with methyl tosylate in the presence of a base.

55. The method of claim 54, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

56. The method of claim 55, wherein the base is sodium f-butoxide.

57. The method of claim 50, wherein R¹ is methyl; and X is Cl.

58. The method for preparing a compound of formula X:

X or a pharmaceutically acceptable salt or solvate thereof, wherein:

Y iS -O-, -S- or -NH-;

R² is H or C₁-C₆ alkyl: R³ is H or C₁-C₆ alkyl: and

R⁴ is C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylhydroxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylamino or C₁-C₆ alkyl C₃-Ci₀ cycloalkyl; comprising, a) coupling a compound of formula Vl with bgenzophenone hydrazone to provide a compound of formula VII, wherein W is a protecting group, and X is Cl₁ Br or I; b) alkylating the compound of formula VII to provide a compound of formula VII; c) cyclizing the compound of formula VIII to provide a compound of formula IX; and d) removing W in the compound of formula IX to provide a compound of formula X:

VI VII vπi

59. The method of claim 58, wherein the compound of formula Vl is coupled with benzophenone hydrazone using a palladium catalyst.

60. The method of claim 59, wherein the palladium catalyst is palladium acetate.

61. The method of claim 58, wherein the compound of formula VII is alkylated with methyl tosylate in the presence of a base.

62. The method of claim 61, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium f-butoxide, sodium f-butoxide, triethylamine, N, N- diisopropyl ethyl amine or mixtures thereof.

63. The method of claim 62, wherein the base is sodium t-butoxide.

64. The method of claim 58, wherein the compound of formula VIII is cyclized in acid with a compound of formula R₃COCH₂CONHR⁴ to form the compound of formula IX, where in R³, and R⁴ are as described.

65. The method of claim 64, wherein the acid is methane sulfonic acid.

66. The method of claim 58, wherein W is benzyl.

67. The method of claim 66, wherein W is removed by catalytic hydrogenation.

68. The method of claim 67, wherein the catalyst is a palladium catalyst.

69. The method of claim 68, wherein the catalyst is palladium hydroxide.

70. The method of claim 69, wherein R², and R³ are methyl; and R⁴ is cyclopropyl.