BENZIMIDAZOLECARBOXAMIDES AS INHIBITORS OF FAK

Background of the Invention

This invention relates to a class of heterocycloaminopyridines that inhibit Focal Adhesion Kinase (FAK), as well as compositions thereof. These compounds treat proliferative diseases.

Tyrosine kinases play an important role in the regulation of many cell processes including cell proliferation, cell survival, and cell migration. It is known that certain tyrosine kinases become activated by mutation or are abnormally expressed in many human cancers. For example, the epidermal growth factor receptor (EGFR) is found mutated and/or overexpressed in breast, lung, brain, squamous cell, gastric, and other human cancers. Selective inhibitors of the tyrosine kinase activity of EGFR have been shown to be of clinical value in treatment of cancers with mutated and/or overexpressed EGFR. Thus, selective inhibitors of particular tyrosine kinases are useful in the treatment of proliferative diseases such as cancer.

FAK (encoded by the gene PTK2) is a non-receptor tyrosine kinase that integrates signals from integrins and growth factor receptors. FAK has been reported to play a role in the regulation of cell survival, growth, adhesion, migration, and invasion (McLean et al 2005, Nat Rev Cancer 5:505-515). Furthermore, FAK is regulated and activated by phosphorylation on multiple tyrosine residues. Overexpression of FAK mRNA and/or protein has been documented in many solid human tumors, including but not limited to, cancers of the breast, colon, thyroid, lung, ovary, and prostate; but also including cancers of hematological origin, including but not limited to leukemia such as acute myeloid leukemia (AML). (Owens et al. 1995, Cancer Research 55: 2752-2755; Agochiya et al. 1999, Oncogene 18: 5646-5653; Gabarro-Niecko et al. 2003, Cancer Metastasis Rev. 22:359-374; Recher et al. 2004, Cancer Research 64:3191-3197; Zhao and Guan, 2009. Cancer Metastasis Rev.). More significantly, there is evidence that phosphorylated FAK is increased in malignant compared to normal tissues (Grisaru-Granovsky et al. 2005, Int. J. Cancer 113: 372-378) and could represent a prognostic marker of metastasis. FAK activity is clearly implicated in advanced and metastatic human cancer.

Inhibition of FAK by RNAi or expression of a FAK dominant negative has been shown to induce loss of adhesion and cell death in human breast and melanoma cell lines, and to augment docetaxel-mediated apoptosis in ovarian cancer cells (Beviglia et al 2003, Biochem J. 373:201- 210, Smith et al 2005, Melanoma Res. 15:357-362, Haider et al 2005, Clin. Cancer Res. 11 :8829- 8836). However, inhibition of FAK in normal human fibroblasts or immortalized mammary cells (MCFlOA) was found not to cause loss of attachment or apoptosis (Xu et al. 1996 Cell Growth and Diff 7:413-418). Inhibition of FAK by dominant negative expression has also been shown to reduce tumor growth and eliminate lung metastasis of mammary adenocarcinoma cells in a syngeneic rat model (van Nimwegen et al 2005, Cancer Res. 65:4698-4706). Similarly, inhibition of FAK by shRNA inhibited lung metastasis and reduced lethality by 40% in a syngeneic mouse model (Mitra et al 2006, Oncogene 25: 4429-4440). In this study, transient re-expression of wild- type, but not kinase-dead FAK, reversed the shRNA phenotypes. Inhibition of FAK by dominant negative expression in mouse 4Tl carcinoma cells reduced tumor growth and angiogenesis in mice (Mitra et al 2006, Oncogene 25:5969-5984). Furthermore, loss of FAK catalytic activity (reconstitution of FAK-/- cells with kinase-dead FAK) reduced growth of v-Src tumors in mice and decreased angiogenesis.

Thus, there is strong evidence to suggest that inhibition of FAK activity induces, for example, apoptosis, loss of adhesion, inhibition of cell growth and migration, and that such inhibition reduces angiogenesis. Accordingly, compounds that inhibit FAK activity would be useful for the treatment of cancer.

Summary of the Invention In a first aspect, this invention relates compounds of formula (I) or a salt thereof

wherein:

R ¹ is H, R ⁵ -Y-N(R ⁶ )-; R ⁷ -N(R ⁶ )-Y-; R ⁷ -N(R ⁶ )- or -COOH; R ² is H or C ₁ -C ₆ -R ⁹ ; R ³ is H, or halo;

X is -NH-SO ₂ - or -SO ₂ -NH-; Y is -C(O)- or -S(O) ₂ -;

R ⁴ is phenyl-(R ⁸ ) _m , C ₅ -C ₆ -heteroaryl-(R ^u ) _p , or C _r C ₆ -alkyl-R ⁹ ; R ⁵ is phenyl-(R ⁸ ) _m , C _r C ₆ -alkyl-R ⁹ , C _r C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, C ₅ -C ₆ - heterocycloalkyl-(R ¹⁰ ) _n ; C ₅ -C ₆ -heteroaryl-(R ^u ) _p or -N(R ¹² ) ₂ ; R ⁶ is H or Ci-Cβ-alkyl;

R ⁷ is phenyl-(R ⁸ ) _m ; C _r C ₆ -alkyl-R ⁹ ; C ₃ -C ₆ -cycloalkyl, C ₅ -C ₆ -heterocycloalkyl-(R ¹⁰ ) _n , or C ₅ -C ₆ -heteroaryl-(R ^u ) _p , or R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, form a 5- to 6- membered heterocycloalkyl group; each R ⁸ is independently Ci-C ₆ -alkyl, Ci-C ₆ -alkoxy, cyano, dimethylamino, trifluoromethyl, fluoro, or chloro;

R ⁹ is H, Ci-C ₆ -alkoxy, -C(O)NH ₂ , -N(R ¹³ ) ₂ , hydroxy; R ¹⁰ is Ci-Cβ-alkyl; each R ¹¹ is independently H, Ci-C ₆ -alkyl each R ¹² is independently H or C _r C ₆ -alkyl, phenyl;

R ¹³ is H, Ci-C ₆ -alkyl, or together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl group; m is O, 1, or 2; n is 0 or 1 ; and p is 0, 1, or 2.

In a second aspect, this invention relates to compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

In yet another aspect, this invention relates to a method for treating proliferative diseases by inhibiting the Focal Adhesion Kinase (FAK) enzyme. In addition, it relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition which can be treated by inhibiting the activity of the FAK enzyme.

Furthermore, this invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.

Detailed description of the Invention As used herein, "halo" refers to fluoro, chloro, or bromo.

"Ci-C ₆ -alkyl" or "Ci-C ₆ -" refers to a linear or branched alkyl group including methyl, ethyl, w-propyl, isopropyl, n-butyl, isobutyl, ?-butyl, «-pentyl, and n-hexyl. "Ci-C ₆ -alkoxy" refers to Ci-C ₆ -alkyl-O- groups, including methoxy, ethoxy, n-propoxy, z ^' so-propoxy, and n-butoxy groups.

"C ₃ -C ₆ -cycloalkyl" refers to a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. As used herein, "5- or 6-membered heterocycloalkyl" refers to a 5- or 6-membered cycloaliphatic group that includes an O, N, or S heteroatom or a combination thereof. Examples of suitable heterocycloalkyl groups include pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholino, and thiomorpholino groups.

The R ⁸ groups may, together with the nitrogen atom to which they are attached, form a 5- to 6-membered cyclic ring, examples of which include pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, oxopiperazinyl, morpholino, and thiomorpholino groups. The term "heteroaryl" refers to a 5- or 6-membered aromatic group containing at least one N, O, or S atom. Examples of suitable heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, furazanyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, and isothiazolyl. As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication.

It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove. It is also to be understood that the present invention encompasses compounds in which a particular group or parameter, e.g. S(0)m, etc. may occur more than once. In such compounds it will be appreciated that each group or parameter is independently selected from the values listed. When any variable occurs more than one time in a formula, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical and veterinary usage. Salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.

The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19. Typically, a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Salts of the compounds of the present invention may, for example, comprise acid addition salts resulting from reaction of an acid with a nitrogen atom present in a compound of formula (I). Suitable addition salts are formed from acids which form non- toxic salts and examples are acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, ethanesulphonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, piruvate, polygalacturonate, saccharate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate and valerate.

Pharmaceutically acceptable base salts include ammonium salts such as a trimethylammonium salt, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula (I), or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water. A complex with water is known as a "hydrate". Solvates of the compound of the invention are within the scope of the invention.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. With regard to stereoisomers, the compounds herein may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

Cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compound of the invention and where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.

Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. A stereoisomeric mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

Furthermore, some of the crystalline forms of the compounds herein may exist as polymorphs, which are included in the present invention.

Exemplified compounds of the compounds of this invention include the racemates, or optically active forms of the compounds of the working examples herein, and pharmaceutically acceptable salts thereof.

Compounds of particular interest are those of formula (I)

wherein:

R ¹ is substituted on the 5 or 6 position, particularly at the 5 position.

As for the definition of R ¹ those of particular interest may be R ⁵ -Y-N(R ⁶ )-, R ⁷ -N(R ⁶ )-Y-, R ⁷ -N(R ⁶ )-, -COOH or H.

For R ² , groups of particular interest are propyl or isopropyl, or a group a Ci-C ₆ alkyl group, or Ci-C ₆ alkyl-R ⁹ or H.

In an R group, those of particular interest are H, F, or Cl.

As for X, the groups of particular interest are -NH-SO ₂ - or -SO ₂ -NH-.

In a Y group, the radicals of greater interest are -C(O)- and -S(O) ₂ -;

In a R ⁴ group those of particular interest are phenyl-(R ⁸ ) _m , C ₅ -C ₆ -heteroaryl-(R ^u ) _p , and Ci- C ₆ -alkyl-R ⁹ ;

As for R ⁵ , the groups C ₅ -C ₆ -heteroaryl-(R ^u ) _p , Ci-C ₆ -alkyl-R ⁹ , phenyl-(R ⁸ ) _m , C ₃ -C ₆ - cycloalkyl, Ci-C ₆ -alkoxy, C ₅ -C ₆ - heterocycloalkyl-(R ¹⁰ ) _n and -N(R ¹² ) ₂ are of interest.

For R ⁶ the methyl or H are of interest.

As regards R ⁷ , the groups Ci-Ce-alkyl-R ⁹ > C ₃ -C ₆ -cycloalkyl > C ₅ -C ₆ - heterocycloalkyl-(R ¹⁰ ) _n > phenyl-(R ⁸ ) _m ; or C ₅ -C ₆ -heteroaryl-(R ^u ) _p , are of interest; or those groups where R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, form a 5- to 6- membered heterocycloalkyl group.

And for R ⁸ the radicals of interest include H, F, Cl, Ci-C ₆ -alkyl, Ci-C ₆ -alkoxy, cyano, dimethylamino, or trifluoromethyl. The radicals set out in the immediate preceding paragraphs as being of interest, are given in descending order of interest.

METHODS OF TREATMENT In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent. Compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be a tablet, the active and, optionally, a carrier can be placed in a hard gelatin capsule in powder or pellet form, or the preparation may be in the form of a troche or lozenge.

The amount of solid carrier will vary widely but preferably will be from about 25mg to about Ig. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

Compounds of Formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.

For all methods of use disclosed herein for the compounds of Formula (I), the daily topical dosage regimen will preferably be from 0.01 mg to 1000 mg, administered one to four times daily. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents, or those for inhalation may include carriers, such as lactose. The compounds of the present invention are prepared according to the following schemes

1-5 described in detail below. The groups and substituents shown in the schemes 1-5, such as X, Y, and the various R groups have same definition in what follows as they have herein above. The solvents and conditions referred to are illustrative and are not intended to be limiting.

Schemes

Scheme 1

Scheme 1 illustrates methods for synthesizing compounds of formula (VI). Treatment of commercially available benzimidazole (I) with an alkyl bromide and potassium hyroxide, in a solvent mixture of tetrahydrofuran and ethanol with heating at 65° C for 72 h furnishes compounds of formula (II). Treatment of (II) with a compound of formula (III) (X = NH-Boc or SO ₂ Cl), which is commercially available or can be prepared by one skilled in the art, under standard amidation conditions followed by removal of the tert-butyl ester group using a strong acid such as hydrochloric acid furnishes a compound of formula (IV). A compound of formula (IV) wherein X = NH ₂ may also be prepared by treating benzimidazole (I) with a compound of formula (VII), which is commercially available or can be prepared by one skilled in the art, under standard amide coupling conditions to afford a compound of formula (VIII). Treatment of (VIII) with an alkyl bromide and potassium carbonate in a solvent mixure of N,N-dimethyl formamide, acetone, and water in a sealed flask at about 20° to 55° C for up to 24 h furnishes a compound of formula (IX). Reduction of the nitro group of (IX) using hydrogen gas (1 atm) and catalytic palladium on carbon in a solvent mixture of ethyl acetate, methanol, and water at 20° C for 2-3 h furnishes compound (IV). Compounds of fomula (VI) can be prepared from (IV) by one skilled in the art, using an appropriate amine or sulfonyl chloride reagent R ⁴ (V) under standard conditions.

Scheme 2

R6

H ₂ N. ,NO, R6 R6

PG -NO ₀ .N

PG -NO ₂

PG

^" NH HTVNH ₂

-N

(X) (Xl) R2 R2

(XII) (XlIl)

Scheme 2 illustrates a method of synthesizing compounds of formula (XVI) and (XVII).

Commercially available 3-nitro-4-fluoro-aniline (X) is protected with either tert-butoxycarbonyl anydride in tetrahydrofuran with heating at about 65° C for up to 48 h, or acetic anhydride (neat) at room temperature for about 3 h. The resultant product may be alkylated on the anilino nitrogen using iodomethane and sodium hydride, in a polar aprotic solvent such as N,N-dimethyl formamide, at a temperature between about 0° and 20° C for 3 h. Treatment of the anilino product (XI) either as its fully substituted (i.e. R ⁶ = methyl) or di-substituted form (R ⁶ = H) with an alkyl amine and base, typically potassium carbonate, in a polar aprotic solvent such as N,N-dimethyl formamide at a temperature between about 20° and 85° C for 3 - 24 h furnishes compound (XII). Reduction of the nitro group of (XII) using hydrogen gas (1 arm) and a catalytic amount of palladium on carbon in a polar solvent such as ethanol, at about 20° C for 3 - 24 h followed by treatment with cyanogen bromide at 20° C for 0.5 - 24 h furnishes a compound of formula (XIII). Treatment of (XIII) with (XIV), which can be prepared by one skilled in the art using commercially available starting materials, under standard amidation conditions affords the coupled product (XV). Removal of the tert-butyl ester group of (XV) can be accomplished using a strong acid, such as trifluoroacetic or hydrochloric acid, under standard conditions. Compounds of formula (XVI) and (XVII) can then be prepared from (XV) by one skilled in the art, using the appropriate reagents under standard reaction conditions.

Scheme 3

(XVIII) (XXJ)

Scheme 3 illustrates a method for synthesizing compounds of formula (XXI). Treatment of compound (XVIII) with a compound of formula (III) under standard amide coupling conditions followed by removal of the tert-butyl ester group using trifluoroacetic acid furnishes a compound of formula (XIX). Treatment of compound (XIX) with a sulfonyl chloride (XX) and base, preferably pyridine, in DCM at room temperature for 3-12 h furnishes a compound of formula (XXI). Scheme 4

) (XXV)

Scheme 4 illustrates a method for synthesizing compounds of formula (XXVII).

Commercially available N-(3-chlorophenyl)acetamide (XXII) is nitrated under standard conditions using nitric acid and sulfuric acid to afford a mixture of 2-nitro and 5-nitro compounds, which can be separated. The desired product N-(5-chloro-2-nitrophenyl)acetamide (XXIII) may be alkylated on the acetamide nitrogen using iodomethane and sodium hydride, in a polar aprotic solvent such as N,N-dimethyl formamide, at a temperature between about 0° and 20° C for 3 h. The acetamide product (XXIV) either as its fully substituted (i.e. R ⁶ = methyl) or di-substituted form (R ⁶ = H) is treated with an alkyl amine and base, typically potassium carbonate, in a polar aprotic solvent such as N-methyl-2-pyrrolidone at a temperature between about 50° and 70° C for about 18 - 24 h to afford (XXV). Reduction of the nitro group of (XXV) using hydrogen gas (1 arm) and catalytic palladium on carbon in a polar solvent such as ethanol at about 20° C for 24 h followed by treatment with cyanogen bromide at about 20° C for 0.5 - I h furnishes benzimidazole (XXVI). Treatment of (XXVI) with compounds of formula (XIV) using standard amidation conditions affords compounds of formula (XXVII).

Scheme 5

(XXVIII) (XXIX) (XXX) (XXXI)

(XXXII) Scheme 5 illustrates a method for synthesizing a compound of formula (XXXIII).

Commercially available 3-nitro-4-fluoro-benzoic acid and 3-fluoro-4-nitro-benzoic acid (XXVIII) are converted to their corresponding tert-butyl esters using tert-butyl 2,2,2-trichloroacetimidate and a catalytic amount of boron trifluoride diethyl etherate in ether at room temperature for 12 h. Treatment of either isomer of (XXIX) with an alkyl amine and potassium carbonate, in a polar aprotic solvent such as N,N-dimethyl formamide at about 20° C for 12 h affords a compound of formula (XXX). Reduction of the nitro group of (XXX) using hydrogen gas (45 psi) and catalytic palladium on carbon in a polar solvent such as ethanol at about 20° C for 1.5 h, followed by treatment with cyanogen bromide at about 20° C for 0.5 - I h furnishes benzimidazole (XXXI). Treatment of (XXXI) with compounds of formula (XIV) using standard amidation conditions affords a compound of formula (XXXII). Removal of the tert-butyl ester of (XXXII) can be accomplished using trifluoroacetic acid, under standard conditions. Compounds of formula

(XXXIII) can then be prepared by one skilled in the art using the appropriate reagents under the reaction conditions descibed herein.

Experimentals

General Experimental Methods

The following abbreviations are used throughout the experimental and have the following meaning: aq aqueous ca. circa

CDCl ₃ -(Z chloroform-<i

CD ₃ OD-(Z ₄ methanol-^

Cs ₂ CO ₃ cesium carbonate CHCl ₃ chloroform

CH ₃ CN acetonitrile

Celite® registered trademark of Celite Corp. brand of diatomaceous earth

DCE dichloroethane

DCM methylene chloride DME l,2 dimethoxyethane

DMF N,N-dimethyl formamide

DIEA diisopropyl ethylamine

DMSO- ⁽ Z ₆ dimethylsulfoxide-(5?6

EtOAc ethyl acetate EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodimmide hydrochloride h hours(s)

¹ H NMR proton nuclear magnetic resonance

HCl hydrochloric acid

HOAT l-hydroxy-7-azabenzotriazole HPLC high performance liquid chromatography

IPA 2-propanol

K ₂ CO ₃ potassium carbonate

KOH potassium hydroxide

LC/MS liquid chromatography/mass spectroscopy LDA lithium diisopropylamide

MgSθ ₄ magnesium sulfate

MeOH methanol min minute(s)

MTBE methyl tert-butyl ether MS mass spectrometry

NaOH sodium hydroxide

Na ₂ Sθ ₄ sodium sulfate

NH ₄ OH ammonium hydroxide

NMM 4-methylmorpholine NMP N-Methyl-2-pyrrolidone

Pd/C Palladium ( 10% by wt) on carbon

PyBop Benzotriazole- 1 -ly-oxy-tris-pyrrolidinophosphonium hexafluorphosphate

SOCl ₂ thionyl chloride

TBTU O-(lH-Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acd

THF tetrahydrofuran

TLC thin layer chromatography

The following guidelines apply to the experimental procedures described herein. All reactions were conducted under a positive pressure of nitrogen using oven-dried glassware, unless otherwise indicated. Temperatures designated are external (i.e. bath temperatures), and are approximate. Air and moisture-sensitive liquids were transferred via syringe. Reagents were used as received. Solvents utilized were those listed as "anhydrous" by vendors. Molarities listed for reagents in solutions are approximate, and were used without prior titration against a corresponding standard. All reactions were agitated by stir bar, unless otherwise indicated. Heating was conducted using heating baths containing silicon oil. Cooling to temperatures below - 70° C was conducted using dry ice/acetone or dry ice/2 -propanol. Magnesium sulfate and sodium sulfate used as drying agents were of anhydrous grade, and were used interchangeably. Solvents removed in vacuo were done so by rotary evaporation. Preparative normal phase silica gel chromatography was carried out using a Teledyne

ISCO CombiFlash Companion instrument with RediSep silica gel cartridges (4 g-330 g). Purification by reverse phase HPLC was conducted using YMC -pack column (ODS-A 75x30mm) as solid phase, and a mobile phase of 25mL/min A (acetonitrile-0.1%TFA) : B (water-0.1% TFA), 10-80% gradient A during lOmin. UV detection was conducted at 214 nM. A PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex, Thornhill, Ontario,

Canada) was operated using electrospray ionization in the positive ion detection mode. The nebulizing gas was generated from a zero air generator (Balston Inc., Haverhill, MA, USA) and delivered at 65 psi and the curtain gas was high purity nitrogen delivered from a Dewar liquid nitrogen vessel at 50 psi. The voltage applied to the electrospray needle was 4.8 kV. The orifice was set at 25 V and mass spectrometer was scanned at a rate of 0.5 scan/sec using a step mass of 0.2 amu and collecting profile data.

Method A LCMS. Samples were introduced into the mass spectrometer using a CTC PAL autosampler (LEAP Technologies, Carrboro, NC) equipped with a hamilton 10 uL syringe which performed the injection into a Valco 10-port injection valve. The HPLC pump was a Shimadzu LC-10ADvp (Shimadzu Scientific Instruments, Columbia, MD) operated at 0.3 mL/min and a linear gradient 4.5% A to 90% B in 3.2 min. with a 0.4 min. hold. The mobile phase was composed of 100% (H ₂ O 0.02% TFA) in vessel A and 100% (CH ₃ CN 0.018% TFA) in vessel B. The stationary phase is Aquasil (C 18) and the column dimensions were 1 mm x 40 mm. Detection was by UV at 214 nm, evaporative light-scattering (ELSD) and MS. Method B, LCMS. Alternatively, an Agilent 1100 analytical HPLC system with an

LC/MS was used and operated at 1 mL/min and a linear gradient 5% A to 100% B in 2.2 min with a 0.4 min hold. The mobile phase was composed of 100% (H ₂ O 0.02% TFA) in vessel A and 100% (CH ₃ CN 0.018% TFA) in vessel B. The stationary phase was Zobax (C8) with a 3.5 urn particle size and the column dimensions were 2.1 mm x 50 mm. Detection was by UV at 214 nm, evaporative light- scattering (ELSD) and MS.

Method C, LCMS. Alternatively, an MDSSCIEX API 2000 equipped with a capillary column of (50 x 4.6 mm, 5 μva) was used. HPLC was done on Agilent- 1200 series UPLC system equipped with column Zorbax SB-Cl 8 (50 x 4.6 mm, 1.8 μm) eluting with CH ₃ CN: ammonium acetate buffer. The reactions were performed in the microwave (CEM, Discover). ¹ H-NMR spectra were recorded at 400 MHz using a Bruker AVANCE 400 MHz instrument, with ACD Spect manager v. 10 used for reprocessing. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, , quint= quintet, sxt= sextet, m=multiplet, dd = doublet of doublets, dt=doublet of triplets etc. and br indicates a broad signal. Analytical HPLC: Products were analyzed by Agilent 1100 Analytical Chromatography system, with 4.5 x 75 mm Zorbax XDB-Cl 8 column (3.5 urn) at 2 mL/min with a 4 min gradient from 5% CH ₃ CN (0.1% formic acid) to 95% CH ₃ CN (0.1% formic acid) in H ₂ O (0.1% formic acid) and a 1 min hold.

The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The compounds were named using ACD Name software [Advanced Chemistry Development, Inc., (ACD/Labs), Toronto, Canada. (http://www.acdlabs.com/products/name lab/)].

Example 1 3-[(Phenylsulfonyl)amino]-N-(l-propyl-lH-benzimidazol-2-yl)b enzamide

1 a) 1 -Propyl- lH-benzimidazol-2-amine

lH-Benzimidazol-2-amine (3.9 g, 22.5 mmol) was dissolved in THF (30 mL) and ethanol

(15 mL) in a sealed flask followed by addition of finely ground KOH (1.52 g, 27.0 mmol). The mixture was stirred at room temperature for 20 min., and then 1 -bromopropane (2.77 g, 22.53 mmol) added. The reaction mixture was heated to 65° C for 72 h, and then allowed to cool to room temperature. The reaction mixture was filtered, and the filtrate concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 1% NH ₄ OH/9% MeOH/90% CHCl ₃ ) to afford the product as a yellow solid (2.5 g, 63%). LC-MS (ES) m/z = 176.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) 57.14 (s, IH), 7.10 (d, J = 8.0 Hz, IH), 6.86-6.92 (m, 2H), 6.38 (s, 2H), 3.90 (t, J = 6.9 Hz, 2H), 1.62-1.68 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). Ib) U-Dimethylethyl (3- {r(l-propyl-lH-benzimidazol-2 yl)aminolcarbonyl}phenyl)carbamate

1 -Propyl- lH-benzimidazol-2-amine (0.600 g, 3.42 mmol), 3-({[(l,l- dimethylethyl)oxy]carbonyl}amino)benzoic acid (0.894 g, 3.77 mmol), EDC (0.722 g, 3.77 mmol), and ΗOAT (0.513 g, 3.77 mmol) were suspended in DMF (10 mL), followed by addition of NMM (0.414 mL, 3.77 mmol). After stirring at room temperature for 72 h, the contents were concentrated in vacuo and the crude product purified by reverse phase ΗPLC (used non-TFA containing mobile phase). The product was collected as a white solid (0.791 g, 59%). LC-MS (ES) m/z = 395.0 (M+Η) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.71 (s, IH), 9.46 (s, IH), 8.36 (s, IH), 7.83 (d, J = 7.6 Hz, IH), 7.62 (d, J = 7.6 Hz, IH), 7.51-7.54 (m, 2H), 7.33-7.35 (m, IH), 7.21- 7.25 (m, 2H), 4.23 (t, J = 6.9 Hz, 2H), 1.92-1.95 (m, 2H), 1.50 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H).

Ic) 3-Amino-N-(l -propyl- lH-benzimidazol-2-yl)benzamide-bis hydrochloride

1,1 -Dimethylethyl(3- { [(I -propyl- 1 H-benzimidazol-2- yl)amino]carbonyl}phenyl)carbamate (0.791 g, 2.0 mmol) was dissolved in DCM (10 mL) and MeOH (3 mL) followed by addition of 2M HCl in ether (8 mL). The mixture was stirred at room temperature for 16 h, after which time the heteogenous contents were filtered and dried in vacuo. The product was collected as an off-white solid (0.725g, 98%). LC-MS (ES) m/z = 294.7 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.5-13.5 (br s, IH), 10.0-11.0 (br s, 2H), 8.22 (s, 2H),

7.52-7.63 (m, 4H), 7.25-7.32 (m, 2H), 4.27 (t, J = 6.9 Hz, 2H), 1.82-1.88 (m, 2H), 0.927 (t, J = 7.3 Hz, 3H).

Id) 3-Amino-N-(l-propyl-lH-benzimidazol-2-yl)benzamide (150 mg. 0.408 mmol) was dissolved in DCM (7 mL) followed by addition of benzenesulfonyl chloride (0.20 mL, 0.408 mmol) and triethylamine (0.200 mL, 1.43 mmol) which was added dropwise at 0 ⁰ C. The contents were stirred with warming to room temperature over a 16 h period, after which time the reaction mixture was quenched with water (2 mL). The organic layer was concentrated down and purified by reverse phase HPLC to afford the final product, the title compound, as a white solid (0.177 g, 46%). LC-MS (ES) m/z = 435.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.72 (s, IH), 10.44 (s, IH), 8.06 (s, IH), 7.86 (d, J = 7.6 Hz, IH), 7.79 (d, J = 7.6 Hz, 2H), 7.52-7.63 (m, 5H), 7.20-7.24 (m, 4H), 4.20 (t, J = 6.9 Hz, 2H), 1.80-1.86 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

Example 2

3-{[(3-Chlorophenyl)sulfonyl]amino}-N-(l-propyl-lH-benzim idazol-2-yl)benzamide

The title compound was prepared from 3-amino-N-(l-propyl-lΗ-benzimidazol-2- yl)benzamide (0.080 g, 0.22 mmol), 3-chloro-benzenesulfonyl chloride (0.046 mL, 0.22 mmol) and triethylamine (0.106 mL, 0.762 mmol) substantially according to the procedure of Example 1 step d. The product was collected as an off-white solid (0.056 g, 55%). LC-MS (ES) m/z = 470.2/471.2 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.73 (s, IH), 10.55 (s, IH), 8.05 (s, IH), 7.91 (d, J = 7.8 Hz, IH), 7.80 (t, J = 1.9 Hz, IH), 7.72 (dt, J = 2.0, 8.1 Hz, 2H), 7.60 (t, J = 8.0 Hz, IH), 7.53 (dt, J = 1.7, 7.5 Hz, 2H), 7.36 (t, J = 7.8 Hz, IH), 7.18 - 7.29 (m, 3H), 4.22 (t, J = 6.8 Hz, 2H), 1.84 (d, J = 7.1 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H).

Example 3

Methyl 3- {2-[( {3-[(phenylsulfonyl)amino]phenyl}carbonyl)amino]- lH-benzimidazol- 1 - yljpropanoate

3a) N-lH-benzimidazol-2-yl-3-nitrobenzamide

N-lΗ-2-amino-benzimidazole (3.0 g, 22.5 mmol,), 3-nitro-benzoic acid (4.14 g, 24.8 mmol g), EDC (4.75 g, 24.8 mmol), HOAT (3.37 g, 24.78 mmol) and NMM (5.45 mL, 49.6 mmol) were suspended in DMF (80 mL) and stirred at room temperature, overight. The mixture was quenched with 200 mL aq. NaHCθ3, filtered, and the filtered solid washed with water. The product was collected as a yellow solid (5.27 g, 83%). LC-MS (ES) m/z = 283.1 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.2-12.9 (br s, 2H), 8.97 (s, IH), 8.54 (d, J = 7.6 Hz, IH), 8.37 (d, J = 7.6 Hz, IH), 7.77-7.81 (m, IH), 7.42-7.46 (m, 2H), 7.17-7.21 (m, 2H). 3b) Methyl 3 -(2- { [(3 -nitrophenvDcarbonyll amino } - lH-benzimidazol- 1 -vDpropanoate

To a sealed flask containing a stir bar was dissolved N- lΗ-benzimidazol-2-yl-3- nitrobenzamide (0.500 g, 1.77 mmol) in acetone (10 mL), DMF (2 mL) and water (0.2 mL). Next , added sequentially, were K ₂ CO ₃ (490 mg, 3.54 mmol) and methyl 3-bromopropanoate (0.296 g, 1.77 mmol). The reaction mixture was stirred at room temperature for 16 h, followed by heating at 55 ⁰ C for 24 h. After cooling to room temperature, the reaction mixture was concentrated to near dryness and then suspended in water (5 mL). The contents were extracted with 10% THF in EtOAc (3x). The combined organic extracts were washed with brine (10 mL), dried over Na ₂ SOz _I , filtered, and the solvent removed under vacuo. The residue was triturated with EtOAc and filtered to afford the product as a yellow solid (0.40 g, 61%). LC-MS (ES) m/z =

368.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.87 (s, IH), 8.94 (s, IH), 8.63 (d, J = 7.6 Hz, IH), 8.35 (d, J = 7.6 Hz, IH), 7.79-7.82 (m, IH), 7.55-7.58 (m, 2H), 7.23-7.29 (m, 2H), 4.50 (t, J = 6.9 Hz, 2H), 3.51 (s, 3H), 2.93-2.96 (m, 2H). 3c) Methyl 3 -(2- { \(3 -aminophenyDcarbonyll amino } - lH-benzimidazol- 1 - vDpropanoate

A solution of methyl 3-(2-{[(3-nitrophenyl)carbonyl]amino}-lH-benzimidazol-l- yl)propanoate (0.400 g, 1.08 mmol) in EtOAc (60 mL), MeOH (20 mL) and THF (12 mL) was purged with N ₂ for 5 min, followed by addition of 10% Pd/C (120 mg). The system was purged with N ₂ for another 5 min, and then stirred under an atmosphere of hydrogen (1 atm) for 2.5 h. The system was purged with N ₂ for 10 min, and the heterogenous contents then filtered through a thin pad of Celite. The filtrate was concentrated to dryness and the crude product purified by reverse phase HPLC. The product was collected as an off-white solid (0.193, 53%). LC-MS (ES) m/z = 338.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.6-12.75 (br s, IH), 7.50-7.52 (m, 2H), 7.44 (br s, 2H), 7.18-7.26 (m, 2H), 7.08-7.11 (m, IH), 6.68-6.71 (m, IH), 5.15 (br s, 2H), 4.45 (t, J = 6.9 Hz, 2H), 3.52 (s, 3H), 2.89 (t, J = 6.9 Hz, 2H).

3d) The title compound was prepared from methyl 3-(2- {[(3- aminophenyl)carbonyl] amino} - lH-benzimidazol- 1 -yl)propanoate (0.190 g, 0.562 mmol), benzenesulfonyl chloride (0.099 g, 0.562 mmol) and pyridine (0.114 mL, 1.40 mmol) substantially according to the procedure of Example 1 , step d, wherein the reaction stir time was 3 h. The final product was collected as a white solid (0.203 g, 76%). LC-MS (ES) m/z = 478.7 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.71 (s, IH), 10.45 (s, IH), 8.01 (s, IH), 7.88 (d, J = 7.6 Hz, IH), 7.78 - 7.83 (m, 2H), 7.48 - 7.64 (m, 5H), 7.29 - 7.35 (m, IH), 7.19 - 7.29 (m, 3H), 4.47 (t, J = 6.8 Hz, 2H), 3.51 (s, 3H), 2.93 (t, J = 6.7 Hz, 2H).

Example 4

N-[l-(5-Amino-5-oxopentyl)-lH-benzimidazol-2-yl]-3[(pheny lsulfonyl)amino]benzamide

4a) Methyl 5-(2- {r(3-nitrophenyl)carbonyl1ammo} - lH-benzimidazol- 1 -vDpentanoate

The product was prepared from N-lΗ-benzimidazol-2-yl-3-nitrobenzamide (0.750 g, 2.62 mmol), acetone (15 mL), DMF (3 mL) water (0.3 mL) K ₂ CO ₃ (0.734 g, 5.31 mmol), and methyl 5-bromopentanoate (0.570 g, 2.92 mmol) substantially according to the procedure of example 3, step b. The product was collected as a yellow solid (0.856 g, 81%). LC-MS (ES) m/z = 396.6 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.87 (s, IH), 8.95 (s, IH), 8.64 (d, J = 8.0 Hz, IH), 8.35 (d, J = 8.0 Hz, IH), 7.78-7.81 (m, IH), 7.57-7.59 (m, 2H), 7.25-7.31 (m, 2H), 4.31 (t, J = 6.9 Hz, 2H), 3.49 (s, 3H), 2.40 (t, J = 6.9 Hz, 2H), 1.82-1.89 (m, 2H), 1.56-1.63 (m, 2H). 4b) Methyl 5-(2-{r(3-ammophenyl)carbonyl1ammo}-lH-benzimidazol-l- yPpentanoate

The product was prepared from methyl 5-(2-{[(3-nitrophenyl)carbonyl]amino}-lH- benzimidazol-l-yl)pentanoate (0.850 g, 2.14 mmol), Pd/C (0.17Og, 10%) and hydrogen gas (1 arm) substantially according to the procedure of example 3, step c, wherein the contents were stirred under at atmosphere of hydrogen for 4 h. The product was collected as a white solid (0.447 g, 57%). LC-MS (ES) m/z = 366.7 (M+Η) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.68 (s, IH), 7.44-7.53 (m, 4H), 7.20-7.24 (m, 2H), 7.07-7.11 (m, IH), 6.68 (dd, J = 7.6, 1.6 Hz, IH), 5.14 (s, 2H), 4.24 (t, J = 6.9 Hz, 2H), 3.52 (s, 3H), 2.38 (t, J = 7.2 Hz, 2H), 1.81-1.85 (m, 2H), 1.57-1.61 (m, 2H). 4c) Methyl 5-{2-r({3-r(phenylsulfonyl)amino1phenyl}carbonyl)ammo ^" |-lH- benzimidazol- 1 -yljpentanoate

Methyl 5-(2- {[(3-aminophenyl)carbonyl]amino} - lH-benzimidazol- 1 -yl)pentanoate (0.445 g, 1.21 mmol), and pyridine (0.246 mL, 3.04 mmol) were stirred in DCM (5 mL) at 0 ⁰ C, followed by dropwise addition of benzenesulfonyl chloride (0.215 g, 1.21 mmol). The contents were stirred with warming to room temperature over a 3 h period. The reaction mixture was concentrated in vacuo, and suspended in water (5 mL) and EtOAc (10 mL). The contents were filtered, and the filtered solid washed with water. The product was collected as a pink solid (0.429 g, 70%). LC- MS (ES) m/z = 507.1 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.72 (s, IH), 10.43 (s, IH), 8.04 (s, IH), 7.88 (d, J = 8.0 Hz, IH), 7.80 (d, J = 8.0 Hz, 2H), 7.51-7.61 (m, 5H), 7.21-7.33 (m, 4H), 4.24 (t, J = 6.9 Hz, 2H), 3.49 (s, 3H), 2.38 (t, J = 7.2 Hz, 2H), 1.80-1.84 (m, 2H), 1.56-1.60 (m, 2H).

4d) 5- {2-IY {3-r(Phenylsulfonyl)aminolphenyl}carbonyl)aminol- lH-benzimidazol- 1 - yljpentanoic acid

Methyl 5-{2-[({3-[(phenylsulfonyl)amino]phenyl}carbonyl)amino]-lΗ- benzimidazol-l- yljpentanoate (379 mg, 0.748 mmol) was dissolved in MeOH (6 mL) followed by addition of 2N NaOH (1.870 ml, 3.74 mmol). The reaction mixture was stirred at room temperature for 5 h, after which time the mixture was concenctrated to dryness. The residue was suspended in water (5 mL), and adjusted the pH 1 -2 using 2N HCl. The heterogenous contents were filtered, washed with water, and dried in vacuo. The product was collected as a white solid (0.325 g, 88%). LC-MS (ES) m/z = 493.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δl2.72 (s, IH), 12.01 (s, IH), 10.43 (s, IH), 8.03 (s, IH), 7.88 (d, J = 8.0 Hz, IH), 7.80 (d, J = 8.0 Hz, 2H), 7.51-7.61 (m, 5H), 7.21- 7.31 (m, 4H), 4.24 (t, J = 6.9 Hz, 2H), 2.27 (t, J = 7.2 Hz, 2H), 1.82-1.86 (m, 2H), 1.52-1.58 (m, 2H).

4e) A mixture of 5- {2-[({3-[(phenylsulfonyl)amino]phenyl}carbonyl)amino]- IH- benzimidazol-l-yl}pentanoic acid (0.075 g, 0.152 mmol) and SOCl ₂ (3.0 mL, 41.1 mmol) was heated at 50 ⁰ C for 2 h, after which time the mixture was concentrated down to dryness under vacuo. The crude residue was suspended in DCM (5 mL), followed by addition OfNH ₃ in MeOH (2N, 1.0 mL) and stirred for 5 min. The reaction mixture was concentrated down to dryness and the crude product purified by reverse phase HPLC (used non-TFA mobile phase) to afford the final product, the title compound, as a white solid (0.029 g, 39%). LC-MS (ES) m/z = 492.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.72 (s, IH), 10.44 (s, IH), 8.00 - 8.06 (m, IH), 7.89 (d, J = 7.8 Hz, IH), 7.70 - 7.85 (m, 2H), 7.53 - 7.70 (m, 3H), 7.48 - 7.53 (m, 2H), 7.29 - 7.36 (m, IH), 7.18 - 7.29 (m, 4H), 6.72 (br. s., IH), 4.24 (t, J = 6.8 Hz, 2H), 2.05 - 2.15 (m, 2H), 1.78 (d, J = 7.8 Hz, 2H), 1.48 - 1.62 (m, 2H).

Example 5

N- [ 1 -(3 -Hydroxypropyl)- lH-benzimidazol-2-yl] -3 - [(phenylsulfonyl)amino]benzamide

5a) 3-|Y2-Nitrophenyl)amino ^" |- 1 -propanol

1 -Fluoro-2-nitrobenzene (1.00 g, 7.09 mmol) and K ₂ CO ₃ (1.96 g, 14.2 mmol) were stirred in DMF (5 mL), followed by addition of amino- 1 -propanol (0.81 mL, 10.6 mmol). After stirring at room temperature for 5 h, the mixture was partioned between EtOAc and diute HCl. The organic extract was washed with brine, dried over MgSO ₄ , and filtered. The filtrate was concentrated in vacuo, and the product collected as a yellow solid (1.26 g, 91%). LC-MS (ES) m/z = 196.7 (M + H) ^{+ 1} H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.10 (d, J = 8.0 Hz, IH), 7.49-7.51 (m, IH), 7.04 (d, J = 8.0 Hz, IH), 6.65-6.67 (m, IH), 3.72-3.75 (m, 2H), 3.49-3.51 (m, 2H), 1.91-1.97 (m, 2H). 5b) 3-(2 -Amino- lH-benzimidazol- 1 -yl)- 1 -propanol

A mixture of 3 -[(2-nitrophenyl)amino]-l -propanol (1.20 g, 6.12 mmol) in ethanol (30 mL) was purged with argon, then Pd/C (0.15 g, 1.41 mmol) was added. The mixture was stirred under an atmosphere of hydrogen (1 atm) for 18 h, after which time a completed reaction was observed by LC/MS analysis. The mixture filtered through a thin pad of Celite. The filtrate was stirred with cyanogen bromide (0.70 g, 6.60 mmol) for 1 h. The reaction mixture was concentrated under reduced pressure and the residue dissolved in 100 mL EtOAc, and then washed with IN NaOH (25 mL). The organic layer was washed with water, brine, and then dried over MgSOφ After filtration and solvent removal, the residue was triturated from chloroform to give the product as a colored solid (0.77 g, 66% overall). LC-MS (ES) m/z = 191.9 (M + H) ⁺

5c) 3-(2-Amino-lH-benzimidazol-l-yl)-l -propanol (0.150 g, 0.78 mmol), 3- [(phenylsulfonyl)amino]benzoic acid (0.326 g, 1.18 mmol), EDC (0.226 g, 1.18 mmol), HO AT (0.160 g, 1.18 mmol) and NMM (0.129 mL, 1.18 mmol) were suspended in DMF (5 mL) and stirred at room temperature for 18 h. Methanol (10 mL) and IN NaOH (5 mL) were added and the resulting mixture stirred for 1 h at room temperature. The mixture was concentrated in vacuo. The crude product was purified first by reverse phase HPLC, and then triturated from EtOAc. The final product, the title compound, was collected as a nearly white solid (0.046 g, 13%). LC-MS (ES) m/z = 450.7 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.64-12.89 (br s, IH), 10.45 (s, IH), 8.01 (s, IH), 7.89 (d, J = 8.0 Hz, IH), 7.80 (d, J = 8.0 Hz, 2H), 7.49-7.66 (m, 5H), 7.19- 7.37 (m, 4H), 4.28 (t, J = 6.9 Hz, 2H), 3.46 (t, J = 6.5 Hz, 2H), 1.92-1.99 (m, 2H) (Note: -OH signal not observed).

Example 6 3 - [(Cyc lopropylamino)sulfonyl] -N-(I -propyl- lH-benzimidazol-2-yl)benzamide

1 -Propyl- lΗ-benzimidazol-2-amine (0.150 g, 0.856 mmol) was dissolved in DCM (5 mL). Then 3-(chlorosulfonyl)benzoyl chloride (205 mg, 0.856 mmol) in DCM (1 mL) and triethylamine (0.131 mL, 0.942 mmol) were added sequentially via syringe, and the mixture was stirred at room temperature for 5 h. Cyclopropylamine (147 mg, 2.57 mmol) was added, and mixture stirred at room temperature for 12 h. The reaction mixture was then diluted with water (3 mL), and the layers separated. The organic layer was concentrated in vacuo and the crude residue was purified by reverse phase HPLC (non-TFA mobile phase used) to afford the final product, the title compound, as a white solid (0.081 g, 32%). LC-MS (ES) m/z = 398.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.80 (s, IH), 8.68 (s, IH), 8.48 (d, J = 8.0 Hz, IH), 8.04 (br s, IH), 7.94 (d, J = 8.0 Hz, IH), 7.71-7.75 (m, IH), 7.56 (d, J = 8.0 Hz, 2H), 7.25-7.29 (m, 2H), 4.26 (t, J = 6.9 Hz, 2H), 2.11-2.18 (m, IH), 1.83-1.88 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.49-0.53 (m, 2H), 0.40- 0.45 (m, 2H).

Example 7

N-(5-Amino- 1 -propyl- lH-benzimidazol-2-yl)-3-[(phenylsulfonyl)amino]benzamide

7a) 1.1 -Dimethylethyl (4-fluoro-3-nitrophenyl)carbamate.

4-Fluoro-3-nitroaniline (7.49 g, 48.0 mmol) was dissolved in 240 mL dry THF. Di-tert butyl-dicarbonate (12.6 g, 57.6 mmol) was added as a 60 mL THF solution over a 30 min period via addition funnel, and the stirring mixture then heated at reflux. Additional di-tert butyl- dicarbonate was respectively added in two portions after 18 h (3.1 g in 9 mL THF) and 24 h reflux (2.2 g in 5 mL THF), as THF solutions via syringe. After a total of 48 h at reflux, the contents were removed from heating and allowed to stir with cooling to room temperature. The mixture was concentrated in vacuo to a thick, nearly black oil. The crude mixture was suspended in 10 mL EtOAc, and purified by silica gel chromatography (eluent: 0 to 15% EtOAc in hexanes). The isolated product was dried on hi-vac for 16 h, and was collected as a fluffy, off-white solid (11.4 g, 93%). LC-MS (ES) m/z (-t-butyl) = 200.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.9 (s, IH), 8.36 (s, IH), 7.74 (d, J = 8.0 Hz, IH), 7.49-7.54 (m, IH), 1.49 (s, 9H). 7b) 1 , 1 -Dimethylethyl r3-nitro-4-(propylamino)phenyllcarbamate.

1 , 1 -Dimethylethyl (4-fluoro-3-nitrophenyl)carbamate (2.82 g, 11.0 mmol) was dissolved in 15 mL dry DMF, and the stirring solution cooled in an ice bath. Potassium carbonate (3.08 g, 22.0 mmol) was added, followed by n-propylamine (1.0 mL, 12.1 mmol). The suspension was stirred with warming to room temperature. After stirring 20 h, additional potassium carbonate (3.08 g, 22.0 mmol), n-propylamine (1.0 mL, 12.1 mmol) and 2 mL DMF were added, and the mixture heated to 70 ⁰ C. After 4 h, the dark red colored contents were removed from heating, and stirred with cooling to room temperature over a 16 h period. Additional potassium carbonate (1.54 g, 11.0 mmol), n-propylamine (1.0 mL, 12.1 mmol) and 10 mL DMF were added, and the mixture then heated to 85°C for 3 h. After cooling to room temperature over a 3 d period, the reaction mixture was poured onto 100 mL ice-water (1 :1), and vigorously stirred for 10 min. The heterogenous contents were filtered to give a sticky maroon colored solid, and a filtrate of the same color. The filtrate was extracted with EtOAc (3 x 100 mL), and the combined organic layers added to the previously filtered solid. The contents were stirred for 20 min, and then washed with brine (100 mL). The organic layer was dried over MgSO ₄ , filtered, and concentrated in vacuo to a thick dark red oil. The crude oil was purified by silica gel chromatography (eluent: 0 to 10% EtOAc in hexanes) with good separation. The product was collected as a fluffy, light orange solid (2.05 g, 63%). LC-MS (ES) m/z = 295.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.29- 9.40 (br. s, IH), 8.32 (s, IH), 8.03 (s, IH), 7.52 (d, J = 8.0 Hz, IH), 7.024 (m, IH), 3.27 (t, J = 6.9 Hz, 2H), 1.60-1.66 (m, 2H), 1.47 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H)

7c) 1.1 -Dimethylethyl r3-amino-4-(propylamino)phenyllcarbamate

1 , 1 -Dimethylethyl [3-nitro-4-(propylamino)phenyl]carbamate (0.295 g, 1.0 mmol) and Pd/C (10 wt%, 0.027 g, 0.025 mmol) were dissolved in 30 mL EtOH under a blanket of argon.

The contents were then stirred under an atmosphere of hydrogen (1 atm) at room temperature for 3 h, after which time a complete reaction as indicated by LC/MS analysis was observed. The contents were purged with argon, and the nearly black suspension then filtered through a thin pad of Celite. The pad was washed with an additional 5 mL EtOH, and the combined filtrates concentrated in vacuo to a dark oil which solidified on hi-vac drying. The product was collected as a grayish colored solid (264 mg, 99%) which was used without further purification. LC-MS (ES) m/z = 265.8 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.52-8.73 (br. s, IH), 6.68- 6.81 (br s, IH), 6.47 (s, IH), 6.26 (d, J = 8.0 Hz, IH), 4.49 (s, 2H), 4.05 (s, IH), 2.88-2.95 (m, 2H), 1.54-1.62(m, 2H), 1.43 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H). 7d) 1.1 -Dimethylethyl (2-amino- 1 -propyl- lH-benzimidazol-5-yl)carbamate

1 , 1 -Dimethylethyl [3-amino-4-(propylamino)phenyl]carbamate (0.94 g, 3.54 mmol) was dissolved in 15 mL MeOH, followed by addition of cyanogen bromide (0.56 g, 5.31 mmol). After stirring at room temperature for 45 min, the contents were concentrated in vacuo to an oil. The crude oil was diluted with water (20 mL), and treated with IN NaOH (0.25 mL) to furnish a pΗ 7 solution. The contents were extracted with EtOAc (5 x 20 mL). The combined organic layers were dried over MgSO/t, and filtered. The contents were concentrated in vacuo to a reddish colored solid. The solid was concentrated from CΗCI3 (3 x 20 mL) to remove resdual EtOAc. The contents were dried under hi-vac and obtained as a dark red solid (0.96 g, 93%). LC-MS (ES) m/z = 290.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.40 (s, IH), 8.17-8.50 (br s, 2H), 7.63 (s, IH), 7.33 (d, J = 8.0 Hz, IH), 7.18-7.24 (m, IH), 4.00-4.06 (m, 2H), 1.65-1.73 (m, 2H), 1.48 (s, 9H), 0.89 (t, J = 7.3 Hz, 3H).

7e) 3-r(Phenylsulfonyl)aminolbenzoic acid

Step 1 : Methyl 3-aminobenzoate (10 g, 66.2 mmol) was dissolved in pyridine (100 mL) and cooled in an ice bath for 15 min. Benzenesulfonyl chloride (8.53 ml, 66.2 mmol) was added via syringe over 5 min, and the solution then stirred with warming to room temperature over a 16 h period. The reaction mixture was poured onto ice and IM HCl (250 mL total volume) to afford a heterogenous acidic mixture (pH 2-3). The solid was filtered and washed with water. The collected solid was dried under hi-vacuum for 12 h to afford the coupled product (19.3, 100%) as an off-white solid.

Step 2: The solid product from step 1 was added to THF (100 mL), and stirred for 15 min. NaOH (110 mL, 331 mmol) was added slowly via an addition funnel and the reaction mixture stirred at room temperature for 16 h. The contents were gently heated at 45°C for 30 min, and the volatiles then removed in vacuo. The crude residue was diluted with water and acidfied to pH 3-4 using IM HCl. The heterogenous contents were allowed to stand at room temperature for 15 min , and then filtered. The filtered solid was further washed with water, and then dried under hi- vacuum for 20 h. The product was collected as an off- white solid (17.5 g, 95% overall) that was used without further purification. LC-MS (ES) m/z = 277.7 (M+H) ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.04 (br. s., IH), 10.53 (br. s., 1 H), 7.72 - 7.83 (m, 2 H), 7.69 (s, 1 H), 7.50 - 7.65 (m, 4 H), 7.30 - 7.41 (m, 2 H).

7f) 1.1 -Dimethylethyl {2-\( (3- |Yphenylsulfonyl)amino ^" |phenyU carbonyl)amino ^" |- 1 - propyl- lH-benzimidazol-5-yU carbamate

1 , 1 -Dimethylethyl (2-amino-l -propyl- lΗ-benzimidazol-5-yl)carbamate (1.24 g, 4.27 mmol) was dissolved in 15 mL dry DMF, followed by sequential addition of 3- [(phenylsulfonyl)amino]benzoic acid (1.42 g, 5.12 mmol), EDC (0.982 g, 5.12 mmol), and HOAT (0.697 g, 5.12 mmol). NMM (0.563 mL, 5.12 mmol) was added dropwise via syringe, and the contents were stirred at room temperature. After 18 h, the contents were diluted with water (75 mL), and stirred for 5 min. The contents were vacuum filtered to furnish a red colored solid, which was washed with an additional 25 mL of water. The collected solid was triturated from MeOH (20 mL) to afford the product as an off-white solid (1.35 g, 58%). LC-MS (ES) m/z = 449.8 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.60 (s, IH), 10.36-10.49 (br. s., 1 H), 9.30-9.47 (br. s, IH), 8.03 (s, IH), 7.75-7.89 (m, 4H), 7.52-7.62 (m, 3H), 7.19-7.43 (m, 4H), 4.12 (t, J = 6.9 Hz, 2H), 1.75-1.86 (m, 2H), 1.49 (s, 9H), 0.86 (t, J = 7.3 Hz, 3H).

7g) 1 , 1 -Dimethylethyl {2- [( {3 - [(phenylsulfonyl)amino]phenyl} carbonyl)amino] - 1 -propyl- lH-benzimidazol-5-yl} carbamate (1.35 g, 2.46 mmol) was dissolved in 16 mL DCM, followed by dropwise addition of trifluoroacetic acid (4 mL, 51.9 mmol). The contents were stirred at room temperature for 75 min, after which time the reaction mixture was concentrated in vacuo. The crude residue was suspended in EtOAc (20 mL), and carefully neutralized with 20 mL sat. NaΗCθ3. The contents were filtered to furnish a light yellow solid which was set aside. The organic layer was dried over MgSOzt, filtered, and concentrated in vacuo to a dark yellowish- brown solid. This solid residue was triturated from EtOAc (7 mL) at 60 ⁰ C to afford additional product as a light yellow solid. The collected solids were combined, concentrated from CHCI3 (3 x 10 mL), and dried in vacuum oven at 40 ⁰ C. The final product, the title compound, was collected as a light yellow solid (1.10 g, 100%). LC-MS (ES) m/z = 449.8 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.22-12.54 (br s, IH), 10.30-10.50 (br s, IH), 7.87 (s, IH), 7.78 (d, J = 8.0 Hz, 2H), 7.67-7.75 (m, IH), 7.43-7.58 (m, 3H), 7.06-7.26 (m, 3H), 6.70 (s, IH), 6.47 (d, J = 4 Hz, IH), 5.04 (s, 2H), 4.05 (t, J = 6.9 Hz, 2H), 1.72-1.83 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H)

Example 8

N-[5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl]-3-k [(phenylsulfonyl)amino]benzamide

8a) 1.1 -Dimethylethyl (4-fluoro-3-nitrophenyl)methylcarbamate.

1 , 1 -Dimethylethyl (4-fluoro-3-nitrophenyl)carbamate (3.69 g, 14.4 mmol) was dissolved in 30 mL dry DMF, and the stirred solution cooled in an ice bath. Sodium hydride (60% in hexanes, 0.69 g, 17.3 mol) was added in portions over a 5 min period, and the suspension stirred at ambient temperature for 1 h. Iodomethane (1.35 mL, 21.6 mmol) was added dropwise via syringe, and the contents were removed from ice bath and stirred with warming to room temperature. After 2 h, the stirring contents were diluted with 100 mL water, and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated in vacuo to a yellow oil. The crude oil was purified by silica gel chromatography (eluent: 0 to 20% EtOAc in hexanes) with good separation. The product was dried on hi-vac for 8 h, and collected as a yellow amber colored oil (3.24 g, 82%). LC-MS (ES) m/z = 214.8 (M+Η) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.10 (s, IH), 7.74-7.78 (br. s., IH), 7.55-7.60 (m, IH), 3.23 (s, 3H), 1.42 (s, 9H). 8b) 1.1 -Dimethylethyl methvir3-nitro-4-(propylamino)phenyllcarbamate

l,l-Dimethylethyl-(4-fluoro-3-nitrophenyl)methylcarbamate (3.24 g, 11.9 mmol) was dissolved in 40 mL dry DMF, followed by addition Of K ₂ CO ₃ (4.99 g, 35.6 mol) and n- propylamine (1.46 mL, 17.8 mmol). After stirring at room temperature for 14 h, the contents were poured onto ice-water (100 mL) and vigorously stirred. The heterogenous reaction mixture was vacuum filtered to afford a 1 ^st crop of solid product. The filtrate was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated in vacuo to a dark orange-red oil which gradually solidified on vacuum drying, affording a 2 ^nd crop of product. The solid product crops were combined, and dried in vacuum oven at 40 ⁰ C. The product was collected as a bright orange-yellow solid (3.46 g, 94%). LC-MS (ES) m/z = 310.3 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.15 (s, IH), 7.91 (s, IH), 7.48 (d, J = 8.0 Hz, IH), 7.03 (d, J = 8.0 Hz, IH), 3.30-3.36 (m, 2H), 3.14 (s, 3H), 1.61-1.67 (m, 2H), 1.39 (s, 9H), 0.95 (t, J = 7.3 Hz, 3H).

8c) 1.1 -Dimethylethyl- [3 -amino-4-(propylamino)phenvHmethylcarbamate

The product was prepared from 1 , 1 -dimethylethylmethyl[3-nitro-4-

(propylamino)phenyl]carbamate (3.82 g, 12.4 mmol), Pd/C (10 wt%, 0.329 g), and hydrogen gas (1 atm), substantially according to the procedure of example 7 step c, wherein the reaction stir time was 4.5 h. The product was collected as a flaky gray colored solid (3.39 g, 98%). LC-MS (ES) m/z = 280.0 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.42 (s, IH), 6.32 (s, IH), 4.54.64 (m, 2H), 4.30-4.36 (m, IH), 3.04 (s, 3H), 2.93-2.99 (m, 2H), 1.55-1.64 (m, 2H), 1.36 (s, 9H), 0.96 (t, J = 7.9 Hz, 3H).

8d) 1 , 1 -Dimethylethyl (2-amino- 1 -propyl- lH-benzimidazol-5-yl)methylcarbamate

1 , 1 -Dimethylethyl [3-amino-4-(propylamino)phenyl]methylcarbamate (3.35 g, 12 mmol) was dissolved in MeoΗ (75 mL), followed by addition of cyanogen bromide (1.91 g, 18.0 mmol). After stirring at room temperature for 45 min, the contents were concentrated in vacuo to an oil. The crude oil was diluted with water (100 mL), and treated with IN NaOH until a pΗ~7 solution was obtained. The heterogenous contents were filtered to give an off-white solid and light brown filtrate. The filtrate was extracted with EtOAc (8 x 100 mL), and CHCl ₃ /MeOH (4: 1, 50 mL). The combined organic layers were dried over MgSO/t, filtered, and concentrated in vacuo to afford a light brown foam. The solid product crops were combined, concentrated from MeOH, and then dried in vacuum oven at 40 ⁰ C overnight. The product was collected as a light brown solid (3.67g, 100%). LC-MS (ES) m/z = 304.9 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.46-7.70 (br. s, 2H), 7.27 (d, J = 8.0 Hz, IH), 7.13 (s, IH), 6.94 (d, J = 8.0 Hz, IH), 3.96 (t, J =6.9 Hz, 2H), 3.17 (s, 3H), 1.63-1.73 (m, 2H), 1.37 (s, 9H), 0.90 (t, J = 7.3 Hz, 3H).

8e) 1.1-Dimethylethyl methyl{2-r({3- [(phenylsulfonvDaminolphenvUcarbonvDaminol-l -propyl- lH-benzimidazol-5-vUcarbamate

1 , 1 -Dimethylethyl (2-amino-l -propyl- lΗ-benzimidazol-5-yl)methylcarbamate (1.83 g, 6 mmol) was dissolved in 25 mL dry DMF, followed by sequential addition of 3- [(phenylsulfonyl)amino]benzoic acid (1.42 g, 5.12 mmol g), EDC (0.982 g, 5.12 mmol), and HOAT (0.697 g, 5.12 mmol). NMM (0.563 mL, 5.12 mmol) was added dropwise via syringe, and the contents were stirred at room temperature. After 16 h, the contents were diluted with water (40 mL), and stirred for 10 min. The contents were vacuum filtered to furnish an off- white colored solid which was triturated from MeOH (2 x 30 mL), and then dried in vacuum oven at 40 ⁰ C. The product was collected as a nearly white solid (2.44 g, 72%). LC-MS (ES) m/z = 505.6 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.65-12.75 (br s, IH), 10.40-10.50 (br s, IH), 8.04 (s, IH), 7.84 (d, J = 8.0 Hz, IH), 7.77 (d, J = 8.0 Hz, 2H), 7.41-7.64 (m, 5H), 7.13-7.34 (m, 3H), 4.16 (t, J = 6.9 Hz, 2H), 3.18 (s, 3H), 1.77-1.88 (m, 2H), 1.38 (s, 9H), 0.93 (t, J = 7.3 Hz, 3H).

8f) N-| ^" 5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl ^" |-3- lYphenylsulfonvDaminolbenzamide

1 , 1 -Dimethylethyl methyl {2- [( {3 - [(phenylsulfonyl)amino]phenyl} carbonyl)amino] - 1 - propyl- lH-benzimidazol-5-yl} carbamate (2.42 g, 4.3 mmol) was dissolved in 30 mL DCM, followed by dropwise addition of trifluoroacetic acid (6 mL, 78 mmol). The contents were stirred at room temperature for 90 min, after which time the reaction mixture was concentrated in vacuo. The crude residue was suspended in EtOAc (30 mL), and carefully neutralized with 75 mL sat. NaHCO ₃ . After stirring for 10 min., the contents were filtered to furnish a light yellow solid which was concentrated from CHCl ₃ (2x 20 mL), and dried in vacuum oven at 40 ⁰ C.

The final product, the title compound, was collected as a light yellow colored solid (1.87g, 94%). LC-MS (ES) m/z = 464.0 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.26-12.54 (br s, IH), 10.32-10.60 (br s, IH), 8.00 (s, IH), 7.77-7.86 (m, 3H), 1.52-1.62 (m, 3H), 7.15-7.33 (m, 3H), 6.70 (s, IH), 6.45 (d, J = 4 Hz, IH), 5.62-5.72 (br s, IH), 4.10 (t, J = 6.9 Hz, 2H), 2.65 (s, 3H), 1.73- 1.84 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). Example 9

N-Methyl-N- {2-[( {3-[(phenylsulfonyl)amino]phenyl}carbonyl)amino]- 1 -propyl- IH- benzimidazol-5-yl}-3-pyridinecarboxamide

N-[5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl]-3-

[(phenylsulfonyl)amino]benzamide (93 mg, 0.20 mmol) was dissolved in 2 mL dry DMF, followed by sequential addition of nicotinic acid (30 mg, 0.24 mmol), EDC (46 mg, 0.24 mmol), and ΗOAT (33 mg, 0.24 mmol). NMM (0.026 mL, 0.24 mmol) was added dropwise via syringe, and the contents were stirred at room temperature. After 36 h, the contents were diluted with water (7 mL), and stirred for 30 min. The reaction mixture was vacuum filtered, and the collected solid triturated from hot MeOH (2 x 2 mL). After drying in vacuum oven at 40 ⁰ C overnight, the product was obtained as an off-white solid (45 mg, 40%). LC-MS (ES) m/z = 569.4 (M+Η) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.47-12.86 (br s, IH), 10.21-10.63 (br s, IH), 8.36-8.49 (m, 2H), 8.01 (s, IH), 7.77-7.84 (m, 3H), 7.52-7.65 (m, 4H), 7.45 (s, IH), 7.14-7.30 (m, 5H), 4.14 (t, J = 6.9 Hz, 2H), 3.42 (s, 3H), 1.77 (quintet, J = 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

The aminobenzimidazole carboxamide compounds illustrated in table 1 were prepared from either N-[5-(methylamino)- 1 -propyl- lH-benzimidazol-2-yl]-3- [(phenylsulfonyl)amino]benzamide or N-(5-amino-l-propyl-lH-benzimidazol-2-yl)-3- [(phenylsulfonyl)amino]benzamide and various carboxylic acids substantially according to the procedure of Example 9. Reaction stir times ranged from 3-36 h. Additional purification by reverse phase ΗPLC was utilized for some examples. In the following tables, the dashed lines indicate the points of attachment. Thus, for Example 10, the compound corresponds to the following structure:

Table 1

Example 47

N- {5-[(Methylsulfonyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide N-(5-Amino- 1 -propyl- lH-benzimidazol-2-yl)-3-[(phenylsulfonyl)amino]benzamide (0.090 g, 0.20 mmol) was dissolved in DCM (2 mL), and the solution was cooled to 0 ⁰ C. Methanesulfonyl chloride (0.016 mL, 0.20 mmol) and pyridine (0.040 mL, 0.5 mmol) were sequentially added to the stirring solution, and the reaction mixture was stirred while warming to room temperature. After 2.5 h, additional methanesulfonyl chloride (0.016 mL, 0.20 mmol) and pyridine (0.040 mL, 0.5 mmol) were added After stirring for an additional 1.5 h, the contents were concentrated in vacuo. The solid residue was washed with water (7 mL), and the solvent layer decanted. The collected solid was triturated from MeOH (2 x 5 mL) and dried in vacuum oven at 40 ⁰ C overnight. The product was collected as an off-white solid (0.061 g, 58%). LC-MS (ES) m/z = 528.1 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.65-12.75 (br s, IH), 10.36-10.53 (br s, IH), 9.56-9.72 (br s, IH), 8.03 (s, IH), 7.84 (d, J = 8.0 Hz, IH), 7.78 (d, 2H), 7.47-7.61 (m, 5H), 7.29-7.34 (s, IH), 7.20 (d, J = 8.0 Hz, IH), 7.10 (d, J = 8.0 Hz, IH), 4.18 (t, J = 6.9 Hz, 2H), 2.95 (s, 3H), 1.78-1.85 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

Example 48

3-[(Phenylsulfonyl)amino]-N-{5-[(phenylsulfonyl)amino]-l -propyl- lH-benzimidazol-2- yljbenzamide

N-(5-Amino- 1 -propyl- lH-benzimidazol-2-yl)-3-[(phenylsulfonyl)amino]benzamide (0.090 g, 0.20 mmol) was dissolved in DCM (2 mL), and the solution was cooled to 0 ⁰ C.

Benzenesulfonyl chloride (0.026 mL, 0.20 mmol) and pyridine (0.040 mL, 0.5 mmol) were sequentially added to the stirring solution, and the reaction mixture was stirred while warming to room temperature. After 3 h, the contents were concentrated in vacuo. The oil was suspended in water (4 mL), stirred for 45 min., and the resultant heterogenous mixture filtered. The collected solid was triturated from MeOH (3 mL) and dried. The product was collected as a nearly white solid (0.060 g, 51%). LC-MS (ES) m/z = 590.1 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.57-12.72 (br s, IH), 10.15-10.30 (br s, IH), 10.35-10.50 (br s, IH), 8.03 (s, IH), 7.72-7 ^' .86 (m, 5H), 7.50-7.64 (m, 6H), 7.27-7.41 (m, 3H), 7.17 (d, J = 8.0 Hz, IH), 6.87 (d, J = 8.0 Hz, IH), 4.10 (t, J = 6.9 Hz, 2H), 1.71-1.81 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). Example 49

N- {5-[Methyl(phenylsulfonyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide

The title compound was prepared from N-[5-(methylamino)-l -propyl- lH-benzimidazol-2- yl]-3 [(phenylsulfonyl)amino]benzamide (0.093 g, 0.20 mmol), benzenesulfonyl chloride (0.026 mL, 0.20 mmol) and pyridine (0.043 mL, 0.5 mmol) substantially according to the procedure of example 47, wherein the reaction stir time was 2 h. The product was collected as an off-white solid (0.098 g, 81%). LC-MS (ES) m/z = 604.4 (M + H) ⁺ ; ¹ H ΝMR (400 MHz, DMSOd ₆ ) δ 12.72 (s, IH), 10.44 (s, IH), 8.04 (s, IH), 7.84 (d, J = 8.0 Hz, IH), 7.78 (d, J = 8.0 Hz, 2H), 7.71-7.76 (m, IH), 7.54-7.63 (m, 7H), 7.46 (d, J = 8.0 Hz, IH), 7.30-7.34 (m, IH), 7.21-7.26 (m, 2H), 6.88 (d, J = 8.0 Hz, IH), 4.16 (t, J = 6.9 Hz, 2H), 3.17 (s, 3H), 1.76-1.86 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

Example 50

N-[5-(2-Oxo- 1 -pyrrolidinyl)- 1 -propyl- lH-benzimidazol-2-yl]-3- [(phenylsulfonyl)amino]benzamide

50a) N- {5-r(4-Chlorobutanoyl)aminol- 1 -propyl- lH-benzimidazol-2-yl} -3- lYphenylsulfonyDaminolbenzamide

N-(5-Amino-l -propyl- lΗ-benzimidazol-2-yl)-3-[(phenylsulfonyl)amino]benzamide (250 mg, 0.556 mmol) was dissolved in DCM (8 mL) followed by addition of pyridine (2 mL) and 4- chlorobutanoyl chloride (94 mg, 0.667 mmol) at 0 ⁰ C. The solution was stirred with warming to room temperature over a 1 h period, and then partitioned between EtOAC and water. The organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated in vacuo to afford the product as an off-white solid (0.232 g, 75%). LC-MS (ES) m/z = 555.2 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSOd ₆ ) 512.62-12.85 (br s, IH), 10.45 (s, IH), 10.08 (s, IH), 8.04 (s, IH), 7.83-7.92 (m, 2H), 7.73-7.83 (m, 2H), 7.51-7.65 (m, 3H), 7.45 (s, 2H), 7.27-7.38 (m, IH), 7.21 (d, J = 8.0 Hz, IH), 4.16 (t, J = 6.9 Hz, 2H), 3.69-3.76 (m, 2H), 3.61-3.69 (m, IH), 2.32-2.41 (m, IH), 2.01-2.12 (m, 2H), 1.88-1.98 (m, IH), 1.74-1.87 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

50b) N- {5-[(4-Chlorobutanoyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide (225 mg, 0.406 mmol) and K ₂ CO3 (112 mg, 0.812 mmol) were suspended in NMP (3 mL) and stirred at 60 ⁰ C for 18 h. After cooling to room temperature, the reaction mixture was poured onto water/EtOAc. The layers were separated and the organic extract was washed with brine, dried, and solvent removed. The crude product was purified by silica gel chromatography (eluent: 0 - 15% CH ₃ OH in chloroform) to afford the final product, the title compound, as a white solid (31 mg, 15%). LC-MS (ES) m/z = 519.2 (M + H) ^{+ 1} H NMR (400

MHz, DMSO-d ₆ ) δ 12.69 (s, 1 H), 10.43 (s, 1 H), 8.05 (s, 1 H), 7.84 - 7.91 (m, 2 H), 7.80 (d, J=7.3 Hz, 2H), 7.41 - 7.66 (m, 5H), 7.32 (t, J=7.7 Hz, IH), 7.22 (d, J=8.1 Hz, IH), 4.20 (t, J=6.9 Hz, 2H), 3.86 (t, J=6.9 Hz, 2H), 2.44 - 2.61 (m, 2H), 2.01 - 2.16 (m, 2H), 1.74- 1.90 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).

Example 51

3 - [(Phenylsulfonyl)amino] -N- [ 1 -propyl-5-(2-pyrimidinylamino)- 1 H-benzimidazol-2- yljbenzamide

N-(5-Amino-l -propyl- lΗ-benzimidazol-2-yl)-3-[(phenylsulfonyl)amino]benzamide (100 mg, 0.222 mmol), 2-chloropyrimidine (127 mg, 1.112 mmol), and Cs ₂ CO ₃ (145 mg, 0.445 mmol) were dissolved in DMSO (2 mL) and stirred in a sealed tube under argon at 150 ⁰ C for 3 h. After cooling to room temperature and releasing pressure, the mixture was partitioned between EtOAc and water. The organic layer was washed with water and then brine. The organic layer was dried over MgSO ₄ , filtered, and concentrated in vacuo to dryness. The crude residue was purified by silica gel chromatography (eluent: 0 - 10% MeOH in chloroform) affording the final product, the title compound, as an off-white solid (105 mg, 90%). LC-MS (ES) m/z = 528.1 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.72 (s, IH), 10.44 (s, IH), 9.70 (s, IH), 8.48 (d, J=4.8 Hz, 2H), 8.11 (d, J=1.3 Hz, IH), 8.03 (s, IH), 7.78 - 7.89 (m, 3H), 7.49 - 7.65 (m, 4H), 7.41 - 7.48 (m, IH), 7.32 (t, J=7.8 Hz, IH), 7.16 - 7.26 (m, IH), 6.84 (t, J=4.8 Hz, IH), 4.20 (t, J=6.6 Hz, 2H), 1.75 - 1.93 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

Example 52

N- {5-[Methyl(2-pyrimidinyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide

N-[5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl] -3

[(phenylsulfonyl)amino]benzamide (130 mg, 0.28 mmol), 2-chloropyrimidine (161 mg, 1.40 mmol) and CS ₂ CO3 (183 mg, 0.561 mmol) were dissolved in DMSO (2 mL) and stirred in a sealed tube under argon at 150 ⁰ C for 8 h, and then at 90 ⁰ C for 8 h. After cooling to room temperature and releasing pressure, the mixture was partitioned between EtOAc and water. The organic layer was washed with water and then brine. The organic layer was dried over MgSOzt, filtered, and concentrated in vacuo to dryness. The crude residue was purified first by silica gel chromatography (eluent: 0 - 10% MeOH in chloroform) which afforded 105 mg of an off- white solid. Half of the material was then purified by reverse phase HPLC, to afford the title compound as a solid (30 mg, 20% overall). LC-MS (ES) m/z = 542.1 (M + H) ^{+ 1} H ΝMR (400 MHz, DMSO- d ₆ ) δl2.72 (s, IH), 10.45 (s, IH), 8.36 (s, 2H), 8.06 (s, IH), 7.87 (d, J = 4.0 Hz, IH), 7.80 (d, J = 8.0 Hz, 2H), 7.50-7.67 (m, 4H), 7.42 (s, IH), 7.28-7.38 (m, IH), 7.14-7.27 (m, 2H), 6.73 (s, IH), 4.20 (t, J = 6.9 Hz, 2H), 3.47 (s, 3H), 1.77-1.95 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

Example 53

N-(5- {Methyl[(phenylamino)carbonyl]amino} - 1 -propyl- lH-benzimidazol-2-yl)-3- [(phenylsulfonyl)amino]benzamide

N-[5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl] -3

[(phenylsulfonyl)amino]benzamide (0.076 g, 0.163 mmol) was dissolved in DCM (2 mL) followed by addition of phenyl isocyanate (0.022 mL, 0.200 mmol), and the reaction mixture was stirred at room temperature. After 1 h, the contents were then diluted with water (5 mL), and the layers were separated. The aqueous layer was extracted with dichoromethane/MeOΗ (4: 1, 3 x 5 mL). The combined organic layers were dried over MgSO/t, filtered, and concentrated in vacuo. The crude residue was triturated from hot hexanes, and the collected solid dried in vacuum oven at 40 ⁰ C. The final product, the title compound, was collected as a white solid (60 mg, 63%). LC-MS (ES) m/z = 583.2 (M + H) ^{+ 1} H ΝMR (400 MHz, DMSOd ₆ ) δl2.77 (s, IH), 10.45 (s, IH), 8.06 (s, IH), 7.98 (s, IH), 7.86 (d, J = 8.0 Hz, IH), 7.80 (d, J = 8.0 Hz, IH), 7.55-7.65 (m, 4H), 7.41-7.45 (m, 3H), 7.30-7.34 (m, IH), 7.19-7.25 (m, 4H), 6.91-6.96 (m, IH), 4.21 (t, J = 6.9 Hz, 2H), 3.27 (s, 3H), 1.80-1.86 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

Example 54

N- {5-[Ethyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide

N-[5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl] -3

[(phenylsulfonyl)amino]benzamide (0.092 g, 0.200 mmol), acetaldehyde (0.017 mL, 0.300 mmol), and acetic acid (0.046 mL, 0.800 mL) were dissolved in DCE (2 mL) followed by portion-wise addition of sodium tri-acetoxyborohydride (0.127 g, 0.600 mmol). The contents were stirred at room temperature for 18 h, and then diluted with water (5 mL), and stirred for 30 min. The reaction mixture was adjusted to pΗ 7 with aq. saturated ΝaΗCθ3, and the layers were then separated. The aqueous layer was extracted with EtOAc (4 x 25 mL). The combined organic layers were dried over MgSO/t, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC. The product was dissolved in 2M HCl in ether, and concentrated from EtOH. After drying at 40 ⁰ C, the product was obtained as a white solid (70 mg, 63%). LC-MS (ES) m/z = 492.1 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.2-13.2 (br s, IH), 10.49 (s, IH), 8.04 (s, IH), 7.71-7.87 (m, 5H), 7.54-7.63 (m, 4H), 7.32-7.36 (m, IH), 7.23 (d, J = 8.0 Hz, IH), 4.19 (t, J = 6.9 Hz, 2H), 3.50-3.62 (m, 2H), 3.15 (s, 3H), 1.79-1.87 (m, 2H), 1.05 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H).

Example 55

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3-aminobenzamide

55a) N-(4-Fluoro-3-nitrophenyl)acetamide 4-Fluoro-3-nitrophenylamine (10 g, 64.1 mmol) was added in portions to a stirred solution of acetic anhydride (35 mL, 371 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then quenched with ice water and neutralized with solid Na ₂ COs. The solid precipitate was filtered and dried in vacuo. The product was collected as a dark brown solid (11.74 g, 92%), and used in the next step without further purification. LC/MS MH+ = 198.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.40 (s, IH), 8.50 (s, IH), 7.77-7.90 (m, IH), 7.47-7.61 (m, IH), 2.05 (s, 3H).

55b) N-(4-Fluoro-3-nitrophenyl)-N-methylacetamide

N-(4-Fluoro-3-nitrophenyl)acetamide (11.74 g, 59.2 mmol) was dissolved in 200 mL THF at 0 ⁰ C, followed by portion wise addition of sodium hydride (3.55 g, 89 mmol, 60% in hexanes). After stirring for 20 min, iodomethane (1 1.11 mL, 178 mmol) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with saturated NaHCθ3, and extracted with EtOAc (3x). The combined organic extracts were washed with brine (2x), dried over Na ₂ SOz _I , and filtered in vacuo. The filtrate was concentrated to afford the product as a dark brown solid (12.52 g, 100%), which was used without further purification. LC/MS MH+ = 212.7. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.20 (s, IH), 7.84 (s, IH), 7.67 (s, IH), 3.18 (s, 3H), 1.82 (s, 3H).

55c) N-Methyl-N- [3 -nitro-4-(propylamino)phenyll acetamide

N-(4-Fluoro-3-nitrophenyl)-N-methylacetamide (12.52 g, 59.0 mmol), potassium carbonate (16.31 g, 118 mmol), and n-propylamine (5.23 g, 89.0 mmol) were sequentially added to a solution of DMF (80 mL), and the mixture was stirred at room temperature for 4 h. The mixture was then poured onto ice water (200 mL) and stirred for 15 min. The dark orange solid precipitate was collected by filtration and dried to give the desired product as 13.56 g (91%). The collected solid was used without further purification. LC/MS MH+ = 251.8. ¹ H ΝMR (400 MHz, DMSO- d ₆ ) δ ppm 8.21-8.24 (br s, IH), 8.00 (s, IH), 7.53 (d, J = 8.0 Hz, IH), 7.11 (d, J = 8.0 Hz, IH), 3.30-3.38 (m, 2H), 3.10 (s, 3H), 1.77 (s, 3H), 1.60-1.67 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 55d) N-(2 -Amino- 1 -propyl- lH-benzimidazol-5-vD-N-methylacetamide

N-Methyl-N-[3-nitro-4-(propylamino)phenyl]acetamide (13.56 g, 54.0 mmol) and 10% Pd/C (2.71 g, 2.55 mmol) were dissolved in ethanol (300 mL) under a blanket of argon. The contents were stirred under an atmosphere of hydrogen (1 arm) for 24 h, after which time LC/MS analysis indicated the reaction was complete. The system was then purged with argon. The reaction mixture was vacuum filtered through a pad of Celite, and the filter cake washed with additional EtOH (100 mL). The combined filtrates (400 mL) were stirred and treated with cyanogen bromide (8.58 g, 81 mmol). After 1 h, the solvent was removed in vacuo. The residue was suspended in water (50 mL) and EtOAc (200 mL), and the mixture neutralized to pΗ 7 with IN ΝaOΗ. A solid precipitate formed in the aqueous layer was vacuum filtered to afford the product as a beige solid (10.58 g, 79% overall). LC-MS (ES) m/z = 247.0 (M+Η) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.14 (d, J = 8.0 Hz, IH), 7.00 (s, IH), 6.75 (d, J = 8.0 Hz, IH), 6.51 (s, 2H), 3.91 (t, J = 6.9 Hz, 2H), 3.12 (s, 3H), 1.74 (s, 3H), 1.63-1.72 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H) .

55e) 1 , 1 -Dimethylethyl {3-IY {5-racetyl(methyl)ammo ^" |- 1 -propyl- lH-benzimidazol-2- yl} amino)carbonyllphenyl} carbamate

N-(2 -Amino- 1 -propyl- lH-benzimidazol-5-yl)-N-methylacetamide (4.0 g, 16.2 mmol) was dissolved in 50 mL dry DMF, followed by sequential addition of 3 -({[(1,1 - dimethylethyl)oxy]carbonyl}amino)benzoic acid (4.24 g, 17.9 mmol), EDC (3.42 g, 17.9 mmol), and ΗOAT (2.43 g, 17.9 mmol). NMM (5.36 mL, 48.7 mmol) was added dropwise via syringe, and the contents were stirred at room temperature. After stirring overnight, additional 3-({[(l,l- dimethylethyl)oxy]carbonyl}amino)benzoic acid (1.06 g, 5.5 mmol), EDC (1.05 g, 5.5 mmol), ΗOAT (0.75 g, 5.5 mmol) and NMM (1.7 mL, 15.2 mmol) were added. After stirring for 60 h, the reaction mixture was quenched with 200 mL aq. Na ₂ COs, and then filtered. The filtered solid was repeatedly washed with water, and then dried. The product was collected as a beige solid (7.56 g, 100%). LC-MS (ES) m/z = 466.0 (M+Η) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.6-12.9 (br s, IH), 9.44 (s, IH), 8.34 (s, IH), 7.81 (d, J = 8.0 Hz, IH), 7.53-7.66 (m, 2H), 7.40 (s, IH), 7.30-7.36 (m, IH), 7.15-7.20 (m, IH), 4.21 (t, J = 6.9 Hz, 2H), 3.17 (s, 3H), 1.80-1.90 (m, 2H), 1.76 (s, 3H), 1.50 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H).

55f) 1 , 1 -Dimethylethyl {3-[( {5-[acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2- yl}amino)carbonyl]phenyl} carbamate (7.56 g, 16.24 mmol) was dissolved in DCM (70 mL) and the contents cooled in an ice bath with stirring. Trifluoroacetic acid (30 mL, 389 mmol) was added slowly, and the solution was stirred with warming to room temperature. After 2 h stirring at room temperature, the volatiles were removed in vacuo. The residue was diluted with DCM and neutralized with sat. Na ₂ COs. The layers were separated, and the aqueous layer extracted with CH ₂ Cl ₂ (3x). The combined organic layers were washed with brine and dried over Na ₂ SOz _I . The contents were concentrated in vacuo to afford the final product, the title compound, as a beige solid in quantitative yield. LC-MS (ES) m/z = 365.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.6-12.9 (br s, IH), 7.54-7.60 (m, IH), 7.40-7.47 (m, 3H), 7.19 (d, J = 8.0 Hz, IH), 7.06- 7.12 (m, IH), 6.67-6.73 (m, IH), 5.12-5.20 (br s, 2H), 4.17-4.25 (m, 2H), 3.17 (s, 3H), 1.80-1.86 (m, 2H), 1.76 (s, 3H), 0.93 (m, 3H). Example 56

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3- {[(3- fluorophenyl)sulfonyl] amino } benzamide

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lΗ-benzimidazol-2-yl} -3-aminobenzamide (100 mg, 0.274 mmol) was dissolved in 5 mL DCM followed by addition of 3-fluorobenzenesulfonyl chloride (53.3 mg, 0.274 mmol) and pyridine (0.066 mL, 0.821 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched with water (3 mL), and the layers were separated. The organic layer was concentrated in vacuo and the crude residue was purified by reverse phase HPLC (used non-TFA mobile phase) to afford the product as a white solid (94 mg, 66%). LC-MS (ES) m/z = 524.0 (M+H) ^{+ 1} H ΝMR (400 MHz, DMSOd ₆ ) δ ppm 12.80 (br. s., IH), 10.55 (s, IH), 8.05 (s, IH), 7.91 (d, J = 7.58 Hz, IH), 7.56 - 7.67 (m, 4H), 7.50 (br. s., IH), 7.36 (t, J = 7.58 Hz, IH), 7.40 (s, IH), 7.18 - 7.29 (m, 2H), 4.22 (t, J = 6.32 Hz, 2H), 3.17 (br. s., 3H), 1.81 - 1.91 (m, 2H), 1.76 (br. s., 3H), 0.94 (t, J = 7.20 Hz, 3H)

The aminobenzimidazole carboxamide compounds illustrated in table 2 were prepared from N- {5-[acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3-aminobenzamide and various sulfonyl chloride-containing compounds substantially according to the procedure of example 56.

Table 2

Example 70

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -4-fluoro-3- [(phenylsulfonyl)amino]benzamide

70a) 4-Fluoro-3-r(phenylsulfonyl)aminolbenzoic acid

4-Fluoro-3-amino-benzoic acid (0.776 g, 5.0 mmol) was suspended in water (10 mL), followed by addition of benzenesulfonyl chloride (0.774 mL, 6.0 mmol) and sodium carbonate (1.17 g, 11.0 mmol) to the stirring mixture. After stirring at room temperature for 5 h, the reaction mixture was poured onto ether (10 mL), and the layers separated. The aqueous layer was acidified to pH 2 with 6N HCl, and the resultant heterogenous mixture filtered. The filter cake was washed with water, and dried in vacuo. The collected solid was triturated from 2: 1 hexanes/EtOAc to furnish the product as an off-white solid (0.900 g, 61%). LC-MS (ES) m/z = 295.8 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 13.17 (s, IH), 10.41 (s, IH), 7.83 (d, IH, J = 8.0 Hz), 7.71- 7.78 (m, 3H), 7.63-7.68 (m, IH), 7.55-7.60 (m, 2H), 7.26-7.30 (m, IH).

70b) The title compound was prepared from N-(2-amino-l -propyl- lH-benzimidazol-5-yl)- N-methylacetamide (0.074 g, 0.3 mmol), 4-fluoro-3-[(phenylsulfonyl)amino]benzoic acid (0.115 g, 0.39 mmol), EDC (0.074 g, 0.39 mmol), HOAT (0.053 g, 0.39 mmol) and NMM (0.043 mL, 0.39 mmol) substantially according to the procedure of Example 7, step f, wherein the reaction stir time was 20 h. The product was collected as an off-white solid (0.144 g, 87%). LC-MS (ES) m/z = 524.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.80 (s, IH), 10.30 (s, IH), 8.12 (d, IH, J = 8.0 Hz), 8.01-8.05 (m, IH), 7.77-7.79 (d, 2H, J = 8.0 Hz), 7.64-7.68 (m, IH), 7.56-7.61 (m, 3H), 7.40 (s, IH), 7.22-7.28 (m, 2H), 4.18 (t, 2H, J = 6.9 Hz), 3.17 (s, 3H), 1.78-1.86 (m, 2H), 1.76 (s, 3H), 0.92 (t, 3H, J = 7.3 Hz). Example 71

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -2-fluoro-5- [(phenylsulfonyl)amino]benzamide

71a) 2-Fluoro-5- lϊphenylsulfonvDaminolbenzoic acid

The product was prepared from 2-fluoro-5-amino-benzoic acid (0.776 g, 5.0 mmol), benzenesulfonyl chloride (0.774 mL, 6.0 mmol) and sodium carbonate (1.17 g, 11.0 mmol) substantially according to the procedure of Example 70, step a. The product was washed with DCM (10 mL), and collected as a wine colored solid (1.02 g, 69%). LC-MS (ES) m/z = 295.7 (M+Η) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 13.36 (s, IH), 10.44 (s, IH), 7.72 (d, 2H, J = 8.0 Hz), 7.61-7.65 (m, IH), 7.54-7.59 (m, 3H), 7.29-7.34 (m, IH), 7.19-7.25 (m, IH). 71b) N- {5-[Acetyl(methyl)amino ^" |- 1 -propyl- lH-benzimidazol-2-yU -2-fluoro-5-

|Yphenylsulfonyl)amino ^" |benzamide

The title compound was prepared from N-(2-amino-l -propyl- lH-benzimidazol-5-yl)-N- methylacetamide (0.074 g, 0.3 mmol), 2-fluoro-5-[(phenylsulfonyl)amino]benzoic acid (0.115 g, 0.39 mmol g), EDC (0.074 g, 0.39 mmol), ΗOAT (0.053 g, 0.39 mmol) and ΝMM (0.043 mL, 0.39 mmol) substantially according to the procedure of Example 7, step f, wherein the reaction stir time was 20 h. The product was collected as an off- white solid (0.123 g, 75%). LC-MS (ES) m/z = 524.1 (M+Η) ^{+ 1} H ΝMR (400 MHz, DMSOd ₆ ) δ ppm 12.81 (s, IH), 10.36 (s, IH), 7.84 (d, IH, J = 8.0 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.55-7.63 (m, 4H), 7.39 (s, IH), 7.22-7.26 (m, IH), 7.17-7.20 (m, IH), 7.10-7.14 (m, IH), 4.14 (t, 2H, J = 6.9 Hz), 3.17 (s, 3H), 1.77-1.84 (m, 2H), 1.75 (s, 3H), 0.90 (t, 3H, J = 7.3 Hz).

Example 72 N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -4-chloro-3-

[(phenylsulfonyl)amino]benzamide

72a) 4-Chloro-3-r(phenylsulfonyl)aminolbenzoic acid

The product was prepared from 4-chloro-3 -amino-benzoic acid (0.257 g, 1.5 mmol), benzenesulfonyl chloride (0.232 mL, 1.8 mmol) and Na ₂ Cθ ₃ (0.334 g, 3.15 mmol) substantially according to the procedure of Example 70, step a, wherein the reaction stir time was 4 h. The product was collected as a white solid (0.210 g, 45 %). LC-MS (ES) m/z = 293.8 (M-OH) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 13.20 (s, IH), 10.22 (s, IH), 7.81 (s, IH), 7.70-7.74 (m, 3H), 7.64-7.68 (m, IH), 7.53-7.59 (m, 3H).

72b) The title compound was prepared from N-(2-amino-l -propyl- lH-benzimidazol-5-yl)- N-methylacetamide (0.074 g, 0.3 mmol), 4-chloro-3-[(phenylsulfonyl)amino]benzoic acid (0.122 g, 0.39 mmol g), EDC (0.074 g, 0.39 mmol), ΗOAT (0.053 g, 0.39 mmol) and ΝMM (0.043 mL, 0.39 mmol) substantially according to the procedure of Example 7, step f, wherein the reaction stir time was 17 h. The product was collected as a nearly white solid (0.075 g, 46%). LC-MS (ES) m/z = 540.1 (M+Η) ^{+ 1} H ΝMR (400 MHz, DMSOd ₆ ) δ ppm 12.82 (s, IH), 10.12 (s, IH), 8.09 (s, IH), 8.01 (d, IH, J = 8.0 Hz), 7.77 (d, IH, J = 8.0 Hz), 7.63-7.70 (m, IH), 7.55-7.65 (m, 5H), 7.41 (s, IH), 7.22 (d, IH, J = 8.0 Hz), 4.17 (t, 2H, J = 6.9 Hz), 3.17 (s, 3H), 1.78-1.86 (m, 2H), 1.76 (s, 3H), 0.89 (t, 3H, J = 7.3 Hz). Example 73

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -4-fluoro-3- {[(3- fluorophenyl)sulfonyl] amino } benzamide

73 a) 3-Amino-4-fluorobenzoic acid

To a solution of 4-fluoro-3-nitrobenzoic acid (15.0 g, 81 mmol) in MeOH (150 mL) under an atmosphere of nitrogen was added 10% Pd/C (0.80 g). The mixture was then stirred under 1 atm H ₂ for 3 h. The reaction mixture was vacuum filtered through a thin pad of Celite, and the filtrate concentrated in vacuo to give the product as a solid, 12.0 g (96%). LC-MS (ES) m/z = 156.2 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 7.49(m, 1 H), 7.23(m, 1 H), 6.88 (m, 1 H), 4.78 (br, 1 H).

73b) N- {5-rAcetyl(methyl)aminol- 1 -propyl- lH-benzimidazol-2-yl} -3-amino-4- fluorobenzamide

To a solution of N-(2 -Amino- 1 -propyl- lH-benzimidazol-5-yl)-N-methylacetamide (4.0 g, 16.2 mmol) in DMF (15 mL) were added 3-amino-4-fluorobenzoic acid (2.64 g, 16.9 mmol), PyBop (10.4 g, 19.4 mmol), 4-methylmorpholine (4.92 g, 48.6 mmol). The resulting mixture was heated to 70 ⁰ C overnight. After cooling to room temperature, the mixture was poured onto water. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over Na ₂ SOz _I , and concentrated in vacuo to give the crude product as a solid (4 g, 65%), which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.68 (m, 1 H), 7.56 (m, 1 H), 7.46 (m, 1 H), 7.39 (m, 1 H), 7.02 (m, 1 H), 5.42 (s, 3 H), 4.21 (m, 2 H), 1.80 (m, 5 H), 0.92 (m, 3 H).

73c) The title compound was prepared from N- {5-[acetyl(methyl)amino]-l -propyl- IH- benzimidazol-2-yl}-3-amino-4-fluorobenzamide, 3-fluoro-benzenesulfonyl chloride, and pyridine substantially according to the procedure of Example 56, wherein the reaction stir time was 3 h. The product was collected as a solid. LC-MS (ES) m/z = 542.2 (M+H) ^{+ 1} H NMR (400 MHz, MeOD) δ ppm 10.41 (br. s., 1 H), 8.06 (m, 2 H), 7.59 (m., 5 H), 7.38 (m, 1 H), 7.20 (m, 2 H), 4.15 (d, J=6.8 Hz, 2 H), 3.13 (s, 3 H), 1.77 (m, 5 H), 0.88 (t, J=7.4 Hz, 3 H).

Example 74

N- {5-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -4-fluoro-3- {[(4- fluorophenyl)sulfonyl] amino } benzamide

The title compound was prepared from N- {5-[acetyl(methyl)amino]- 1 -propyl- IH- benzimidazol-2-yl}-3-amino-4-fluorobenzamide, 4-fluoro-benzenesulfonyl chloride, and pyridine substantially according to the procedure of example 56, wherein the reaction stir time was 3 h. The product, the title compound, was collected as a solid. LC-MS (ES) m/z = 542.2 (M+Η) ^{+ 1} H ΝMR (400 MHz, MeOD) δ ppm 12.76 (br. s., 1 H), 10.28 (br. s., 1 H), 8.06 (m, 2 H),7.79 (m, 2 H),7.58 (m, 1 H), 7.38 (m, 3 H),7.21 (m, 2 H),4.15 (t, J=6.8 Hz, 2H), 3.13 (s, 3 H),1.80 (m, 5 H), 0.87 (t, J=7.4 Hz, 3H).

Example 75

N- {5-[Acetyl(methyl)amino]-l -propyl- lH-benzimidazol-2-yl}-4-fluoro-3-({[3- (trifluoromethyl)phenyl]sulfonyl} amino)benzamide

The title compound was prepared from N- {5-[acetyl(methyl)amino]-l -propyl- IH- benzimidazol-2-yl} -3-amino-4-fluorobenzamide, 3-trifluoro-benzenesulfonylchloride, and pyridine substantially according to the procedure of example 56, wherein the reaction stir time was 3 h. The product was collected as a solid. LC-MS (ES) m/z = 592.2 (M+Η) ^{+ 1} H ΝMR (400 MHz, MeOD) δ ppm 10.51 (br. s., 1 H), 8.07 (m, 5 H),7.80 (m, 1 H),7.56 (m, 1 H), 7.36 (s, 1 H),7.21 (m, 2 H),4.14 (t, J=6.8 Hz, 2H), 3.18 (s, 3 H),1.76 (m, 5 H), 0.87 (t, J=7.2 Hz, 3H). Example 76

4-Fluoro-N-[5-(methylamino)-l -propyl- lH-benzimidazol-2-yl]-3-( {[2- (trifluoromethyl)phenyl]sulfonyl}amino)benzamide

76a) Methyl 4-fluoro-3-nitrobenzoate

To a solution of 4-fluoro-3-nitrobenzoic acid (2 g, 11 mmol) in MeOH (20 mL) was slowly added SOCl ₂ (2.6 g, 22 mmol). The mixture was heated to reflux overnight before it was concentrated in vacuo to give the crude product. The crude product was washed with 2N aq. NaOH, and then extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , and concentrated in vacuo to give the desired product as a solid (2 g, 91%). ¹ H NMR (400 MHz, CDCl ₃ -d ₃ ) δ ppm 8.71 (m, 1 H), 8.34 (m, 1 H), 7.42 (m, 1 H), 4.00 (s, 3 H).

76b) Methyl 3-amino-4-fluorobenzoate

To a stirring solution of 4-fluoro-3-nitrobenzoic acid (25 g, 126 mmol) in MeOH (20 mL) was added Fe (28 g, 502 mmol), followed by addition of con. HCl (5 mL). The mixture was heated to reflux for two days, cooled to room temperature, and then filtered. The filtrate was concentrated in vacuo to give the desired product as a solid (15 g, 68%). LC-MS (ES) m/z = 170.1 (M+H) ^{+ 1} H NMR (400 MHz, MeOD) δ ppm 7.39 (m, 2 H), 6.94 (m, 1 H), 3.91 (br, 5 H). 76c) 4-Fluoro-3-({[2-(trifluoromethyl)phenyl]sulfonyUammo)benzoic acid

Methyl 3-amino-4-fluorobenzoate (2 g, 13 mmol) and pyridine (2.1 g, 76.4 mmol) were suspended in DCM (25 mL), and to the stirring solution was slowly added 2-trifluoromethyl- benzenesulfonyl chloride (3.24 g, 13 mmol) at room temperature. After stirring for 2 h, the reaction mixture was washed with water and then extracted with DCM. The combined organic layers were dried over Na ₂ SOz _I , filtered, and concentrated in vacuo. The crude residue was suspended in water (30 mL) followed by slow addition of NaOH (1.1 g, 28 mmol), and the mixture heated at reflux overnight. After cooling to room temperature, the reaction mixture was extracted with DCM. The layers were separated. The aq. layer adjusted to pH 5 with aq. 5N HCl, and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford the final product as a solid (4.0 g, 83% overall). LC-MS (ES) m/z = 364.1 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.61 (br, 1 H), 10.37 (br, 1 H), 8.78 (m, 1 H), 8.37 (m, 1 H), 8.01 (m, 2 H), 7.71 (m, 2 H), 7.31 (m, 2 H).

76d) U-dimethylethyl \2-( (r4-fluoro-3-f(r2-

(trifluoromethyl)phenyllsulfonyU amino)phenyllcarbonyU amino)- 1 -propyl- lH-benzimidazol-5- yllmethylcarbamate

To a stirring solution of 1 , 1 -dimethylethyl (2-amino-l -propyl- lH-benzimidazol-5- yl)methylcarbamate (3.3 g, 10.8 mmol) in 20 mL of DMF was added 4-fluoro-3-({[2- (trifluoromethyl)phenyl]sulfonyl}amino)benzoic acid (4.0 g, 11.0 mmol), PyBop (6.76 g, 13 mmol), ΗOBT (0.7 g, 5.4 mmol) and Et ₃ N (3.3 g, 32.4 mmol). The mixture was stirred overnight at room temperature before it was poured onto water. The solid was filtered, dissolved in DCM, and washed with water. The combined organic layers were dried over Na ₂ SO ₄ , and concentrated in vacuo to give the desired product as a solid (6 g, 88%). LC-MS (ES) m/z = 650.3 (M+Η) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.50 (br, 1 H), 8.08 (m, 4 H), 7.81 (m, 2 H), 7.43 (m, 2 H), 7.21 (m, 1 H), 7.07 (m, 1 H), 4.15 (m, 2 H), 3.19 (s, 3 H), 1.74 (m, 2 H), 1.38 (s, 9 H), 0.81 (m, 3 H).

76e) 1,1 -Dimethylethyl [2-({[4-fluoro-3-({[2- (trifluoromethyl)phenyl]sulfonyl} amino)phenyl]carbonyl} amino)- 1 -propyl- lH-benzimidazol-5- yljmethylcarbamate (6 g, 9.5 mmol) was suspended in DCM (30 mL). Trifluoroacetic acid (5.4 g, 47.5 mmol) was added slowly to the stirring solution. After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The crude residue was adjusted to pH 8 with aq. NaHCO ₃ , and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , and concentrated in vacuo to give the desired product as a solid (4.5 g, 89%) (4.5 g, 89%). LC-MS (ES) m/z = 550.2 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.36 (br, 1 H), 8.02 (m, 4 H), 8.84 (m, 2 H), 7.25 (m, 2 H), 6.66 (s, 1 H), 6.48(m, 1 H), 4.02 (m, 2 H) 2.69 (s, 3 H), 1.71 (m, 2 H), 0.78 (m, 3 H).

Intermediate 1

3 - { [(3 -Fluorophenyl)sulfonyl] amino } benzoic acid

The product was prepared from methyl 3-aminobenzoate (2.0 g, 13.2 mmol), 3-fluoro- benzenesulfonyl chloride (2.57 g, 13.2 mmol), pyridine (2.1 g, 26.4 mmol), and sodium hydroxide (0.9 g, 22.6 mmol) substantially according to the procedure of example 76c. The product was collected as a solid (2.42 g, 62%). LC-MS (ES) m/z = 296.1 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.77 (br, 1 H), 7.71 (m, 6 H), 7.40 (m, 2 H).

Intermediate 2 3-({[2-(Trifluoromethyl)phenyl]sulfonyl}amino)benzoic acid

The product was prepared from methyl 3-aminobenzoate (2.0 g, 13.0 mmol), 2- trifluoromethyl-benzenesulfonyl chloride (3.24 g, 13.0 mmol), pyridine (2.1 g, 26.4 mmol), and sodium hydroxide substantially according to the procedure of example 76c. The product was collected as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.95 (br, 1 H), 10.86 (br, 1 H), 8.04 (m, 1 H), 7.96 (m, 1 H), 7.79 (m, 2 H), 7.65 (s, 1 H), 7.56 (m, 1 H), 7.31 (m, 2 H). Intermediate 3

3-({[4-(Methyloxy)phenyl]sulfonyl}amino)benzoic acid

The product was prepared from methyl 3-aminobenzoate (2.0 g, 13.0 mmol), 4-methoxy- benzenesulfonyl chloride (2.7 g, 13.0 mmol), pyridine (2.7 g, 26.0 mmol), and sodium hydroxide (1.1 g, 28.0 mmol) substantially according to the procedure of example 76c. The product was collected as a solid. LC-MS (ES) m/z = 330.1 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 7.68 (m, 3 H), 7.57 (m, 1 H), 7.32 (m, 2 H), 7.02 (m, 2 H), 3.76 (s, 3 H).

Intermediate 4

3- {[(3,5-Difluorophenyl)sulfonyl]amino}benzoic acid

The product was prepared from methyl 3-aminobenzoate (1.3 g, 8.6 mmol), 3,5-difluoro- benzenesulfonyl chloride (1.51 g, 8.6 mmol), pyridine (1.3 g, 17,.2 mmol), and sodium hydroxide (0.59 g, 14.6 mmol) substantially according to the procedure of example 76c. The product was collected as a solid (2.0 g, 70%). LC-MS (ES) m/z = 336.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.71 (m, 1 H), 7.63 (m, 1 H), 7.31 (m, 4 H), 6.92 (m, 1 H).

Intermediate 5

4-Fluoro-3- {[(3 -fluorophenyl)sulfonyl] amino} benzoic acid

The product was prepared from methyl 4-fluoro-3-aminobenzoate (2.0 g, 11.8 mmol), 3- fluoro-benzenesulfonyl chloride (2.3 g, 11.8 mmol), pyridine (1.87 g, 23.6 mmol), and sodium hydroxide (0.93 g, 23.2 mmol) substantially according to the procedure of example 76c. The product was collected as a solid (3.0 g, 81%). LC-MS (ES) m/z = 314.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.51 (br, 1 H), 7.71 (m, 2 H), 7.63 (m, 1 H), 7.49 (m, 3 H), 7.21 (m, 1 H).

Intermediate 6

4-Fluoro-3-({[4-(methyloxy)phenyl]sulfonyl}amino)benzoic acid

The product was prepared from methyl 4-fluoro-3-aminobenzoate (2.0 g, 11.8 mmol), 4- methoxy-benzenesulfonyl chloride (2.44 g, 11.8 mmol), pyridine (1.79 g, 23.6 mmol), and sodium hydroxide (1.0 g, 26.0 mmol) substantially according to the procedure of example 76c. The product was collected as a solid (3.7 g, 88%). ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 13.15 (br, 1 H), 10.25 (br, 1 H), 7.81 (m, 1 H), 7.69 (m, 1 H), 7.59 (m, 2 H), 7.21 (m, 1 H), 7.02 (m, 2 H), 3.77 (s, 3 H).

Intermediate 7 3-{[(3,5-difluorophenyl)sulfonyl]amino}-4-fluorobenzoic acid

The product was prepared from methyl 4-fluoro-3-aminobenzoate (1.6 g, 9.46 mmol), 3,5- difluoro-benzenesulfonyl chloride (2.0 g, 9.46 mmol), pyridine (1.5 g, 18.92 mmol), and sodium hydroxide (0.74 g, 18.6 mmol) substantially according to the procedure of example 76c. The product was collected as a solid (3.0 g, 96%). ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 10.70 (br, 1 H), 7.81 (m, 2 H), 7.67 (m, 1 H), 7.39 (m, 3 H).

The aminobenzimidazole carboxamide compounds illustrated in table 3 were prepared from 1 , 1 -dimethylethyl (2-amino-l -propyl- lH-benzimidazol-5-yl)methylcarbamate and the bisphenylsulfonyl carboxylic acids listed as intermediates 1 -7, and the product from step c of Example 76, substantially according to the procedures of Example 76, steps d-e. In the following table, the position number listed corresponds to the attachment point on the molecule. Thus, for Example 77, the compound corresponds to the following structure:

Table 3

Example 84

2-Fluoro-N-methyl-N- [ 1 -propyl-2-( { [3 -( { [2-

(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]carbonyl} amino)- lΗ-benzimidazol-5- yl]benzamide

N-[5-(Methylamino)- 1 -propyl- lH-benzimidazol-2-yl] -3-( { [2-

(trifluoromethyl)phenyl]sulfonyl}amino)benzamide (0.250 g, 0.47 mmol), 2-fluorobenzoic acid (0.066 g, 0.47 mmol), ΗOBT (0.032 g, 0.24 mmol), PyBop (0.294 g, 0.56 mmol), and Et ₃ N (0.143 g, 1.41 mmol) were dissolved in DMF (4 mL) and stirred at room temperature overnight. The crude product in DMF was purified by reverse phase ΗPLC (non-TFA mobile phase). The final product was collected as a solid (0.104 g, 45%) LC-MS (ES) m/z = 654.2 (M+Η) ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.76 (br. s., 1 H), 10.85 (br. s., 1 H), 8.12 (m, 3 H), 8.08 (m, 3 H), 7.39 (m, 6 H), 7.11 (m, 3 H),4.16 (t, J=6.8 Hz, 2 H), 3.52 (s, 3 H), 1.78 (m, 2 H), 0.88 (t, J=7.4 Hz, 3H). The aminobenzimidazole carboxamide compounds illustrated in table 4 were prepared from the substituted N-[5-(methylamino)- 1 -propyl- lH-benzimidazol-2-yl]-3- [(phenylsulfonyl)amino]benzamides (Examples 77-83) and various carboxylic acids substantially according to the procedure of Example 84. Reactions were typically conducted at room temperature, or with heating up to 80 ⁰ C. In the following table, the dashed lines indicate point of attachment. The position number listed corresponds to the attachment point on the molecule as per the numbering shown. Thus, for Example 85, the compound corresponds to the following structure:

Table 4

Examplel57

N-[5-[Acetyl(methyl)amino]- 1 -(I -methylethyl)- lH-benzimidazol-2-yl]-3- [(phenylsulfonyl)amino]benzamide

157a) N-methyl-N- {4-r(l-methylethyl)aminol-3-nitrophenyl}acetamide

The product was prepared from N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (4.0 g, 18.8 mmol), isopropylamine (1.67 g, 28.3 mmol), K ₂ CO ₃ (5.2 g, 37.7 mmol), and DMF (30 mL) substantially according to the procedure of Example 55, step c, wherein the reaction stir time was overnight. The product was collected as a solid, 0.5 g (11 %). LC-MS (ES) m/z = 252.2 (M+H) ^{+ 1} H NMR (400 MHz, MeOD) δ ppm 8.06 (m, 1 H), 7.44 (m, 1 H), 7.21 (m, 1 H), 3.91 (m, 1 H), 3.23 (s, 3 H), 1.86 (s, 3 H), 1.36 (m, 6 H).

157b) N- [2- Amino- 1 -( 1 -methylethyl)- lH-benzimidazol-5-yll-N-methylacetamide

N-Methyl-N- {4-[(l-methylethyl)amino]-3-nitrophenyl}acetamide (0.50 g, 1.99 mmol) and 10% Pd/C (0.050 g) in ethanol (10 mL) were stirred under an atmosphere of hydrogen (1 atm) for 4 h. The reaction mixture was vacuum filtered through a pad of Celite. The filtrate was treated with cyanogen bromide (0.316 g, 2.98 mmol) and stirred at room temperature overnight. The reaction mixture was poured onto water, stirred for 15 min, and neutralized to pΗ 7 with IN NaOH. The aq. layer was separated and extrated with EtOAc. The combined organic layers were washed with brine, dried over MgSOzt, filtered, and concentrated in vacuo. The final product was collected as a solid (0.42 g, 86%). ¹ H NMR (400 MHz, CDC13) δ ppm 7.27 (m, 1 H), 7.21 (m, 1 H), 6.85 (m, 1 H),4.72 (br, 2 H),4.43 (m, 1 H), 3.27 (s, 3 H), 1.82 (s, 3 H), 1.62 (m, 6 H).

157c) N-(2 -Amino- 1 -butyl- lH-benzimidazol-5-yl)-N-methylacetamide (0.30 g, 1.22 mmol), 3-[(phenylsulfonyl)amino]benzoic acid (0.37 g, 1.34 mmol), triethylamine (0.246 g, 2.44 mmol) and ΗATU (0.463 g, 1.22 mmol) were dissolved in 20 mL CH ₃ CN, and stirred at room temperature overnight. The crude product was purified by reverse phase HPLC to afford the product, the title compound, as an orange solid (0.149 g, 24%). LC-MS (ES) m/z = 506.2 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.94 (s, IH), 7.79-7.80 (m, IH), l.lA-1.1% (m, m, 2H), 7.62-7.66 (m, IH), 7.48-7.58 (m, 3H), 7.36 (s, IH), 7.24-7.29 (m, IH), 7.13-7.18 (m, 2H), 5.10- 5.10 - 5.18 (m, IH), 3.10 (s, 3H), 1.71 (s, 3H), 1.58 (d, J = 3 Hz, 6H). Example 158

N- {5-[Acetyl(methyl)amino]- 1 -butyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide

158a) N-[4-fButylaminoV3-nifrophenyll-N-methylacetamide

The product was prepared from Ν-(4-fluoro-3-nitrophenyl)-Ν-methylacetamide (4.0 g, 18.8 mmol),n-butylamine (1.67 g, 28.3 mmol), K ₂ CO ₃ (5.2 g, 37.7 mmol), and DMF (30 mL) substantially according to the procedure of Example 55, step c, wherein the reaction stir time was overnight. The product was collected as a solid (4.0 g, 80%). LC-MS (ES) m/z = 266.1 (M+Η) ^{+ 1} H NMR (400 MHz, MeOD) δ ppm 8.05 (m, 1 H), 7.94 (m, 1 H), 6.83 (m, 1 H), 3.31 (m, 2 H), 3.12 (s, 3 H), 1.82 (s, 3 H), 1.67 (m, 2 H), 1.45 (m, 2 H), 0.92 (m, 3 H).

158b) N-(2 -Amino- 1 -butyl- lH-benzimidazol-5-yl)-N-methylacetamide

The product was prepared from N-[4-(butylamino)-3-nitrophenyl]-N-methylacetamide (4.0 g, 15.1 mmol) using 10% Pd/C (0.427 g, 0.395 mmol), EtOH (40 mL), and cyanogen bromide (2.4 g, 22.6 mmol), substantially according to the procedure of example 158 step b. LC-MS (ES) m/z = 261.2 ¹ H ΝMR (400 MHz, MeOD ₄ ) δ ppm 7.17 (m, 1 H), 7.04 (m, 1 H), 6.83 (m, 1 H), 3.98 (m, 2 H), 3.24 (s, 3 H), 1.80 (s, 3 H), 1.65 (m, 2 H), 1.36 (m, 2 H), 0.91 (m, 3 H). 158c) N-(2 -Amino- 1 -butyl- lH-benzimidazol-5-yl)-N-methylacetamide (0.40 g, 1.44 mmol), 3-[(phenylsulfonyl)amino]benzoic acid (0.41 g, 1.59 mmol), triethylamine (0.29 g, 2.88 mmol) and ΗATU (0.55 g, 1.44 mmol) were dissolved in 10 mL CH ₃ CN, and stirred at 80 ⁰ C overnight. After cooling to room temperature, the mixture was washed with water, and extracted with EtOAc. The organic layer was concentrated in vacuo, washed with CH ₃ CN, and then filtered to afford the product, the title compound, as an off-white solid (0.32 g, 43%). LC-MS (ES) m/z 520.2 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.03 (s, 1 H), 7.86 (m, 1 H),7.78 (m, 2 H),7.54 (m, 4 H),7.36 (m, 1 H), 7.27 (m, 1 H),7.20 (m, 2 H),4.23 (t, J=6.8 Hz, 2H), 3.14 (s, 3 H), 1.76 (m, 5H), 1.34 (m, 2H),0.90 (t, J=7.2 Hz, 3H).

Example 159

N- {5-[Acetyl(methyl)amino]- 1 -phenyl- lH-benzimidazol-2-yl} -3- [(phenylsulfonyl)amino]benzamide

159a) N-Methyl-N- [3 -nitro-4-(phenylamino)phenyll acetamide

Ν-(4-Fluoro-3-nitrophenyl)-Ν-methylacetamide (0.1 g, 0.47 mmol), and K ₂ CO ₃ (0.13 g, 0.94 mmol) were added to a stirring solution of aniline (5 mL), and stirred at room temperature overnight. The reaction mixture was poured onto ice-water, and stirred for 15 min. The contents were extracted with EtOAc, and then purified by preparative TLC to afford the product as a solid (0.070 g, 52%). LC-MS (ES) m/z = 286.2 (M+Η) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ ppm 8.11 (s, 1 H), 7.46 (m, 2 H), 7.15 (m, 2 H), 6.72 (m, 1 H), 6.61 (m, 2 H), 3.21 (s, 3 H), 1.96 (s, 3 H).

159b) N-(2 -Amino- 1 -phenyl- lH-benzimidazol-5-vD-N-methylacetamide

The product was prepared from N-methyl-N- [3 -nitro-4-(phenylamino)phenyl] acetamide using Pd/C, EtOH, and cyanogen bromide, substantially according to the procedure of Example 157, step b. LC-MS (ES) m/z = 281.1 (M+Η) ^{+ 1} H ΝMR (400 MHz, CDCl ₃ ) δ ppm 7.65 (m, 2 H), 7.51 (m, 1 H), 7.48 (m, 2 H), 7.21 (m, 1 H), 6.98 (m, 1 H), 6.82 (m, 1 H), 5.01 (br, 2 H), 3.28 (s, 3 H), 1.88 (s, 3 H).

159c) N-(2 -Amino- 1 -phenyl- lH-benzimidazol-5-yl)-N-methylacetamide (0.30 g, 1.07 mmol), 3-[(phenylsulfonyl)amino]benzoic acid (0.326 g, 1.18 mmol), triethylamine (0.216 g, 2.14 mmol) and triethylamine (0.401 g, 1.07 mmol) were dissolved in 20 mL CH ₃ CN, and stirred at 80 ⁰ C overnight. The crude product was purified by reverse phase HPLC to afford the product, the title compound, as a white solid (0.406, 70%). LC-MS (ES) m/z = 540.2 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 7.67 (m, 7 H), 7.42 (m, 6 H), 7.16 (m, 2 H), 7.05 (m, 2 H), 3.17 (s, 3 H), 1.78 (s, 3 H).

Example 160

N-[5-[Acetyl(methyl)amino]- 1 -(3-amino-3-oxopropyl)- lH-benzimidazol-2-yl]-3- [(phenylsulfonyl)amino]benzamide

160a) Ethyl N- {4-racetyl(methyl)aminol-2-nitrophenyl}-β-alaninate

The product was prepared from N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (0.62 g, 2.92 mmol), K ₂ CO ₃ (0.492 g, 3.51 mmol), ethyl β-alaninate (0.90 g, 5.84 mmol) and DMF (8 mL) substantially according to the procedure of Example 8, step b, with a reaction stir time of 20 h. The product was suspended in an equal volume of DCM and hexanes, concentrated in vacuo, and dried under hi-vacuum for 3 h. The product was collected as a dark reddish-brown solid (0.90 g, 100%). The collected solid was used without further purification. LC-MS (ES) m/z = 309.8 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.28 (t, J=5.4 Hz, IH), 7.84 - 8.06 (m, IH), 7.56 (dd, J= 8.9, 2.1 Hz, IH), 7.17 (d, J=9.3 Hz, IH), 4.09 (q, J=7.2 Hz, 2H), 3.65 (q, J=6.3 Hz, 2H), 3.10 (s, 2H), 2.61 - 2.78 (m, 3H), 1.77 (s, 3H), 1.10 - 1.22 (m, 3H). 160b) Ethyl 3- {5-racetyl(methyl)amino ^" |-2-ammo- lH-benzimidazol- 1 -yljpropanoate

Ethyl N- {4-[acetyl(methyl)amino]-2-nitrophenyl}-β-alaninate (0.94 g, 3.04 mmol) and Pd/C (0.29 g, 0.274 mmol) were dissolved in 25 mL EtOH under a blanket of argon. The contents were then stirred under an atmosphere of hydrogen (1 atm) at room temperature for 18 h, after which time a complete reaction as indicated by LC/MS analysis was observed. The contents were purged with argon, and the nearly black suspension then filtered through a thin pad of Celite. The pad was washed with an additional 10 mL MeOH. The combined filtrates were transferred to a 250 mL round bottom flask, followed by addition of cyanogen bromide (0.438 g, 4.56 mmol). After stirring at room temperature for 2 h, the contents were concentrated in vacuo. The crude residue was diluted with 9:1 CΗCl ₃ /MeOΗ (50 mL), treated with Silicylce ammonium carbonate resin (3 g), and stirred at 37°C for 30 min. The mixture was cooled to room temperature and then filtered through Celite, washing with 10% MeOH/CHCl ₃ . The volatiles were removed in vacuo and the residue dried under hi-vacuum. The crude residue was treated with 7 mL DCM, sonicated at RT, and then placed in freezer for 1 h. The solution was removed and filtered to afford a minor amount of a sticky solid. The filtrate was concentrated in vacuo. The crude residue purified by silica gel chromatography (eluent: l%NH ₄ 0H/9%Me0H/CHCl ₃ ) and furnished the final product as a white solid (0.40 g, 43% overall). LC-MS (ES) m/z = 304.7 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 7.19 (d, J=8.3 Hz, IH), 7.02 (d, J=2.0 Hz, 1 H), 6.79 (dd, J=8.0, 2.0 Hz, IH), 6.56 (s, 2H), 4.23, (t, J=7.0 Hz, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.13 (s, 3H), 2.71 (t, J=6.9 Hz, 2H), 1.72 (s, 3H), 1.10 (t, J=7.0 Hz, 3H).

160c) Ethyl 3-{5-racetyl(methyl)aminol-2-r({3- r(phenylsulfonyl)aminolphenyl}carbonyl)aminol-lH-benzimidazo l-l-yl}propanoate

Ethyl 3-{5-[acetyl(methyl)amino]-2-amino-lΗ-benzimidazol-l-yl}pro panoate (.30 g, 0.99 mmol) and 3-[(phenylsulfonyl)amino]benzoic acid (0.328 g, 1.18 mmol) were dissolved in DMF (10 mL). DIEA (0.38 ml, 2.17 mmol) and then solid TBTU (0.38 g, 1.18 mmol) were added, and the mixture stirred at room temperature for 2 h. The reaction mixutre was poured onto water/ice (150 mL) and stirred for 15 min, wherein solid precipitation was observed. The heterogenous mixture was extracted with EtOAc (2x). The combined organic layers were washed with 10% aq. LiCl and then dried over MgSO ₄ . The contents were filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: l%NH ₄ 0H/9%Me0H/CHCl ₃ ). The isolated product was suspended in MTBE, sonicated, and then concentrated in vacuo. The product was dried in vacuum oven, and obtained as an off-white solid (0.54g, 92%). LC-MS (ES) m/z = 564.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.79 (br. s., IH), 10.46 (s, IH), 8.02 (s, IH), 7.75 - 7.94 (m, 3H), 7.49 - 7.68 (m, 4H), 7.28 - 7.42 (m, 2H), 7.23 (d, J=8.0 Hz, 2H), 4.47 (t, J=6.5 Hz, 2H), 3.95 (q, J=7.2 Hz, 2H), 3.16 (s, 3H), 2.93 (t, J=6.6 Hz, 2H), 1.75 (s, 3H), 0.97 - 1.07 (m, 3H).

16Od) 3-(S-rAcetylfmethvnaminol-2-rf(3- r(phenylsulfonyl)aminolphenyl}carbonyl)aminol-lH-benzimidazo l-l-yl}propanoic acid

Ethyl 3- {5-[acetyl(methyl)amino]-2-[({3-

[(phenylsulfonyl)amino]phenyl}carbonyl)amino]-lΗ-benzimi dazol-l-yl}propanoate (0.48 g, 0.85 mmol) was dissovled in ethanol (10 ml) and THF (2 mL), followed by addition of NaOH (1.42 ml, 4.3 mmol) via syringe. After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo to dryness. The residue was suspended in water (5 mL) and adjusted to pH 5 with IN HCl. The heterogenous mixture was extracted with hot THF/EtOAc (1 :4), and the combined organic layers were dried over MgSO ₄ , filtered, and concentrated in vacuo. The isolated solid was suspended in water (10 mL), stirred for 30 min, and vacuum filtered. After drying in vacuum oven at 45°C for 12 h, the product was collected as a nearly white solid (0.29 g, 62% yield). LC-MS (ES) m/z = 535.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.78 (br. s., 2 H), 10.47 (br. s., 1 H), 8.00 (s, 1 H), 7.89 (d, J=7.58 Hz, 1 H), 7.74 - 7.85 (m, 2 H), 7.50 - 7.68 (m, 4 H), 7.29 - 7.43 (m,2 H), 7.12 - 7.29 (m, 2 H), 4.42 (t, J=6.82 Hz, 2 H), 3.16 (s, 3 H), 2.76 - 2.93 (m, 2 H), 1.75 (s, 3 H).

16Oe) The title compound was prepared from 3-{5-[acetyl(methyl)amino]-2-[({3- [(phenylsulfony^aminolphenyljcarbony^aminol-lH-benzimidazol- l-yljpropanoic acid (0. H g, 0.21 mmol), ammonium chloride (0.220 g, 4.11 mmol), HOAT (0.070 g, 0.513 mmol), EDC (0.098 g, 0.513 mmol), NMM (0.565 ml, 5.13 mmol), and DMSO (2.5 mL) substantially according to the procedure of Example 7, step f, with a reaction stir time of 20 h. The product was collected as a white solid (0.10 g, 89 % yield). LC-MS (ES) m/z = 535.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.78 (br. s., IH), 10.46 (s, IH), 7.88 - 8.06 (m, 2H), 7.74 - 7.87 (m, 2H), 7.50 - 7.68 (m, 4H), 7.28 - 7.49 (m, 3H), 7.16 - 7.28 (m, 2H), 6.93 (br. s., IH), 4.41 (t, J=6.7 Hz, 2H), 3.16 (s, 3 H), 2.65 (t, J=6.7 Hz, 2H), 1.75 (s, 3H).

Example 161 N-[6-(Acetylamino)-l-propyl-lH-benzimidazol-2-yl]-3-

[(phenylsulfonyl)amino]benzamide

161a) N-(5-Chloro-2-nitrophenyl)acetamide

N-(3-Chlorophenyl)acetamide (6.2 g, 36.6 mmol) in acetic acid (16.2 ml, 283 mmol) and

Η ₂ SO ₄ (10 mL, 188 mmol) was stirred at 0 ⁰ C followed by dropwise addition of nitric acid (2.0 ml, 44.8 mmol). The solution was stirred at room temperature for 18 h and then poured onto ice water. The precipitated solid was collected by vacuum filtration, affording a mixture of 2-nitro and 4- nitro regioisomers in nearly equal ratio. The mixture was separated by silica gel chromatography (eluent: EtOAc/ hexane) affording the less polar isomer (2.38 g, 30%) and more polar isomer (2.43g, 31%) in nearly equal amounts. Subsequent reactivity studies for each separated isomer would establish the less polar isomer as the 2-nitro, and the more polar isomer as the 5-nitro isomer. LC-MS (ES) m/z = 214.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.36 (s, IH), 7.99 (d, J = 6 Hz, IH), 7.82 (s, IH), 7.42 (d, J = 6.0 Hz, IH), 2.10 (s, 3H). 161b) N-r2-Nitro-5-(propylammo)phenyl1acetamide

N-(3-Chloro-4-nitrophenyl)acetamide (0.50 g, 2.33 mmol) and K ₂ CO3 were suspended in NMP (5 mL) at room temperature followed by addition of n-propylamine (0.575 mL, 6.99 mmol) to the stirring mixture. The contents were stirred at 50 ⁰ C for 18 h then at 65°C for 8 h. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO/t, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 10 - 70% EtOAc/hexanes) to afford the final product as a yellow solid (0.340 g, 62%). LC-MS (ES) m/z = 237.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 10.32 (s, IH), 8.19-8.33 (br s, IH), 8.02 (d, J = 8 Hz, IH), 7.48 (s, IH), 6.78 (d, J = 8.0 Hz, IH), 3.22 (t, J = 6.9 Hz, 2H), 2.10 (s, 3H), 1.57-1.77 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

161c) N-(2 -Amino- 1 -propyl- lH-benzimidazol-6-yl)acetamide

The product was prepared from N-[2-nitro-5-(propylamino)phenyl]acetamide (0.900 g,

3.79 mmol), palladium on carbon (10%, 0.100 g, 0.940 mmol), and cyanogen bromide (0.402 g, 3.79 mmol) substantially according to the procedures of Example 7, steps c-d, wherein the reaction stir times were 1 h for both steps. The product was collected as a dark solid (0.465g, 53% overall). LC-MS (ES) m/z = 232.8 (M+Η) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 9.74 (s, IH), 7.53 (s, IH), 6.96-7.02 (m, 2H), 6.29 (s, 2H), 3.84 (t, J = 6.9 Hz, 2H), 2.01 (s, 3H), 1.59-1.68 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H).

161 d) The title compound was prepared from N-(2-amino- 1 -propyl- lH-benzimidazol-6- yl)acetamide (0.100 g, 0.431 mmol), 3-[(phenylsulfonyl)amino]benzoic acid (0.155 g, 0.560 mmol), EDC (0.197 g, 0.560 mmol), ΗOAT (0.076 g, 0.560 mmol) and NMM (0.062 mL, 0.560 mmol) substantially according to the procedure of Example 7, step f. The crude product was purified by reverse phase ΗPLC and was collected as a nearly white solid (0.076 g, 35%). LC-MS (ES) m/z = 492.1 (M+Η) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 12.66 (s, IH), 10.45 (s, IH), 10.07 (s, IH), 8.04 (s, IH), 7.91 (s, IH), 7.86 (d, J = 8.0 Hz, IH), 7.79 (d, J = 8.0 Hz, 2H), 7.51- 7.66 (m, 3H), 7.41 (d, J = 8.0 Hz, IH), 7.28-7.37 (m, IH), 7.16-7.27 (m, 2H), 4.14 (t, J = 6.9 Hz, 2H), 2.06 (s, 3H), 1.79-1.85 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

Example 162 N- {6-[Acetyl(methyl)amino]- 1 -propyl- lH-benzimidazol-2-yl} -3-

[(phenylsulfonyl)amino]benzamide

162a) N-(3-Chloro-4-nitrophenyl)-N-methylacetamide

To a stirred ice-cooled solution of Ν-(3-chloro-4-nitrophenyl)acetamide (0.80 g, 3.73 mmol) in DMF (5 mL) was added NaH (0.186 g, 4.66 mmol, 60% in hexanes). The ice bath was removed and the mixture stirred for 15 min. The solution was cooled, and iodomethane (0.350 mL, 5.59 mmol) was added. The ice bath was removed and the mixture stirred for 30 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSθ ₄ , and concentrated in vacuo. The product was collected as an off- white solid (0.865g, 100%). LC-MS (ES) m/z = 228.9 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.13 (d, J = 8.0 Hz, IH), 7.87 (s, IH), 7.59 (d, J = 8.0 Hz, IH), 3.27 (s, 3H), 2.03 (s, 3H). 162b) N-Methyl-N- r4-nitro-3 -(propylamino)phenyll acetamide

N-(3-Chloro-4-nitrophenyl)-N-methylacetamide (0.800 g, 3.50 mmol) and K ₂ CO ₃ (1.45g,

10.5 mmol) were suspended in ΝMP (5 mL) at room temperature followed by addition of n- propylamine (0.863 ml, 10.5 mmol) to the stirring mixture. The contents were stirred at room temperature for 18 h then at 70 ⁰ C for 5 h. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: 10 - 70% EtOAc/hexanes) to afford the final product as a yellow solid (0.615 g, 70%). LC-MS (ES) m/z = 251.7 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.24 (s, IH), 8.08 (d, J = 8.0 Hz, IH), 7.01 (s, IH), 6.63 (d, J = 8.0 Hz, IH), 3.26-3.43 (m, 2H), 3.20 (s, 3H), 1.97 (s, 3H), 1.54-1.71 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 162c) N-(2 -Amino- 1 -propyl- lH-benzimidazol-6-yD-N-methylacetamide

A solution of N-methyl-N-[4-nitro-3-(propylamino)phenyl]acetamide (600 mg, 2.388 mmol) in Ethanol (100 mL) was purged with argon, then Pd/C (60 mg, 0.564 mmol) was added. The mixture was stirred under an atmosphere of hydrogen (1 arm) for 18 h, after which time LCMS indicated a completed reaction. The mixture was purged with argon, Celite was added, and the mixture filtered. The filtrate was treated with cyanogen bromide (365 mg, 3.45 mmol) and stirred for 4 h at room temperature. The volatiles were removed, and the residue dissolved in water. The mixture was made basic with 6N NaOH (1 mL), and then extracted with EtOAc. The organic extract was washed with brine, dried over MgSO ₄ , and concentrated in vacuo. The residue was triturated from chloroform to give the desired product as a solid (0.376g, 66% overall). LC- MS (ES) m/z = 246.9 (M+Η) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.16 (s, IH), 7.09 (d, J = 8.0 Hz, IH), 6.82 (d, J = 8.0 Hz, IH), 6.50 (s, 2H), 3.91 (t, J = 6.9 Hz, 2H), 3.15 (s, 3H), 1.73 (s, 3H), 1.55-1.70 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H).

162d) The title compound was prepared from N-(2-amino-l -propyl- lH-benzimidazol-6- yl)-N-methylacetamide (0.159 g, 0.609 mmol), 3-[(phenylsulfonyl)amino]benzoic acid (0.220 g, 0.792 mmol), EDC (0.152 g, 0.792 mmol), ΗOAT (0.108 g, 0.792 mmol) and NMM (0.087 mL, 0.792 mmol) substantially according to the procedure of example 7 step f. The crude product was purified by reverse phase ΗPLC. The product was collected as a nearly white solid (0.162 g, 53%). LC-MS (ES) m/z = 505.9 (M+Η) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.78 (s, 1 H), 10.45 (s, 1 H), 8.01 - 8.12 (m, 1 H), 7.88 (d, J=7.6 Hz, IH), 7.76 - 7.84 (m, 2H), 7.48 - 7.68 (m, 5H), 7.32 (t, J=7.8 Hz, IH), 7.12 - 7.25 (m, 2H), 4.20 (t, J=7.1 Hz, 2H), 3.19 (s, 3H), 1.71 - 1.92 (m, 5H), 0.94 (t, J=7.3 Hz, 3H). Example 163

2-[({3-[(Phenylsulfonyl)amino]phenyl}carbonyl)amino]-l -propyl- lH-benzimidazole-5- carboxylic acid

163a) 1 , 1 -Dimethylethyl 4-fluoro-3-nitrobenzoate

4-Fluoro-3-nitrobenzoic acid (5.O g, 27.0 mmol) was dissolved in diethyl ether (70 mL) followed by addition of tert-butyl 2,2,2-trichloroacetimidate (6.05 ml, 32.4 mmol). BF ₃ OEt ₂ (0.137 mL, 1.08 mmol) was added dropwise via syringe, and the contents were stirred at room temperature overnight. Solid NaHCO ₃ (1.5 g) was added, and the mixture was stirred for an additional 30 min. The reaction mixture was diluted with ether, and the contents then concentrated in vacuo to dryness. The crude residue was purified by silica gel chromatography (eluent: 5-10% EtOAc in hexanes) to afford the product as an oil which solidifies on hi-vacuum drying (3.78 g, 58%). LC-MS (ES) m/z = 185.5 (M - t-butyl) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (dd, J=I.3, 2.0 Hz, IH), 8.28 (ddd, J=8.6, 4.29, 2.3 Hz, IH), 7.73 (dd, J=I L l, 8.8 Hz, IH), 1.59 (s, 9 H).

163b) 1.1 -Dimethylethyl 3-nitro-4-(propylamino)benzoate

1 , 1 -Dimethylethyl 4-fluoro-3-nitrobenzoate (3.78 g, 15.67 mmol) was dissolved in 100 mL THF and the stirring solution cooled in an ice bath for 15 min, followed by addition of n- propylamine (2.74 ml, 32.9 mmol) via syringe. The stirring solution was allowed to warm to room temperature, and then stirred overnight. The reaction mixture was concentrated to dryness, and the residue dissolved in EtOAc (100 mL) and brine (100 mL). The layers were separated, and the aqueous layer extracted with additional EtOAc (100 mL). The combined organic layers were dried over MgSO/t, filtered, and concentrated in vacuo. The collected product was dried on hi-vac pump at room temperature for 4 h to afford the product as a yellow-orange solid (4.28 g, 97%). LC-MS (ES) m/z = 281.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 - 8.64 (m, 2 H), 7.92 (dd, J=8.8, 2.0 Hz, IH), 7.13 (d, J=9.4 Hz, IH), 3.35 - 3.45 (m, 2H), 1.59 - 1.71 (m, 2H), 1.48 - 1.59 (m, 9H), 0.94 (t, J=7.3 Hz, 3H).

163c) 1 , 1 -Dimethylethyl 3-amino-4-(propylamino)benzoate

To a 500 mL Parr vessel under argon stream was introduced 10% palladium on carbon

(.50 g, 0.470 mmol) as a solid and 2 mL ethanol. 1,1 -Dimethylethyl 3-nitro-4- (propylamino)benzoate (4.26 g, 15.2 mmol) was added as an 80 mL ethanol solution to the Parr vessel. The reaction mixture was shaken at 45 psi hydrogen gas for 90 min. The reaction mixture was then filtered through a thin pad of Celite, and the filter pad washed with additional 10% MeOH/CH ₂ Cl ₂ . The combined dark filtrates were concentrated in vacuo and dried on hi-vac for 1 h to afford the product as a solid (4.2, 100%). LC-MS (ES) m/z = 250.9 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 7.04 - 7.19 (m, 2H), 6.39 (d, J=8.3 Hz, IH), 5.12 (br. s., IH), 4.81 (br.s., 2H), 3.05 (t, J=7.1 Hz, 2H), 1.61 (sxt, J=7.3 Hz, 2H), 1.44 - 1.54 (m, 9H), 0.95 (t, J=7.5 Hz, 3H). 163d) 1.1 -Dimethylethyl 2-amino- 1 -propyl- lH-benzimidazole-5-carboxylate

1 , 1 -Dimethylethyl 3-amino-4-(propylamino)benzoate (4.0 g, 14.38 mmol) was dissolved in MeOH (100 mL) and stirred for 15 min. Cyanogen bromide (2.29 g, 21.6 mmol) was added at once and the contents were allowed to stir at room temperature for 2 h. The reaction mixture was concentrated in vacuo to dryness. The residue was suspended in EtOAc (50 mL) and washed with IM NaOH (50 mL). The layers were separated, and the aqueous layer back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSOzt, filtered, and concentrated in vacuo to dryness. The collected solid was triturated with 40 mL cold DCM, and isolated as an off-white solid (3.5 g, 88 %). LC-MS (ES) m/z = 219.9 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (d, J=1.3 Hz, IH), 7.51 (dd, J=8.3, 1.5 Hz, IH), 7.20 (d, J=8.3 Hz, IH), 6.57 - 6.78 (m, 2H), 3.96 (t, J=7.2 Hz, 2H), 1.59 - 1.74 (m, 2H), 1.54 (s, 9H), 0.86 (t, J=7.3 Hz, 3H). 163e) 1 , 1 -Dimethylethyl 2-r({3-r(phenylsulfonyl)ammo1phenyl}carbonyl)ammo ^" |- 1 - propyl- lH-benzimidazole-5-carboxylate

1 , 1 -Dimethylethyl 2-amino-l -propyl- lH-benzimidazole-5-carboxylate (1.15 g, 4.18 mmol) was dissolved in 10 mL DMSO, followed by sequential addition of 3-

[(phenylsulfonyl)amino]benzoic acid (1.27 g, 4.59 mmol), EDC (0.961 g, 5.01 mmol), and ΗOAT (0.682 g, 5.01 mmol). NMM (0.689 ml, 6.26 mmol) was added and the contents were allowed to stir at room temperature for 12 h. Additional EDC (0.961 g, 5.01 mmol), ΗOAT (0.682 g, 5.01 mmol), and NMM (0.550 mL, 6.26 mmol) were added, and the contents were allowed to stir at room temperature for 4 h. The reaction mixture was poured onto water (130 mL) and stirred for 5 min. The heterogenous mixture was allowed to stand at room temperature for 20 min, and then filtered. The crude solid was purified by silica gel chromatography (eluent: 2-8% MeOH in CHCl ₃ ) to afford the product as an off-white solid (1.6 g, 72%). LC-MS (ES) m/z = 535.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1 H), 10.47 (s, IH), 7.99 - 8.17 (m, 2H), 7.73 - 7.94 (m, 4H), 7.50 - 7.69 (m, 4H), 7.33 (t, J=7.8 Hz, IH), 7.18 - 7.29 (m, IH), 4.23 (t, J=6.8 Hz, 2H), 1.77 - 1.92 (m, 2H), 1.57 (s, 9H), 0.93 (t, J=7.45 Hz, 3H).

163 f) 1,1 -Dimethylethyl 2- [( {3 - [(phenylsulfonyl)amino]phenyl} carbonyl)amino] - 1 - propyl-lH-benzimidazole-5-carboxylate (1.52 g, 2.84 mmol) was dissolved in 30 mL CΗ ₂ CI ₂ , followed by addition of TFA (6.57 ml, 85 mmol). The reaction mixture was stirred at room temperature overnight, after which time the volatiles were removed in vacuo. The residue was suspended in toluene (100 mL) and the solvent removed to afford a tan solid. The solid was dissolved in water and carefully adjusted to pH 7 with aq. saturated NaHCO ₃ , and stirred for 15 min. The heterogenous contents were filtered, and the solid obtained dissolved in EtOAc/THF (1 : 1, 50 mL). The organic layer was washed with brine (50 mL), and the layers were separated. The organic layer was dried over MgSOzt, filtered, and concentrated in vacuo. The collected solid was dried on hi-vac for 2 h to afford the final product, the title compound, as a tan solid (1.32 g, 96%). LC-MS (ES) m/z = 478.8 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (br. s., 2H), 10.46 (s, IH), 7.99 - 8.15 (m, 2H), 7.72 - 7.95, (m, 4H), 7.49 - 7.68 (m, 4H), 7.33, (t, J=7.8 Hz, IH), 7.23 (dd, J=8.0, 1.1 Hz, IH), 4.23 (t, J=6.8 Hz, 2H), 1.78 - 1.90 (m, 2H), 0.93 (t, J=7.5 Hz, 3H). Example 164

2-[({3-[(Phenylsulfonyl)amino]phenyl}carbonyl)amino]-l -propyl- lH-benzimidazole-6- carboxylic acid

164a) 1 , 1 -Dimethylethyl 3-fluoro-4-nitrobenzoate

The product was prepared from 3-fluoro-4-nitrobenzoic acid (5.13 g, 27.7 mmol), tert- butyl 2,2,2-trichloroacetimidate (6.200 ml, 33.2 mmol, 1.2 eq), and BF ₃ OEt ₂ (0.140 ml, 1.108 mmol) substantially according to the procedure of Example 163, step a. The product was obtained as an off-white solid. LC-MS (ES) m/z = 185.5 (M - t-butyl) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 8.51 (dd, J=7.3, 2.0 Hz, IH), 8.28 (ddd, J=8.6, 4.3, 2.3 Hz, IH), 7.73 (dd, J=I 1.1, 8.8 Hz, IH), 1.59 (s, 9H).

164b) The product was prepared from 1,1 -dimethylethyl 3-fluoro-4-nitrobenzoate (4.0 g, 16.6 mmol) and n-propylamine (2.0 g, 34.0 mmol) substantially according to the procedure of Example 163, step b. The product was obtained as a yellow-orange solid (4.3g, 93%). LC-MS (ES) m/z = 281.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 8.05 - 8.20 (m, 2H), 7.46 (d, J=I.8 Hz, IH), 7.08 (dd, J=9.0, 1.6 Hz, IH), 3.34 - 3.40 (m, 2H), 1.60 - 1.74 (m, 2H), 1.50 - 1.59 (m, 9H), 0.96 (t, J=7.3 Hz, 3H).

164c) 1 , 1 -Dimethylethyl 4-amino-3-(propylamino)benzoate

The product was prepared from 1,1 -dimethylethyl 4-nitro-3-(propylamino)benzoate (4.63 g, 161.5 mmol) and 10% palladium on carbon (0.879 g, 0.826 mmol), according to the procedure of Example 163, step c. The product was obtained as a solid (4.13g, 100%). LC-MS (ES) m/z = 250.3 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.07 (dd, J=8.1, 2.0 Hz, IH), 6.92 (d, J=1.8 Hz, IH), 6.50 (d, J=8.1 Hz, IH), 5.32 (s, 2H), 4.53 (t, J=5.3 Hz, IH), 2.93 - 3.06 (m, 2H), 1.57 - 1.68 (m, 2H), 1.42 - 1.53 (m, 9H), 0.97 (t, J=7.3 Hz, 3H).

164d) 1 , 1 -Dimethylethyl 2-amino- 1 -propyl- lH-benzimidazole-6-carboxylate

The product was prepared from 1,1 -dimethylethyl 4-amino-3-(propylamino)benzoate (4.17 g, 16.7 mmol) and cyanogen bromide (2.65 g, 25.0 mmol), according to the procedure of Example 163, step d. The product was obtained as a solid (3.61g, 79%). LC-MS (ES) m/z = 276.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 7.63 (d, J=I.5 Hz, IH), 7.57 (dd, J=8.2, 1.6 Hz, IH), 7.11 (d, J=8.3 Hz, IH), 6.79 (s, 2H), 3.97 (t, J=7.2 Hz, 2H), 1.60 - 1.73 (m, 2H), 1.54 (s, 9H), 0.88 (t, J=7.3 Hz, 3H).

164e) 1.1 -Dimethylethyl 2-r({3-r(phenylsulfonyl)aminolphenvUcarbonyl)aminol- 1 - propyl- lH-benzimidazole-6-carboxylate

The product was prepared from 1 , 1 -dimethylethyl 2-amino- 1 -propyl- lH-benzimidazole-6- carboxylate (1.15 g, 4.18 mmol), 3-[(phenylsulfonyl)amino]benzoic acid (1.74 g, 6.26 mmol), EDC (1.68 g, 8.77 mmol), ΗOAT (1.19 g, 8.77 mmol), and NMM (1.38 ml, 12.5 mmol) substantially according to the procedure of Example 163, step e. The product was collected as an off-white solid (1.6 g, 71%). LC-MS (ES) m/z = 535.0 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.93 (br. s., IH), 10.46 (s, IH), 8.07 (s, IH), 7.96 (s, 1 H), 7.75 - 7.92 (m, 4H), 7.49 - 7.65 (m, 4H), 7.33 (t, J=7.8 Hz, IH), 7.18 - 7.28 (m, IH), 4.26 (t, J=7.0 Hz, 2H), 1.76 - 1.92 (m, 2H), 1.52 - 1.64 (m, 9H), 0.82 - 1.04 (m, 3H).

164f) The title compound was prepared from 1 , 1 -dimethylethyl 2- [( {3 - [(phenylsulfonyl)amino]phenyl}carbonyl)amino]-l -propyl- lH-benzimidazole-6-carboxy late ( 1.51 g, 2.82 mmol) and TFA (10.9 mL, 141 mmol) substantially according to the procedure of Example 163, step e, wherein the isolated product was dried under hi-vacuum for 20 h. The product was collected as an off-white solid (1.34g, 99%). LC-MS (ES) m/z = 478.8 (M + H) ^{+ 1} H NMR (400 MHz, DMSOd ₆ ) δ 12.93 (br. s., 2H), 10.46 (s, 1 H), 7.96 - 8.14 (m, 2H), 7.73 - 7.93 (m, 4H), 7.49 - 7.67 (m, 4H), 7.33 (t, J=7.8 Hz, IH), 7.16 - 7.28 (m, IH), 4.26 (t, J=7.1 Hz, 2H), 1.73 - 1.91 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).

Example 165

N-[5-(4-Morpholinylcarbonyl)- 1 -propyl- lH-benzimidazol-2-yl]-3- [(phenylsulfonyl)amino]benzamide

2-[({3-[(Phenylsulfonyl)amino]phenyl}carbonyl)amino]-l -propyl- lH-benzimidazole-5- carboxylic acid (.096 g, 0.201 mmol), morpholine (0.035 ml, 0.401 mmol), EDC (0.058 g, 0.301 mmol), and ΗOAT (0.041 g, 0.301 mmol) were dissolved in DMSO (3.0 ml). Next added was

NMM (0.066 ml, 0.602 mmol) and the mixture stirred at room temperature for 24 h. The reaction mixture was poured onto water (30 mL), stirred for 5 min., and then extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated in vacuo. The crude solid was purified by silica gel chromatography (eluent: l%NΗ ₄ 0Η/9%Me0Η/CΗCl3). The product was concentrated from MTBE and dried in vacuo to afford the final product, the title compound, as a white solid (45 mg, 41%). LC-MS (ES) m/z = 548.1 (M + H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.81 (s, IH), 10.45 (s, IH), 8.06 (s, 1 H), 7.74 - 7.93 (m, 3H), 7.50 - 7.69 (m, 5H), 7.27 - 7.38 (m, 2H), 7.18 - 7.27 (m, IH), 4.22 (t, J=7.0 Hz, 2H), 3.62 (br. s., 8H), 1.75 - 1.91 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). The aminobenzimidazole carboxamide compounds illustrated in table 5 were prepared from either the 5- or 6-carboxylates of 1,1-dimethylethyl 2-[({3

[(phenylsulfonyl)amino]phenyl}carbonyl)amino]-l-propyl-lH -benzimidazole and various amines substantially according to the procedure of Example 165. In the following table, the dashed lines indicate point of attachment. The position number listed corresponds to the attachment point on the molecule as per the numbering shown. Thus, for Example 166, the compound corresponds to the following structure:

Table 5 Biochemical assay for FAK activity

GST-tagged FAK (GST - glutathione-S-transferase) was purchased from Invitrogen [www.Invitrogen.com]. The activity of FAK was measured by monitoring the phosphorylation of the tyrosine residues of the FAK-tide substrate (PerkinElmer CUSN64935, NH ₂ -(ULight™)- CSETDDYAEIID-COOH, i.e - NH2-Cysteine(S-ULight)-Serine-Glutamic Acid-Threonine- Aspartic Acid-Aspartic Acid- Tyrosine -Alanine-Glutamic Acid-Isoleucine-Isoleucine-Aspatic Acid-COOH) in the presence of ATP and peptide. To measure inhibitors of FAK, compounds were first prepared as a 10Ox stock in 100 % DMSO. A small portion of each solution (50 nL) was added to a 384-well plate (Greiner Bio-one GmbH, Frichenhausen, Germany; http://www.selectscience.net/?u=C362B921-4E9D-4021-93ED-A3AE DF036EE9: 784076). A 1.2 nM GST-FAK solution was prepared in 1 x reaction buffer containing 40 mM Tris/Tris-HCl pH=7.5, 10 mM MgCl ₂ , 1 mM DTT and 3 mM CHAPS. Then, 5 μL of the 1.2 nM GST-FAK solution was preincubated with the compounds for 30 minutes at room temperature. The reaction was initiated by adding 5 μL of substrate (100 nM FAK-tide substrate and 10 μM ATP) prepared in the above reaction buffer. The plates were centrifuged at 500 RPM for one minute and the reaction was allowed to proceed at room temperature for 120 minutes. The reaction was quenched with 5 μL of Stop and Detect solution containing 20 mM EDTA and 5 nM LANCE ^® Eu-W 1024 Anti-pTry Antibody (PerkinElmer PT66) in Ix LANCE ^® Detection Buffer (PerkinElmer CR97- 100; http://www.perkinelmer.com/default.htm). The plates were centrifuged at 500 RPM for one minute and allowed to develop at room temperature for 30 minutes. The time-resolved fluorescence was measured on a ViewLux plate imager (PerkinElmer) using 320-340 nm cutoff excitation and 615 and 665 nm cutoff emission filters. In this assay, the compounds set out in Examples 1-72, 160-179 had an IC ₅ O range between -300 nM and 2 nM.

Biochemical assay for FAK activity

Flag-His-TEV-FAKl was prepared in-house. The activity of FAK was measured by monitoring the phosphorylation of LANCE Ultra NH2-(ULight)-CSETDDYAEIID-COOH substrate (purchased from Perkin Elmer Life Sciences). To measure inhibitors of FAK, compounds were first prepared as a IOOX stock in 100% DMSO. A small portion of each compound solution (50 nL) was added to a black 384-well low-volume microtiter plate (Greiner 784076). A 1.2nM Flag-His-TEV-FAKl solution was prepared in IX reaction buffer containing 4OmM Tris/Tris-HCL, 1OmM MgC12, ImM CHAPS, at a pH of 7.5, with ImM DTT added. 2.5ul of the 1.2 nM Flag-FAK solution was added to the plates and pre-incubated with the compounds for 30 min at room temperature. Then, 2.5 μL of substrate solution (0.1 μM of P2 FAK-tide specific substrate (Lance Ultra NH2-(ULight)-CSETDDYAEIID-COOH from Perkin Elmer), lOμM ATP and the Ix reaction buffer described above), was added to the plate to initiate the reaction. After incubating for 120 minutes at room temperature, the reaction is quenched by adding 5 uL of 2OmM EDTA and 5nMEu-Anti-pTyr antibody in IX LANCE detection buffer. After a 30 minute incubation at room temperature, the plate is read on a Perkin Elmer Viewlux with a 320- 340nm excitation filter and measuring emission at 615nm and 665nm. The ratio of 665nm/615nm is used for data normalization. In this assay, the compounds set out in Examples 73-76, 84-159 had an IC ₅ O range between -500 nM and 2 nM.

The foregoing examples and assay have been set forth to illustrate the invention, not limit it. What is reserved to the inventors is to be determined by reference to the claims.