ZA200609808B

ZA200609808B - Certain chemical entities, compositions and methods

Info

Publication number: ZA200609808B
Application number: ZA200609808A
Authority: ZA
Inventors: Qian Xiangping; Andrew I Mcdonald; Zhou Han-Jie; Luke W Ashcraft; Yao Bing; Jiang Hong; Huang Jenifer Kuo Chen; Wang Jianchao; Morgans David J Jr; Bradley P Morgan; Bergnes Gustave; Dhanak Dashyant; Steven D Knight; Nicholas D Adams; Cynthia A Parrish; Duffy Kevin; Fitch Duke; Tedesco Rosanna
Original assignee: Cytokinetics Inc; Smithkline Beecham Corp
Priority date: 2004-05-06
Filing date: 2006-11-24
Publication date: 2008-01-30
Also published as: CN101023057A

Description

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS 0001] This application claims the benefit of U.S. Patent Application No. 60/569,510, filed May 6, 2004, which is hereby incorporated by reference.

[0002] This invention relates to chemical entities which are inhibitors of one or more mi totic kinesins and are useful in the treatment of cellular proliferative diseases, for example cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders, fungal disorders, and inflammation.

[0003] Among the therapeutic agents used to treat cancer are the taxanes and vinca alkaloids, which act on microtubules. Microtubules are the primary structural element of the mitotic spindle. The mitotic spindle is responsible for distribution of replicate copies of the genome to each of the two daughter cells that result from cell division. It is presumed that disruption of the mitotic spindle by these drugs results in inhibition of cancer cell division, and induction of cancer cell death. However, microtubules form other types of cellular stzuctures, including tracks for intracellular transport in nerve processes. Because these agents do not specifically target mitotic spindles, they have side effects that limit their usefulness. [G004) Improvements in the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms. Examples of this include not only the taxanes, but also the camptothecin class of topoisomerase I inhibitors. From both of these perspectives, mitotic kinesins are attractive targets for new anti-cancer agents.

[0005] Mitotic kinesins are enzymes essential for assembly and function of the mitotic spindle, but are not generally part of other microtubule structures, such as in nerve processes.

Mitotic kinesins play essential roles during all phases of mitosis. These enzymes are **molecular motors” that transform energy released by hydrolysis of ATP into mechanical force which drives the directional movement of cellular cargoes along microtubules. The : catalytic domain sufficient for this task is a compact structure of approximately 340 amino acids. During mitosis, kinesins organize microtubules into the bipolar structure that is the ritotic spindle. Kinesins mediate movement of chromosomes along spindle microtubules, as well as structural changes in the mitotic spindle associated with specific phases of mitosis.

Ex perimental perturbation of mitotic kinesin function causes malformation or dysfunction of the mitotic spindle, frequently resulting in cell cycle arrest and cell death.

[0006] In one aspect, the invention relates to methods for treating cellular proliferative diseases, and for treating disorders by inhibiting the activity of one or more mi totic kinesins.

[0007] Provided is at least one chem ical entity chosen from compounds of Formula 1

Rs hl

X w

Re oe Sg,

Rp

Formula l arad pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein

Rj is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;

X is -CO or -SO;-;

R5 is hydrogen or optionally substituted lower alkyl;

W is —CRs-, -CH,CRy-, or N;

R 3 is -CO-R,, hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl;

R_,; is hydrogen or optionally substituted alkyl;

R 5 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl;

R ¢ is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteraryloxy, optionally substituted alkoxycarbonyl-, optionally substituted aminocarbonyl-, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aralkyl; and

R; is optionally substituted lower alkyl, optionally substituted aryl, hydroxyl, optionally substituted amino, optionally substituted aralkoxy, or optionally substituted alkoxy.

[0008] In some ermbodiments, if W is N, then Rs is not hydrox yl or optionally substituted amino, and Re is not optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, or optionally substituted amino.

[0009] Also provided is at least one chemical entity chosen from compounds of

Formula II

Rs Re

UY

Riz x NTN Nk

Jo

Rez

R14 (Formula II) and pharmaceutically acceptable salts, solvates, chelates, non-covalerat complexes, prodrugs, and mixtures thereof, wherein Ry, Rs, Rs, Rs, and W are as described for compounds of

Formula I and wherein

Ry, is optionally substituted heterocyclyl, optionally substituted lower alkyl, nitro, cyano, hydrogen, sulfonyl, or halo;

R 2 is hydrogen, halo, optionally substituted alkyl, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optiona lly substituted aryloxy, optionally substituted heterocyclyl, or optionally substituted heteroaryloxy; and

R,3 is hydrogen, acyl, optionally substituted alkyl-, optionally substituted alkoxy, halo, hydroxyl, nitro, cyano, optionally substituted amino, alkylsulfonyl-, alkylsulfonamido-, alkylsulfonyl-, carboxyalkyl-, aminocarbonyl-, optionally substituted aryl or optionally substituted heteroaryl-.

[0010] Also provided is at least one chemical entity chosen from compounds of

Formula ITI

Re oO

LC

A x N Rs

Jo

RZ

Ri (Formula III) and pharmaceuticall y acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, . + and mixtures thereof, wherein Ry, R3, Rs, Ry, Ryz, and Ry are as described for compounds of

Formula Il.

[0011] Also provided is at least one chemical entity chosen from compounds of

Formula IV

Rs o] "A JON

IAN | OH

R

Ry Z ’

Ry4 (Formula IV) and pharmaceutically’ acceptable salts, solvates, chelates, non-co valent complexes, prodrugs, and mixtures thereof, wherein Ry, Re, R11, R12, and Ry; are as de scribed for compounds of

Formula III.

[0012] Also provided is at least one chemical entity chosen from compounds of

Formulay

_F Rig 0 X

Ris

IAN | Rs ~~ _F Ra

Riz

Ris (Formula V) and pharmaceutically acceptable salts, solvates, chelates, no-n-covalent complexes, prodrugs, and mixtures thereof, wherein Rj, Rs, Rij, Riz, and R;3 are as described for compounds of

Formula III and wherein

R 4 is optionally substituted heteroaryl; and

Ris is chosen from hydrogen, halo, hydroxyl, and lovver alkyl.

[0013] Also provided is at least one chemical entity «chosen from compourads of

Formula VI

Rg 0] 0]

R13

SERN N oo | So :

OH a Ra

R12 : R11 (Formula VI) : and pharmaceutically acceptable salts, solvates, chelates, non—covalent complexes, prodrugs, and mixtures thereof, wherein Ry, Re, Ri1, R12, and Ry; are as described for compounds of

Formula IIL

[0014] Also provided is at least one chemical entity ckosen from compounds of

Formula VII

Re 0

R13 J Re

Nx N hi

CTT TT

Riz : R11 (Formula VII) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures tlmereof, wherein Ra, Rg, Ri1, Riz, and Ry 3 are as described for compounds of

Formula III andl wherein

Ro is chosen from optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted arylalkoxy, optionally substituted amino and optionally substinzted lower alkyl. -

[0015] Also provided is composition comprising a pharmaceutical excipient and at least one chem ical entity described herein.

[0016] Also provided is a method of modulating CENP-E kinesin activity which : comprises contacting said kinesin with an effective armount of at least one chemical entity described herein. 10017) Also provided is a method of inhibitin g CENP-E which comprises contacting said kinesin with an effective amount of at least one chemical entity described herein.

[0018] Also provided is a method for the treatment of a cellular proliferative disease comprising ad ministering to a subject in need thereof at least one chemical entity described herein, 0019] Also provided is a method for the trea tment of a cellular proliferative disease comprising ad ministering to a subject in need thereof a composition comprising a pharmaceutical excipient and at least one chemical entity described herein.

[0020] Also provided is the use, in the manufacture of a medicament for treating cellular proliferative disease, of at least one chemical entity of described herein.

[0021] Also provided is the use of at least on.e chemical entity described herein for the manufacture Of a medicament for treating a disorder associated with CENP-E kinesin activity.

[0022] As used in the present specification, the following words and phrases are generally intended to haave the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout:

[0023] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definktion at every other occurrence.

[0024] The fol lowing abbreviations and terms have the indicated meanings throughout: - Ac = acetyl

Boc = t-butyloxy carbonyl

Bu = butyl c- = cyclo :

CBZ = carbobenzoxy = benzyloxycarbony!

DCM = dichloromethane = methylene chloride = CH,C12

DCE = dichloroethane

DEAD = diethyl azodicarboxylate

DIC = diisopropylcarbodiimide

DIEA = N,N-diisopropylethylamine

DMAP = 4-N,N-dimethylaminopyridine

DMF = IN, N-dimethylfonnamide

DMSO = dimethyl sulfoxide

Et = ethyl

Fmoc = 9-fluorenylmethoxycarbonyl

GC = gas chromatography

HATU = O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate

HOAc = acetic acid

HOBt = hydroxybenzotriazole

LAH = lithium aluminum hydride

Me = rmethyl mesyl = rmethanesulfonyl

NCS = IN-chlorosuccinimide

Ph = phenyl

Py = pyridine rt = room temperature sat’d = saturated §- = secondary t- = tertiary

TES = triethylsilyl

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TMS = trimethylsilyl tosyl = p-toluenesulfonyl

[0025] A dash (““*) that is not between two le€&ters or symbols is used to indicate a point of attachment for a substituent. For example, -<CCONHS is attached through the carbon atom.

[0026] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which iat does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing ore or more substituents, that such groups are not intended to introwduce any substitution or stibstitution patterns that are sterically impractical, synthetically non-feasible and/or inherent ly unstable.

[0027] “Alkyl” encompasses straight chain aned branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to § carbon atoms, such as 1 to 6 carbon atoms. For example C;-Cgalkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. Ex_amples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, —pentyl, 2-pentyl, isopentyl , neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. Alkylene is another subset of alkyl, referring to the same residues as alkyl, but having twos points of attachment. Allkylenc groups will usually have from 2 to 20 carbon atoms, for exarraple 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, Co alkylene indicate=s a covalent bond and C, alkylene is a methylene group. When an alkyl residue having a spe=cific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "butyl" is meant to include n-butyl, sec-buty-1, isobutyl and t-butyl; "propyl!" includes n-propyl and isopropyl. “Lower alkyl” refers to alkyl groups having one to four carbons, q

J

[0028] “Cycloalkyl” indicates a saturat ed hydrocarbon ring group, having the specified number of carbon atoms, usually frorm 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as wvell as bridged and caged saturated ring groups such as norbornane.

[0029] By “alkoxy” is meant an alkyl group of the indicated number of cartoon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxs~, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, n.eopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to 6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy groups having one to four carbons.

[0030] “Acyl” refers to the groups (alky)-C(O)-; (cycloalkyl)-C(O)-; (aryl)—C(O)-; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. Accyl groups have the indicated numbeer of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C; acy! group is an acetyl group having the formula CH;(C=Q)-

[0031] By “alkoxycarbonyl” is meant an ester group of the formula (alkoxy) (C=0)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a C;-Cgalkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.

[0032] By “amino” is meant the group -INH,.

[0033] The term “aminocarbonyl” refers to the group -CONRPRS, where

RY is chosen from H, optionally substituted Cy-Cg alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R€ is chosen from hydrogen and optional 1y substituted C;-Cy alkyl; or

RP and R® taken together with the nitrogen to which they are bound, form an optionally substituted S- to 7-membered nitrogen-containin g heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, NI, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C,-C4 alkyl, aryl, heteroaryl, aryl-C,-C; alkyl-, heteroaryl-C,-C, alkyl-, C;-Cq haloalkyl-, -OC,-C, alkyl, -OC;-C4 alkylphenyl, -

Ci-C4 alkyl-OH, -OC,-C, haloalkyl, halo, -OH, -NH,, -C;-C, alkyl-NH,, -N(Cy-Cy4 alkyl)(C,-C, alkyl), -NH(Ci-Cs alkyl), -N(C,-C, alkyl)(C1-C, alkylpihenyl),

-NH(C;-C, alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl), -CO:H, -C(0)OC;-C; alkyl, -CON(C)-C4 alkyl)(Cy-C4 alkyl), -CONH(C,-C4 alkyl), -CONH,, -NHC(O)(C1-C: alkyl), -NHC(O) (phenyl), -NCC)-Cs alkyDC(O)(Cy-Cy alkyl), -N(C;-C, alkyl)C(O)(phenyl), -C(O)C,-C, alk 3, -C(O)C,-C4 phenyl, -C(0)C,-C4 haloalkyl, -OC(O)C,-C, alkyl, -SC,(C-Cs alkyl), -SO. (phenyl), -

SO4(C;-C4 haloalkyl), -SONH3, -SO,NH(C,-€C; alkyl), -SO,NH(phenyl), -

NHSO,(C)-C, alkyl), -NHSO, (phenyl), and -NHSO2(C,-C4 haloalkyl).

[0034] “Aryl” encompasses: 5- and 6-membered carbocyclic aromatic ringss, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetraalin; and tricyclic ring systems wherein at least one rings is carbocyclic and aromatic, for example, fluorene.

For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7- membered heterocycloalkyl ring containing 1 or more= heteroatoms chosen from N, O, and S.

For such fused, bicyclic ring systems wherein only on € of the rings is a carbocyclic arommatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocyclo alkyl ring. Bivalent radicals formed from substituted benze=ne derivatives and having the free valences at ring atoms are named as substituted pheny~lene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free vallence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, oes not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromraatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein,

[0035] The term “aryloxy” refers to the group -O-aryl.

[0036] The term “aralkyl” refers to a residue im which an aryl moiety is attached to the parent structure via an alkyl residue. Examples include benzyl-, phenethyl-, phenylviny/I-, phenylallyl and the like.

[0037] The term “heteroaralkyl” refers to a residue in which a heteroaryl moiety is attached to the parent structure via an alkyl residue. FE-xamples include furanylmethyl-, pyridinylmethyl-, pyrimidinylethyl and the like.

[ 0038] The term “halo” includes fluoro, chloro, bromo, and iodo, and the term ““halogen” includes fluorine, chlorine, bromine, and iodine. [ 0039] “Haloalkyl” indicates alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable raumber of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluorcethyl. [ 0040] “Heteroaryl” encompasses: 5-to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from

N, O, and S, with the remaining ring atoms being carbon; and bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2.

In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3 ,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, imidazopyridinyl, and §,6,7,8-tetrahydroisoquinoline. Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.

[0041] In the term “heteroaralkyl,” heteroaryl and alkyl are as defined herein, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to,

pyridylmethyl, thiophenylmethyl, and (pyrrolyl)1-ethyl.

[0042] A “leaving group” or “atom” is any group or atom that will, under the zeaction conditions, cleave from the starting material, thus promoting reaction at a specified site.

Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.

[0043] “Optional” or “optionally” means that the subsequently described evermt or circumstance may or may not occur, and that the description includes instances wheres said event or circumstances occurs and instances in which it does not. For example, “optionally substituted alkyl” includes “alkyl” and “substituted alkyl” as defined herein. It will bee understood by those skilled in the art with respect to any group containing one or mor-e substituents that such groups are not intended to introduce any substitution or substittation patterns that are sterically impractical and/or synthetically non-feasible and/or inhererntly unstable.

[0044] “Protecting group” has the meaning conventionally associated withit im organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively” on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in

T.H. Greene and P. G. M. Wats, Protective Groups in Organic Synthesis, Third Edition, John

Wiley & Sons, New York (1999), which is incorporated herein by reference in its enti rety.

For example, a hydroxyl protected form is where at least one of the hydroxyl groups present in. a compound is protected with a hydroxyl protecting group. Likewise, amines and cwther reactive groups may similarly be protected.

[0045] By “heterocycloalkyl” is meant a single aliphatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at leasst one of the foregoing heteroatoms. Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolinyl, 2,4-imidazolidimyl, 2,3- pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5-piperzinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered whereim the oxygen is assigned priority 1).

[0046] As used herein, “modulation” refers to a change in CENP-E activity as a direct or indirect response to the presence at least one chemical entity described herein, relative to the activity of CENP-E in the absence of the chemical entity. The <hange may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the chemical entity with CENP-E, or due to the interaction of the compound with one or more other factors that in turn affect CENP-E activity.

[0047] The term “sulfanyl” includes the groups: -S-( optiomally substituted (C;-

Ce)alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Hence, sulfanyl includes the group C;-Cs alkylsulfanyl. {0048] The term “sulfinyl” includes the groups: -S(O)-H, —S(0)-( optionally substituted (C;-Cg)alkyl), -S(0)-optionally substituted aryl), -S(O) -optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S (O)-(optionally substituted amino).

[0049] The term “sulfonyl” includes the groups: -S(02)-H , -S(O;)-( optionally substituted (C-Cg)alkyl), -S(O2)-optionally substituted aryl), -S(O 5)-optionally substituted heteroaryl), -S(O2)-(optionally substituted heterocycloalkyl) ,-S(O2)-(optionally substituted alkoxy), -S(O,)-optionally substituted aryloxy), -S(O;)-optionally substituted heteroaryloxy), ~S(01)-(optionally substituted heterocyclyloxy); and -S(O2)-(optiomally substituted amino).

[0050] The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceede«. When a substituent is 0x0 (i.e., =O) then 2 hydrogens on the atom are replaced. Combimations of substituents and/or variables are permissible only if such combinations result im stable compounds or useful synthetic intennediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility". Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.

[0051] The terms “substituted” alkyl, cycloalkyl, aryl, hetesrocycloalkyl, and heteroaryl, unless otherwise expressly defined, refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from: -R?, -OR®, -O(C;-C; alkyl)O- (e.g., methylenedioxy-), -SRP, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lowewr-alkyl group, -NRPR’, halo, cyano, nitro, -COR®, -CO2R®, -CONR’R’, -OCOR®, -OCO, R®, -OCONR'R’, -NR’COR?, -NR°CO,R?, -NR°CONR'R’, -CO,R”, -CONRPR’, -NR°COR™, -SOR?, -SO:R?, -SO,NR’R®, and -NR°SO,R’, where R® is chosen from optionally substituted C;-Cs alkyl, optioraally substituted aryl, and optionally substituted heteroaryl;

R® is chosen from H, optionally substituted C,-Cs alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R® is chosen from hydrogen and optionally substituted C,-C4 alky]; where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently sselected from

C,-C4 alkyl, aryl, heteroaryl, aryl -C,-C4 alkyl-; heteroaryl-C;-C, alkyl-, C2,-C4 haloalkyl-, -OC,-C, alkyl, -OC;-C,4 alkylphenyl, -C;-C, alkyl-OH, -OC,-C; haloalky~], halo, -OH, -NH,, -C;-C4 alkyl-NH,, -N{C,-C4 alky1}(C;-C4 alkyl), -NH(C,-C4 alkyl), oo -N{(C;-C4 alkyD)(C,-C, alkylphenyl), -NH(C,-C, alkylphenyl), cyano, nitr-o, oxo (as a substitutent for heteroaryl), -COzH, -C(O)OC,-C, alkyl, -CON(C,-C4 alk=y1)(C,-C, alkyl), -CONH(C;-C, alkyl), -CONH;, ~-NHC(O)C;-Cj alkyl), -NHC(O)pheny 1), -N(C-C4 alky)C(OXC-C, alkyl), 2N(C 1-C4 alky)C(O) (phenyl), ~C(O)C;-C4 alkyl, -C(0)C,-C4 phenyl, -C(O)C,-C4 haloalkyl, -OC(O)C;-C4 alkyl, -SO(C1—Ca alkyl), -

SOa(phenyl), -S0,(C1-C4 haloalkyl), -SO,NH,, -SO;NH(C;-C, alkyl), -S O;NH(phenyl), -

NHSO0,(C,-C4 alkyl), -NHSO, (phenyl), and -NHSO,(C,-C4 haloalkyl).

[0052] The term “substituted acyl” refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteeroaryl)-C(O)-; and (substituted heterocycloalkyl)-C (O)-, wherein the group is attached to th. e parent structure through the carbonyl functionality and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one ox more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from: -R?, -OR®, -O(C)-C; alky1)O- (e.g., methylenedioxy-), -SR®, guamidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRPR’, halo, cyano, nitro, -COR?®, -CO:R®, -CONRPR®, -OCOR?, -OCO,R?, -OCONR’R’, -NR°COR’, -NR°CO;R?, -NR°CONRR’, -CO:R®, -CONRR’, -NR°COR", -SOR?, -SO:R?, -SO:NRR’, and -NR°SO;R?,

where R? is chosen from optionally substituted C;-Cs alkyl, optionally substi tuted aryl, and optionally substituted heteroaryl; :

R® is cho sen from H, optionally substituted C ;-C; alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R® is chosen from hydrogen and optionally substituted C,-C, alkyl; where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from

C,-C4 alkyl, aryl | heteroaryl, aryl-C,-C4 alkyl-, heteroaryl-C;-Cy alkyl-, C;-C4 haloalkyl, *OC;-C, alkyl, -QC,-Cy alkylphenyl, -C-C, alkyl-OH, -OC,-C4 haloalkyl, halo, -OX, -NH;, -C)-C4 alkyl-NH 5, -N(C;-Cj alkyl)(C,-C, alkyl), -NHI(C;-Cs alkyl), -N(C,-C4 alkyl)( C,-C, alkylphenyl), -NH(C,-C, alky1phenyl), cyano, nitro, oxo (as a substitutent for hreteroaryl), -CO-H, -C(O)OC,-C, alkyl, -CON(C;-C; alkyl)(C,-C4 alkyl), -CONH(C,-C;4 alkyl), -CONH;, -NHC(O)(C,-C,4 alkyl), -NHC(O)(phenyl), . =N(C;-C,; alkyl)C(O)(C;-C4 alkyl), -N(C-C4 alkyl)C(O) (phenyl), -C(O)C;-C4 alkyl, -C(0)C,-C4 phenyl, -C(0)C;-C, haloalkyl, -OC(Q)C,-C; alkyl, -SO»(C,-C4 alkyl), -

SOs(phenyl), -SCO1(C;-C4 haloalkyl), -SO-NH,, -SO2 NH(C,-Cs alkyl), -SO,NH(phemyl), -

NHSO,(C,-C alkyl), -NHSO; (phenyl), and -NHSO» (C,-C; haloalkyl).

[0053] T he term “substituted alkoxy” refers to alkoxy wherein the alkyl con stituent is substituted (i.e., -O-(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from: -R®%, -OR®, -O(C,-C; alkyl)O- (e.g., methylenedioxy-), -SR®, guanidine, guanidine wherein one or rmore of the guanidine hydrogens are replaced with a lower-alkyl group, -NRPR®, halo, cyano, nitro, -COR®, -CO;R®, -CONRPR®, -OCOR®, -OCO:R?, -OCOINR'R®, -NRSCOR®, -NR_°CO,R?, -NR°CONRR’, -CO;R®, ~CONRR’, -NR°COR®, -SOR?, - SO,R?, -SO,NRR’, and -NR°SO:R", where R® is chosen from optionally substituted C,-C¢ alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R® is chosen from H, optionally substituted C;-Cg alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R°® is chorsen from hydrogen and optionally substituted C,-C; alkyl; where each optionally substituted group is unsubstituted or independently suabstituted with one or more, such as one, two, or three, substituents independently selected from

C)-C4 alkyl, aryl, heteroaryl, aryl-C;-Cy alkyl-, heteroaryl-C;-C, allyl, C,-C4 haloalkyl-, -0C,-C,4 alkyl, -OC, -Cy4 alkylphenyl, -Ci-C4 alkyl-OH, -OC,-C4 haloalkyl, halo, -OH, -NHa, -C1-C4 alkyl-NH,, -IN(C-C4 alkyl}(C;-C4 alkyl), -NH(C;-C4 alkyl), -N(C;-C4 alkyl)(Cy-<C4 alkylphenyl), -NH(C,;-C, alkylphenyl), cyan ©, nitro, oxo (as a substitutent for heteroaryl), -CO2H, -C(0)OC;-C, alkyl, -CON(C,-C4 alkyl)(C,-C4 alkyl), -CONH(C,-C, alkyl), -CONH,, -NHC(O)(C;-Cy alkyl), -NHC(O)(phenyl), -N(C-C4 alky)C(O)C,-C4 alkyl), -N(C;-C, alkyl)C(O)(phenyl), -€C(O)C)-C; alkyl, -C(0)C,-C,4 phenyl, -C(0)C,-C4 haloalkyl, -OC(O)C,-Cs alkyl, -SCQ(C,-C4 alkyl), -

SO;,(phenyl), -SO2(C;-C4 haloalkyl), -SO;NH3, -SO;NH(C;-C, alkyl), -SONH(phenyl), -

NHSO,(C,-C,4 alkyl), -NHSO(phenyl), and -NHSO,(C,-C4 haloalkyl). In some embodiments, a substituted alkoxy group is “polyalkoxy” or -O-(o ptionally substituted alkylene)-(optional ly substituted alkoxy), and includes groups such as ~-OCH,CH;OCH3, and residues of glycol ethers such as polyethyleneglycol, and -O(CH2CH20)xCHs, where x is an integer of 2-20, such as 2-10, and for example, 2-5. Another substituted alkoxy group is hydroxyalkoxy or —QCH,(CH,),OH, where y is an integer of 1-10. such as 1-4.

[0054] The term “substituted alkoxycarbonyl” refers to the group (substituted alkyl)-

O-C(0O)- wherein the group is attached to the parent structure thro ugh the carbonyl functionality and wherein substituted refers to alkyl wherein one ©r more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent imdependently chosen from: -R%, -OR®, -0(C)-C; alkyl)O- (e.g., methylenedioxy-), -SR.", guanidine, guanidine wherein one or mote of the guanidine hydrogens are replaced with a lower-alkyl group, -NRR®, halo, cyano, nitro, -COR®, -CO:R®, -CONR®R®, -OCOR®, -OCO,R?, -OCONR’R, -NR°COR?, -NR°CO-R®, -NR°CONR'R®, -CO;R®, -CONRR’, -NJR°COR®, -SOR?, -SO:R", -SO;NRR", and -NR°SO:R?, where R* i s chosen from optionally substituted C;-Cs alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R° is chos en from hydrogen and optionally substituted Cy -Cy4 alkyl; where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from

C)-C, alkyl, aryl, heteroaryl, aryl-C,-C4 alkyl-, heteroaryl-C,-C4 alkyl-, C;-C; haloalkyl-, -0C,-C, alkyl, -OC;-C; alkylphenyl, -C;-C,4 alkyl-OH, -OC,-C,4 haloalkyl, halo, -OH, -NH3,

-C1-C4 alkyl-NHa, -N(C,-Cy alkyl)(C,-Cs alkyl), -NH(C;-C4 alkyl), -N(C1-C4 alkyl)(C)-C4 alkylphenyl), -NH(C,-C, alkylpheny!), cyano, nitro, oxo (as a substitutent for heteroaryl), -CO;H, -C(O)OC;-Cq alkyl, -CON(C,-C 4 alkyl)(C,-C; alkyl), -CONH(C,-C4 alkyl), -CONH,, -NHC(O)(C,-C; alkyl), -NHC(O)(plaenyl), -N(C;-C4 alkyl)C(QXC)-C4 alkyl), -N(C-C4 alkyl)C(O)(phenyl), -C€0)C)-Cs alkyl, -C(0)C1-Cq phenyl, -C(0)C;-C; haloalkyl, ~OC(0)C;-Cy alkyl, -SO»(C)-Cy alkyl), -

SOx(phenyl), -SO2(C,-C4 haloalkyl), -SO2NH,, -SO:NH(C,-C, alkyl), -SO,NH (phenyl), -

NHSO2(C,-C, alkyl), -NHSOz(phenyl), and -NHSO,(C,-Cy4 haloalky~1). 10055] The term “substituted amino” refers to the group —-NFIR® or -NRR? where each RY is independently chosen from: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, op=tionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein orne or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from: -R%, -OR", -O(C)-C; alkyl)O- (e.g., methylenedioxy-), -SR?, g=uanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a Hower-alkyl group, -NRR, halo, cyano, nitro, -COR’, -CO:R®, -CONRPRS, -OCOR?, -O» COR, -OCONRPRS, -NR°COR®, -NR°CO,R?, -NR°CONR'R®, -CO,R?, -CONR'R®, -NR°CTOR?, -SOR?, -SO;R?, -SO:NRR’, and -NR°SO,R?, where R*® is chosen from optionally substituted C-Cg alkyl, opotionally substituted aryl, and optionally substituted heteroaryl;

R® is chosen from H, optionally substituted C,-Cs alkyl, optiomally substituted aryl, and optionally substituted heteroaryl; and

R® is chosen from hydrogen and optionally substituted C,-C4 alkyl; where each optionally substituted group is unsubstituted or incdependently substituted with one or more, such as one, two, or three, substituents independen€ly selected from

Ci-C, alkyl, aryl, heteroaryl, aryl-C-C, alkyl-, heteroaryl-C,-C, alkyl—, C,-C, haloalkyl-, -0C,-C4 alkyl, -OC,-C, alkylphenyl, -C)-C4 alkyl-OH, -OC,-C, haloa_lkyl, halo, -OH, -NH,, -C1-C4 alkyl-NHa, -N(C,-C, alkyl}(C,-Cy alkyl), -NH(C,-Cy alkyl), -N(C-Cy4 alkyl)(C1-C, alkylphenyl), -NH(C)-C, alkylphenyl), cyano, m1itro, oxo (as a substitutent for heteroaryl), -CO-H, -C(0)OC;-C, alkyl, -CON(C,-C4 alkyl)(C;-C, alkyl),

-CONH(C,-Cs alkyl), -CONH», -NHC(O)(C,-C; alkyl), -NHC(O)(phvenyl), -N(C,-C; alkyl)C(O)(C,-<Cs alkyl), -N(C,-C4 alkyl)C(O)(phenyl), -C( 0)C,-C, alkyl, -C(0)Ci-C,4 phenyl, -C(O)C1-Cq haloalkyl, -OC(0)C1-C4 alkyl, -8024(C1-C4 alkyl), -

SO,(phenyl), -SO,(C,-C.a haloalkyl), -SO;NH;, -SO:NH(C;-C4 alkyl), -SO,NH(phenyl), -

NHSO2(C1-Cs alkyl), -NHSO (phenyl), and -NHSO2(C;-C4 haloalkyl); and wherein optionally substituted acyl, alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

[0056] The term “substituted amino” also refers to the group —NR°R wherein R® and

RY, together with the nitrogen to which they are bound, form an optionally substituted 5- to 7- membered nitrogen-cont aining, non-aromatic, heterocycle which op tionally contains 1 or 2 additional heteroatoms chosen from nitrogen, oxygen, and sulfur.

[0057] Compounds of Formula I-XIII include, but are not lirmited to, optical isomers of compounds of Formu 1a [-X11I, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for exam ple, by conventional methods such as crystallization in the presence of a resolving agent, or <hromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds of Formwla [-XIII include Z- and

E- forms (or cis- and treans- forms) of compounds with carbon-carbon double bonds. Where compounds of Formula I-XIII exists in various tautomeric forms, chemical entities of the present invention inclucle all tautomeric forms of the compound. Compounds of Formula [-

XIII also includes crystal forms such as polymorphs and clathrates.

[0058] Chemical entities of the present invention include, b ut are not limited to compounds of Formula 1-XIII and all pharmaceutically acceptable forms thereof.

Pharmaceutically accep table forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof.

In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Hence, the terms “chemical entity” and “chemical entities” also encompass pharmaceutically accep table salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures.

[0059] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hycrobromate, sulfate, sulfinate, nitrate, and li ke salts; as well as salts with an organic acid, such as malate, maleate,

fumarate, tartrate, succinate, citrate, acetate, lactate, methanesu 1fonate, p-toluenesulfonate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkan«oate such as acetate, HOOC- (CH;),-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium,

[0060] In addition, if the compound of Formula I-XIII iis obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable «organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recoggnize various synthetic methodologies that may be used to prepare non-toxic pharmac eutically acceptable addition salts.

[0061] As noted above, prodrugs also fail within the scope of chemical entities, for example ester or armide derivatives of the compounds of Form ula I-XII. The term “prodrug” includes any compound that becomes a compound of Formula I-XIII when administered to a patient, e.g., upon rmetabolic processing of the prodrug. Exam ples of prodrugs include, but are not limited to, acetate, formate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I-XIII. In some embodiments, the prodrug is a phosphate ester. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Deli very Systems, Vol. 14 of the

A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreverssible Carriers in Drug Design,

American Pharmaceutical Association and Pergamon Press, 19987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985, each of which are incorporated herein by reference.

[0062] The term “solvate” refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.

[0063] The term “chelate” refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.

[0064] The term “non-covalent complex” refers to the: chemical entity formed by the interaction of a coampound and another molecule wherein a co-valent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic imteractions (also called ionic bonding).

[0065] The term “active agent” is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example an active agent may be an anti-cancer therapeutic.

[0066] The term “antimitotic” refers to a drug for inhibiting or preventing mitosis, for example, by causing metaphase arrest. Some antitumour drugs block proliferatiora and are considered antimitotics.

[0067] The term "therapeutically effective amount" of a chemical entity off this invention means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease e.g., a therapeutically effective amount may bean amount sufficient to decrease the symptoms of a disease responsive to CENP-E inhibition. In some embodiments, a therapeutically effective amount is an amount sufficient to reduce cancer symptoms. In some embodiments a therapeutically effective amount is an amount sufficient to decrease the number of detectable cancerous cells in an organism, detectably slow, or stop the growth of a cancerous tumor. In some embodiments, a therapemmtically effective amount is an amount sufficient to shrink a cancerous tumor.

[0068] The term “inhibition” indicates a significant decrease in the baseli ne activity of a biological activity or process. “Inhibition of CENP-E activity” refers to a decrease in

CENP-E activity as a direct or indirect response to the presence of at least one chxemical entity described herein, relative to the activity of CENP-E in the absence of the at least one chemical entity. The decrease in activity may be due to the direct interaction of the chemical entity with CENP-E, or due to the interaction of the chemical entity(ies) described herein with one or mote other factors that in turn affect CENP-E activity. For example, the presence of the chemical entity(ies) may decrease CENP-E activity by directly binding to CEENP-E, by causing (directly or indirectly) another factor to decrease CENP-E activity, or by (directly or indirectly) decreasing the amount of CENP-E present in the cell or organism.

[0069] A “disease responsive to CENP-E inhibition” is a disease in which inhibiting

CENP-E provides a therapeutic benefit such as an amelioration of symptoms, decrease in disease progression, prevention or delay of disease onset, or inhibition of aberramt activity of certain cell-types.

[0070] “Treatment or treating means any treatment of a disease in a patient, including:

a) preventing the disease, that is, causing the clinical symptoms of the disease not to devel op; b) inhibitirg the disease; ©) slowing or arresting the development of clinical symptoms; and/or d) relievin g the disease, that is, causing the regressi on of clinical symptoms.

[0071] “Patien&” refers to an animal, such as a mammal, that has been or will be the object of treatment, ob servation or experiment. The methods off the invention can be useful in both human therapy amd veterinary applications. ‘In some embo-diments, the patient is a inammal; in some emb»odiments the patient is human; and in soane embodiments the patient is chosen from cats and logs.

[0072] The present invention is directed to a class of novel chemical entities that are inhibitors of one or more mitotic kinesins. According to some embodiments, the chemical entities described here3n inhibit the mitotic kinesin, CENP-E, p articularly human CENP-E.

CENP-E is a plus end—directed microtubule motor essential for achieving metaphase chromosome alignmerat. CENP-E accumulates during interphase and is degraded following completion of mitosis. Microinjection of antibody directed aga inst CENP-E or overexpression of a dosminant negative mutant of CENP-E causes mitotic arrest with prometaphase chromossomes scattered on a bipolar spindle. The tail domain of CENP-E mediates localization to kinetochores and also interacts with the mitotic checkpoint kinase hBubR1. CENP-E also associates with active forms of MAP kimase. Cloning of human (Yen, et al., Nature, 359(639 5):536-9 (1992)) CENP-E has been repox-ted. In Thrower, et al., EMBO

J., 14:918-26 (1995) p artially purified native human CENP-E was reported on. Moreover, the study reported that CE NP-E was a minus end-directed microtut>ule motor. Wood, et al., Cell, 91:357-66 (1997)) discloses expressed Xenopus CENP-E in E. coli and that XCENP-E has motility as a plus end directed motor in vitro. CENP-E See, PCT Publication No. WO 99/13061, which is incorporated herein by reference.

[0073] In some embodiments, the chemical entities inhi bit the mitotic kinesin, CENP-

E, as well as modulatizng one or more of the human mitotic kinessins selected from HSET (see,

U.S. Patent No. 6,361, 993, which is incorporated herein by reference); MCAK (see, U.S.

Patent No. 6,331,424, ~which is incorporated herein by references); RabK-6 (see U.S. Patent

No. 6,544,766, which ds incorporated herein by reference); Kif4 (see, U.S. Patent No. 6,440,684, which is in«corporated herein by reference); MKLP1 (see, U.S. Patent No. 6,448,025, which is in«corporated herein by reference); Kifl$ (see, U.S. Patent No. 6,355,466,

which is incorporated herein by reference); Kid (see. U.S. Patent No. 6,387,644, which is incorporated herein by reference); Mppl, CMKirp, Kinl-3 (see, U.S. Patent No. 6,461,855, which is incorporated herein by reference); Kip3a (see, PCT Publication No. WO 01/96593, which is incorporated herein by reference); Kip3d (see, U.S. Patent No. 6,492,151, which is incorporated herein by reference); and KSP (see, U.S. Patent No. 6,617,115, which is incorporated herein by reference).

[0074] The methods of inhibiting a mitotic kinesin comprise contacting an inhibitor of the invention with one or more mitotic kinesin, particularly a human kinesin; or fragments and variants thereof. The inhibition can be of the ATP hydrolysis activity of the mitotic kinesin and/or the mitotic spindle formation activity, such that the mitotic spindles are . disrupted.

[0075] The present invention provides inhibitors of one or more mitotic kinesins, in particular, one or more human mitotic kinesins, for the treatment of disorders associated with cell proliferation. The chemical entities compositions and methods described herein can differ in their selectivity and are used to treat diseases of cellular proliferation, including, but . not limited to cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders, fungal disorders and inflammation. 10076] Accordingly, the present invention provides at least one chemical entity chosen from compounds of Formula 1

De

NN s

Formula I and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein

R, is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;

X is -CO or ~S0,-;

R; is hydrogen or optionally substituted lower alkyl;

W is —-CRy-, -CH,CRy-, or N;

R; is —CO-R1, hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfony1, or optionally substituted aryl,

R, is hydrogen or optionally substituted alkyl;

R; is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl;

R; is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteraryloxy, optionally substituted ’ alkoxycarbonyl-, optionally substituted aminocarbonyl-, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aralkyl; and

Ris optionally substituted lower alkyl, opti onally substituted aryl, hydroxyl, optionally substituted amino, optionally substituted aralkoxy, or optionally substituted alkoxy; provided that if W is N, then Rs is not hydroxyl or optionally substituted amino, and Rg is rot optionally substituted alkoxy, optiomally substituted aralkoxy, optionally substitutecl heteroaralkoxy, or optionally substituted amino.

[0077] In some embodiments, R, is optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R; is optionally substituted aryl. In some embodiments, R; is optionally substituted phenyl. In some embodiments, R, is phenyl substituted with one, two or three groups independently selected from optionally substitute d

Teterocyclyl, optionally substituted alkyl, sulfonyl, halo, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxw, optionally substituted heteroaryloxy; acyl, hydroxyl, nitro, cyano, optionally substituted ary], and optionally substituted heteroaryl-. In some embodiments, R; is chosen from 3-halo-4- isopropoxy-phenyl, 3-cyano-4-isopropoxy-phenyl, 3-cyano-4-isopropylamino-phenvl, 3- <hloro-4-isopropylamino-phenyl, 3-cyano-4--triflucroisopropyloxyphenyl, 3-chloro-4- trifluoroisopropyloxyphenyl, 3-cyano-4-cylobutyloxyphenyl, 3-chloro-4-cylobutyloxyphenyl, 3-cyano-4-cylopropyloxyphenyl, and 3-chloro-4-cylopropyloxyphenyl. In some embodiments, R; is 3-halo-4-isopropoxy-phenyl or 3-cyano-4-isopropoxy-phenyl.

[0078] In some embodiments, R, is hydrogen.

[0079] In some embodiments, X is ~CO-.

[0080] In some embodiments, W is —CR4- and R4 is hydrogen.

[0081] In some embodiments, the compounds des cribed herein possess a potentially chiral center, for example, when W is —CRy-. The invention contemplates the use of pure enantiomers and mixtures of enantiomers, including racernic mixtures, although the use of a : substantially optically pure enantiomer will generally be oreferred. The term “substantially optically pure” or “‘enantiomerically pure” means having -at least about 95% of the described enantiomer with no single impurity greater than about 1%& and particularly, at least about 07.5% enantiomeric excess. In some embodiments, the stereogenic center at W is as shown below: :

Rj,

PP re Rg

[0082] In some embodiments, R3 is -CO-R7; hydrogen; optionally substituted lowex alkyl; cyano; optionally substituted sulfonyl; optionally s=mubstituted aryl; or optionally substituted heterocyclyl. In some embodiments, R; is optionally substituted lower alkyl. In some embodiments, R; is lower alkyl that is optionally siabstituted with a hydroxyl or a phosphate ester thereof, lower alkyl that is optionally sub stituted with a lower alkoxy, lower alkyl that is optionally substituted with an optionally subsstituted amino group, or lower alkyl that is optionally substituted with CO-Rg where Rs is hydroxyl or optionally substituted amino.

[0083] In some embodiments, Rs is hydrogen, hydroxyl, or optionally substituted lower alkyl. In some embodiments, Rs is hydrogen.

[0084] In some embodiments, the compounds desscribed herein possess a potentially chiral center when Rs is not hydrogen. The invention cortemplates the use of pure enantiomers and mixtures of enantiomers, including racemmnic mixtures, although the use of a substantially optically pure enantiomer will generally be poreferred. The term “substantially” optically pure” or “‘enantiomerically pure” means having at least about 95% of the described enantiomer with no single impurity greater than about 1¥& and particularly, at least about

97.5% enantiomeric excess.

[0085] In some embodiments, Rg is optionally substituted aryl, optionally substi mted heteroaryl, optionally substituted heterocyclyl, or optionally substituted alkyl (such as veherein the alkyl group is substituted with an optionally substituted amino group or wherein the= alkyl group is optionally substituted cycloalkyl-). In some embodiments, R¢ is phenyl substituted with one or two of the following substituents: optionally substituted heteroaryl, optionally substituted amino, aralkoxy, halo, hydroxymethyl-, hydroxy, cyano, alkoxy, phenyl, phenoxy, methylenedioxy, ethylenedioxy, sulfonyl, aminocarbonyl, carboxy, alkoxycarbonyl, nitro, heteroaralkoxy, aralkoxy, and optionally substituted heterocyclyl.

[0086] Also provided is at least one chemical entity chosen from compounds of

Formula I1

Rs Rs

CY

Ris

J

Rq2

R11 (Formula II) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodmrugs, and mixtures thereof, wherein Ry, Rs, Rs, Rg, and W are as described for compounds of

Formula I and wherein

R); is optionally substituted heterocyclyl, optionally substituted lower alkyl, nitro, cyano, hydrogen, sulfonyl, or halo;

R2 is hydrogen, halo, optionally substituted alkyl, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heterocyclyl, or optionally substituted heteroaryloxy; and

R,; is hydrogen, acyl, optionally substituted alkyl-, optionally substituted alkoxy, halo, hydroxyl, nitro, cyano, optionally substituted amino, alkylsulfonyl-, alkylsulfonamido-, alkylsulfonyl-, carboxyalkyl-, aminocarbonyl-, optionally substituted aryl or optionally substituted heteroaryl-.

[0087] In some embodiments, R;; is hydrogen, cyano, nitro, or halo. In some embodiments, Ry; is chloro or cyano.

[0088] In some embodiments, R)2 is optionally substituted lower alkoxy, optionally substituted lower alkyl, or optionally substituted amino-. In some embodiments, Ri; is chosen from isopropoxy, isopropylamino, triflu oroisopropyloxy, cylobutyloy, and cyl opropyloxy. In some embodiments, R); is lower alkoxy (such as propoxy~) or 2,2,2- trifluoro-1-methyl-ethoxy. In some embodiments, R;, is propoxy or 2,2,2-trifluoro-1-methyl- ethoxy. In some embodiments, R;; is not ~O-(CH;),NH; or —O-(CH;);NH(CH;) wherein n is 4 or5.

[0089] In some embodiments Rj; and R.),, taken together, form an optionally substituted carbocyclic or heterocyclic ring. In some embodiments, Rj; and Rj, taken . together, form a methylenedioxy or ethylenedicexy ring. In some embodiments, Ry2 and Ry, taken together, form an optionally substituted c arbocyclic or heterocyclic ring. In some embodiments, R;; and R;3, taken together, form an optionally substituted cambocyclic or heterocyclic ring.

[0090] In some embodiments, R;3 is hydrogen.

[0091] In some embodiments, R; and R_3, taken together, form an optionally substituted carbocyclic or heterocyclic ring, i.e. , Rj, X, N, and R,, taken together, form an optionally substituted carbocyclic or heterocycl ic ring. In certain embodiments, a substituted 2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl ring is formed, e.g,

H 0 ~ . ~~. AL

A lo Rs wherein the phenyl ring is optionally substituted. In other embodiments, a 4-oxo-4H- quinazolin-3-yl ring is formed, e.g.,

: N

N Rs :

N PY hi Re 0} Ra wherein the phenyl ring is optionally substituted. In certain embodiments, a 4-oxo0-4H- pyridopyrimidin-3-yl ring is formed, e.g.,

R N

. i | N Rs , xy Rs fo) Rs wherein one of R, S, T, and U is nitrogen with the others being —CH and wherein the pyridine ring is optionally substituted.

[0092] Also provided is at least one chemical entity chosen from <ompounds of

Formula III

Re 0

Ri3

A x | Ry

GF Ra

Riz

Ri (Formula III) and pharmaceutically acceptable salts, solvates, chelates, non-covalent cornplexes, prodrugs, and mixtures thereof, wherein Ry, Rs, Re, R}|, R}2, and R;3 are as describe=d for compounds of

Formula II.

[0093] Also provided is at least one chemical entity chosen from ¢c ompounds of

Formula IV

Re

Oo

Ria

CY

= Ra

Riz

R11 (Formula IV) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R,, Re, Ri, R13, and Ry; are as described for compounds of

Formula HI.

[0094] Also provided is at least one chemical entity chosen from compounds of

Formula V

Ria = 0 NX

Ris

Ria he

SF Re

Riz

Ruy (Formula V) and pharmaceutically acceptable salts, solvates, chelates, non-covalent c omplexes, prodrugs, and mixtures thereof, wherein Ry, Ra, Ry, Ra, and Ry; are as described for compounds of

Formula II and wherein

R,4 is optionally substituted heteroaryl; and

Rs is chosen from hydrogen, halo, hydroxyl, and lower alkyl.

[0095] In some embodiments, Ri4 is chosen from 7,8-dihydro~imidazo[1,2-c][ 1,3Joxazin-2-yl, 3a,7a-dihydro-1H-benzoimi dazol-2-yl,

Claims

Claims 1-19. (Canceled)

20. (Amended) At least one chemical entity chosen from compounds of Formula V Ry4 = 0 NX Ris R13 8 Xx Rs R; Ry2 Z Riq (Formula V) wherein R2 is hydrogen or optionally substituted lower alkyl; Rs is —CO-R;7, hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl; Ry is optionally substituted lower alkyl, optionally substituted aryl, hydroxyl, optionally substituted amino, optionally substituted aralkoxy, or optionally substituted alkoxy; R11 is optionally substituted heterocyclyl, optionally substituted lower alkyl, nitro, cyano, hydrogen, sulfonyl, or halo; Rj2 is hydrogen, halo, optionally substituted alkyl, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heterocyclyl, or optionally substituted heteroaryloxy; R43 is hydrogen, acyl, optionally substituted alkyl, optionally substituted alkoxy, halo, hydroxyl, nitro, cyano, optionally substituted amino, alkylsulfonyl-, alkylsulfonamido-, alkylsulfonyl-, carboxyalkyl-, aminocarbonyl-, optionally substituted aryl or optionally substituted heteroaryi-; R14 is optionally substituted heteroaryl; and 311 AMENDED SHEET

Ris is chosen from hydrogen, halo, hydroxyl, and lower alkyl.

21. (Original) Atleast one chemical entity of claim 20, wherein R14 is chosen from 7,8-dihydro-imidazo[1,2-c][1,3]ox&azin-2-yl, 3a,7a-dihydro-1H-benzoimidazol-2-yl, imidazo|2,1-bJoxazol-6-yl, oxazol-4-yl, 5,6,7 ,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 1H-[1,2,4]triazol-3-¥l, 2,3-dihydro-imidazol-4-yl, 1H-imidazol-2-yl, imidazo[1,2-a]pyridin-2-yl, thiazol -2-yl, thiazol-4-yl, pyrazol-3-yl, and 1H-imidazol-4-yl, each of which is optionally substituted with one, two, or three groups chosen from optionally substituted lower alkyl, halo, &cyl, sulfonyl, cyano, nitro, optionally substi tuted amino, and optionally substituted heteroaryl.

22. (Original) At least one chemical entity of claim 21, wherein R14 is chosen from 1H-imidazol-2-yl, imidazo[1,2-a]pyridin-2-yl; and 1H-imidazol-4-yl, each of which is optionally substituted with one or two groups chosen from optionally substituted lower alkyl, halo, and acyl. 312 AMENDED SHEET

23. (Original) At least one chemical entity Of any one of claims 20 to 22 wherein R15 is hydrogen. 24-27 .(Canceled)

28. (Amended) At least one chemical entity of claim 20 wherein R11 is hydrogen, cyano, nitro, or halo.

29. (Original) At least one chemical entity of claim 28 wherein R11 is chloro or cyano.

30. (Amended) At least one chemical entity of claim 20 wherein R12 is optionally substituted lower alkoxy, optionally sub» stituted lower alkyl, or optional ly substituted amino-.

31. (Original) Atleast one chemical entity of claim 30 wherein R12 is lower alkoxy or 2,2,2-trifluoro-1-methyl-ethoxy.

32. (Original) Atleast one chemical entity of claim 31 wherein R12 is pro poxy or 2,2,2-trifluoro-1-methyl-ethoxy.

33. (Amended) At least one chemical entity of claim 20 wherein R13 is hydrogen.

34. (Amended) At least one chemical entity of claim 20 wherein R2 is hydrogen.

35. (Amended) At least one chemical entity of claim 20 chosen from: i N-{1-[4-(8-Bromo-5-methyl-imidazo[1 ,2-a]pyridin-2-yl)-benzyl]-3-hyd roxy-propyi}-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-Acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1-meethyl-ethoxy)-benzamide; 313 AMENDED SHEET

N-(1-{4-[2-ace tyl-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chior«-4- (isopropoxy)-b enzamide; N-{1-[4-(8-ethyl-imidazo[1,2-a)pyridin-2-yl)-ben=yl]-3-hydroxy-propyl}-3-cyan 0-4- isopropoxy-bemnzamide;

N-{1-[4-(8-isop ropenyl-imidazo[1,2-a]pyridin-2-y/l)-benzyl]-3-hydroxy-propyl}- 3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-Acetylamino-propyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(isopropoxy)-benzamide; N-(1-{4-[2-(1-Acetylamino-ethyl)-1-ethyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-[1-(4-{2-[1-(Acetyl-methyl-amino)-ethyl]-1-eth yl-1H-imidazol-4-yl}-benzyl)-3- hydroxy-propyl]-3-chloro-4-(2,2,2-trifluoro-1-me thyl-ethoxy)-benzamide; N-(1-{4-[2-(1-Acetylamino-ethyl)-1-propyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-chloro-imidazo[1,2-a]pyridin-2-yl)}-bemnzyl]-3-hydroxy-propyl}-3-cya no-4- isopropoxy-be nzamide; N-{1-[4-(8-trifllaoromethyl-imidazo[1,2-a]pyridin- 2-yl)-benzyl]-3-hydroxy-propyyl}-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-[1-(Acetyl-methyl-amino)-ethyl]-1-eth yl-1H-imidazol-4-yi]-benzyl}-3- hydroxy-propyl)-3-cyano-4-isopropoxy-benzam ide; N-{1-[4-(8-Bromo-imidazo[1,2-a]pyridin-2-yl)-bex nzyl]-3-hydroxy-propyl}-3-chl oro-4- isopropoxy-be nzamide; N-(1-{4-[2-(1-Acetylamino-ethyl)-1-isopropyl- 1 Hi-imidazol-4-yl]-benzyl}-3-hyd roxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-Acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy - propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(2-(2-amino-2-methyl-propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1 ,2- a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isoprop oxy-benzamide; N-(1-{4-[2-[1-(3-methyl-ureido)-ethyl]-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-mexthyl-imidazo[1,2-a]pyridin-2-wi]- 314 AMENDED SHEET benzyl}-ethyl)-3-cyano-4-isopropoxy-ben zamide; N-(1-{4-[ 2-Acetyl-1-ethyl-1H-imidazol-4-yI]-benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide; N-(1-{4-[ 2-(1-Acetylamino-2-methyl-prop yl)-1-ethyl-1H-imidazol-4-yl]-benzyi}—3- hydroxy—propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-{1-[4-(8-chloro-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hyd roxy-butyl}-3-cyano-4- isopropOxy-benzamide, N-{1-[4-(8-Bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4- isopropOxy-benzamide; N-(1-{4-[2-(1-(isopropoxycarbonylamino )-ethyl)-1-ethyl- 1H-imidazol-4-yl]-berzyl}- 3-hydrox<y-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl-propyi}-3-cyano- 4-isopro» poxy-benzamide; N-(2-(2- dimethylamino-acetylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2- a)pyridin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-{1-[4- (8-acetyl-imidazo[1,2-a)pyridin-2-yl}-benzyl]-3-hydroxy-propyl}-3-cya no-4- isopropoxy-benzamide; N-{1-[4- (8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4- isopropoxy-benzamide; N-(2-(2- dimethylamino-acetylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2- ajJpyridin-2-yl]-benzyi}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4—[2-(1-Acetylamino-ethyl)-1-cyclo propylmethyl-1H-imidazol-4-yl]-benzyl}-3- hydroxy -propyl)-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-isopropyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano- 4-isopropoxy-benzamide; N-(2-(2—amino-2-methyl-propionylamino )-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl}- benzyl}—ethyl)-3-cyano-4-isopropoxy-bemnzamide; N-(1-{4—[2-(1-formylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy/- propyl)- 3-chloro-4-isopropoxy-benzamide; N-(1-{3—fluoro-4-[2-(1-methyl-1hydroxy-ethyl)-1-ethyl-1H-imidazol-4-yl}-benz yi}-3- hydroxy/-propyl)-3-chloro-4-isopropoxy-benzamide;

315 AMENDED SHEET

N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-b» romo-imidazo[1,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamiide; N-{1-[2-fluoro-4-(8-methyl-imidazo[1,2-a]pyridlin-2-yl)}-benzyl]-3-hydreoxy-propy!}-3- cyano-4-isopropoxy-benzamide;

N-(1-{4-[2-acetyl-1-(3-hydroxypropy!)-1H-imidl azol-4-yl}-benzyl}-3-hy droxy-propyl)- 3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-acetyl-5-methyl-imidazo[1,2-a]pyricdin-2-y!)-benzyl]-3-hydr-oxy-propyl}-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-Acetylamino-2-methyl-propyl)-1 —ethyl-1H-imidazol-4-ylI}-benzyl}-3- hydroxy-propyl)-3-chloro-4-isopropoxy-benzaamide; N-[1-[4-(2-acetyl-1-ethyl-1H-imidazol-4-yl)-be=nzyl]-2-(2-hydroxy-ace= tylamino)- ethyl]-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethxy)-benzamide; N-(1-{4-[2-t-butyl-1-ethyl-1H-imidazol-4-yl]-beanzyl}-3-hydroxy-propyll )-3-cyano-4- isopropoxy-benzamide; N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-koromo-imidazo[1,2-a]pyyridin-2-yl}- benzyl }-ethyl)-3-cyano-4-isopropoxy-benzamuide; N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-iemidazol-4-yl]-benzyl}-2— dimethylcarbamoyi-ethyl)-3-chloro-4-isoprop «xy-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)—benzyl]-3-hydroxy-butyw/l}-3-cyano-4- isopropoxy-benzamide; N-(1-{2-fluoro-4-[2-t-butyl-1-methyl-1H-imidaazol-4-yl]-benzyl}-3-hyd woxy-propyl )-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-methyl- 1H-imidazol-4-yl]—-benzyl}-3-carbamoyl-p ropyl)-3-chloro- 4-isopropoxy-benzamide; N-(1-{4-[2-isobutyryl-1-methyl-1H-imidazol-4--yl]-benzyl}-3-hydroxy- propyl)-3- chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-(2-hydroxy-ethyl)- 1H-imicdazol-4-yl]-benzyl}-3-hysdroxy-propyl)- 3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethy~I-1H-imidazol-4-yl]-berw zyl}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-e=thoxy)-benzamide,

316 AMENDED SHEET

N-(1-{3-fluoro-4-[2-acetyl- 1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3- cyano—4-isopropoxy-benzamide,

N-(1-{a-[2-(3-hydroxy-pent-3-yl)-1-ethyl- 1 H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl )-3-cyano-4-isopropoxy-benzamide; N-(1-{a-{2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4- (2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-{1-[a4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}- 3-cyano-4-isopropoxy-benzamide; N-(1-{a-[2-(1-hydroxy-1-methyl-ethyl)-1-(2,2,2-trifluoroethyl)- 1H-imidazol-4-yl]- benzyl }-3-hydroxy-propyl)-3-chloro-4-isop ropoxy-benzamide; N-[1-[@-(2-acetyl-1-ethyl-1H-imidazol-4-yl)-benzyl]-2-(2-hydroxy-acetylamino)- ethyl]-3-chloro-4-isopropoxy-benzamide; N-(1-{a-[2-acetyl-1-(2-methoxyethyl)-1H-imidazol-4-yi]-benzyl}-3-hydroxy-propyl)- 3-chloro-4-isopropoxy-benzamide; N-(2-(2-amino-2-methyl-propionylamino)- 1 -{4-[8-(1-hydroxy-ethyl)-imidazo[1,2- alpyridlin-2-yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-(2-(2-amino-propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2- yl]-berezyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{a-[2-acetyl-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide; N-(1-{a4-(5,5-dimethyl-7,8-dihydro-imidazo[ 1,2-c][1,3]oxazin-2-yl)-benzyi}-3- hydrox y-propyl)-3-chloro-4-isopropoxy-bemnzamide; N-(1-{A-[2-isobutyryl-1-methyl-1H-imidazol -4-yl]-benzyl}-3-hydroxy-propyl )-3- cyano—4-isopropoxy-benzamide; N-(1-{a4-(8-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzyi}-3-hydroxy- propyl )-3-cyano-4-isopropoxy-benzamide; N-(1-{A-[2-acetyl-1-propyl-1H-imidazol-4-y1]-benzyl}-3-hydroxy-propyl)-3-chioro-4- isopropoxy-benzamide; N-(1-{&-[2-acetyl-1-ethyl-1H-imidazol-4-yl]-benzyl}-2-carbamoyi-ethyl)-3-chioro-4- isopropoxy-benzamide; N-(1-{4&-[2-acetyl- 1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4- 317 AMENDED SHEET isopropoxy-benzamide; N-(2-(2-amino-propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]—benzyl}- ethyl)-3-cyano-4-isopropoxy-benzamide;

N-(1-{4-[2-(1-hydroxy-2-methyl-propyl)- 1-ethyl-1H-imidazol-4-yi]-benzyl}-3- hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{3-fluoro-4-[2-(1-hydroxy-1-methyl -ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{4-[2-propionyl-1-methyl-1H-imida=ol-4-yi]-benzyl}-3-hydroxy-propyl »-3- Cy ano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-<-yl]- benzyl}-3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-formylamino-ethyl)- 1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-hydroxy-acetylamino)-1-{4-[8-(1 -hydroxy-ethyl)-imidazo[1,2-a]pyri din-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(3-fluoro-1-{4-[2-(1-hydroxy-1-methyi-ethyl)-1-methyl-1H-imidazol-4-yl]- benzyl}- 3-hydroxy-propyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-acetylamino-ethyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hyd roxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-chloro-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4- isopropoxy-benzamide; N-(2-(2-amino-2-methyl-propionylamina)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yi]- be nzyl}-ethyi)-3-cyano-4-isopropoxy-be nzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-«hloro-4- isopropoxy-benzamide; N-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide; N-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}- 3-carbamoyl-butyl)-3 -cyano- 4-jsopropoxy-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl-propyl}- 3-chloro- 4-i sopropoxy-benzamide;

318 AMENDED SHEET

N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-ethyl- 1H-imidazol-4- wyl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{3-fluoro-4-[2-acetyl-1-methyi-1H-imidazol-4-yl]-benzyl}—3-hydroxy-propyl)-3- chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-carbarmoyl-propyl)-3-chloro- 4-isopropoxy-benzamide;

N-(1-{3-fluoro-4-[2-acetyl- 1-ethyl-1H-imidazol-4-yl]-benzyl}-3—hydroxy-propyl)-3- chloro-4-isopropoxy-benzamide; N-(1-{4-[2-propionyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3- chloro-4-isopropoxy-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydrox><y-propyl}-3-cyano-4- (2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(2-(2-hydroxy-acetylamino)-1-{4-[8-methyl-imidazo[1,2-a] pyyridin-2-yl]-benzyl}- ethyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxyimino-ethyl)- 1-methyl-1H-imidazol-4-yl]-bbenzyl}-3-hydroxy- propyl)-3-chloro-4-isoprop oxy-benzamide; N-(1-{4-[2-(3-hydroxy-pent-3-yl)-1-ethyl-1H-imidazol-4-yl]-ben zyl}-3-hydroxy- propyl)-3-chloro-4-isoprop oxy-benzamide; N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-methyl-imidazo[1 ,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-(2,2,2-trifluoro-ethyl)- 1H-imidazol-4-yl]-berzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(3-hydroxy-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a Jpyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-hydroxy-acetylamino)-1-{4-[8-bromo-imidazo[1,2-alpyridin-2-yl]-benzyi}- ethyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-amino-2-methyl-propionylamino)- 1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-[1-[4-(2-t-butyl-1-methyl- 1H-imidazol-4-yl)-benzyl]-2-ureido-ethyl}-3-cyano-4- isopropoxy-benzamide;

319 AMEND ED SHEET

N-{1-[4-(8-m ethyl-imidazo[1,2-a]pyridin-2-yl)-ben zyl]-3-carbamoyl-propyl}-3-chloro- 4-isopropoxy-benzamide;

N-(1-{4-[2-(1 -hydroxypropyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3- chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-ben=yl}-2-carbamoyl-ethyl)-3-chloro- 4-isopropoxy-benzamide; N-(2-(2-hydroxy-acetylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl}-3-chloro-4- (2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{4-[2-isobutyryl-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro- 4-isopropoxy-benzamide; N-{1-[4-(8-(1 -hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl- propyl}-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1 -hydroxy- 1-methyl-ethyl)- 1-ethyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl-propyl}-3-chloro- 4-isopropoxy-benzamide; N-(2-(2-hydroxy-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]- benzyl}-ethyl )-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-(carbamoyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3- cyano-4-isop ropoxy-benzamide; N-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin -2-yl)-benzyl]-3-hydroxy-propyl}- 3-cyano-4-isopropoxy-benzamide; N-[1-[4-(2-t-b utyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-(acetylamino)-ethyl]-3- cyano-4-isopropoxy-benzamide; N-{1-[2-fluoro-4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3- chloro-4-isopropoxy-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4- (2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- 320 AMENDED SHEET propyl)-3-cyano-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{4-[2-(1-Acetylamino-ethyl)- 1-m ethyl- 1H-imidazol-4-yl]-benzyl}-3—hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide;

N-(1-{4-[2-t-butyl-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-carbamoyl-propyl)-3-cyano- 4-isopropoxy-benzamide; N-{1-[4-(4-methyl-3a,7a-dihydro-1H-benzoimidazol-2-yl)-benzyl]-3-hydroxy- propyl}-3-chloro-4-isopropoxy-benzamide; N-(1-{2,3,5,6-tetrafluoro-4-[2-t-butyl- 1-methyl- 1H-imidazol-4-yl]-benzyl }-3-hydroxy- propyt)-3-cyano-4-isopropoxy-benzammide; N-(1-{4-[2-acetyl-1-methyl-1H-imidaz ol-4-yl]-benzyl}-3-hydroxy-propyl )-3-cyano-4- (1-fluoro-prop-2-yloxy)-benzamide; N-(1-{4-[2-t-butyl-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl )-3-chloro-4- isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl )-1-ethyl-1H-imidazol-4-yl]-benzyl }-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-{1-[4-(8-(3,5-dimethyl-isoxazol-4-yl }-imidazo[1,2-a]pyridin-2-yl)-benz=yl]-3- hydroxy-propyl}-3-cyano-4-isopropox y-benzamide; N-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[ 1,2-a]pyridin-2-yl)-benzyl]-3-carbamoyl- propyl}-3-cyano-4-isopropoxy-benzarmide; N-(1-{4-[2-(1-hydroxy-2-methyl-propyl)- 1-ethyl- 1H-imidazol-4-yl]-benzy/i}-3- hydroxy-propyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazol-4-yl]-benz yl}-3- hydroxy-propyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-isopropenyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-isopropyl-1H-imid azol-4-yl]-benzyl}-3-hydroxy-prop yl )-3-chloro- 4-isopropoxy-benzamide; IN-(1-{4-[2-trifluoromethyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3- cyano-4-isopropoxy-benzamide; IN-{1-[3-chloro-4-(8-methyl-imidazo[1 , 2-a]pyridin-2-yl)-benzyl]-3-hydro><y-propyl}-3- cyano-4-isopropoxy-benzamide;

321 AMENDED SHEET

N-{1-[4-(3-methyl-imidazo[2, 1-bJoxazol-6-yl)-benzyl] -3-hydroxy-butyl}-3-cyano-4- isopropoxy-benzamide;

N-(2-(2-hydroxy- propionylamino)-1-{4-[8-(1-hydroxy—ethyl)-imidazo[1,2-a)pyridin-2— yl}-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-hydroxy-1-{4-[2-t-butyl-1-methyl-1H-imidazol-4 —yl]-phenyl}-4-hydroxy-butyl)-3— chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-ethyl-1H-imidazol-4-yl}-benzyl}-2 -(N,N-dimethylcarbamoyl)- ethyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-hydroxy- propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-yi]- benzyi}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-[1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl] -2-(3-methyl-ureido}-ethyl]-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-methyl-1H-innidazol-4-yl]-benzyl}-3- hydroxy-propyl)- 3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-[1-(acetylamino)-propyl]-1-ethyl-1H-imida zol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-tbenzamide; N-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yl)-benzyl] -2-(3-methyl-ureido)-ethyl]-3- cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(cyclo propylcarbonyl)-1-methyl- 1H-imida=ol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-2- carbamoyl-ethyl )-3-chloro-4-isopropoxy-benzamide ; N-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yl)-benzyl J-2-(1-methyl-ureido)-ethyl]-3- chloro-4-isopropoxy-benzamide; N-{1-[4-(8-hydroxymethyl-imidazo[1,2-a]pyridin-2-yl )-benzyl]-3-hydroxy-propyl}-3- cyano-4-isoprop oxy-benzamide; N-(1-{4-[2-t-butyl-1-(2-hydroxyethyl)-1H-imidazol-4- yl]-benzyl}-3-hydroxy-propyl)-3- cyano-4-isoprop oxy-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl ]-2-ureido-ethyl]-3-cyano-4- isopropoxy-benzamide;

322 AMENDED SHEET

N-(1-{4-[2-(m ethylsulfonyl)-1-methyl-1H-imidazol-4-yl]-benzyl }-3-hydroxy-propyl)-3- cyano-4-isopropoxy-benzamide; N-(1-{3-fluoro-4-[2-acetyl-1-ethyl-1H-imidazol-4-yl}-benzyl}-3-hydroxy-propyl)-3- chloro-4-(2,2, 2-trifluoro-1-methyl-ethoxy)-benzamide; N-[1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-2-ureido-ethyl]-3-cyano-4- isopropoxy-benzamide; N-{1-[2,6-difluoro-4-(8-chloro-imidazo[1,2-a]pyridin-2-yl)}-benzyi]-3-hydroxy-propyl}- 3-cyano-4-isopropoxy-benzamide; : N-(1-{4-[2-(1-hydroxy-2,2-dimethyl-propyl)-1-methyl-1H-imida=oi-4-yl]-benzyi}-3- hydroxy-prop yl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-formylamino-ethyl}-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3- carbamoyl-propyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-amino-propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2- yl]-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-1methyl-ethyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3- hydroxy-prop yl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)

-benzamide; N-(2-(2-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]p yridin-2-yl}-benzyl}- ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-ben zyl}-2- methylcarbamnoyi-ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-ethyl-1H-imidazol-4-yl]-benzyl}-2-dimethylcarbamoyl-ethyl)-3- chloro-4-(2,2, 2-trifluoro-1-methyl-ethoxy)-benzamide; N-(2-(2-hydroxy-propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]pyridin-2-y1]- benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-{1-[4-(8-cyano-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4- isopropoxy-benzamide; N-(2-(2-amino-2-methyl-propionylamino)-1-{4-[8-methyl-imida=o[1,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide;

323 AMENDED SHEET

N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-b»enzyl}-3-hydroxy-propyl}-2,3- dichhloro-4-isopropoxy-benzamide;

N-(1-{4-[2-acetyl-1-ethyl-1H-imidazol-4-yl]-berr zyl}-3-hydroxy-propyl )-3-chloro-4- (2,2, 2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{3-fluoro-4-[2-acetyl-1-methyl-1H-imidazo 1-4-yl}-benzyl}-3-hydroxy- propyl)-3- cyano-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyricdin-2-yl)-benzyl}-3-hydrox y-propyl}- 3-chloro-4-isopropoxy-benzamide; N-[1-[4-(2-t-butyl-1-methyl- 1H-imidazol-4-yl)-be nzyl]-3-hydroxycarbamoyl-propyl]- 3-cyano-4-isopropoxy-benzamide; N -{1-[4-(5-methyl-imidazo[1,2-a]pyridin-2-yl)-be mzyl}-3-hydroxy-propyl}-3—cyano-4- is opropoxy-benzamide; N-(1-{4-[2-acetyl-1-methyl-1H-imidazol-4-yl]-bermzyl}-3-hydroxy-propyl)-3- cyano-4- (isopropylamino)-benzamide; N-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yi)-berm zyi]- 2- (formylamino)-ethy1]-3- Cy ano-4-ispropoxy-benzamide; N-(1-{4-(2-Acetyl-oxazol-4-yl)-benzyl}-3-hydroxy— propyl)-3-cyano-4-isopro poxy- be nzamide; N-(2-(2-amino-acetylamino)-1-{4-[8-bromo-imida=o[1,2-a]pyridin-2-yl}-ben=yl}- eth yl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-hydroxy-2-methyl-propionylamino)-1-{4-[88-bromo-imidazo[1,2-alpyridin-2- yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamicie; N-(1-{4-[2-t-butyl-1-methyl- 1H-imidazol-4-yl]-benz W}-3-hydroxy-propyl)-2-armino-3- chioro-4-isopropoxy-benzamide; N-( 1-{4-[2-(1-acetylamino-ethyl)- 1-ethyl-1H-imidaz=ol-4-yl}-benzyl}-3-carbameoyi- propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy »-benzamide; N-(2-(2-amino-3-hydroxy-propionylamino)- 1-{4-[8-oromo-imidazo[1,2-a]pyridin-2- yi}-b enzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-{1-[2,6-difluoro-4-(8-methyl-imidazo[1,2-a]pyridirm-2-yl)-benzyl]-3-hydroxy- prop yi}-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-amino-imidazo[1,2-a]pyridin-2-yl)-benzyl}-3-hydroxy-propyl}-3-cya no-4- 324 AMENDED SHEET isopropoxy-benzamide; N-{1-[4-(8-acetyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chlo ro-4- isopropoxy-benzamide; N-{1-[4-(8-(1-methyl-1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl}-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-(1-(methoxycarbonylamino)-ethyl)- 1-methyl-1H-imidazol-4-yl]-ben=yl}-3- hydroxy-propyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-(methoxycarbonylamino)-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzy}-3- hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(2-(2-hydroxy-acetylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin -2-yl]- benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-carbamoyl-ethyl]-3-ch loro- 4-ispropoxy-benzamide; N-(1-{4-[2-(1-(ethoxycarbonylamino)-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-{1-[4-(imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-cyano-4- isopropoxy-benzamide N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}-3-chloro-4- (isopropylamino)-benzamide; N-[1-[4-(8-bromo-imidazo[1,2-a]pyridin-2-yl)-benzyl]-2-(3-methyl-ureido)-ethyl}-3- chloro-4-isopropoxy-benzamide; N-{1-[4-(8-(1-hydroxypropyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}- 3-chloro-4-isopropoxy-benzamide;

N-[1-[4-(2-t-butyl-1-(2-aminoethyl)- 1H-imidazol-4-yl)-benzyl]-2-(2-hydroxy- acetylamino)-ethyl]-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chl oro-4- isopropoxy-benzamide; N-(2-(2-hydroxy-propionylamino)-1-{4-[8-methyl-imidazo[1,2-a)pyridin-2-yi]- benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-[1-[4-(2-t-butyl-1-methyl-1H-imidazol-4-yl)-benzyl]-2-(3-hydroxy-ureido)-ethyi]-3- cyano-4-isopropoxy-benzamide;

325 AMENDED SHEET

N-(2-(3-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl}-benzyl}- ethyl)-3-chloro-4-isopropoxy-benzamide; N-(2-(2-amino-3-hydroxy-propionylamino)-1-{4-[8-bromo-imida=o[1,2-a]pyridin-2- yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy-benzamide; N-{1-[4-(8-nitro-imidazo[1,2-a]pyridin-2-yl)-benzyl)-3-hydroxy-pr-opyl}-3-cyano-4- isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-ethyi-1H-imidazol-4-yl}-benzyl}-2-methylcartoamoyl-ethyl)-3- chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(2-(2-amino-propionylamino)-1-{4-[8-methyl-imidazo[1,2-a]py ridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy-benzamide;

N-[1-[4-(2-(1-hydroxy-1-methyl-ethyl)- 1-methyl-1H-imidazol-4-yl )-benzyl]-2-(2- amino-propionylamino)-ethyl]-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-acetyl-1-butyl-1H-imidazol-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4- isopropoxy-benzamide; N-(1-{4-[2-(1-acetylamino-ethyl)- 1-ethyl-1H-imidazol-4-yl]-benzy1}-2-carbamoyl- ethyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[4-t-butyl-1H-imidazol-2-yl]-benzyl}-3-hydroxy-propyl)-3—cyano-4- isopropoxy-benzamide,; N-(1-{4-[2-(2,2-dimethyl-prop yl)-1-methyl- 1H-imidazol-4-yl]-ben=yi}-3-hydroxy- propyl)-3-cyano-4-isopropoxy-benzamide; N-(2-(2-hydroxy-propionylamino)-1-{4-[8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2- yl]l-benzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-(1-{4-[2-isobutyryl-1-methyl-1H-imidazol-4-yi}-benzyl}-3-hydroy-propyl)-3- chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-{3-fluoro-4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidaazol-4-yl}-benzyl}- 3-hydroxy-propyl)-3-chloro-4-isopropoxy-benzamide; N-(1-{4-[2-(1-hydroxy-ethyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)- 3-cyano-4-isopropoxy-benzamide; N-(1-{4-[5-t-butyl-1-methyl-1H-[1,2,4]triazol-3-yi]-benzyl}-3-hydro xy-propyl)-3- cyano-4-isopropoxy-benzamide; N-[1-[4-(2-t-butyl-1-(2-amino-ethyl)- 1H-imidazol-4-yl)-benzyl]-2-(2-dimethylamino- 326 AMENDED SHEET acetyl amino)-ethyl]-3-chloro-4-isopropoxy-benzamide; N-[1-{4-[1-(3-(t-butoxycarbonylamino)-propyl)-2-t-butyl-2, 3-dihydro-imidazol-4-yl]- benzy/l}-3-hydroxy-propyl]-3-chloro-4-iso propoxy-benzamide; N-(2-(2-hydroxy-propionylamino)-1-{4-[8 -(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2- yl]-be nzyl}-ethyl)-3-cyano-4-isopropoxy-benzamide; N-(2-Cacetylamino)-1-{4-[8-methyl-imida=zo[1,2-a]pyridin-2-yl]-benzyl}-ethyl)-3- cyano-4-isopropoxy-benzamide;

N-(1-{4-[2-t-butyl-1-(2-aminoethyl)- 1H-imidazol-4-yl}-benzyl}-3-hydroxy-propyl)-3- cyanO-4-isopropoxy-benzamide; N-(1-{4-[2-(1-methoxyimino-ethyl)-1-metyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-isopropoxy-benzamid e; N-{1-[4-(8-(3-hydroxy-propenyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl}-3-cyano-4-isopropoxy-benzamid e; N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-carbamoyl-imidazo[1,2-a]pyridin-2-yi]- benzy/l}-ethyl)-3-cyano-4-isopropoxy-bernzamide; N-(1-g3-fluoro-4-[2-acetyl-1-methyl- 1H-irnidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3- chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy )-benzamide, N-(2-2-amino-acetylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}- ethyl) -3-cyano-4-isopropoxy-benzamide; N-(1-g4-[5-t-butyl-4-methyl- 1H-imidazol-2-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide; N-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-propyl}- 3-cya no-4-isopropoxy-benzamide; N-(1-{4-[5-t-butyl-4-methyl- 1H-imidazol- 2-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4- isopropoxy-benzamide; N-(1-{4-[2-(1-acetylamino-ethyl)-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzamide; N-(1-€4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-2-amino-butyl)-3-cyano-4- isopropoxy-benzamide; N-{1-[4-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy-butyl}-3-cyano-4- 327 AMENDED SHEET isopropoxy-benzamide; N-(1-{4-[2-t-butyl-1-methyl—-1H-imidazol-4-yl]-benzyl}-2-hydroxy- propyl )-3-cyano-4- isopropoxy-benzamide; N-(2-(2-amino-propionylamino)-1-{4-[8-bromo-imidazo[1,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy-benzamide;

N-(1-{4-[2-acetyl-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4- isopropylamino-benzamide, N-(1-{4-[2-t-butyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide; N-{1-[4-(8-methyl-imidazo[ 1,2-a]pyridin-2-yl)-benzyl]-3-hydroxy- propyt}-2-nitro-4- triffluoromethyl-benzamide; N-(1-{4-[2-t-butyl-1-methyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy- propyl )-3-iodo-4- isopropoxy-benzamide; (S)-3-chloro-N-(1-(4-(1-eth yl-2-(2-hydroxypropan-2-yi)-1H-imidazol-4-yl)phenyl)-4- hydroxybutan-2-yi)-4-isopropoxybenzamide; (S)-N-(1-(4-(2-acetyl-1-eth yl-1H-imidazol-4-yt)phenyl)-4-hydroxybutan-2-yl)-3- chloro-4-isopropoxybenzarmide; N-((S)-1-(4-(2-(1-acetamid oethyl)-1-ethyl-1H-imidazol-4-yl) phenyl )-4- hydroxybutan-2-y1)-3-chloro-4-isopropoxybenzamide; 3-chloro-N-((S)-1-(4-(1-eth yl-2-(2-hydroxypropan-2-yi)- 1H-imidazol-4-yl)phenyl)-4- hydroxybutan-2-yi)-4-(1,1, “1-trifluoropropan-2-yloxy)benzamide; N-((S)-1-(4-(2-(1-acetamid oethyl)-1-ethyl-1H-imidazol-4-yl)phenyl)-4- hydroxybutan-2-yi)-3-chloro-4-(1,1,1-trifluoropropan-2-yloxy)bemnzamide; (S)-N-(1-(4-(2-acetyl-1-(2,2,2-trifluoroethyl)- 1H-imidazol-4-yl)ph enyl)-4- hydroxybutan-2-y1)-3-chloro-4-isopropoxybenzamide; 3-chloro-N-((S)-4-hydroxy- 1-(4-(8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2- yl)phenyl)butan-2-yl)-4-iso propoxybenzamide; (S)-3-chloro-N-(1-(2-(dime thylamino)acetamido)-3-(4-(8-methyli midazo[1,2- a)pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide; 3-chloro-N-((S)-1-(2-(dime thylamino)acetamido)-3-(4-(8-(1- hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yi)-4-

328 AMENDED SHEET isopropoxybenzamide; 3-Cyano-N-{(1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2- yl) henyllmethyl}propyl)-4-[(1-methylethyl)oxy]benzamide; 3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8- (1-hydroxyethyl)imidazo[1,2-a]pyridin-2- yl]p henylimethyl)propyl]-4-[(1-methyl ethyl)oxylbenzamide; 3-Chloro-N-[(1S)-2-[(N,N-dimethyiglycyl)amino]-1-({4-[8-(1- hyd roxyethyl)imidazo[1,2-a)pyridin-2 -ylJphenyl}methyl)ethyl]-4-[(1- me thylethyl)oxy]benzamide;

N-((1S)-2-(D-Alanylamino)-1-{[4-(8-b romoimidazo[1,2-a]pyridin-2-

yl) henyllmethyl}ethyl)-3-chloro-4-[( 1 -methylethyl)oxy]benzamide;

3-Chloro-N-((1S)-2-[(2-methylalanyl) amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-

y)phenyllmethyl}ethyl)-4-[(1-methylethyl)oxy]benzamide;

3-Chloro-N-((1S)-2-[(N,N-dimethylglycyl)amino]-1-{[4-(8-methylimidazo[1,2-

alp yridin-2-yl)phenyllmethyl}ethyl)-4—[(1-methylethyl)oxy]benzamide;

N-( (1R)-4-Amino-1-{[4-(8-methylimid azo[1,2-a]pyridin-2-yl)phenyllmethyl}-4-

oxoObutyl)-3-chloro-4-[(1-methylethyl) oxylbenzamide;

N-( (1R)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyllmethyl}-4-amino-4-

oxObutyl)-3-chloro-4-[(1-methylethyl) oxylbenzamide;

3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8- (1-hydroxyethyl)imidazo[1,2-a]pyridin-2-

ylJphenylimethyl)propyl]-4-[(1-methylethyl)oxy]benzamide;

3-Chloro-N-((1S)-3-hydroxy-1-{[4-(8- methylimidazo[1,2-a]pyridin-2-

yl) henyllmethyl}propyl)-4-[(1-methylethyl)oxy]benzamide;

3-Cyano-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-

hydroxyethyl)imidazo[1,2-a]pyridin-2 -ylJphenyl}methyl)ethyi]-4-[(1-

me thylethyl)oxy]benzamide;

3-Cyano-N-((1S)-2-[(N,N-dimethylgly/cyl)amino]-1-{[4-(8-methylimidazo[1,2-

alp yridin-2-yl)phenyllmethyl}ethyl)-4—[( 1-methylethylJoxy]benzamide;

N-( (1R)-1-{[4-(2-Acetyl-1-methyl- 1H-imidazol-4-yl)phenyl]methyl}-4-amino-4-

oxobutyl)-3-cyano-4-[(1-methylethyl) oxy]benzamide;

N-[ (1R)-4-Amino-1-({4-[2-(1-hydroxy-1-methylethyl)- 1-methyl-1H-imidazol-4-

yljohenyl}methyl)-4-oxobutyl]-3-cyan o0-4-[(1-methylethyl)oxylbenzamide; 329 AMENDED SHEET

, *

N-[(1S)-2-(D-Alanylamino)-1-({4-[1-(2-aminoethyl)-2-(1,1-dimethylethyl)-1H- imidazol-4-ylJphenyl}methyl)ethyl]-3-chloro-4-[( 1-methylethyl)oxylbenzamide; N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethy)- 1H-imnidazol-4-yl]phenyl}-1- {l(2-methylalanyl)amino]methyl}ethyl)-3-chloro-4-[( 1-meth ylethyl)oxylbenzamide; N-[(1S)-2-(D-Alanylamino)-1-({4-[1-(2-aminoethyl)-2-(1,1-dimethylethyl)-1H- imidazol-4-yl)phenyl}methyl)ethyl]-3-cyano-4-[(1-methylethyl)oxylbenzamide; N-((1S)-2-{4-[1-(2-Amiinoethy!}-2-(1,1-dimethylethyl)- 1H-imidazol-4-yl]phenyl}-1- {[(hydroxyacetyl)amino]methyl}ethyl)-3-cyano-4-[( 1-methylethyl)oxy]benzamide; N-((1S)-2-{4-[1-(2-Aminoethyl)-2-(1,1-dimethylethyl)- 1H-irmidazol-4-yl]Jphenyl}-1- {[(2-methylalanyt)amino]methyl}ethyl)-3-cyano-4-[( 1-meth ylethyl)oxy]benzamide; N-((1S)-2-{4-[1-(2-Aminoethyl})-2-(1,1-dimethylethyl)- 1H-irmidazol-4-yl]phenyi}-1- {[(N,N-dimethyiglycyl )amino]methyl}ethyl)-3-cyano-4-[(1- methylethyl)oxylbenzamide; 3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyrridin-2-yl]phenyl}-1- ({[(2R)-2-hydroxypropanoyl]amino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide; N-((1S)-2-[(Aminocarbonyi)amino]- 1-{[4-(8-bromoimidazo [1,2-a]pyridin-2- yl)phenyllmethyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]berzamide; 2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}cartbonylJamino]-3-[(1,2,3- thiadiazol-4-ylcarbonyl)amino]propyl}phenyl)imidazo[1,2-a]pyridine-8- carboxamide;

(3S)-3-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl) amino]-4-{4-[2-(1,1- dimethylethyl)-1-methyl-1H-imidazol-4-ylJphenyl}butanoic acid; N-((1S)-1-{[4-(1H-Benzimidazol-2-yl)phenyljmethyl}-3-hydroxypropyl)-3-chloro-4- [(1-methylethyl)oxy]benzamide ; 3-Chloro-N-[(1S)-3-hydroxy-1-({4-[5-(trifluoromethyl)-1 H-tbenzimidazol-2- ylJphenylimethyl)propyl]-4-[(1-methylethyl)oxylbenzamide ; 3-Chloro-N-((1S)-1-{[4-(5,6-dimethyl-1H-benzimidazol-2-y/1)phenyljmethyl}-3- hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-[(1S)-3-h ydroxy-1-({4-[5-(methyloxy)-1H-benzimidazol-2- yllphenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-((1S)-1-{[4-(5-chloro-1H-benzimidazol-2-yl)phyenyljmethyl}-3-

hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ;

330 AMENDED SHEET

3-Chloro-N-((1S)-3-hydroxy-1-{[4-(4-methy8-1H-benzimidazol-2- yl)phenylmethyi}propyl)-4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-((1S)-1-{[4-(6-chloro-1H-imidaz o[4,5-b]pyridin-2-yl)pheny I]methyl}-3- hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ;

Ethyl 2-(4-{(2S)-2-[({3-chloro-4-[(1-methylethyl)oxy]phenyi}carbonyl)amino]-4- hydroxybutyl}phenyl)-1H-benzimidazole-5-«carboxylate ; 2-(4-{(2S)-2-[({3-Chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino)-4- hydroxybutyl}pheny!)-1H-benzimidazole-5-«carboxylic acid ; N-((1S)-3-Amino-1-{[4-(1H-benzimidazol-2—yl)phenyl]methyl}propyl)-3-chloro-4-[(1- methylet hyl)oxy]benzamide ; 3-Cyano-N-((1S)-1-{[4-(8-cyanocimidazo[1,2-a]pyridin-2-yl)phenyllmethyl}-3- hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ; N-((1S)-1-{[4-(8-Chloroimidazo[1,2-a]pyridi n-2-yl)phenyllmethyl}-3-hysdroxypropyl)- 3-cyano-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(trifluoromethyl)imidazo[1,2-a] py ridin-2- yllphenyi}methyl)propyl]-4-[(1-methylethyl)exy]benzamide ; 3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-hydro><yimidazo[1,2-a]pyridin-2- yh)phenyllmethyl}propyl)-4-[(1-methylethyl)oxy]benzamide ; 2-(4-{(2 S)-2-[({3-Cyano-4-[(1-methylethyl)a»xy]phenyl}carbonyl)Jaminc]-4- hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-7-carboxamide ; Ethyl 2-(4-{(2S)-2-[({3-cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[1,2-a]pyridine-7-carboxylate ; 3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-nitroimidazo[1,2-a]pyridin-2- yl)phenyl]methyl}propyl)-4-[(1-methylethyl) ©xy]benzamide ; N-((1S)- 1-{[4-(8-Aminoimidazo[1,2-a]pyridi n-2-yl)phenyl]methyl}-3-hydroxypropyl)- 3-cyano-4-[(1-methylethyl)oxylbenzamide z 2-(4-{(2S)-2-[({3-Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[1,2-alpyridine-8-carboxamide ; 3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(hydro xymethyl)imidazo[1,2-a]lpyridin-2- yllpheny Ilmethyl)propyi]-4-[(1-methylethyl)oxy]benzamide ;

331 AMENDED SHEET

N-[(1S)-1-({4-[8-(Aminomethyl)imidazo[1,2-a]pyridin-2- yi]phenyl}methyl)-3- hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxylbenzamide ; N-((1S)-1-{[4-(8-Acetylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)- 3-cyano-4-[( 1-methylethyl)oxy]benzamide ; 3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxy-1-meth ylethyl)imidazo[1,2- a]pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)o xy]benzamide ; 3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)im idazo[1,2-a]pyridin-2- yllphenylimethyl)propyl]-4-[(1-methylethyl)oxylbenzami de ; 3-Cyano-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)- 1-(2-hydroxyethyl)- 1 H-imidazol-4- yllphenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide ; N-{(1S)-1-({4-[1-[2-(Acetylamino)ethyl]-2-(1,1-dimethylexthyl)-1H-imidazol-4- yllphenyl}m ethyl)-3-hydroxypropyl]-3-cyano-4-[(1-meth ylethyl)oxy]benzamide ; 3-Cyano-N-{(1S)-3-hydroxy-1-[(4-{8-[(1R)-1-hydroxyettwyllimidazo[1,2-a]pyridin-2- yl}phenyl)m ethyl]propyl}-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-{(1S)-3-hydroxy-1-[(4-{8-[(1S)-1-hydroxyetha yl]imidazo[1,2-a]pyridin-2- yl}phenyl)m ethyl]propyl}-4-[(1-methylethyl)oxy]benzam ide ; 3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxypropyl)irmidazo[1,2-a]pyridin-2- yllphenyl}methyl)propyl]-4-[(1-methylethyl)oxylbenzami de ; N-((1S)-1-{[4-(8-Bromoimidazo[1,2-a]pyridin-2-yl)phenylimethyl}-3-hydroxypropyl)- 3-chloro-4-[ (1-methylethyl)oxy]benzamide ; 3-Chloro-N- ((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-2 -yl)phenyllmethyl}-3- hydroxypropyl )-4-[(1-methylethylJoxy]benzamide ; 3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxy-2-meth ylpropyi)imidazo[1,2- a)pyridin-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)o xy]benzamide ; N-[(1R)-4-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-&]pyridin-2- yllphenyl}methyl)-4-oxobutyl}-3-chloro-4-[(1-methylethy l)oxy]benzamide ; N-[(1R)-4-A mino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-&]pyridin-2- yllphenyl}m ethyl)-4-oxobutyl]-3-cyano-4-[(1-methylethy I)oxylbenzamide ; 3-Chloro-N-((15)-1-{[4-(3-fluoro-8-methylimidazo[1,2-af pyridin-2-yl)phenyl]methyl}- 3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-((1S)-1-{[4-(3-fluoro-8-methylimidazo[1,2-a] pyridin-2-yl)phenylmethyl}-

332 AMENDED SHEET

3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-((1S)-2-hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyri din-2- yl)phenyllmethyl}ethyi)-4-[(1-methylethyl)oxylbenzamide ; 3-Chloro-4-[(1-methylethyl)oxy]-N-((1S)-2-[4-(8-methylimidazo[1,2-alpyridin-2- yhphenyl}-1-{[(2,2,2-trifluoroethyl)amino]methyi}ethyl)benzamide ; 3-Chloro-N-((1S)-2-[(2-hydroxyethyl)amino]- 1-{[4-(8-methylim idazo[1,2-a]pyridin-2- yl)phenyllmethyl}ethyl)-4-[(1-methylethyl)oxylbenzamide ; 3-Cyano-N-((1S)-1-{[4-(8-ethyl-5-methylimidazo[1,2-a]pyridin- 2-yl)phenyljmethyi}- 3-hydroxypropyt }-4-[(1-methylethyl)oxylbenzamide ; 3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-methyl-5-0x0-5,6-dihydroi midazo[1,2- cJpyrimidin-2-yl )phenyl]methyl}propyt)-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-ox0-7,8-dihydroimidazo[1 ,2-a]pyrazin-2- yhphenyllmethyl}propyl)-4-[(1-methylethyl)oxy]benzamide ; 2,3-Dichloro-N-((1S)-3-hydroxy-1-{[4-(8-methylimidazo[1,2-a]p yridin-2- yl)phenyllmethyl}propyl)-4-[(1-methylethyl)oxy]benzamide ; N-((1S)-3-Hydroxy-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)ph enylimethyl}propyl)- 4-[(1-methylethyl)oxy]-3-nitrobenzamide ; 3-Chloro-N-[(1S)-2-[(hydroxyacetyl)amino]-1-({4-[8-(1-hydroxyexthyl)imidazo[1,2- a)pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamnide ; 3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}-1- ({[(2R)-2-hydroxypropanoylJamino}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide; 3-Chloro-N-[(1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yljphenyl}-1- ({[(2S)-2-hydroxypropanoyllamino}methyl)ethyl}-4-[(1-methyleth yi)oxylbenzamide; N-[(1S)-2-(D-Alanylamino)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2—a]pyridin-2- yllphenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxylbenzamidie ; 3-Chloro-N-((1S)-2-{4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yllphenyl}-1-{[(2- methylalanyl)amino]methyl}ethyl)-4-[(1-methylethyl)oxy]benzam ide ; 3-Chioro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyridin-6-ylphen yl)methyl]propyi}- 4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)imidazo[1,2-a]pyridin-6- ylJphenyl}methyl)-3-hydroxypropyl}-4-[(1-methylethyljoxy]benzannide ;

333 AMENDED SHEET

3-Chloro-N-{(1S)-3-hydroxy-1-[(4-imidazo[1,2-a]pyridin-2-yl phenyl )methyl]propyl}- 4-[(1-methylethyl)oxy]be nzamide ; 3-Chloro-N-{(1S)-3-hydreoxy-1-[(4-imidazo[1,2-a]pyrimidin-2- ylphenyl)methyl]propyl}-<-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-((1S)-3-hydroxy-1-{[4-(5-methylimidazo[1,2-a]p yridin-2- yl)phenyljmethyl}propyl)—4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-((1S)-3-hydroxy-1-{[4-(7-methylimidazo[1,2-a]p yrimidin-2- yl)phenyljmethyl}propyl)—4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-{(1S)-3-hydroxy-1-[(4-imidazo[2,1-b][1,3]thiazol -6- ylphenyl)methyl]butyl}-4—[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-((1S)-3-hydroxy-1-{[4-(3-methylimidazo[2,1-b][1 ,3]thiazol-6- yl)phenyllmethyl}butyl)-A-[(1-methylethyl)oxylbenzamide ; N-[(1S)-1-({4-[1-(3-Amin opropyl)-2-(1,1-dimethylethyl)-1H-imidazol-4- yllphenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-[(1S)-1-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[1,2-a]pyridin-2- yllphenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-((1S)-3-hydroxy-1-{[4-(8-phenylimidazo[1,2-a]p yridin-2- yh)phenyllmethyl}propyl)—4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(1H-pyrazol-4-yl)imida=zo[1,2-a]pyridin-2- yllphenyl}methyl)propyl}—4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-[(1S)-3-hydroxy-1-({4-[8-(4-isoxazolyl)imidazo[ 1 ,2-a]pyridin-2- yllphenyl}methyl)propyl]—4-[(1-methylethyl)oxylbenzamide ; N-((1S)-1-{[4-(8-Acetylimidazo[1,2-a]pyridin-2-yl)phenyllmethyl}-3-hydroxypropyl)- 3-chloro-4-[(1-methyleth yl)oxy]benzamide ;

Ethyl (2E)-3-[2-(4-{(2S)-2-[({3-cyano-4-[(1- methylethyl)oxy]phenyl}carbonyl)amino]-4-hydroxybutyl}ph enyl)imidazo[1,2- a)pyridin-8-yl]-2-propenoate ; (2E)-3-[2-(4-{(2S)-2-[({3—Cyano-4-[(1-methylethyl)oxy]phenyl}carbonyl Jamino]-4- hydroxybutyl}phenyl)imicdazo[1,2-a]pyridin-8-yl]-2-propenoic acid ; N-{(1S)-1-[(4-{8-[(1E)-3-.Amino-3-oxo-1-propen-1-yllimidazo[1,2-a]pyridin-2- yl}phenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide ; 334 AMENDED SHEET

N-[(1S)-1-({4-[8-(3-Amino-3-oxopropyl)imidazo[1,2-a]p yridin-2-yl]phenyl}methyl)-3- hydroxyprop yl}-3-cyano-4-[(1-methylethyl)oxy]benzam ide ; 3-Chloro-N-( (1S)-1-{[4-(3-chloro-8-methylimidazo[1,2- &]pyridin-2- yl)phenylJmethyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ; N-((1S)-1-{[4-(3-Chloro-8-methylimidazo[1,2-a]pyridin—2-yl)phenylJmethyl}-3- hydroxyprop yl)-3-cyano-4-[( 1-methylethyljoxy]benzamuide ; 3-Cyano-N-[(1S)-1-({3-fluoro-4-[2-(1-hydroxy-1-methyl ethyl)-1-methyl-1H-imidazol- 4-yl]phenyl}rmethyl)-3-hydroxypropyl]-4-[( 1-methylethy #)oxylbenzamide ; 3-Chloro-N-[ (1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl —1 H-imidazol-4-yl]-2- fluorophenyl 3methyl)-3-hydroxypropyl]-4-[(1-methyleth yl)oxylbenzamide ; 3-Chloro-N-[ (1S)-1-({2-chloro-4-[2-(1,1-dimethylethyl)— 1-methyl-1H-imidazol-4- yllphenyl}methyl)-3-hydroxypropyl]-4-[(1-methylethyl)Oxy]benzamide ; 3-Chloro-N-{(1S)-1-{[2-chloro-4-(8-methylimidazo[1,2- a]pyridin-2- yl)phenyllmethyl}-3-hydroxypropyl)-4-[(1-methylethyl)Oxylbenzamide ; 3-Chloro-N-((1S)-1-{[2-chloro-4-(8-chloroimidazo[1,2-a]pyridin-2-yl)phenylJmethyl}- 3-hydroxypropyl)-4-[(1-methylethyl)oxylbenzamide ; 3-Chloro-N-{(1S)-1-{[3-chloro-4-(8-methylimidazo[1,2- a]pyridin-2- yl)phenyllmethyl}-3-hydroxypropyl)-4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-[(1S)-1-({4-[2-(1,1-dimethylethyl)-1-methyl -1H-imidazol-4- yllphenyl}methyl)-3-(methylamino)-3-oxopropyl]-4-[(1- methylethyl)oxylbenzamide ; 3-Cyano-N-[(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl- 1H-imidazol-4-yl]phenyl}-1- ({[{phenylamino)carbonyl]Jamino}methyl)ethyl]-4-[(1-m ethylethyl)oxy]benzamide ; 3-Cyano-N-[(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl- 1H-imidazol-4-yl]phenyl}-1- ({[(ethylamino)carbonyllamino}methyl)ethyl]-4-[(1-met hylethyl)oxy]benzamide ; N-[(1S)-2-(Aminosulfonyl)-1-({4-[2-(1,1-dimethylethyl )—1-methyl-1H-imidazol-4- ylJphenyl}m ethyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide ; 3-Cyano-N-((1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl—1H-imidazol-4-yl]phenyi}-1- {[(methylsul fonyl)amino]methyl}ethyl)-4-[(1-methyleth yl)oxylbenzamide ; 3-Cyano-N-{(1S)-2-{4-[2-(1,1-dimethylethyl)-1-methyl—1H-imidazol-4-yi]phenyl}-1- [({[(2-hydroxyethyl)amino]carbonyl}amino)methyllethyi}-4-[(1- methylethyl )oxy]benzamide ;

335 AMENDED SHEET

(4R)-4-[({3-Cyano-4-[(1-methyleth yl)oxy]phenyl}carbonyl)amino]-5-{4-[2-(1,1- dimethylethyl)-1-methyl-1H-imidazol-4-yl]phenyl}pentanoic acid ; N-((1S)-2-Amino-1-{[4-(8-methylinnidazo[1,2-a]pyridin-2-yl)phenyl]methyl}eth y)-3- cyano-4-[(1-methylethyl)oxy]benzamide ; N-((1S)-2-(Acetylamino)-1-{[4-(8-methylimidazo[1,2-a]pyridin-2- yl)phenyllmethyl}ethyl)-3-cyano-4—-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-((1S)-2-{[(2R)-2-hydroxypropanoyl]amino}-1-{[4-(8-methylimidazo[1,2- a]pyridin-2-yl)phenylJmethyl}ethyl)-4-[(1-methylethyl)oxy]benzamide ; 3-Chloro-N-[(1S)-2-[(N,N-dimethyl glycyl)amino]-1-({4-[2-(1-hydroxy-1-methyl ethyl)- 1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamnide ; 3-Cyano-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[2-(1-hydroxy-1-methyl ethyl)- 1-methyl-1H-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide.

36. (Amended) At least one chemical entity as defined in claim 20 chosen from the compounds described in Tables 2, 3, 4, or 5.

37. (Amended) A composition comprising a pharmaceutical excipient and at least one chemical entity of claim 20. 38-44. (Canceled)

45. (Amended) At least one chemical entity of claim 20 for use in the manufacture of a pharmaceutical composition for treating cancer, wherein the cancer is associated with CENP-E kinesin activity.

46. (Canceled)

47. (New) At least one chemical entity chosen from: N-(1-{4-[2-(1-Acetylamino-ethyl)- 1-ethyl-1H-imidazol-4-yl]-benzyi}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro-1- methyl-ethoxy)-benzamide; 336 AMENDED SHEET

3-Chloro-N-[(1S)-2-[(N,N-dime thyiglycyl)amino]-1-({4-[8-(1- hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1- methylethyl)oxy]benzamide; N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyi-1H-imidazol-4-yl]-benzyi}-3- hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzam ide; (S)-3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidaazo[1,2- alpyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide; N-(1-{4-[2-(1-hydroxy-1-methyl -ethyl)-1-methyl-1H-imidazol-4-yl]-berzyl}-3- hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzam ide; 3-Chloro-N-((1S)-2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[ 1B ,2-a]pyridin- 2-yl)phenyllmethyl}ethyl)-4-[(1- methylethyl)oxy]benzamide; and 3-Chloro-N-[(1S)-3-hydroxy-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]p yridin-2- yllphenyl}methyl)propyl]-4-[(1-rmethylethyl)oxy]benzamide.

48. (New) A composition comprising at least one phamaceutical excipient and at least one compound or pharmaceutically acceptable salt according t © claim 35.

49. (New) The composition of clairm 48 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intraveno us, intranasal, transdemal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

50. (New) The composition of claim 49 wherein the composition is formulated for oral administration. 337 AMENDED SHEET

51. (New) The composition of claim 50 wherein the composition is formulated as a tablet, capsule, or liquid.

52. (New) The composition of claim 50 wherein the at least one pharmaceutical excipient is selected from diluents, binders, glidants, lubricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes and other solubil ity-retarding materials.

53. (New) The composition of claim 49 wherein the composition is formul ated for intravenous administration.

54. (New) The composition of claim 53 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

55. (New) The composition of claim 53 wherein the at least one pharmaceutical excipient is water for injection USP.

56. (New) The composition of claim 48 wherein the composition is formu lated for parenteral administration.

57. (New) The composition of claim 56 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

58. (New) The composition of claim 56 wherein the at least one pharmaceutical excipient is water for injection USP.

59. (New) A compound chosen from N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-(1- hydroxy-ethyl)-imidazo[1 ,2-a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide and pharmaceutically acceptable salts thereof. 338 AMENDED SHEET

LJ ’

60. (New) A composition comprising at least one phammaceuti cal excipient and a compound or phamacedtically acceptable salt thereof according to claim 59.

61. (New) The composition of claim 60 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intravenous, intranasal, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

62. (New) The composition of claim 61 wherein the composition is formulated for oral administration.

63. (New) The composition of claim 62 wherein the composition is formulated as a tablet, capsule, or liquid.

64. (New) The composition of claim 62 wherein the at least on e pharmaceutical excipient is selected from diluents, binders, glidants, lubricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes and © ther solubility-retarding materials.

65. (New) The composition of claim 61 wherein the composition is formulated for intravenous administration.

66. (New) The composition of claim 65 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

67. (New) The composition of claim 65 wherein the at least one pharmaceutical excipient is water for injection USP.

68. (New) The composition of claim 60 wherein the compositio n is formulated for parenteral administration. 339 AMENDED SHEET

69. (New) The composition of claim 68 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acid s or electrolytes.

70. (New) The composition of claim 68 wherein the at least one pharmaceutical excipient is water for injection USP.

71. (New) A compound chosen from N-{1-[4-(8-(1-hydroxy-ethyl)-imidazo[1,2- a)pyridin-2-yl)}-benzy1]-3-hydroxy-propyl}-3-chloro-4-isoprop oxy-benzamide and pharmaceutically acceptable salts thereof.

72. (New) A compositions comprising at least one pharmaceutic al excipient and a compound or pharmaceutically acceptable salt thereof according to claim 71.

73. (New) The composition of claim 72 wherein the compositior is formulated for administration by a route chosen from oral, subcutaneous, i ntravenous, intranasal, transdermal, intraperitoneal, intramuscular, intragulmonary, vaginal, rectal, and intraocular.

74. (New) The composition of claim 73 wherein the compositior is formulated for oral administration.

75. (New) The composition of claim 74 wherein the compositior is formulated as a tablet, capsule, or liquid.

76. (New) The composition of claim 74 wherein the at least one» pharmaceutical excipient is selected from diluents, binders, glidants, lubrica nts, disintegrants, colors, flavors, sweetening agents, polymers, waxes and other solubility-retarding materials.

77. (New) The composition of claim 73 wherein the compositior is formulated for intravenous administration. 340 AMENDED SHEET

78. (New) The composition of claim 77 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, a mino acids or electrolytes.

79. (New) The composition of claim 77 wherein the atleast one pharmaceutical excipient is water for injection USP.

80. (New) The composition of claim 72 wherein the composition is formulated for parenteral administration.

81. (New) The composition of claim 80 wherein the atleast one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

82. (New) The composition of claim 80 wherein the atleast one pharmaceutical excipient is water for injection USP.

83. (New) A compound chosen from N-(2-(2-dimethydamino-acetylamino)-1-{4-[8- methyl-imidazo[1,2-a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide and pharmaceutically acceptable salts thereof.

84. (New) A composition comprising at least one pha maceutical excipient and a compound or pharmaceutically acceptable salt th ereof according to claim 83.

85. (New) The composition of claim 84 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intravenous, intranasal, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

86. (New) The composition of claim 85 wherein the composition is formulated for oral administration. 341 AMENDED SHEET

L] »

87. (New) The composition of claim 86 wherein the composition is formulated as a tablet, capsule, or liquid.

88. (New) The composition of claim 86 wherein the at least one pharma ceutical excipient is selected from diluents, binders, glidants, lubricants, disimtegrants, colors, flavors, sweetening agents, polymers, waxes and other solubility-retarding materials.

89. (New) The composition of claim 85 wherein the composition is formulated for intravenous administration.

90. (New) The composition of claim 89 wherein the at least one pharma ceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

91. (New) The composition of claim 89 wherein the at least one pharma ceutical excipient is water for injection USP.

92. (New) The composition of claim 84 wherein the composition is formulated for parenteral administration.

93. (New) The composition of claim 92 wherein the at least one pharma ceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

94. (New) The composition of claim 92 wherein the at least one pharma ceutical excipient is water for injection USP.

95. (New) A compound chosen from N-(2-(2-amino-2-methyl-propionylamino)-1-{4- [8-methyl-imidazo[1,2-a]pyridin-2-yl]-benzyl}-ethyl)-3-chloro-4-isopro poxy- benzamide and pharmaceutically acceptable salts thereof. 342 AMENDED SHEET e »

96. (New) A composition comprising at least one pharmaceutical excipient an«d a compound or pharmaceutically acceptable salt thereof according to claim 95.

97. (New) The composition of claim 96 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intravenous, intranasal, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

98. (New) The composition of claim 97 wherein the composition is formulated for oral administration.

99. (New) The composition of claim 98 wherein the composition is formulated as a tablet, capsule, or liquid.

100. (New) The composition of claim 98 wherein the at least one pharmaceutical excipient is selected from diluents, binders, glidants, lubricants, disintegrarits, colors, flavors, sweetening agents, polymers, waxes and other solubility-restarding materials.

101. (New) The composition of claim 97 wherein the composition is formulated for intravenous administration.

102. (New) The composition of claim 101 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

103. (New) The composition of claim 101 wherein the at least one pharmaceutiecal excipient is water for injection USP.

104. (New) The composition of claim 96 wherein the composition is formulated For parenteral administration. 343 AMENDED SHEET e >

105. (New) The composition of claim 104 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

106. (New) The composition of claim 104 wherein the at least one pharmaceutical excipient is water for injection USP.

107. (New) A compound chosen from N-(1-{4-[2-(1-Acetylarnino-ethyi)-1-ethyi-1H- imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2 2-trifluoro-1-methyi- ethoxy)-benzamide and pharmaceutically acceptable salts thereof.

108. (New) A composition comprising at least one phamaceutical excipient and a compound or pharmaceutically acceptable salt thereof according to claim 107.

109. (New) The composition of claim 108 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intravenous, intranasal, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

110. (New) The composition of claim 109 wherein the composition is formulated for oral administration.

111. (New) The composition of claim 110 wherein the composition is formulated as a tablet, capsule, or liquid.

112. (New) The composition of claim 110 wherein the at least one pharmaceutical excipient is selected from diluents, binders, glidants, lu bricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes amd other solubility-retarding materials.

113. (New) The composition of claim 109 wherein the composition is formulated for intravenous administration. 344 AMENDED SHEET hd [J

114. (New) The composition of claim 113 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

115. (New) The composition of claim 113 wherein the at least one pharmaceutical excipient is water for injection USP.

116. (New) The composition of claim 108 wherein the composition is formulated for parenteral administration.

117. (New) The composition of claim 116 vvherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

118. (New) The composition of claim 116 vvherein the at least one pharmaceutical excipient is water for injection USP.

119. (New) A compound chosen from N-(1 -{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl- 1 H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2-trifluoro-1-methyl- ethoxy)-benzamide and pharmaceutically acceptable salts thereof.

120. (New) A composition comprising at le ast one phamaceutical excipient and a compound or pharmaceutically accep table salt thereof according to claim 119.

121. (New) The composition of claim 120 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intravenous, intranasal, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

122. (New) The composition of claim 121 wherein the composition is formulated for oral administration. 345 AMENDED SHEET h J [3

123. (New) The composition of claim 122 wherein the composition is formulated as a tablet, capsule, or liquid.

124. (New) The composition of claim 122 wherein the at least one pharmaceutical excipient is selected from diluents, binders, glidants, lubricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes and other solubility-retarding materials.

125. (New) The composition of claim 121 wherein the composition is formulated for intravenous administration.

126. (New) The composition of claim 125 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

127. (New) The composition of claim 125 wherein the at least one pharmaceutical excipient is water for injection USP.

128. (New) The composition of claim 120 wherein the composition is formulated for parenteral administration.

129. (New) The composition of claim 128 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

130. (New) The composition of claim 128 wherein the at least one pharmaceutical excipient is water for injection USP.

131. (New) A compound chosen from N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl- 1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2, 2 -trifluoro- 1-methyl- ethoxy)-ben=zamide and pharmaceutically acceptable salts thereof. 346 AMENDED SHEET

< [2

132. (New) A composition comprising at least one phamaceutical excipient and a compound or pharmaceutically acceptable salt thereof according to claim 131.

133. (New) The composition of claim 132 wherein the composition is formulated for administration by a route chosen from oral, subcutaneous, intravenous, intranasal , transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, and intraocular.

134. (New) The composition of claim 133 wherein the composition is formulated for oral administration.

135. (New) The composition of claim 134 wherein the composition is formulated as a tablet, capsule, or liquid.

136. (New) The composition of claim 134 wherein the at least one pharmaceutical excipient i s selected from diluents, binders, glidants, lubricants, disintegrants, colors, flas/ors, sweetening agents, polyrmers, waxes and other solubility-retarding materials.

137. (New) The composition of claim 133 wherein the composition is formulated for intravenous administration.

138. (New) The composition of claim 137 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

139. (New) The composition of claim 137 wherein the at least one pharmaceutical excipient i s water for injection USP.

140. (New) The composition of claim 132 wherein the composition is formulated for parenteral administration. 347 AMENDED SHEET

4 >

141. (New) The composition of claim 140 wherein the at least one pharmaceutical excipient comprises a sterile solution of sugars, amino acids or electrolytes.

142. (New) The composition of claim 140 wherein the at least one pharmaceutical excipient is water for injection USP. 348 AMENDED SHEET